METHODS OF TREATING PATIENTS SUFFERING FROM BRAIN INJURY AND METHODS OF INCREASING THE VALUE OF THE EXTENDED GLASGOW OUTCOME SCALE OF PATIENTS SUFFERING FROM BRAIN INJURY

PROCEDES DE TRAITEMENT DE PATIENTS ATTEINTS D'UNE LESION CEREBRALE ET PROCEDES D'AUGMENTATION DE LA VALEUR DE L'ECHELLE DE RESULTATS DE GLASGOW ETENDUE DE PATIENTS ATTEINTS D'UNE LESION CEREBRAL

English Abstract

The present invention relates to the use of biopterin compounds such as 4-Amino-(6R,S)- 5,6,7,8-tetrahydro-L-biopterin for treatment of patients suffering from brain injury. The invention also relates to the use of such biopterin compounds for increasing the value of the extended Glasgow Outcome Scale (eGOS) of patients suffering from brain injury, thereby improving the condition of the patient.

French Abstract

La présente invention concerne l'utilisation de composés de bioptérine tels que la 4-Amino-(6R,S)-5,6,7,8-tétrahydro-L-bioptérine pour le traitement de patients atteints d'une lésion cérébrale. L'invention concerne également l'utilisation de tels composés de bioptérine pour augmenter la valeur de l'échelle de résultats deGlasgow étendue (GOS-E) de patients atteints d'une lésion cérébrale, ce qui permet d'améliorer l'état du patient.

Claims

CLAIMS
What is claimed is:
1. A method of treating a human patient suffering from
brain injury, wherein the
method comprises (starting) administering to the patient within a time period
of < 12 hours
after the occurrence of the brain injury a therapeutically effective amount of
a compound
having the formula (I):
<IMG>
2. The method of claim 1, comprising starting administering to the patient
a
therapeutically effective amount of the compound having the formula (I) within
a time
period of between 6 to 12 hours after the occurrence of the brain injury.
3. The method of claim 1 or 2, wherein the compound having the formula (I)
is
administered by infusion.
4. The method of any of claims 1 to 3, wherein the compound having the
formula (I) is
administered at a maximal daily dose in the range of 2.5 mg/kg body weight to
30.0
mg/kg body weight.
5. The method of claim 4, wherein the compound having the formula (I) is
administered
at a total dose of 2.5, 5.0, 7.5, 10.0, 12.5, 15.0, 17.0, 20.0, or 30.0 mg/kg
body weight.
6. The method of any of claims 4 or 5, wherein the compound having the
formula (I) is
administered over a period of 12 to 96 hours.
7. The method of claim 6, wherein the compound having the formula (I) is
administered
over a period of 24 to 48 hours or over a period of 24 to 72 hours.
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8. The method of claim 7, wherein the compound having the formula (I) is
administered
by infusion in a total dose of 17 mg/kg body weight over 48 hours,
corresponding to a
daily dose of 8.5 mg/kg body weight.
9. The method of claim 7, wherein the compound having the formula (I) is
administered
by infusion in a total dose of 30.0 mg/kg body weight over 72 hours,
corresponding to
a daily dose of 10 0 mg/kg body weight
10. The method of any of the forgoing claims, wherein the brain injury is
selected from
the group consisting of traumatic brain injury, non-traumatic brain injury,
elevated
intracranial pressure, and secondary brain injury.
11 The method of claim 10, wherein the secondary brain injury
comprises a condition
selected from the group consisting of edema formation from local or global
hypoxia,
ischemia, inflammation with and without infection, and neoplasms.
12. The method of claim 11, wherein the neoplasm is selected from the group
consisting
of benign neoplasms, and malignant neoplasms.
13. The method of claim 10, wherein the non-traumatic brain injury is
selected from the
group consisting of ischemic/ hypoxic/hemorrhagic brain injury (e.g. stroke),
post-
resuscitation (after e.g. cardiac arrest), subarachnoid haemorrhage,
anticoagulation-
induced haemorrhage or wherein the non-traumatic brain injury is caused by
inflammation and infection.
14. The method of claim 13, wherein the inflammation is Systemic
Inflammatory
Response Syndrome (SIRS) or wherein the infection is selected from meningitis
or
encephalitis.
15. "f he method of claim 10, wherein the brain injury is traumatic brain
injury.
16. The method of claim 15, wherein the patient to be treated has been
diagnosed with
complicated mild, moderate or severe traumatic brain injury.
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17. The method of claim 15 or 16, wherein the patient to be treated has
been diagnosed
with traumatic brain injury of a Glasgow Coma Score (GCS) > 3.
18. The method of claim 16 or 17, wherein the traumatic brain injury
requires intracranial
pressure (ICP) monitoring.
19. The method of any of the forgoing claims wherein the patient is up to
39 years old or
is 40 years or older.
20. The method of claim 19, wherein the patient has an age in the range of
18 to 39 years.
21. The method of claim 20, wherein the value of the Extended Glasgow
Outcome Scale
(eGos) of the patient (as a measure of the reduction of traumatic brain
injury) increases
by at least 1 level when assessed six months after the occurrence of the
traumatic brain
injury and compared to the eGOS value of the patient determined three months
after
the occurrence of the traumatic brain injury.
22. The method of claim 21, wherein the value of the Extended Glasgow
Outcome Scale
(eGOS) of the patient increases by at least 2 levels when assessed six months
after the
occurrence of the traumatic brain injury and compared to the eGOS value of the
patient determined three months after the occurrence of the traumatic brain
injury.
23. The method of claim 21 or 22, wherein the eGOS value when assessed six
months
after the occurrence of the traumatic brain injury increases by 2, 3, 4 or 5
levels,
compared to the eGOS value of the patient determined three months after the
traumatic
brain injury.
24. The method of any of claims 20 to 23, wherein the patient reaches eGOS
level 7 or
eGOS level 8 six months after the traumatic brain injury.
25. The method of any of claims 22 to 24, wherein the patient is male.
26. The method of claim 20, wherein the patient reaches eGOS level 7 or
eGOS level 8
three months after or six months after the occurrence of the traumatic brain
injury.
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27. The method of claim 26, wherein the patient is female.
28. The method of any of claims 26 to 27, wherein the eGOS value when
assessed six
months after the occurrence of the traumatic brain injury increases by at
least 1 level
or at least 2 levels and compared to the eGOS value of the patient determined
three
months after the traumatic brain injury.
29. The method of any of claims 26 to 28, wherein the eGOS value when
assessed six
months after the occurrence of the traumatic brain injury increases by 2, 3, 4
or 5
levels, compared to the eGOS value of the patient determined three months
after the
traumatic brain injury.
30. The method of claim 19, wherein the patient has an age in the range of
40 to 90 years,
40 to 80 years, 40 to 70 years or 40 to 65 years.
31. The method of claim 30, wherein the patient has an age in the range of
40 to 60 years.
32. The method of claim 30 or 31, wherein the patient is female.
33. The method of claim 32, wherein the patient reaches eGOS level 7 or
eGOS level 8 six
months after the occurrence of the traumatic brain injury.
34. The method of claim 32 or 33, wherein the value of the Extended Glasgow
Outcome
Scale (eGOS) of the patient increases by at least 1 level six months after the
occurrence of the traumatic brain injury and compared to the eGOS value of the
patient determined three months after the occurrence of the traumatic brain
injury.
35. The method of any of claims 32 to 34, wherein the value of the Extended
Glasgow
Outcome Scale (eGOS) of the patient increases by at least 2 levels when six
months
after the occurrence of the traumatic brain injury and compared to the eGOS
value of
the patient determined three months after the occurrence of the traumatic
brain injury.
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36. The method of any of claims 31 to 35, wherein the eGOS value when
assessed three
months after the occurrence of the traumatic brain injury increases by 2, 3, 4
or 5
levels and compared to the eGOS value of the patient determined three months
after
the occurrence of the traumatic brain injury.
37. The method of any of claims 20 to 36, wherein the treatment comprises
providing
within a period of 14 days after occurrence of the traumatic brain injury the
patient
with a low Therapy Intensity Level (TIL) treatment.
38. The method of claim 37, wherein the low Therapy Intensity Level (TIL)
treatment has
a therapy index level between 3 and 10.
39. The method of any of the claims 1 to 39, wherein the compound of
formula (I) is 4-
Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin having the formula (la):
<IMG>
40. The method of claim 39, wherein the compound (Ia) is a diastereomeric
mixture that
comprises more (6R)-4-Amino-5, 6, 7, 8-tetrahydro-L-biopterin than (6S)-4-
Amino-5,
6, 7, 8-tetrahydro-L-biopterin.
41. The method of any of claims 39 to 40, wherein infusion of the compound
of formula
(I) is carried out with a reconstituted solid composition of the compound of
formula
(I), wherein a unit dosage of the solid composition contains 650 60 mg of
the free
base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 140 30 mg of water of
crystallization, 70 7 mg Na2HPO4 = 2 H20, 16.5 2 mg NaH2PO4 = 2 H20, and
350
30 mg NaC1 or wherein a unit dosage of the composition contains 650 60 mg of
the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 60 50 mg of
water
of crystallization, 7U 7 mg Na2HPO4 = 2 H20, 12 2.5 mg NaH2PO4 = 2 H20,
and
350 30 mg NaCl.
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42. The method of claim 41, wherein reconstitution comprises providing a
vial containing
lg of the unit dosage and adding 50 ml water to lg of the unit dosage.
43. A method of increasing the value of the Extended Glasgow Outcome Scale
(eGOS) of
a human patient suffering from brain injury, thereby improving the condition
of the
patient, wherein the value of the Extended Glasgow Outcome Scale (eGOS) of the
patient reaches eGOS level 7 or eGOS level 8 six months after the occurrence
of the
brain injury, wherein the method comprises (starting) administering to the
patient
within a time period of < 12 hours after the occurrence of the brain injury a
therapeutically effective amount of a compound having the formula (I):
<IMG>
44. The method of claim 43, wherein the eGOS value of the patient when
assessed six
months after the occurrence of the traumatic brain injury has increased by 2,
or 3, or 4,
or 5 eGOS levels compared to the eGOS value of the patient determined three
months
after the occurrence of the traumatic brain injury.
45. A method of increasing the value of the Extended Glasgow Outcome Scale
(eGOS) of
a human patient suffering from brain injury, thereby improving the condition
of the
patient, wherein the value of the Extended Glasgow Outcome Scale (eGOS) of the
patient has increased by 2 or more six months after the occurrence of the
brain injury
and compared to the eGOS value determined three months after the occurrence of
the
brain injury, wherein the method comprises (starting) administering to the
patient
within a time period of < 12 hours after the occurrence of the brain injury a
therapeutically effective amount of a compound having the formula (I):
<IMG>
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46. The method of claim 45, wherein the value of the Extended Glasgow
Outcome Scale
(eGOS) of the patient has increased by 3, or 4 or 5 six months after the
occurrence of
the brain injury and compared to the eGOS value determined three months after
the
occurrence of the brain injury.
47. The method of claim 45 or 47, wherein the value of the Extended Glasgow
Outcome
Scale (eGOS) of the patient reaches eGOS level 7 or eGOS level 8 six months
after the
occurrence of the brain injury.
48. The method of any of claims 43 to 47, comprising starting administering
to the patient
a therapeutically effective amount of the compound having the formula (I)
within a
time period of between 6 to 12 hours after the occurrence of the brain injury.
49. The method of claim 48, wherein the compound having the formula (1) is
administered
by infusion.
50. The method of claim 49, wherein the compound having the formula (I) is
administered
at a maximal daily dose in the range of 2.5 mg/kg body weight to 30.0 mg/kg
body
weight.
51. The method of claim 50, wherein the compound having the formula (I) is
administered
at a total dose 2.5, 5.0, 7.5, 10.0, 12.5, 15.0, 17.0, 20.0, or 30.0 mg/kg
body weight.
52. The method of any of claims 50 or 51, wherein the compound having the
formula (I) is
administered over a period of 12 to 96 hours or over a period of 24 to 72
hours.
53. The method of claim 53, wherein the compound having the formula (1 is
administered
over a period of 24 to 48 hours.
54. The method of claim 53, wherein the compound having the formula (I) is
administered
by infusion in a total dose of 17 mg/kg body weight over 48 hours,
corresponding to a
daily dose 8.5 mg/kg body weight.
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55. The method of claim 53, wherein the compound having the formula (I) is
administered
by infusion in a total dose of 30.0 mg/kg body weight over 72 hours,
corresponding to
a daily dose of 10.0 mg/kg body weight.
56. The method of any of the forgoing claims 43 to 55, wherein the brain
injury is selected
from the group consisting of traumatic brain injury, non-traumatic brain
injury,
elevated intracranial pressure, and secondary brain injury
57. The method of claim 56, wherein the secondary brain injury comprises a
condition
selected from the group consisting of edema formation from local or global
hypoxia,
ischemia, inflammation with and without infection, and neoplasms.
58 The method of claim 57, wherein the neoplasm is selected from
the group consisting
of benign neoplasms and malignant neoplasms.
59 The method of claim 56, wherein the non-traumatic brain injury
is selected from the
group consisting of ischemic/ hypoxic/hemorrhagic brain injury (e.g. stroke),
post-
resuscitation (after e.g cardiac arrest), subarachnoid haemorrhage,
anticoagulation-
induced haemorrhage or wherein the non-traumatic brain injury is caused by
inflammation and infection.
60. The method of claim 59, wherein the inflammation is Systemic
Inflammatory
Response Syndrome (SIRS) or wherein the infection is selected from meningitis
or
encephalitis.
61. The method of claim 56, wherein the brain injury is traumatic brain
injury.
62. The method of claim 61, wherein the patient to be treated has been
diagnosed with
mild complicated, moderate or severe traumatic brain injury.
63. The method of claim 61 or 62, wherein the patient to be treated has
been with
diagnosed with traumatic brain injury of a Glasgow Coma Score (GCS) > 3.
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64. The method of claim 62 or 63, wherein the traumatic brain injury
requires intracranial
pressure (ICP) monitoring.
65. The method of any of the forgoing claims 43 to 64 wherein the patient
is up to 39
years old or is 40 years or older.
66. The method of claim 65, wherein the patient has an age in the range of
18 to 39 years.
67. The method of claim 66, wherein the patient has an age in the range of
40 to 90 years,
40 to 80 years, 40 to 70 years or 40 to 65 years.
68. The method of any of claims 65 to 67, wherein the treatment comprises
providing
within a period of 14 days after occurrence of the traumatic brain injury the
patient
with a low Therapy Intensity Level (TIL) treatment.
69. The method of claim 68, wherein the low Therapy Intensity Level (TIL)
treatment has
a therapy index level between 3 and 10.
70. The method of any of the claims 43 to 69, wherein the compound of
formula (I) is 4-
Amino-(6R, S)-5,6,7,8-tetrahydro-L-biopterin having the formula (Ia):
<IMG>
71. The method of claim 70, wherein the compound (la) is a diastereomeric
mixture that
comprises more (6R)-4-Amino-5, 6, 7, 8-tetrahydro-L-biopterin than (6S)-4-
Amino-5,
6, 7, 8-tetrahydro-L-biopterin.
72. The method of any of claims 70 to 71, wherein infusion of the compound
of formula
(I) is carried out with a reconstituted solid composition of the compound of
formula
(I), wherein a unit dosage of the solid composition contains 650 60 mg of
the free
base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 140 30 mg of water of
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crystallization, 70 7 mg Na2i-11304 = 2 H20, 16.5 2 mg NaH2PO4 = 2 H20,
and 350
30 mg NaC1 or wherein a unit dosage of the composition contains 650 60 mg of
the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 60 50 mg of
water
of crystallization, 70 7 mg Na2HPO4 = 2 H20, 12 2.5 mg NaH2PO4 = 2 H/0,
and
350 30 mg NaCl.
73. The method of claim 72, wherein reconstitution comprises providing a
vial containing
lg of the unit dosage and adding 50 ml water to lg of the unit dosage.
74. A method of treating a human patient suffering from brain injury,
wherein the patient
is a female of an age of 40 years or older, and wherein the method comprises
(starting)
administering to the patient within a time period of > 12 hours after the
occurrence of
the brain injury a therapeutically effective amount of a compound having the
formula
(1):
<IMG>
75. The method of claim 74, comprising starting administering to the
patient a
therapeutically effective amount of the compound having the formula (I) within
a time
period of between 12 to 18 hours after the occurrence of the brain injury.
76. The method of claim 74 or 75, wherein the compound having the formula
(I) is
administered by infusion.
77. The method of any of claims 74 to 76, wherein the compound having the
formula (I) is
administered at a maximal daily dose in the range of 2.5 mg/kg body weight to
30.0
mg/kg body wei ght.
78. The method of claim 77, wherein the compound having the formula (I) is
administered
at a total dose of 2.5, 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0, or 30.0 mg/kg
body weight.
79. The method of any of claims 77 or 78, wherein the compound having the
formula (I) is
administered over a period of 12 to 96 hours.
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80. The method of claim 79, wherein the compound having the formula (I) is
administered
over a period of 24 to 48 hours or over a period of 24 to 72 hours.
81. The method of claim 80, wherein the compound having the formula (I) is
administered
by infusion in a total dose of 17 mg/kg body weight over 48 hours,
corresponding to a
daily dose of 8 5 mg/kg body weight
82. The method of any of the forgoing claims 74 to 81, wherein the brain
injury is selected
from the group consisting of traumatic brain injury, non-traumatic brain
injury,
elevated intracranial pressure, and secondary brain injury.
83 The method of claim 82, wherein the brain injury is traumatic
brain injury_
84. The method of claim 83, wherein the patient to be treated has been
diagnosed with
mild complicated, moderate or severe traumatic brain injury.
85. The method of claim 83 or 84, wherein the patient to be treated has
been with
diagnosed with traumatic brain injury of a Glasgow Coma Score (GCS) > 3.
86. The method of claim 84 or 85, wherein the traumatic brain injury
requires intracranial
pressure (ICP) monitoring.
87. The method of any of claims 83 to 86, wherein the value of the Extended
Glasgow
Outcome Scale (eGOS) of the patient increases by at least 1 level or by at
least 2 levels
when assessed six after the occurrence of the traumatic brain injury and
compared to
the eGOS value of the patient determined three months after the occurrence of
the
traumatic brain injury.
88. The method of claim 87, wherein the eGOS value when assessed six months
after the
occurrence of the traumatic brain injury increases by 2, 3.4 or 5 levels and
compared
to the eGOS value of the patient determined three months after the occurrence
of the
traumatic brain injury.
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89. The method of any of claims 87 to 88, wherein the patient reaches eGOS
level 7 or
eGOS level 8 six months after the traumatic brain injury.
90. The method of any of the claims 74 to 89, wherein the compound of
formula (I) is 4-
Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin having the formula (Ia):
<IMG>
91. The method of claim 90, wherein the compound (Ia) is a diastereomeric
mixture that
comprises more (6R)-4-Amino-5, 6, 7, 8-tetrahydro-L-biopterin than (6S)-4-
Amino-5,
6, 7, 8-tetrahydro-L-biopterin.
92. The method of any of claims 76 to 91, wherein infusion of the compound
of formula
(I) is carried out with a reconstituted solid composition of the compound of
formula
(I), wherein a unit dosage of the solid composition contains 650 60 mg of
the free
base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 140 30 mg of water of
crystallization, 70 I 7 mg Na2IIP04 2 1120, 16.5 _L 2 mg NaII2PO4 - 2 1120,
and 350
30 mg NaC1 or wherein a unit dosage of the composition contains 650 60 mg of
the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 60 50 mg of
water
of crystallization, 70 7 mg Na2RPO4 = 2 H20, 12 2.5 mg NaH2PO4 = 2 ILO,
and
350 30 mg NaCl.
93. The method of claim 92, wherein reconstitution comprises providing a
vial containing
lg of the unit dosage and adding 50 ml water to lg of the unit dosage.
94. A compound having the formula (I):
<IMG>
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for use in treating a human patient suffering from brain injury, wherein the
use
comprises (starting) administering to the patient within a time period of < 12
hours
after the occurrence of the brain injury a therapeutically effective amount of
the
compound having the formula (I).
95 A compound having the formula (I)-
<IMG>
for use in a method of increasing the value of the Extended Glasgow Outcome
Scale
(eGOS) of a human patient suffering from brain injury, thereby improving the
condition of the patient, wherein the value of the Extended Glasgow Outcome
Scale
(eGOS) of the patient reaches eGOS level 7 or eGOS level 8 six months after
the
occurrence of the brain injury, wherein the use comprises (starting)
administering to
the patient within a time period of < 12 hours after the occurrence of the
brain injury a
therapeutically effective amount of a compound having the formula (I).
96. A compound having the formula (I):
<IMG>
for use in a method of increasing the value of the Extended Glasgow Outcome
Scale
(eGOS) of a human patient suffering from brain injury, thereby improving the
condition of the patient, wherein the value of the Extended Glasgow Outcome
Scale
(eGOS) of the patient has increased by 2 or more six months after the
occurrence of
the brain injury, compared to the eGOS value of the patient determined three
months
after the occurrence of the traumatic brain injury, wherein the use comprises
(starting)
administering to the patient within a time period of < 12 hours after the
occurrence of
the brain injury a therapeutically effective amount of the compound having the
formula (1).
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97. A compound havi ng the formul a (I):
<IMG>
for use in treating a human patient suffering from brain injury, wherein the
patient is a
female of an age of 40 years or older, and wherein the method comprises
(starting)
administering to the patient within a time period of > 12 hours after the
occurrence of
the brain injury a therapeutically effective amount of a compound having the
formula
(T).
98. The use of a compound having the formula (I):
<IMG>
for preparing a pharmaceutical composition for treating a human patient
suffering
from brain injury, wherein the use comprises (starting) administering to the
patient
within a time period of < 12 hours after the occurrence of the brain injury a
therapeutically effective amount of the compound having the formula (I).
99. The use of a compound having the formula (I).
<IMG>
for preparing a pharmaceutical composition for increasing the value of the
Extended
Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury,
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PCT/EP2021/084183
thereby improving the condition of the patient, wherein the value of the
Extended
Glasgow Outcome Scale (eGOS) of the patient reaches eGOS level 7 or eGOS level
8
six months after the occurrence of the brain injury, wherein the use comprises
(starting) administering to the patient within a time period of < 12 hours
after the
occurrence of the brain injury a therapeutically effective amount of a
compound
having the formula (I).
100. The use of a compound having the formula (I):
<IMG>
for preparing a pharmaceutical composition for increasing the value of the
Extended
Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury,
thereby improving the condition of the patient, wherein the value of the
Extended
Glasgow Outcome Scale (eGOS) of the patient has increased by 2 or more six
months
after the occurrence of the brain injury, compared to the eGOS value of the
patient
determined three months after the occurrence of the traumatic brain injury,
wherein the
use comprises (starting) administering to the patient within a time period of
< 12 hours
after the occurrence of the brain injury a therapeutically effective amount of
the
compound having the formula (I).
101. The use of a compound having the formula (I):
<IMG>
for preparing a pharmaceutical composition for treating a human patient
suffering
from brain injury, wherein the patient is a female of an age of 40 years or
older, and
wherein the method conlprises (starting) administering to the patient within a
time
period of > 12 hours after the occurrence of the brain injury a
therapeutically effective
amount of a compound having the formula (I).
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Description

WO 2023/099013
PCT/EP2021/084183
METHODS OF TREATING PATIENTS SUFFERING FROM BRAIN INJURY AND
METHODS OF INCREASING THE VALUE OF THE EXTENDED GLASGOW
OUTCOME SCALE OF PATIENTS SUFFERING FROM BRAIN INJURY
FIELD OF THE INVENTION
The present invention relates to the use of biopterin compounds such as 4-
Amino-(6R,S)-
5,6,7,8-tetrahydro-L-biopterin for treatment of patients suffering from brain
injury. The
invention also relates to the use of such biopterin compounds for increasing
the value of the
extended Glasgow Outcome Scale (eGOS) of patients suffering from brain injury,
thereby
improving the condition of the patient.
BACKGROUND OF THE INVENTION
Traumatic brain injury (TRT) is a major cause of mortality and long-term
disability, with
enormous impact on patients and their families (Stocchetti et al, Severe
traumatic brain injury:
targeted management in the intensive care unit. Lancet Neurol. 2017;16:452-
464). In Europe
an overall incidence rate of 262 per 100,000 of hospital admitted TBI was
reported in a meta-
analysis, see Maas et al., Epidemiology of traumatic brain injury in Europe.
Acta Neurochir
(Wien) 2015 157:1683-96 The TBI related costs are high and accounted for 33
billion Euros
in Europe in 2010. The high costs are owed to mostly to lifetime productivity
losses,
particularly when young people are affected, see Maas et al, vide supra.
Clinical trials in TBI with pharmacological interventions have failed so far
most likely due to
the heterogeneous complexity of the disease with a plethora of different
treatment influences,
See Bragge et al., A State-of-the-Science Overview of Randomized Controlled
Trials
Evaluating Acute Management of Moderate-to-Severe Traumatic Brain Injury. J
Neurotrauma. 2016 and Stein et al, Chapter 1 - Why Did the Phase III Clinical
Trials for
Progesterone in TBI Fail? An Analysis of Three Potentially Critical Factors in
New
Therapeutics for Traumatic Brain Injury: Prevention of Secondary Brain Damage
and
Enhancement of Repair and Regeneration, 2017, pages 3-18, ISBN 978-0-12-802686-
1.
Pathophysiology of TBI is complex and involves a variety of processes
including ¨ among
others - neuroinflammation, brain oedema formation and excitotoxicity (Jarrahi
et al,
Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic
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Interventions. Biomedicines. 2020;8(10):389). Nitric oxide has been discussed
as key player
in the development of secondary injury after TBI. Inhibitors of Nitric oxide
synthase have
been tested in animal models of Till with 4-amino-tetrahy-drobiopterin
(Ronopterin, VAS203)
having been shown been shown to be beneficial in animal models of TBI
(Terpolilli et al, The
novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents
brain edema
formation and intracranial hypertension following traumatic brain injury in
mice. J
Neurotrauma 2009; 26 1963-1975 and a phase II clinical trial (Stover et al.,
Nitric Oxide
Synthase Inhibition with the Antipterin VAS203 Improves Outcome in Moderate
and Severe
Traumatic Brain Injury: A Placebo-Controlled Randomized Phase Ha Trial
(NOSTRA),
Journal of Neurotrauma, 2014 31:1-8). However, it is not yet clear whether 4-
amino-
tetrahydrobiopterin (Ronopterin, VAS203) is indeed suitable for treating brain
injury such as
traumatic brain injury.
It is thus an object of the present invention to provide methods of treating
patients suffering
from brain injury.
SUMMARY OF THE INVENTION
This object is solved by the aspects of the invention as defined in the
claims, described in the
description, and illustrated in the Examples and Figures.
In a first aspect, the invention provides a method method of treating a human
patient suffering
from brain injury, wherein the method comprises administering to the patient
within a time
period of < 12 hours after the occurrence of the brain injury a
therapeutically effective amount
of a compound having the formula (I):
frr12
N CH,
H2N N N OH
In a second aspect, the invention provides a method of increasing the value of
the Extended
Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury,
thereby
improving the condition of the patient, wherein the value of the Extended
Glasgow Outcome
Scale (eGOS) of the patient reaches eGOS level 7 or eGOS level 8 six months
after the
occurrence of the brain injury, wherein the method comprises administering to
the patient
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within a time period of < 12 hours after the occurrence of the brain injury a
therapeutically
effective amount of a compound having the formula (I):
NH, cm
CH
N ss=-=
H,N N N
In a third aspect, the invention provides a method of increasing the value of
the Extended
Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury,
thereby
improving the condition of the patient, wherein the value of the Extended
Glasgow Outcome
Scale (eGOS) of the patient has increased by 2 or more six months after the
occurrence of the
brain injury, compared to the eGOS value of the patient determined three
months after the
occurrence of the traumatic brain injury, wherein the method comprises
administering to the
patient within a time period of < 12 hours after the occurrence of the brain
injury a
therapeutically effective amount of a compound having the formula (I):
NH, OH
N
OH
H,N N N
(I).
In a fourth aspect, the invention provides a method of treating a human
patient suffering from
brain injury, wherein the patient is a female of an age of 40 years or older,
and wherein the
method comprises (starting) administering to the patient within a time period
of > 12 hours
after the occurrence of the brain injury a therapeutically effective amount of
a compound
having the formula (I):
NH
CH
N 3
H2NNN OH
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In one illustrative embodiment of this fourth aspect, the compound having the
formula (I) is
administered by infusion in a total dose of 17 mg/kg body weight over 48
hours,
corresponding to a daily dose of 8.5 mg/kg body weight.
In a fifth aspect, the invention provides a method of treating a human patient
suffering from
brain injury, wherein the patient is of an age of 39 years or younger, and
wherein the method
comprises (starting) administering to the patient within a time period of > 12
hours after the
occurrence of the brain injury a therapeutically effective amount of a
compound having the
formula (I):
NH
.CH,
N
OH
H2N N N
1-I
In one illustrative embodiment of this fifth aspect, the compound having the
formula (I) is
administered by infusion in a total dose of 20 mg/kg body weight or in a total
dose of 30
mg/kg body weight.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood with reference to the detailed
description when
considered in conjunction with the non-limiting examples and the drawings, in
which:
Fig.1 shows the Extended Glasgow Outcome Scale (eGOS) with its levels 1 to 8
as used
herein as an outcome measure as brain injury;
Fig. 2 shows a standard questionnaire that is used for determining the eGOS
level of a
patient
Fig. 3A shows an overview of the Therapy Intensity Level (TIL) treatment with
the
typical types of interventions used in the treatment of patients with brain
injury together
with the intensity of the intervention and their respective score, while Fig.
3B shows an
exemplary TIL treatment with an index between 3 and 10 that can be used in the
present
invention
Fig. 4 shows the distribution of proportion of patients between Placebo and
Ronopterin
(VAS203)-treated patients reflecting changes in eGOS from 3 to 6 months for
all patients
and all times to infusion. Fig. 4A shows the change in eGOS from 3 to 6 months
by eGOS
level, Fig. 4B shows the change in eGOS from 3 to 6 months by category, Fig.
4C shows the
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increase of eGOS level by number of patients and Fig. 413 shows the odds-ratio
for the eGOS
increase. As seen from Fig. 4A Ronopterin-treated patients show an increase in
eGOS levels
up to 4 levels and the overall increase in eGOS by at least 2 levels is
encountered more often
in Ronopterin-treated patients (24 vs. 13 for the Ronopterin group, Fig. 4C).
Fig. 4 shows for
the Ronopterin-treated group more patients with higher increase in eGOS over
time, however
the increase is not (statistically) significant (Fig. 411). In addition, Fig.
4 shows for the
Ronopterin-treated group that there are less patients with a decrease in eGOS
over time,
however this decrease is not (statistically) significant.
Fig. 5 shows the distribution of proportion of patients of all ages between
Placebo and
Ronopterin-treated patients with changes in eGOS from 3 to 6 months, depending
on the time
to infusion within 12 hours and after 12 hours after traumatic brain injury.
Fig. 5 shows for
the Ronopterin-treated group a significant increase in proportion of patients
with increased
eGOS.
In more detail Figs.5A to 5D show the results for early infusion (< 12 hours),
with Fig. 5A
showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 5B showing
the change
in eGOS from 3 to 6 months by category, Fig. 5C showing the increase of eGOS
level by
number of patients and Fig. 511 showing the odds-ratio for the eGOS increase.
Figs.SA to 511
show that for early infusion (< 12 hours) Ronopterin-treated patients show an
increase in
eGOS levels up to 4 levels (Fig. SA). Fig. SC shows that overall, an increase
in eGOS by at
least 2 levels is encountered more often in Ronopterin-treated patients
compared to placed (9
vs 3). The increase in proportion of patients with an increase by at least 1
level is significant
compared to Placebo-treated patients. Figs.SE to 5H show the results for late
infusion (>12
hours), with Fig. SE showing the change in eGOS from 3 to 6 months by eGOS
level, Fig. SF
showing the change in eGOS from 3 to 6 months by category, Fig. 5G showing the
increase
of eGOS level by number of patients and Fig. 5H showing the odds-ratio for the
eGOS
increase. Ronopterin-treated patients show an increase in eGOS levels up to 4
levels (Fig.
5E). Overall, increase in eGOS by at least 2 levels is encountered more often
in Ronopterin-
treated patients (15 vs 10), see Fig 5G.
Fig. 6 shows the change in eGOS levels from 3 to 6 months, for patients with
an age of 18-39
years and at all times to infusion. Fig. 6A shows the change in eGOS from 3 to
6 months by
eGOS level, Fig. 6B shows the change in eGOS from 3 to 6 months by category,
Fig. 6C
shows the increase of eGOS level by number of patients and Fig. 6D shows the
odds-ratio for
the eGOS increase. Distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 18-
39 years.
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Ronopterin-treated patients show an increase in eGOS levels up to 3 levels
(Fig. 6A) Overall,
increase in eGOS by at least 2 levels is encountered more often in Ronopterin-
treated patients
(14 vs 9), see Fig. 6C. Fig. 6 shows that in the Ronopterin-treated group,
there are more
patients with higher increase in eGOS over time, however this increase is not
significant (see
Fig. 6D) while in the Ronopterin-treated group, there are less patients with
decrease in eGOS
over time, however this decrease is not significant.
Fig. 7 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 18-
39 years,
depending on the time to infusion within 12 hours and after 12 hours after
traumatic brain
injury. In more detail Figs.7A to 7D show the results for early infusion (< 12
hours), with Fig.
7A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 7B
showing the
change in eGOS from 3 to 6 months by category, Fig. 7C showing the increase of
eGOS level
by number of patients and Fig. 7D showing the odds-ratio for the eGOS increase
Figs.7A to
7D show that for early infusion (< 12 hours) Ronopterin-treated patients show
an increase in
eGOS levels up to 3 levels (Fig. 7A). Fig. 7C shows that overall, an increase
in eGOS by at
least 2 levels is encountered more often in Ronopterin-treated patients
compared to placed (4
vs 1). The increase in proportion of patients with an increase by at least 1
level is significant
compared to Placebo-treated patients, see Fig. 7B and Fig. 7D. Figs.7E to 711
show the
results for late infusion (>12 hours), with Fig. 7E showing the change in eGOS
from 3 to 6
months by eGOS level, Fig. 7F showing the change in eGOS from 3 to 6 months by
category,
Fig. 7G showing the increase of eGOS level by number of patients and Fig. 7H
showing the
odds-ratio for the eGOS increase. Ronopterin-treated patients show an increase
in eGOS
levels up to 3 levels (Fig. 7E). Overall, increase in eGOS by at least 2
levels is encountered
more often in Ronopterin-treated patients (10 vs 8), see Fig. 7G.
Fig. 8 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 40-
60 years. Fig.
8A shows the change in eGOS from 3 to 6 months by eGOS level, Fig. 8B shows
the change
in eGOS from 3 to 6 months by category, Fig. 8C shows the increase of eGOS
level by
number of patients and Fig. 8D shows the odds-ratio for the eGOS increase. As
seen from
Fig. 8A Ronopterin-treated patients show an increase in eGOS levels up to 4
levels and the
overall increase in eGOS by at least 2 levels is encountered more often in
Ronopterin-treated
patients (10 vs. 4), see Fig. 8C. Fig. 8 shows for the Ronopterin-treated
group more patients
with higher increase in eGOS over time, however the increase is not
(statistically) significant
(Fig. 8D). In addition, Fig. 8 shows for the Ronopterin-treated group that
there are less
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patients with a decrease in eGOS over time, however this decrease is not
(statistically)
significant.
Fig. 9 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 40-
60 years,
depending on the time to infusion within 12 hours and after 12 hours after
traumatic brain
injury. In more detail Figs.9A to 9D show the results for early infusion (< 12
hours) with Fig.
9A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 9B
showing the
change in eGOS from 3 to 6 months by category, Fig. 9C showing the increase of
eGOS level
by number of patients and Fig. 9D showing the odds-ratio for the eGOS
increase. As seen
from Fig. 9A Ronopterin-treated patients show an increase in eGOS levels up to
4 levels and
the overall increase in eGOS by at least 2 levels is encountered more often in
Ronopterin-
treated patients (5 vs. 2), see Fig. 9C. Fig. 9A to Fig. 9D show for patients
with an age > 40
years and administration of Ronopterin < 12 hours a trend to more patients
with an increase in
their eGOS levels (eGOS responders). Figs.9E to 9H show the results for late
infusion (>12
hours), with Fig. 9E showing the change in eGOS from 3 to 6 months by eGOS
level, Fig. 9F
showing the change in eGOS from 3 to 6 months by category, Fig. 9G showing the
increase
of eGOS level by number of patients and Fig. 9H showing the odds-ratio for the
eGOS
increase. Ronopterin-treated patients show an increase in eGOS levels up to 4
levels (Fig.
9E). Overall, increase in eGOS by at least 2 levels is encountered more often
in Ronopterin-
treated patients (5 vs 2), see Fig. 9G.
Fig. 10 shows a summary of the Odds Ratios (OR) for increases in eGOS levels
from 3 to 6
months for early and late infusion and the age groups 18-39 and 40-60 years (<
40 and > 40
years). Generally speaking, the odds ratio is a measure of the strength of
association with an
exposure and an outcome. An OR > 1 means greater odds of association with the
exposure
and outcome. An OR = 1 means there is no association between exposure and
outcome. An
OR < 1 means there is a lower odds of association between the exposure and
outcome. In the
present context of comparing two groups such a first group of patients that
are being treated
with Ronopterin and a second group of patients that are being treated with a
placebo, an odds
ratio of 1 means that there no difference between the odds in both groups,
while an odds ratio
of >1 means that the odds of the first group are higher and an odds ratio of
<1 means, that the
odds of the first group are lower. Generally speaking, an OR > 1.8 is
clinically relevant,
meaning a compound of interest shows the desired therapeutic efficacy. Using
here, as an
illustrative example, as first group the population of patients in the age
groups 18-39 (< 40)
that receive an early infusion (< 12 hours) of Ronopterin for treatment of TBI
and as a second
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group the population of patients in the age groups 18-39 (<40) that receive an
early infusion
(< 12 hours) of placebo, the odds ratio is 4.398 This means, the chance of
recovering from
TBI is about 4.4 times higher for the patient population that is treated with
Ronopterin than it
is for the patient population that receives placebo.
Fig. 11 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for male patients
Fig. 11A shows
the change in eGOS from 3 to 6 months by eGOS level, Fig. 11B shows the change
in eGOS
from 3 to 6 months by category, Fig. 11C shows the increase of eGOS level by
number of
patients and Fig. 11D shows the odds-ratio for the eGOS increase. As seen from
Fig. 11A
Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and
the overall
increase in eGOS by at least 2 levels is encountered more often in Ronopterin-
treated patients
(22 vs. 9), see Fig. 11C. Fig. 11 shows for the Ronopterin-treated group more
patients with
higher increase in eGOS over time, however the increase is not (statistically)
significant (Fig.
11D). In addition, Fig. 11 shows for the Ronopterin-treated group that there
are significantly
less patients with a decrease in eGOS over time (1)=0.04).
Fig. 12 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for male patients,
depending on the
time to infusion within 12 hours and after 12 hours after traumatic brain
injury. In more detail,
Figs.12A to 12D show the results for early infusion (< 12 hours) with Fig. 12A
showing the
change in eGOS from 3 to 6 months by eGOS level, Fig. 12B showing the change
in eGOS
from 3 to 6 months by category, Fig. 12C showing the increase of eGOS level by
number of
patients and Fig. 12D showing the odds-ratio for the eGOS increase. As seen
from Fig. 12A
Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and
the overall
increase in eGOS by at least 2 levels is encountered more often in Ronopterin-
treated patients
(9 vs 2), see Fig. 12C. Fig. 12A to Fig. 12D show for male patients and
administration of
Ronopterin < 12 hours that the increase in proportion of patients with an
increase by at least 1
level is significant compared to Placebo-treated patients. Figs.12E to Fig.12H
show the
results for late infusion (>12 hours), with Fig. 12E showing the change in
eGOS from 3 to 6
months by eGOS level, Fig. 12F showing the change in eGOS from 3 to 6 months
by
category, Fig. 12G showing the increase of eGOS level by number of patients
and Fig. 12H
showing the odds-ratio for the eGOS increase. Ronopterin-treated patients show
an increase
in eGOS levels up to 4 levels (Fig. 12E). Overall, increase in eGOS by at
least 2 levels is
encountered more often in Ronopterin-treated patients (13 vs 7), see Fig. 12G.
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Fig. 13 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for female patients
Fig. 13A
shows the change in eGOS from 3 to 6 months by eGOS level, Fig. 13B shows the
change in
eGOS from 3 to 6 months by category, Fig. 13C shows the increase of eGOS level
by number
of patients and Fig. 1310 shows the odds-ratio for the eGOS increase. As seen
from Fig. 11A
Ronopterin-treated patients show an increase in eGOS levels up to 2 levels and
the overall
increase in eGOS by at least 2 levels is encountered less often in Ronopterin-
treated patients
(2 vs 4), see Fig. 13C. Fig. 13 shows for the Ronopterin-treated group less
female patients
with higher increase in eGOS over time, however the increase is not
(statistically) significant
(Fig. 1311).
Fig. 14 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for female patients,
depending on
the time to infusion within 12 hours and after 12 hours after traumatic brain
injury In more
detail, Figs.14A to 1411 show the results for early infusion (< 12 hours) with
Fig. 14A
showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 14B showing
the
change in eGOS from 3 to 6 months by category, Fig. 14C showing the increase
of eGOS
level by number of patients and Fig. 1411 showing the odds-ratio for the eGOS
increase. As
seen from Fig. 14A Ronopterin-treated patients show an increase in eGOS levels
up to 2
levels and the overall increase in eGOS by at least 2 levels is encountered
less often in
Ronopterin-treated patients (0 vs 1), see Fig. 14C. Fig. 14A to Fig. 1411 show
for female
patients and administration of Ronopterin < 12 that there are less female eGOS
responders but
that there is higher Good Recovery at 3 months. Figs.14E to Fig.14H show the
results for late
infusion (>12 hours), with Fig. 14E showing the change in eGOS from 3 to 6
months by
eGOS level, Fig. 14F showing the change in eGOS from 3 to 6 months by
category, Fig. 14G
showing the increase of eGOS level by number of patients and Fig. 14H showing
the odds-
ratio for the eGOS increase. Ronopterin-treated female patients show an
increase in eGOS
levels up to 2 levels (Fig. 14E). Overall, increase in eGOS by at least 2
levels is encountered
less often in Ronopterin-treated patients (2 vs 3), see Fig. 14G.
Fig. 15 shows the impact of time to infusion, sex, and age on the proportion
of Good
Recovery (eGOS value of 7 or 8) in Placebo and Ronopterin-treated patients
expressed as
Odds Ratio with 95% Confidence Intervals. As evident from Fig. 15, early
infusion (< 12
hours) is associated with higher Odds Ratio in favor of Ronopterin in female
and male
patients, mainly for the tested female patient population with an age of 18 to
39 years, i.e. <
40 years and in male patients with an age of > 40 years. Late infusion (> 12
hours) is
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associated with higher Odds Ratio in favor of Ronopterin in female patients,
mainly in the
female patient population with an age > 40 years. (The high Confidence
Intervals are related
to the small number of patients in the sex- and age-dependent subgroups of
analysis.) At 3
months, the Odds Ratios reveal that female patients show highest impact of
Ronopterin
compared to male patients: early infusion: 1.4, 0.02-8.2 vs 0.4, 0.09-1.9;
late infusion: 10.2,
0.5-204 vs 0.2, 0.05-0.6). At 6 months, the Odds Ratios are higher in male
patients compared
to female patients (2.2, 0.6-7.6 vs 1.5, 0.2-23), especially with early
infusion With late
infusion, the Odds Ratios are higher in female patients compared to male
patients (5.5, 0.6-53
vs 0.6, 0.3-1.4).
Fig. 16 shows the distribution of proportion of patients for the 8 eGOS levels
in Placebo and
Ronopterin-treated patients at 3 and 6 months in male and female patients,
with males
(n=179) and females (n=44). Fig.16A shows the proportion of patients for the 8
eGOS levels
in Placebo and Ronopterin-treated patients at 3 months in male patients,
Fig.16B shows the
proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated
patients at 6
months in male patients, Fig. 16C shows the proportion of patients for the 8
eGOS levels in
Placebo and Ronopterin-treated patients at 3 months in female patients and
Fig. 160 shows
the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-
treated patients at
6 months in female patients. As can be seen from Fig.16, at 3 months, male
patients show
lower proportion of eGOS levels 7 and 8 (Good Recovery) compared to female
patients,
reflecting more beneficial impact in female patients. At 6 months, male
patients show an
increase in proportion of eGOS levels 7 and 8 compared to 3 months. Female
patients show
an increase in Good Recovery from 3 to 6 months.
Fig. 17 shows the distribution of proportion of patients for the 8 eGOS levels
in Placebo and
Ronopterin-treated male patients with early and late infusion, with 179 male
patients (n =
179) being included. Fig.17A shows the proportion of patients for the 8 eGOS
levels in
Placebo and Ronopterin-treated patients at 3 months in male patients for early
infusion (< 12
hours), Fig.17B shows the proportion of patients for the 8 eGOS levels in
Placebo and
Ronopterin-treated patients at 6 months in male patients for late infusion (>
12 hours), Fig.
17C shows the proportion of patients for the 8 eGOS levels in Placebo and
Ronopterin-treated
patients at 6 months in male patients for early infusion (< 12 hours) and Fig.
171) shows the
proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated
patients at 6
months in male patients for late infusion (> 12 hours). As can be seen from
Fig. 17, early
infusion (< 12 hours) is associated with an increase in proportion of male
patients with Good
Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated patients
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months. Late infusion (> 12 hours) is associated with an increase in
proportion of male
patients with Good Recovery (eGOS 7 and 8) which, however, is less pronounced
compared
to Placebo-treated patients from 3 to 6 months. Overall, early infusion is
associated with
higher proportion of Good Recovery at 6 months in the Ronopterin-treated male
patients.
Fig. 18 shows the distribution of proportion of patients for the 8 eGOS levels
in Placebo and
Ronopterin-treated female patients with early and late infusion, with 44
female patients
(n=44) being included Fig.18A shows the proportion of patients for the 8 eGOS
levels in
Placebo and Ronopterin-treated patients at 3 months in female patients for
early infusion (<
12 hours), Fig.18B shows the proportion of patients for the 8 eGOS levels in
Placebo and
Ronopterin-treated patients at 6 months in female patients for late infusion
(> 12 hours), Fig.
18C shows the proportion of patients for the 8 eGOS levels in Placebo and
Ronopterin-treated
patients at 6 months in female patients for early infusion (< 12 hours) and
Fig. 18D shows the
proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated
patients at 6
months in female patients for late infusion (> 12 hours). As evident from Fig.
18, early
infusion (< 12 hours) is associated with an increase in proportion of female
patients with
Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated
patients from 3
to 6 months. Late infusion (> 12 hours) is associated with an increase in
proportion of female
patients with Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-
treated
patients from 3 to 6 months Overall, early infusion is associated with higher
proportion of
Good Recovery at 6 months in the Ronopterin-treated female patients.
DETAILED DESCRIPTION OF THE INVENTION
While 4-amino-tetrahydrobiopterin (also known by its international
nonproprietary name
(INN) Ronopterin, or as VAS203) has been assumed to be therapeutically
effective in the
treatment of brain injury such as traumatic brain injury, it has been
surprisingly found in the
present application that the therapeutic efficacy of 4-amino-
tetrahydrobiopterin depends on a)
the time point at which 4-amino-tetrahydrobiopterin is administered and b) on
the patient
population that is to be treated.
So, it has been surprisingly found here that administering Ronopterin to
patients suffering
from brain injury and who are 39 years or younger within a time period of < 12
hours after the
occurrence of the brain injury leads to patients reaching Extended Glasgow
Outcome Scale
(eGOS) level 7 or eGOS level 8, that means full neurologic recovery. In this
group of patients
at an age of 39 or younger it has also been found that female patients reach
eGOS levels 7 or
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8 already three months after the occurrence of the brain injury, while male
patients reach
eGOS levels 7 or 8 only six months after the occurrence of the brain injury
(see, for example
Figs. 10 and 16). To the contrary, it has been found herein that female
patients of an age of 40
years or older reach eGOS levels 7 or 8 when administration of Ronopterin is
started within a
time period of > 12 hours after the occurrence of the brain injury. Notably,
in all patient
groups/populations examined herein it has been found that Ronopterin is
therapeutically
effective with patients of all subpopulations reaching eGOS levels 7 or 8,
meaning full
neurologic recovery from the brain injury. This therapeutic efficacy of
Ronopterin found
herein is also reflected by its ability to increase the eGOS level of the
patient by 1, 2, 3, or
even 4 levels, six months after the occurrence of the brain injury, compared
to the eGOS
value determined three months after the occurrence of the brain injury. Thus,
administration
of Ronopterin as practiced here will allow patients who, after three months
may still be
determined to have an eGOS value of 2 or 3 to reach an eGOS value of 7 or 8
six months after
occurrence of the traumatic brain injury.
Thus, the present invention provides for the first time a drug (Ronopterin)
that allows patients
suffering from brain injury to fully recover from their brain injury, thereby
finally providing a
long-awaited solution to the unmet medical need to be able to treat, for
example, traumatic
brain injury. Accordingly, the present invention provides a real breakthrough,
far and
foremost by allowing patients to fully recover from traumatic brain injury but
also in terms of
reducing the TBI related high costs described above. In this context, it is
exemplary referred
to the population of female patients at an age of 40 years and older, for
which administration
of Ronopterin at a time period > 12 hours after occurrence of the traumatic
brain injury allows
such female patients to reach an eGOS level of 7 or 8 even only three months
after occurrence
of the traumatic brain injury. Such fully recovered patients can thus be
released from hospital
or from rehabilitation early, thereby reducing the treatment costs
significantly. It is also noted
here that the present invention provides the added advantage that patients
receiving
Ronopterin as described herein only require, while being hospitalized, an
accompanying low
Therapy Intensity Level (TIL) treatment and not a high Therapy Intensity Level
(TIL)
treatment which has so far been used in trying to treat patients with
traumatic brain injury (see
Huijben et al, Use and impact of high intensity treatments in patients with
traumatic brain
injury across Europe: a CENTER-TDI analysis, Crit Care (2021) pages 25-78).
The invention will be further explained in the following making reference to
either, several or
all of these aspects. If reference is only made to one of these aspects, it is
understood by the
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person skill in the art, that this reference nevertheless includes references
to all other aspects
of the invention, if applicable.
Starting with the first aspect, the invention provides a method of treating a
human patient
suffering from brain injury, wherein the method comprises administering to the
patient within
a time period of < 12 hours after the occurrence of the brain injury a
therapeutically effective
amount of a compound having the formula (I).
NH
2 H
N),..Xy.1 CH3
H NN OH
In this context, "administering to the patient within a time period of < 12
hours after the
occurrence of the brain injury" means that the administration of the compound
of formula (I)
such as Ronopterin starts within any time in between the time period of < 12
hours after the
occurrence of the brain injury and will continue as long as necessary. For
example, the
administration can start as early as 3 hours or 4.5 hours after the occurrence
of the brain injury
(for example, if a patient is hospitalized very shortly after, for example, an
accident that leads
to the brain injury). The administration may, however, also start within a
time period of
between 6 to 12 hours after the occurrence of the brain injury, for example,
6, 7, or 10 hours
after the occurrence of the brain injury. Regardless of whether the
administration starts earlier
or later than 6 hours after occurrence of the brain injury, the administration
will in any case
continue for a suitable time period as specified herein.
In this context, also the aspect of the invention, in which the administration
of the compound
of formula (I) such as Ronopterin starts within any time later than 12 hours
after the
occurrence of the brain injury is addressed. With respect to this aspect
"administering to the
patient within a time period of >12 hours after the occurrence of the brain
injury" means that
the administration of the compound of formula (I) such as Ronopterin can start
within any
time later than 12 hours after the occurrence of the brain injury as long as
the administration is
considered therapeutically useful. Also in this aspect the administration will
continue as long
as necessary. For example, the administration can start as early as 12 hours,
for example, 12.1
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hours after the occurrence of the brain injury (if such an accurate
determination of the time
that has lapsed since the brain injury can be made) but also only 13, 14, 15,
16, 17, 18, 19 or
even 20 hours after the occurrence of the brain injury.
The compound having the formula (I) can be administered by any suitable route
of
administration. Usually, the compound of formula (I) is administered by
infusion. The term
"infusion" is used herein its regular meaning to refer to a continuous
administration that takes
place over a certain period of time. The administration/infusion can be
carried over any time
that has been found suitable. For example, such an administration may take
over a period of
about 12 to about 96 hours, a period of about 24 to about 72 hours or over a
period of about
24 to about 48 hours. Thus, the administration may take place for about 1, 2,
3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 32, 40, 48, 56,
68, 72, 86, or 96
hours. However, the administration via injection or infusion can also take
longer than the time
periods given above, if considered advantageous or necessary. For example, if
the body
weight of the patient is very high (which can be case of an obese patient) and
a total dose of,
for example 30 mg/kg body weight, cannot be administered within 72 hours, the
administration time may be extended to over 72 hours. As another example, a
higher total
dosage to be administered may also require a longer infusion time. It is also
possible to
stop/pause the administration/infusion for a certain period of time, for
example to avoid
unwanted side effects of the compound of formula (I) such as nephrotoxicity.
Such a pause
may thus prolong an intended administration time of, for example, 48 or 72
hours by several
hours. Typically, intravenous administration is used herein for the infusion.
Intravenous
administration is used in its regular term to mean the infusion or injection
of a liquid directly
into a vein, typically with a syringe and a hollow needle which is pierced
through the skin to a
sufficient depth for the material to be administered into the body of the
subject.
The compound of formula (I) such as Ronopterin can be administrated in any
dose that is
therapeutically effective. The upper limit of the daily dose is usually a dose
that is still safe to
administer in terms of side effects such as nephrotoxicity. Typically, a
compound of formula
(1) such as Ronopterin is administered at a total dose in the range of 2.5
mg/kg body weight to
30.0 mg/kg body weight. Illustrative examples of suitable total doses of the
compound
formula (I) include 2.5, 5.0, 7.5, 8.5, 10.0, 12.5, 15.0, 17.5, 20.0, 22.5,
25.0 or 27.5 mg/kg
body weight.
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If a total dose of the compound of formula (I) of, for example, 17 mg/kg body
weight of the
patient is to be administered, the compound of formula (I) may be administered
by infusion
over 48 hours, corresponding to a daily dose of 8.5 mg/kg body weight. In yet
another
example, if a total dose of the compound of formula (I) of 20 mg/kg body
weight is to be
administered, the compound of formula (I) may be administered by infusion over
48 hours,
corresponding to a daily dose of 10.0 mg/kg body weight. In yet another
example, if a total
dose of the compound of formula (I) of 30 mg/kg body weight is to be
administered, the
compound of formula (I) may be administered by infusion over 72 hours,
corresponding
(also) to a daily dose of 10.0 mg/kg body weight.
In this context, administration of a daily dose of 10 .0 mg/kg body weight is
in particular
suitable for treating a patient suffering from brain injury, wherein the
patient is of an age of
39 years or younger, and wherein the method comprises (starting) administering
to the patient
within a time period of > 12 hours after the occurrence of the brain injury a
therapeutically
effective amount of a compound having the formula (1):
NH2 H
N
LYN CH
II
H2N N N
If the compound of formula (I) is administered to this patient group (either
male or female
patients that are 39 years or younger) in a total dose of 20 mg/kg body
weight, the compound
of formula (I) may be administered by infusion over 48 hours, thus in a daily
dose of 10.0
mg/kg body weight. Alternatively, if the compound of formula (I) is
administered to this
patient group in a total dose of 30 mg/kg body weight, the compound of formula
(I) may be
administered by infusion over 72 hours, and thus also in a daily dose of 10.0
mg/kg body
weight.
Any type of brain injury can be treated by administration of the compound of
formula (I) as
described here. The brain injury may for example be traumatic brain injury,
non-traumatic
brain injury, elevated intracranial pressure, or secondary brain injury.
The term "traumatic brain injury" or "brain trauma" occurs when an external
force
traumatically injures the brain. TBI can be classified based on severity,
mechanism (closed or
penetrating head injury), or other features (e.g., occurring in a specific
location or over a
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widespread area). A traumatic brain injury can occur as a consequence of a
focal impact upon
the head, by a sudden acceleration/deceleration within the cranium or by a
complex
combination of both movement and sudden impact, as well as blast waves, or
penetration by a
projectile or sharp, or dull object. The Glasgow Coma Scale (GCS), the most
commonly used
system for classifying TBI severity, grades a person's level of consciousness
on a scale of 3-
15 based on verbal, motor, and eye-opening reactions to stimuli. In general,
it is agreed that a
TBI with a GCS of 13 or above is mild, 9-12 is moderate, and 8 or below is
severe Similar
systems exist for young children. From the diagnostic point of view, it is
further distinguished
between open and closed TBIs. An open TBI is considered to be an injury in
which the
protective barrier under the bone (cerebral meninges, dura mater) is
mechanically destroyed
and the brain is in contact with the external environment through this
opening. Often, an open
TBI is associated with the exit of liquor and brain tissue debris. In a closed
TBI the skull or
cranium remains intact, and the primary damage of the brain (trauma) is
characterized by
local lesions such as contusions or hematomas and/or diffuse cerebral tissue
damage. The
term -cranium" when referred to herein is the set of out of the neurocranium
(braincase) and
the viscerocranium (craniofacial) existing bony and cartilaginous head
skeleton of vertebrates
"Intracranial" means within the cranium.
In accordance with the above, traumatic brain injury of any severity can be
treated by the
administration of the compound of formula (I) as described herein. Thus, the
patient to be
treated may, for example, have been diagnosed with complicated mild, moderate,
or severe
traumatic brain injury. In another illustrative example, patient to be treated
may have been
diagnosed with traumatic brain injury of a Glasgow Coma Score (GCS) > 3. The
patient being
assessed of having a Glasgow Coma Score (GCS) > 3 may require intracranial
pressure (ICP)
monitoring and thus may be taken care of in an intensive care unit (ICU).
However, it is also
possible that the patient does not require ICP monitoring and can, thus, be
treated in a normal
hospital ward. This may be in particular the case if the patient exhibits a
TBI with a GCS of 9
or more, for example, a mild TBI (with a GCS above 13, see above) or a
moderate TBI with a
GCS of 9-12.
To the contrary, a "non-traumatic brain injury" does not involve external
mechanical force to
acquire a brain injury. Causes for non-traumatic brain injury may include lack
of oxygen,
glucose, or blood. Infections can cause encephalitis (brain swelling),
meningitis (meningeal
swelling), or cell toxicity as e.g. caused by fulminant hepatic failure, as
can tumours or
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poisons. These injuries can occur through stroke, heart attack, near-drowning,
strangulation or
a diabetic coma, poisoning or other chemical causes such as alcohol abuse or
drug overdose,
infections or tumours and degenerative conditions such as Alzheimer's disease
and
Parkinson's disease. An acute neurodegenerative disease is represented by
"stroke", which
refers to the loss of brain function due to disturbances in the blood supply
to the brain,
especially when it occurs quickly, and is often associated with
cerebrovascular disease. This
can occur following ischemia (lack of blood flow) caused by blockage
(thrombosis, arterial
embolism), or a haemorrhage of central nervous system (CNS), or intracranial
blood-vessels.
As a result, the affected area of the brain cannot function normally. In
accordance with the
above, non-traumatic brain injury that can be treated with the invention as
described here,
may be ischemic/ hypoxic/hemorrhagic brain injury (e.g. stroke), post-
resuscitation (after e.g.
cardiac arrest), subarachnoid haemorrhage, anticoagulation-induced haemorrhage
or non-
traumatic brain injury that is caused by inflammation and infection_
As an illustrative examples of a such an infection (disease) which can be
treated is
"meningitis", which is an acute inflammation of the membranes covering the
brain and spinal
cord, known collectively as the meninges. The inflammation may be caused by
infection with
viruses, bacteria, or other microorganisms, and less commonly by certain
drugs. Encephalitis
is another example of an infection that can be treated with the compound of
formula (I) as
described herein. In another example, the inflammation may be Systemic
Inflammatory
Response Syndrome (SIRS).
In addition to the damage caused at the moment of injury, brain trauma (non-
traumatic or
traumatic brain injury) causes "secondary injury" or secondary brain injury",
which refers to a
variety of events that take place in the minutes and days following the
injury. These
processes, which include alterations in cerebral blood flow and the pressure
within the skull,
contribute substantially to the damage from the initial injury. Secondary
injury events may
include local changes for example damage to the blood¨brain barrier, release
of factors that
cause inflammation, free radical overload, excessive release of the
neurotransmitter glutamate
(excitotoxicity), influx of calcium and sodium ions into neurons, and
dysfunction of
mitochondria. Injured axons in the brain's white matter may separate from
their cell bodies as
a result of secondary injury, potentially killing those neurons. Other factors
in secondary
injury are changes in the blood flow to the brain; repeated transient
disintegrity of the blood
brain barrier; ischemia (insufficient blood flow); cerebral hypoxia
(insufficient oxygen in the
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brain), cerebral oedema (swelling of the brain); and raised intracranial
pressure (the pressure
within the skull). In addition to local alterations, systemic influences from
SIRS, infections,
low or elevated blood glucose levels, low or very high blood pressure, low
oxygen, or low or
elevated carbon dioxide levels may also cause secondary and additional brain
injury. Thus, a
secondary brain injury that can treated as described herein may comprise a
condition selected
from the group consisting of edema formation from local or global hypoxia,
ischemia,
inflammation with and without infection, acute and chronic neuroinflammation
after traumatic
brain injury and neoplasms with both benign neoplasms and malignant neoplasms
being
treatable.
It can also be that the intracranial pressure may elevate due to swelling or a
mass effect from a
lesion, such as a haemorrhage. As a result, cerebral perfusion pressure (the
pressure of blood
flow in the brain) is reduced; ischemia results When the pressure within the
skull rises too
high, it can cause brain death or herniation, in which parts of the brain are
squeezed by
structures in the skull. The term -intracranial pressure" (ICP) means the
pressure inside the
cranium and thus in the brain tissue and cerebrospinal fluid (CSF) The body
has various
mechanisms by which it keeps the ICP stable, with CSF pressures varying by
about 1 mmHg
in normal adults through shifts in production and absorption of CSF. ICP is
measured in
millimeters of mercury (mmHg) and, at rest, is normally 7-15 mmHg for a supine
adult.
Changes in ICP are attributed to volume changes in one or more of the
compartments
contained in the cranium. An "elevated pressure in the cranium" or "elevated
intracranial
pressure" means an increased pressure in the cranium of a subject in
comparison to a normal,
healthy subject. As the ICP is normally between 7-15 mm Hg; thus at 20-25 mm
Hg, the
upper limit of normal, is already considered an elevated ICP and a treatment
to reduce this
pressure may be needed. Thus, as an elevated ICP can be considered any
pressure higher that
20 mm Hg in the cranium of a supine subject, preferably a pressure is higher
than 25 mm Hg,
higher than 26 mm Hg, higher than 27 mm Hg, higher than 28 mm Hg, higher than
29 mm
Hg, higher than 30 mm Hg, higher than 31 mm Hg, higher than 32 mm Hg, higher
than 33
mm Hg, higher than 34 mm Hg or higher than 35 mm Hg.
As mentioned above, it has been found in the present invention that the age
and the sex of the
patient has to be considered for the treatment. Addressing first the age of
the patient, the
patient may be up to 39 years old. Alternatively, the patent may be 40 years
or older. If the
patient is 39 years or younger, the patient may either be a child of an age
between 1 year to 10
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years, or a teenager or adolescent of an age of 11 to 17 or an adult that has
an age in the range
of 18 to 39 years. If the patient is 40 years of age or older, the patient can
have any age above
for 40 years. Such a patient may have an age in the range of 40 to 90 years,
40 to 80 years, 40
to 70 years or 40 to 65 years or 40 to 60 years. The patient may thus have an
age of 40, 41, 42,
43, 44, 45, 46, 47, 48, 49, 50, 51, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,
65, 66, 67, 68, 69, 70,
71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or
90 years.
The therapeutic methods and uses of a compound of formula (I) as described
herein comprise
an improvement of the physiological condition of the patients suffering from
brain injury such
as traumatic or non-traumatic brain injury. The condition of the patient (as a
result and a
measure of the efficacy of the treatment, i.e. typically reduction of the
severity of the brain
injury) can be expressed by the Extended Glasgow Outcome Scale (eGOS). It is
noted here
that the original GOS and the subsequently developed extended GOS (eGOS or
GOSE) are
the most widely used outcome measure in studies of brain injury, as summarized
in, for
example, in the review article of McMillan et al., The Glasgow Outcome Scale -
40 years of
application and refinement, Nature Reviews Neurology volume 12, pages 477 -
485 (2016).
As explained by McMillan et al, 2016, vide supra, the original GOS and the
subsequently
developed extended eGOS are recommended by several national public health
bodies
including the National Institute of Health (NIFI) in the U.S. as the outcome
measure for major
trauma and head injury, respectively. As also explained by McMillan et al,
vide supra, the
suitability of the GOS and eGOS is inter alia based on its simplicity, short
administration
time, reliability and validity, stability, flexibility of administration (face-
to-face, over the
telephone and by post), cost-free availability and ease of access. While the
original Glasgow
Outcome Scale (GOS) rates patient status into one of five categories: Dead,
Vegetative State,
Severe Disability, Moderate Disability or Good Recovery, the Extended GOS
(eGOS) as used
herein provides a more detailed categorization into eight categories by
subdividing the
categories of severe disability, moderate disability and good recovery into a
lower and upper
category as follows:
Table 1: Extended Glasgow Outcome Scale (eGOS)
Level/Value Category/condition of the Abbreviation
patient
1 Death
2 Vegetative state, VS
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Condition of unawareness,
only reflex responses,
periods of spontaneous eye
opening
3 Lower severe disability, SD-
Condition of mental and/or
physical disability, patient
can be left alone for less
than 8 h/day
4 Upper severe disability. SD+
Patient can be left alone for
more than 8 h/day
Lower moderate disability, MD-
Some disability, independent
at home and dependent
outside, no return to work
6 Upper moderate disability, MD+
Some disability, independent
at home and dependent
outside, able to return to
work
7 Lower good recovery, GR-
Resumption of normal life
with some disabling due to
neurological and/or
psychological deficits
8 Upper good recovery, GR-H
Fully returned to normal life
For the sake of clarity, it is noted that the eGOS levels/value as used herein
refer to the Level
as in given in Table and as also provided by Fig. 1. Thus, an eGOS level of 7
indicates lower
good recovery of a patient, wherein the patient is able to resume normal life
with some
disabling due to neurological and/or psychological deficits, while the eGOS
level of 8 refers
to upper good recovery, with the patient having fully returned to normal life.
The eGOS
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level/value of a patient can be determined by the respective standard
questionnaire that is
shown in Fig. 2 and that is available, for example, at https://www. sralab
.org/rehabi tati on-
measures/glasgow-outcome-scale-extended. The questionnaire of Fig. 2 also
illustrates the
simplicity and flexibility of the eGOS determination via a face-to-face
meeting, a telephone
interview or and by post. It is also noted here that the eGOS value as an
"outcome score" is
assessed not immediately after the occurrence of the brain injury but after a
certain period of
time "post-injury" such a 3 months, 6 months, or 12 months after the
occurrence of the brain
injury. Indeed, assessment of the eGOS 3 months, 6 months, and 12 months post
injury are
the standard approach for assessing brain injury such as traumatic brain
injury. In line with
this standard practice, "3 months eGOS values" and "6 months eGOS values" have
been used
herein. It is of course also possible to use eGOS values determined at a
different point to time
In this context, we note that the assessment of the eGOS value may not be
taken at exactly the
day that is 3 or 6 months after the brain injury but that day can deviate by a
couple of days
For example, if the traumatic brain injury occurred on 1 February, the 3
months eGOS value
does not necessarily have to be determined on 1 May but can also be determined
in late April
or early May, for example on 29 April or 5 May.
Before further discussing the eGOS levels observed herein after administration
of a
compound of formula (I), it is noted that the neurological condition of a
patient that has
suffered from brain injury such as traumatic brain injury can also be
assessed/evaluated herein
by other commonly used outcome scores such as the Disability Rating Scale
(DRS) or the
Functional Independence Measure (FIN'!). See, for example, Salter et al,
Module 17
"Assessment of Outcomes Following Acquired Brain Injury" available at
https://erabi.ca/module-list/ which describes the Disability Rating Scale
(page 14), the
Functional Independence Measure (page 19) as well as the eGOS (page 30), or
the
corresponding book chapter of Salter et al. "Assessment of Outcomes Following
Acquired
Brain Injury" in Teasell R, Cullen N, Marshall S, Janzen S, Bayley M, editors.
Evidence-
Based Review of Moderate to Severe Acquired Brain Injury. Version 11.0: p1-75.
See also
Marquez de la Plata e al, Arch Phys Med Rehabil. 2008 May; 89(5): 896-903
which
compares the Disability Rating Scale, the Functional Independence Measure and
the eGOS
under clinical trial conditions.
Turning now to the observed changes in the eGOS values, the 3 months eGOS
value is taken
in the present invention as the reference to which a subsequent eGOS value
such as the 6
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months eGOS value is compared. Thus, a difference in the eGOS value of +1
means herein
that the eGOS value at 6 month is 1 level higher than the eGOS value at 3
months, for
example, since the patient has improved from eGOS level 4 to eGOS level 5
within the
respective 3 months period.
Having this in mind it has been found herein that administration of the
compound of formula
(I) increases the value of the Extended Glasgow Outcome Scale (eGos) of the
patient by at
least 1 or at least 2 eGOS levels when assessed six months after the
occurrence of the brain
injury such as traumatic brain injury and when compared to the eGOS level of
the patient 3
months after the occurrence of the trauma. Notably, regardless of which
patient population is
treated and the time point when the administration is started (i.e. either at
a time < 12 hrs our
at a time > 12 hrs), it has been found herein that administration of the
compound of formula
(I) increases the eGOS level of a patient by 2, 3, 4, 5 or even 6 levels six
months after the
occurrence of the brain injury compared to the eGOS level of the patient at 3
months (cf. the
Experimental Section). Thus, the eGOS level of a patient can increase, for
example, increase
from 2 after three months to eGOS level 4, 5, 6, 7 or even 8 six months after
the brain injury.
In another example, the eGOS level of a patient can increase, for example,
increase from 3
after three months to eGOS level 5, 6, 7 or 8 six months after the brain
injury.
In this context it is also noted that regardless of which patient population
is treated and the
time point when the administration is started (i.e. either at a time < 12 hrs
our at a time > 12
hrs), by means of the administration of the compound of formula (I) patients
reach eGOS
level 7 or eGOS level 8 either already three months after or at least six
months after the
occurrence of the traumatic brain injury.
In one embodiment of the invention in which the compound of formula (I) is
administered
within time period of < 12 hours after the occurrence of the traumatic brain
injury, the patient
is a male patient having an age of 39 years or below. Such a male patient may
reach eGOS
level 7 or eGOS level 8 six months after the traumatic brain injury. In
accordance with this, in
such a male patient (population), the value of the Extended Glasgow Outcome
Scale (eCios) of
the patient increases by at least 1 level, or at least 2 level, including by
3, 4 or 5 levels, when
assessed six months after the occurrence of the traumatic brain injury,
compared to the eGOS
value of the patient determined three months after the traumatic brain injury,
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In another embodiment of the invention in which the compound of formula (I) is
administered
within a time period of < 12 hours after the occurrence of the traumatic brain
injury, the
patient is a male patient having an age of 40 years or higher. Such a male
patient may reach
eGOS level 7 or eGOS level 8 six months after the traumatic brain injury.
Accordingly, in
such a male patient (population), the value of the Extended Glasgow Outcome
Scale (eGos) of
the patient increases by at least 1 level, or at least 2 levels, including by
3, 4 and 5 levels,
when assessed six months after the occurrence of the traumatic brain injury,
compared to the
eGOS value of the patient determined three months after the traumatic brain
injury.
In yet another embodiment of the invention in which the compound of formula
(I) is
administered within a time period of < 12 hours after the occurrence of the
brain injury, the
patient is a female patient having an age of 39 years or below. Such a female
patient may
reach eGOS level 7 or eGOS level 8 already three months after, but at least
six months after
occurrence of the traumatic brain injury. In such a female patient
(population), the value of
the Extended Glasgow Outcome Scale (eGOS) of the patient increases by at least
1 level or at
least 2 levels, including 3, 4 and 5 levels, when assessed six months after
the occurrence of
the traumatic brain injury, compared to the eGOS value of the patient
determined three
months after the traumatic brain injury.
Turning now to an embodiment of the invention in which the compound of formula
(I) is
administered within a time period of > 12 hours (for example, 12, 13, 14, 15,
16, 17, 18, 19 or
20 hours, see above) after the occurrence of the brain injury, the patient is
a female patient
having an age of 40 years or older, for example, an age in the range of 40 to
60 years, or an
age of 40 to 70 years, or an age in the range of 40 to 80 years or an age in
the range of 40 to
90 years. For such a female patient (population), it has surprisingly been
found that such an
administration of the compound of formula (I) results in the female patient
reaching eGOS
level 7 or eGOS level 8 either already three months or at least six months
after the traumatic
brain injury. In such a female patient (population), the value of the Extended
Glasgow
Outcome Scale (eGOS) of the patient increases by at least 1 level or at least
2 levels,
including 3, 4 and 5 levels, when assessed six months after the occurrence of
the traumatic
brain injury, compared to the eGOS value of the patient determined three
months after the
traumatic brain injury.
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Turning now to a further advantage of the therapeutic use of the compound of
formula (I) as
described herein, the treatment comprises providing within a period of 14 days
after
occurrence of the traumatic brain injury the patient with (only) a low Therapy
Intensity Level
(TIL) treatment. The low Therapy Intensity Level (TIL) treatment may have a
therapy index
level of only between 3 and 10. The term "Therapy Intensity Level (TIL)
treatment" is used
herein in its regular meaning (cf in this respect, for example, Huijben et al,
Crit Care (2021,
vide supra) and as illustrated by Fig. 3A which shows an overview of the
Therapy Intensity
Level (TIL) treatment with the typical types of interventions used in the
treatment of patients
with brain injury together with the intensity of the intervention and their
respective score. Fig.
3B shows options for exemplary low T1L treatments that can be used herein and
which yield
an index between 3 and 10. In accordance with Fig. 3B a low Tit treatment used
here may
only comprise as interventions "Head elevation", "Sedation" and "Increased
oxygenation"
which together have a low Tit score of only 3 In another illustrative example
of such a low
TIL score treatment, this treatment may comprise as interventions "Head
elevation",
"Sedation", "Increased oxygenation ", Cooling" and "Osmotherapy" which
together have a
low TIL score of only 6 The person skilled in the art is able to deteimine the
appropriate low
TIL treatment for each patient. In this context, it is pointed out again that
it is an advantage of
the present invention that patients receiving a compound of formula (I) such
as Ronopterin as
described herein require, while being hospitalized, only such a
(supporting/accompanying)
low Therapy Intensity Level (TIL) treatment. As evident, this reduces the work
load and
burden of the clinical staff taking care of the patients in the hospital
significantly, in particular
when patients are treated in the ICU.
Turning now to the compound of formula, the compound is typically 4-Amino-
(6R,S)-5,6,7,8-
tetrahydro-L-biopterin having the formula (Ia):
NH OH
N N s CH,
OH
H2N
(Ia).
In accordance with the disclosure of, for example, European Patent 2 926 805,
the
corresponding US patent 10,016,431 or the corresponding International Patent
Application
WO 2015/150294, the compound (Ia) may be a diastereomeric mixture that
comprises more
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(6R)-4-Amino-5,6,7,8-tetrahydro-L-biopterin than (6S)-4-Amino-5, 6, 7, 8-
tetrahydro-L-
biopterin
For administration of 4-Amino-5,6,7,8-tetrahydro-L-biopterin (Ronopterin) any
suitable
pharmaceutical composition containing 4-Amino-5,6,7,8-tetrahydro-L-biopterin
can be used.
Suitable formulations are described in International Patent Application WO
2004/084906, or
the corresponding US patent 8,222,828 as well as in European Patent 2 926 805,
US patent
10,016,431 or International Patent Application WO 2015/150294. The solid
formulations
described in US patent 10,016,431 or WO 2015/150294 are particularly
convenient for being
used here since these solid formulations are stable for 36 months and provide
a ready-to-use
isotonic infusion solution with physiological pH (between 6.5 to 7.6) after
reconstitution of a
unit dosage with 50 mL water. The final concentration of Ronopterin in such a
ready-to-use
infusion solution is 20 mg/mL
Accordingly, infusion of the compound of formula (I) such as Ronopterin can be
carried out
with a reconstituted solid composition of the compound of formula (I), wherein
a unit dosage
of the solid composition contains, as described in US patent 10,016,431 or WO
2015/150294,
650 60 mg of the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin,
140 30 mg
of water of crystallization, 70 7 mg Nazi-Mai = 2 FLO, 16.5 2 mg NaELP04 =
2 ELO, and
350 30 mg NaCl. Alternatively, and as also described in US patent 10,016,431
or WO
2015/150294, a unit dosage of the solid composition may contain 650 60 mg of
the free
base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 60 50 mg of water of
crystallization, 70 7 mg Na211PO4 = 2 H20, 12 2.5 mg NaH2PO4 = 2 H20, and
350 30
mg NaCl. In accordance with the above, the reconstitution then comprises
providing a vial
containing lg of the unit dosage and adding 50 ml water to lg of the unit
dosage to yield a
ready-to-use infusion solution with a concentration of Ronopterin of 20 mg/mL.
Such an
infusion solution can then be administered (infused) to a patient (population)
as described
here, for a suitable period of time (such as 12 to 96 hours) starting with the
administration
either within a time period of < 12 hours or within a time period of > 12
hours.
In accordance with the above disclosure, a further aspect of the invention is
directed to a
method of treating a human patient suffering from brain injury, wherein the
patient is a female
of an age of 40 years or older, and wherein the method comprises (starting)
administering to
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the patient within a time period of > 12 hours after the occurrence of the
brain injury a
therapeutically effective amount of a compound having the formula (I):
NH2 OH
N
OH
H2N N N
The patient populations, dosages, administration times and formulations as
disclosed for the
use of a compound of formula (I) in the first aspect of the invention equally
apply to this
second aspect.
A third aspect of the present invention relates to a method of increasing the
value of the
Extended Glasgow Outcome Scale (eGOS) of a human patient suffering from brain
injury,
thereby improving the condition of the patient, wherein the value of the
Extended Glasgow
Outcome Scale (eGOS) of the patient reaches eGOS level 7 or eGOS level 8 six
months after
the occurrence of the brain injury, wherein the method comprises (starting)
administering to
the patient within a time period of < 12 hours after the occurrence of the
brain injury a
therapeutically effective amount of a compound having the formula (I):
NH
N
H2N N N
(0.
In this aspect, the eGOS value of the patient when assessed six months after
the occurrence of
the traumatic brain injury can have increased by 1, 2, 3, 4, 5, or 6 eGOS
levels compared to
the eGOS value of the patient determined three months after the occurrence of
the traumatic
brain injury.
The patient populations, dosages, administration times and formulations as
disclosed for the
use of a compound of formula (I) in the first aspect of the invention equally
apply to this third
aspect.
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A fourth aspect of the present invention relates to a method of increasing the
value of the
Extended Glasgow Outcome Scale (eGOS) of a human patient suffering from brain
injury,
thereby improving the condition of the patient, wherein the value of the
Extended Glasgow
Outcome Scale (eGOS) of the patient has increased by 2 or more six months
after the
occurrence of the brain injury and compared to the eGOS value determined three
months after
the occurrence of the brain injury. This method comprises (starting)
administering to the
patient within a time period of < 12 hours after the occurrence of the brain
injury a
therapeutically effective amount of a compound having the formula (I):
OH
H,N N N
By means of this method, the value of the Extended Glasgow Outcome Scale
(eGOS) of the
patient can have increased by 1, 2, 3, 4, 5, or 6 level six months after the
occurrence of the
brain injury, when compared to the eGOS value determined three months after
the occurrence
of the brain injury. Also in this method administering a compound of formula
(I) results in
the value of the Extended Glasgow Outcome Scale (eGOS) of the patient reaching
eGOS
level 7 or eGOS level 8 six months after the occurrence of the brain injury.
The dosages, administration times and formulations as disclosed for the use of
a compound of
formula (I) in the first aspect of the invention equally apply to this fourth
aspect.
The invention will be further illustrated by the following non-limiting
Experimental
Examples.
EXAMPLES
The following examples further illustrate the invention. These examples should
however not
be construed as to limit the scope of this invention. The examples are
included for purposes of
illustration and the present invention is limited only by the claims.
Example 1: Manufacturing of Ronopterin
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Ronopterin (VAS203) is prepared in a multistep synthesis starting from
commercially
available L-biopterin as described in Example 1 of, for instance, US patent
10,016,431 or WO
2015/150294.
Example 2: Manufacturing of solid Ronopterin containing composition (Drug
Product)
Ronopterin (VAS203) is supplied as a sterile, white to pale red or brown
lyophilised powder
filled in 50 mL glass vials under nitrogen as a protective atmosphere. Each
vial contains 650
60 mg of the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin and
140 30 mg of
water of crystallisation. Additionally, the vials contain 350 30 mg sodium
chloride (NaC1),
70 7 mg disodium hydrogen phosphate dihydrate (Na2HPO4 2 H20), and 16.5 2
mg
sodium dihydrogen phosphate dihydrate (NaH2PO4 2 H20). The limits of tolerance
of the
drug product composition are relatively high ( 10 %). The reason for this is
the variation of
the hydrochloride content of Ronopterin. The hydrochloride content of
Ronopterin varies
from batch to batch up to 10 % (from 2.03 HC1 to 2.24 HC1). During the
preparation of the
drug product the hydrochloride was neutralised in the present invention by
addition of sodium
hydroxide and sodium-phosphate buffer to obtain an isotonic solution with a
physiological pH
value. Therefore, also the content of the molecules generated during
neutralisation (sodium
chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate) varies
according
to the hydrochloride content of the respective Ronopterin batch. The given
limits of tolerance
are necessary to meet the specifications of the quality relevant parameters pH
and osmolality.
The qualitative composition of lg Ronopterin vials is listed in Table 2.
Table 2
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Rt!ference
Component to Function
standards-
4-Amino-(6R,S)-5,6,7,8-
in lunt.s.e Active ingredient
tetrahydro-L-hiopterin
Sodium chloride* Pk Fur_ 0.smolJrny
Otsodium hydrogen phosphate
Ph.Eur. PIOT
di hydrate
Sodium &hydrogen phosphate
Ph.Eur. 1.3lqjf&r
titer for ;ilici_tion (aqua ad Solvent used for
Ph.Lur.
inject.) reconstitution
Protective
trogen Ph.Eur.
atmosphere
* Sodium chloride is generated during the preparation of the formulation when
the hydrochloride of
the drug substance reacts with the sodium hydroxide solution. Both ingredients
comply with the
European Pharmacopoeia.
Pharmaceutical Composition
A solid lyophilised dosage form of Ronopterin as described in US patent
10,016,431 or WO
2015/150294 was used here for the preparation of the infusion solutions used
in the clinical
study.
1 g Ronopterin ad 1 Og sodium hydroxide/sodium hydrogen phosphate solution
buffer with a
final pH of 7.4 as described in US patent 10,016,431 or WO 2015/150294 was
selected to be
aseptically processed, sterilised by membrane filtration and filled into 50 mL
glass vials.
Subsequently, this solution was freeze-dried according to a selected
lyophilisation program
that produced a lyophilised product with excellent stability. In this solid
composition,
Ronopterin is present as free base 4-Amino-5,6,7,8-tetrahydro-L-biopterin. The
vials are
closed under nitrogen, sealed with freeze-drying stoppers and closed with
white vacuum
closures. The excipients are added in order to provide an isotonic solution
with physiological
pH after reconstitution with 50 mL water ad inject. The pH of the final
isotonic solution is 6.5
to 7.6. The final concentration of the drug substance VAS203 (Ronopterin) is
20 mg/mL.
Example 3: Phase III clinical trial
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A phase III trial of Ronopterin infusion to adult TBI patients (18-60 years)
with acute
moderate and severe TBI was performed. Based on the results of the earlier
phase IT study, the
NOSTRA (NO Synthase in TRAumatic Brain Injury) phase III trial was designed to
detect
clinically relevant differences in clinical outcome (Extended Glasgow Outcome
Score at 6
months after injury) as primary endpoint.
Methods/Design
Trial design and participants
NOSTRA III was a multicentre, prospective, two parallel groups, blinded,
placebo-controlled,
randomised phase III trial of Ronopterin infusion for 48 hours in adult
intensive care patients
with acute moderate and severe TBI. The primary objective was to demonstrate
that the
extended Glasgow Outcome Score (eGOS) 6 months after injury is improved
following
administration of Ronopterin compared to placebo. The detailed study protocol
is described
by Tegtmeier et al. Efficacy of Ronopterin (VAS203) in Patients with Moderate
and Severe
Traumatic Brain Injury (NOSTRA phase III trial): study protocol of a
confirmatory, placebo-
controlled, randomised, double blind, multi-centre study. Trials. 2020_ A
total of 224
evaluable patients with moderate and severe TBI were enrolled in 32 centres in
Austria,
France, Germany, Spain, and United Kingdom. The trial started on 24 August
2016 with last-
patient last-visit on 17 June 2020.
Eligibility
Patients between 18 and 60 years of age with Glasgow Coma Score > 3 requiring
intracranial
pressure (ICP) monitoring were enrolled. Other inclusion criteria were TBI
within the last 18
hours but at least 6 hours after the injury, which were expected to survive
more than 24 hours
after admission. The upper limit of age was set to 60 years for safety
reasons, as in the
NOSTRA-II trial in particular elderly patients exhibited renal dysfunction.
Key exclusion criteria were penetrating head injury, concurrent spinal cord
injury, bilateral
fixed and dilated pupils (> 4 mm), renal dysfunction (serum creatinine values
> 1.2 mg/dL),
rhabdomyolysis and decompressive craniectomy planned prior to randomisation.
The inclusion and exclusion criteria were designed to exclude patients with
unsurvivable
injuries and patients at risk of renal failure. For complete inclusion and
exclusion criteria see
Tegtmeier et al., Trial 2020, vide supra.
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The centres treated the patients according to their established standard of'
care; all centres
were requested to follow the standardised TBI clinical practice according to
the current
guidelines [Carney].
Randomisation and blinding
Patients were assigned to receive Ronopterin and placebo in a ratio of 1-1 via
a confidential
internet-based system with block randomisation. Balance in treatment
allocation across the
study participants was enhanced through stratification by the age of the
included patient (two
age groups 18-39 and 40-60 years) per enrolling site.
The trial was conducted as a double blinded trial. Patients, site
investigators, site research
coordinators, the sponsor, central CT scan assessor and the staff in charge of
treating the
patients and evaluating the outcome were blinded.
Because the infusion solution of Ronopterin is slightly yellowish, the ready-
to-use infusion
solution of Ronopterin and placebo (saline) was prepared in an opaque syringe
by unblinded
staff not involved in the care of trial patients. Depending on the local
organisation this was a
medical employee from another ward or the central pharmacy.
Trial interventions
Ronopterin and placebo (0.9% saline) were infused continuously via central
venous catheter
at a constant rate. A total dose of 17 mg/kg body weight of Ronopterin was
infused for 48
hours (daily dose 8.5 mg/kg body weight).
The dose for each patient was calculated automatically based on the individual
body weight,
resulting in an individual infusion rate for each patient.
Sample size estimation
The main primary and secondary analyses followed a modified intention-to-treat
approach to
define the full analysis patient set, based on all randomly assigned patients
except those
withdrawing consent for use of all trial data and those not fulfilling
inclusion criteria and
never receiving the intervention.
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Study objectives and endpoints
The primary outcome was the difference between eGOS in Ronopterin and placebo
treated
patients at 6 months after trauma. The eGOS was determined by a face to face
meeting by
trained assessors.
The prognostic factor according to Steyerberg et al. (Steyerberg et al.
Predicting outcome
after traumatic brain injury. PLoS Med 2008 5(8)) predicts the probability of
6 months
mortality or probability of 6 months unfavorable outcome. The prognostic
factor was
analyzed by a t-test on a two-sided alpha level of 0.05. The mean difference
of the score under
Ronopterin and Placebo with its 95%-confidence interval were summarized for
comparability
at baseline.
Statistical analysis
Based on the results of the NOSTRA II trial, sample size estimation of the
current NOSTRA
Phase III study was based on an assumed odds ratio of 2.3.
The NOSTRA phase III trial was designed to detect a treatment effect as
statistically
significant on an alpha level of 0.05 with a statistical power of 92%, 220
evaluable patients
were needed for the full analysis set. To account for patients lost for follow
up and
withdrawals, number of recruited patients was increased by 5% to 232 patients.
However, as
number of withdrawals and lost-to-follow up was very low, the study was
successfully
completed after recruitment of evaluable 224 patients.
The null-hypothesis of no shift across the 8 ordered categories of eGOS for
the two treatment
groups was tested after six months based on a proportional odds model
stratified by age (18-
39 years and 40-60 years). The treatment effect was estimated using ordinal
Logistic
regression model as the (proportional) odds ratio of Ronopterin versus
Placebo. Treatment
and age (18-39 years and 40-60 years) were included in the model. The
proportional odds
assumption was tested using a Chi-Square Score Test.
As secondary efficacy endpoint the eGOS at 3 months was analysed using the
same statistics.
Data monitoring and interim analyses
An independent Data and Safety Monitoring Committee (DMC) reviewed the safety
data on
an on-going basis. Three safety interim analyses were scheduled after
inclusion of 40, 80, and
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110 patients, respectively. After enrolment of 110 FAS-evaluable patients an
unblinded
interim analysis was conducted. The result of this interim analysis was the
recommendation to
continue and finalize the study as planned,
Safety and adverse event analyses
Safety analyses was performed using standard descriptive methods.
The total number of treatment-emergent adverse events (TEAE) and the total
number of
patients with TEAEs, the total number of TEAEs related to the study drug
(certain, probable,
possible), the total number of patients with TEAEs related to the study drug,
the total number
of TEAEs and the total number of patients with serious TEAEs, the total number
of patients
with TEAEs leading to discontinuation of study treatment and the total number
of patients
with TEAEs leading to death were summarised by treatment arm
Ethical Approval
This trial was conducted in patients unable to consent with patient's legal
representatives
providing consent for the patient according to local regulations. All patients
who recovered
were asked to re-consent. Approval for this protocol was obtained from
competent regulatory
authorities and ethics committees according to local regulations.
Description of the post hoc analysis
The main objective of the post hoc analyses was to estimate the effect size of
VAS203
compared with placebo for the primary endpoint eGOS-I in the subgroups time to
infusion
<12 hours and >12 hours. Supportive analyses were conducted by age group (<40
years, >40
years) because age group was used as a stratification factor in the study.
Comparability
between treatment groups regarding demographics as well as severity and
location of disease
was investigated using similar methods as in the main CSR.
The proportions of patients per eGOS-I level at 3 months and at 6 months were
calculated.
For the change in eGOS-I over time, the proportion of patients with changes
from 3 to 6
months were calculated by eGOS-I level, and in addition categorised as
decreased (i.e. any
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decrease in eGOS-I level from 3 to 6 months), unchanged (i.e no change in eGOS-
I level
from 3 to 6 months), and increased (i.e. any increase in eGOS-I level from 3
to 6 months).
Ordinal logistic regression was used for the analysis of eGOS-I at 3 months
and at 6 months,
including treatment group and age group (<40 years, >40 years) as factors in
the model.
Estimated odds ratios for the comparison of the VAS203 and placebo groups of
>1 mean that
eGOS-I was higher in the VAS203 group than in the placebo group across the 8
levels,
whereas odds ratios of <1 mean that eGOS-I was lower in the VAS203 group than
in the
placebo group. Odds ratios together with their 95% CIs were used to estimate
and assess the
size of the treatment effect of VAS203 compared to placebo. Proportional
hazards were
assumed as valid for all these analyses because ordinal logistic regression
analysis is known
to be robust against deviations from this assumption, also, the power of
assumption checking
would be low for small subgroups.
The binary variable eGOS-I increase was defined as -yes" if there was an
increase of at least
1 level from 3 to 6 months. If there was no change or a decrease of at least 1
level from 3 to 6
months, the variable was defined as "no". For the analysis of eGOS-I increase,
nominal
logistic regression was used, including treatment group and age group (<40
years, >40 years)
as factors and eGOS-I at 3 months as covariate to adjust for potential
differences at 3 months.
Obtained odds ratios for the comparison of the VAS203 and placebo groups of >1
mean that
the eGOS-I increase occurred more often in the VAS203 group than in the
placebo group,
whereas odds ratios of <1 mean that the eGOS-I increase occurred less often in
the VAS203
group than in the placebo group.
The analyses were done for all patients in the full analysis set (FAS) and for
the subgroups
defined by time to infusion (<12 h, >12 h) and age group (<40 years, >40
years).
The analyses were based on ADaM datasets produced for the main CSR in 2020.
For the
eGOS-I dataset, 4 missing values for time to infusion were imputed in
collaboration with the
Sponsor based on calculation from related variables. Four eGOS-I values were
missing at 3
months; the respective patients were excluded from analyses of this variable.
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A corrected value for time to admission to study centre (for 1 patient, the
date for admission
to study centre had been incorrectly captured in the CRF). This value was
changed via hard
coding following authorisation of a post-lock database change by the Sponsor.
Consistent with the rounding applied for the main CSR, the variables "time
from injury to
admission [hours]" and "time from injury to infusion [hours] were rounded to 1
decimal place
(i.e. 6-minute intervals) Sensitivity analyses based on the exact times for
both variables
yielded consistent results; specifically, patient allocation to the subgroups
defined by time to
infusion (<12 h, >12 h) was not affected. Thus, rounding had no impact on the
post hoc
analyses of eGOS-I.
An interim analysis with possible sample size increase had been planned and
conducted for
the study; the resulting 2 study stages were not considered in the post hoc
analyses All
statistical analyses were done using SAS Version 9.4 (SAS Institute Inc.,
Cary, NC, USA).
Results
Demographics
Between August 2017 and December 2020, a total of 1940 patients were screened
for
eligibility. Of these patients, 228 were randomized and assigned to receive
Ronopterin (115)
or placebo (113). Major reasons for exclusion were age of the patients, no
informed consent
and early allocation to craniectomy. Four randomized patients did not receive
treatment
because of withdrawal of consent and because the IMP could not be prepared in
time. In total,
224 (98.2%) patients received treatment and were considered part of the Safety
Analysis Set.
One patient was lost to follow-up. Thus, 223 (97.8%) patients were part of the
Full Analysis
Set and 208 (91.2%) patients were considered part of the Per Protocol Set.
The majority of patients were male (180 [80.4%] patients) and caucasian (211
[94.2%]
patients). The mean age was 39.3 years (SD+/-13.2) the mean body mass index
was 25.5
kg/m2 (SD +/-3.9).
The demographic parameters (age, body weight) and baseline characteristics
(injury severity,
prognostic factor, time from injury to randomisation) were well balanced
between the two
treatment arms, indicating the populations were comparable at baseline..
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Efficacy Results:
No difference was seen between the Ronopterin and placebo groups for overall
eGOS-I rating
at 6 months (using the ordinal logistic regression inverse-normal approach)
and, therefore, the
primary efficacy endpoint was not met.
A difference was seen when comparing age groups in the entire patient
population
independent of treatment (age > 40 group vs age < 40 group) with an odds ratio
of 0 270
(95% CI: 0.134, 0.547; p<0.001), indicating a difference in recovery in favour
of patients
aged < 40 years of age.
Patient overall eGOS-I rating at 6 months was controlled for country and
centre, country, age
and additional covariates. Differences between Ronopterin and placebo were
seen in some
centres, however, caution must be taken when interpreting the results, due to
the low patient
numbers in each centre. No difference was seen when controlling by country,
however, a
marginal effect in favour of Ronopterin was seen for France (odds-ratio: 3.640
[95% CI:
0979, 135351; p=0 054) No difference was seen when controlling for age as a
continuous
variable.
Based on the time-dependent activation of pathologic cascades during the early
phase after
TBI and the benefits observed with an infusion of VAS203 during the initial 12
hours after
TBI in the Phase Ha trial [Stover], a post-hoc-analysis was performed to
determine whether
patients in whom VAS203 was infused <12 hours after TBI, show better clinical
improvement
compared to patients in whom infusion was started > 12 hours after TBI.
In patients with time to infusion <12 hours, eGOS was higher by 1 eGOS level
in the
Ronopterin compared to placebo treated patients (median 6 vs 5; ns); in
patients with time to
infusion > 12 hours, eGOS was similar in both treatment groups at 6 months
(median 5 vs 5).
In patients with time to infusion <12 hours, the proportion of patients with
Good Recovery
(eGOS 7 and 8) was higher in the Ronopterin compared to placebo treated
patients (37 vs
23%; ns; NNT= 8). In the Ronopterin-treated group the proportion of patients
with a Good
Recovery at 6 months was increased by 61% compared to the Placebo group. In
patients with
time to infusion > 12 hours, the proportion of patients with Good Recovery was
similar in
both treatment groups at 6 months (25 vs 28%).
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In more detail, and with reference to Figs. 4 to Figs. 18 the results of this
present study are as
follows:
Fig. 4 shows the distribution of proportion of patients between Placebo and
Ronopterin
(VAS203)-treated patients reflecting changes in eGOS from 3 to 6 months for
all patients and
all times to infusion Fig. 4A shows the change in eGOS from 3 to 6 months by
eGOS level,
Fig. 4B shows the change in eGOS from 3 to 6 months by category, Fig. 4C shows
the
increase of eGOS level by number of patients and Fig. 4D shows the odds-ratio
for the eGOS
increase. As seen from Fig. 4A Ronopterin-treated patients show an increase in
eGOS levels
up to 4 levels and the overall increase in eGOS by at least 2 levels is
encountered more often
in Ronopterin-treated patients (24 vs. 13 for the Ronopterin group, Fig. 4C).
Fig. 4 shows for
the Ronopterin-treated group more patients with higher increase in eGOS over
time, however
the increase is not (statistically) significant (Fig. 4D). In addition, Fig. 4
shows for the
Ronopterin-treated group that there are less patients with a decrease in eGOS
over time,
however this decrease is not (statistically) significant
Fig. 5 shows the distribution of proportion of patients of all ages between
Placebo and
Ronopterin-treated patients with changes in eGOS from 3 to 6 months, depending
on the time
to infusion within 12 hours and after 12 hours after traumatic brain injury.
Fig. 5 shows for
the Ronopterin-treated group a significant increase in proportion of patients
with increased
eGOS.
In more detail Figs.5A to 5D show the results for early infusion (< 12 hours),
with Fig. 5A
showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 5B showing
the change
in eGOS from 3 to 6 months by category, Fig. 5C showing the increase of eGOS
level by
number of patients and Fig. 5D showing the odds-ratio for the eGOS increase.
Figs.5A to 5D
show that for early infusion (< 12 hours) Ronopterin-treated patients show an
increase in
eGOS levels up to 4 levels (Fig. 5A). Fig. 5C shows that overall, an increase
in eGOS by at
least 2 levels is encountered more often in Ronopterin-treated patients
compared to placed (9
vs 3). The increase in proportion of patients with an increase by at least 1
level is significant
compared to Placebo-treated patients. Figs.5E to 5H show the results for late
infusion (>12
hours), with Fig. 5E showing the change in eGOS from 3 to 6 months by eGOS
level, Fig. 5F
showing the change in eGOS from 3 to 6 months by category, Fig. 5G showing the
increase
of eGOS level by number of patients and Fig. 5H showing the odds-ratio for the
eGOS
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increase. Ronopterin-treated patients show an increase in eGOS levels up to 4
levels (Fig.
5E). Overall, increase in eGOS by at least 2 levels is encountered more often
in Ronopterin-
treated patients (15 vs 10), see Fig 5G.
Fig. 6 shows the change in eGOS levels from 3 to 6 months, for patients with
an age of 18-39
years and at all times to infusion. Fig. 6A shows the change in eGOS from 3 to
6 months by
eGOS level, Fig. 6B shows the change in eGOS from 3 to 6 months by category,
Fig. 6C
shows the increase of eGOS level by number of patients and Fig. 6D shows the
odds-ratio for
the eGOS increase. Distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 18-
39 years.
Ronopterin-treated patients show an increase in eGOS levels up to 3 levels
(Fig. 6A) Overall,
increase in eGOS by at least 2 levels is encountered more often in Ronopterin-
treated patients
(14 vs 9), see Fig. 6C Fig. 6 shows that in the Ronopterin-treated group,
there are more
patients with higher increase in eGOS over time, however this increase is not
significant (see
Fig. 6D) while in the Ronopterin-treated group, there are less patients with
decrease in eGOS
over time, however this decrease is not significant
Fig. 7 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 18-
39 years,
depending on the time to infusion within 12 hours and after 12 hours after
traumatic brain
injury. In more detail Figs.7A to 7D show the results for early infusion (< 12
hours), with Fig.
7A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 7B
showing the
change in eGOS from 3 to 6 months by category, Fig. 7C showing the increase of
eGOS level
by number of patients and Fig. 70 showing the odds-ratio for the eGOS
increase. Figs.7A to
70 show that for early infusion (< 12 hours) Ronopterin-treated patients show
an increase in
eGOS levels up to 3 levels (Fig. 7A). Fig. 7C shows that overall, an increase
in eGOS by at
least 2 levels is encountered more often in Ronopterin-treated patients
compared to placed (4
vs 1). The increase in proportion of patients with an increase by at least 1
level is significant
compared to Placebo-treated patients, see Fig. 7B and Fig. 7D. Figs.7E to 7H
show the
results for late infusion (>12 hours), with Fig. 7E showing the change in eGOS
from 3 to 6
months by eGOS level, Fig. 7F showing the change in eGOS from 3 to 6 months by
category,
Fig. 7G showing the increase of eGOS level by number of patients and Fig. 7H
showing the
odds-ratio for the eGOS increase. Ronopterin-treated patients show an increase
in eGOS
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levels up to 3 levels (Fig. 7E). Overall, increase in eGOS by at least 2
levels is encountered
more often in Ronopterin-treated patients (10 vs 8), see Fig. 7G
Fig. 8 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 40-
60 years. Fig.
8A shows the change in eGOS from 3 to 6 months by eGOS level, Fig. 8B shows
the change
in eGOS from 3 to 6 months by category, Fig. 8C shows the increase of eGOS
level by
number of patients and Fig. 8D shows the odds-ratio for the eGOS increase. As
seen from
Fig. 8A Ronopterin-treated patients show an increase in eGOS levels up to 4
levels and the
overall increase in eGOS by at least 2 levels is encountered more often in
Ronopterin-treated
patients (10 vs 4), see Fig. 8C. Fig. 8 shows for the Ronopterin-treated group
more patients
with higher increase in eGOS over time, however the increase is not
(statistically) significant
(Fig. 8D) In addition, Fig. 8 shows for the Ronopterin-treated group that
there are less
patients with a decrease in eGOS over time, however this decrease is not
(statistically)
significant.
Fig. 9 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for patients aged 40-
60 years,
depending on the time to infusion within 12 hours and after 12 hours after
traumatic brain
injury. In more detail Figs.9A to 9D show the results for early infusion (< 12
hours) with Fig.
9A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 9B
showing the
change in eGOS from 3 to 6 months by category, Fig. 9C showing the increase of
eGOS level
by number of patients and Fig. 9D showing the odds-ratio for the eGOS
increase. As seen
from Fig. 9A Ronopterin-treated patients show an increase in eGOS levels up to
4 levels and
the overall increase in eGOS by at least 2 levels is encountered more often in
Ronopterin-
treated patients (5 vs. 2), see Fig. 9C. Fig. 9A to Fig. 9D show for patients
with an age > 40
years and administration of Ronopterin < 12 hours a trend to more patients
with an increase in
their eGOS levels (eGOS responders). Figs.9E to 9H show the results for late
infusion (>12
hours), with Fig. 9E showing the change in eGOS from 3 to 6 months by eGOS
level, Fig. 9F
showing the change in eGOS from 3 to 6 months by category, Fig. 9G showing the
increase
of eGOS level by number of patients and Fig. 9H showing the odds-ratio for the
eGOS
increase. Ronopterin-treated patients show an increase in eGOS levels up to 4
levels (Fig.
9E). Overall, increase in eGOS by at least 2 levels is encountered more often
in Ronopterin-
treated patients (5 vs 2), see Fig. 9G.
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Fig. 10 shows a summary of the Odds Ratios (OR) for increases in eGOS levels
from 3 to 6
months for early and late infusion and the age groups 18-39 and 40-60 years
(<40 and > 40
years). In this context, it is noted that an odds ratio of 1 means that there
no difference
between the odds in both groups, while an odds ratio of >1 means that the odds
of the first
group are higher and an odds ratio of <1 means, that the odds of the first
group are lower.
Fig. 11 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for male patients.
Fig. 11A shows
the change in eGOS from 3 to 6 months by eGOS level, Fig. 11B shows the change
in eGOS
from 3 to 6 months by category, Fig. 11C shows the increase of eGOS level by
number of
patients and Fig. 11D shows the odds-ratio for the eGOS increase. As seen from
Fig. 11A
Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and
the overall
increase in eGOS by at least 2 levels is encountered more often in Ronopterin-
treated patients
(22 vs. 9), see Fig. 11C. Fig. 11 shows for the Ronopterin-treated group more
patients with
higher increase in eGOS over time, however the increase is not (statistically)
significant (Fig.
11D). In addition, Fig. 11 shows for the Ronopterin-treated group that there
are significantly
less patients with a decrease in eGOS over time (p=0 04)
Fig. 12 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for male patients,
depending on the
time to infusion within 12 hours and after 12 hours after traumatic brain
injury. In more detail,
Figs.12A to 12D show the results for early infusion (< 12 hours) with Fig. 12A
showing the
change in eGOS from 3 to 6 months by eGOS level, Fig. 12B showing the change
in eGOS
from 3 to 6 months by category, Fig. 12C showing the increase of eGOS level by
number of
patients and Fig. 12D showing the odds-ratio for the eGOS increase. As seen
from Fig. 12A
Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and
the overall
increase in eGOS by at least 2 levels is encountered more often in Ronopterin-
treated patients
(9 vs 2), see Fig. 12C. Fig. 12A to Fig. 12D show for male patients and
administration of
Ronopterin < 12 hours that the increase in proportion of patients with an
increase by at least 1
level is significant compared to Placebo-treated patients. Figs.12E to Fig.12H
show the
results for late infusion (>12 hours), with Fig. 12E showing the change in
eGOS from 3 to 6
months by eGOS level, Fig. 12F showing the change in eGOS from 3 to 6 months
by
category, Fig. 12G showing the increase of eGOS level by number of patients
and Fig. 12H
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showing the odds-ratio for the eGOS increase. Ronopterin-treated patients show
an increase
in eGOS levels up to 4 levels (Fig. 12E). Overall, increase in eGOS by at
least 2 levels is
encountered more often in Ronopterin-treated patients (13 vs 7), see Fig. 12G.
Fig. 13 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for female patients
Fig. 13A
shows the change in eGOS from 3 to 6 months by eGOS level, Fig. 13B shows the
change in
eGOS from 3 to 6 months by category, Fig. 13C shows the increase of eGOS level
by number
of patients and Fig. 13D shows the odds-ratio for the eGOS increase. As seen
from Fig. 11A
Ronopterin-treated patients show an increase in eGOS levels up to 2 levels and
the overall
increase in eGOS by at least 2 levels is encountered less often in Ronopterin-
treated patients
(2 vs 4), see Fig. 13C. Fig. 13 shows for the Ronopterin-treated group less
female patients
with higher increase in eGOS over time, however the increase is not
(statistically) significant
(Fig. 13D).
Fig. 14 shows the distribution of proportion of patients between Placebo and
Ronopterin-
treated patients with changes in eGOS from 3 to 6 months for female patients,
depending on
the time to infusion within 12 hours and after 12 hours after traumatic brain
injury. In more
detail, Figs.14A to 14D show the results for early infusion (< 12 hours) with
Fig. 14A
showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 14B showing
the
change in eGOS from 3 to 6 months by category, Fig. 14C showing the increase
of eGOS
level by number of patients and Fig. 14D showing the odds-ratio for the eGOS
increase. As
seen from Fig. 14A Ronopterin-treated patients show an increase in eGOS levels
up to 2
levels and the overall increase in eGOS by at least 2 levels is encountered
less often in
Ronopterin-treated patients (0 vs 1), see Fig. 14C. Fig. 14A to Fig. 14D show
for female
patients and administration of Ronopterin < 12 that there are less female eGOS
responders but
that there is higher Good Recovery at 3 months. Figs.14E to Fig.14H show the
results for late
infusion (>12 hours), with Fig. 14E showing the change in eGOS from 3 to 6
months by
eGOS level, Fig. 14F showing the change in eGOS from 3 to 6 months by
category, Fig. 14G
showing the increase of eGOS level by number of patients and Fig. 14H showing
the odds-
ratio for the eGOS increase. Ronopterin-treated female patients show an
increase in eGOS
levels up to 2 levels (Fig. 14E). Overall, increase in eGOS by at least 2
levels is encountered
less often in Ronopterin-treated patients (2 vs 3), see Fig. 14G.
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Fig. 15 shows the impact of time to infusion, sex, and age on the proportion
of Good
Recovery (eGOS value of 7 or 8) in Placebo and Ronopterin-treated patients
expressed as
Odds Ratio with 95% Confidence Intervals. As evident from Fig. 15, early
infusion (< 12
hours) is associated with higher Odds Ratio in favor of Ronopterin in female
and male
patients, mainly for the tested female patient population with an age of 18 to
39 years, i.e. <
40 years and in male patients with an age of? 40 years. Late infusion (> 12
hours) is
associated with higher Odds Ratio in favor of Ronopterin in female patients,
mainly in the
female patient population with an age > 40 years. (The high Confidence
Intervals are related
to the small number of patients in the sex- and age-dependent subgroups of
analysis.) At 3
months, the Odds Ratios reveal that female patients show highest impact of
Ronopterin
compared to male patients: early infusion: 1.4, 0,02-8.2 vs 0.4, 0.09-1.9;
late infusion: 10.2,
0.5-204 vs 0.2, 0.05-0.6). At 6 months, the Odds Ratios are higher in male
patients compared
to female patients (2.2, 0.6-7.6 vs 1.5, 0.2-23), especially with early
infusion With late
infusion, the Odds Ratios are higher in female patients compared to male
patients (5.5, 0.6-53
vs 0.6, 0.3-1.4).
Fig. 16 shows the distribution of proportion of patients for the 8 eGOS levels
in Placebo and
Ronopterin-treated patients at 3 and 6 months in male and female patients,
with males
(n=179) and females (n=44). Fig.16A shows the proportion of patients for the 8
eGOS levels
in Placebo and Ronopterin-treated patients at 3 months in male patients,
Fig.16B shows the
proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated
patients at 6
months in male patients, Fig. 16C shows the proportion of patients for the 8
eGOS levels in
Placebo and Ronopterin-treated patients at 3 months in female patients and
Fig. 16D shows
the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-
treated patients at
6 months in female patients. As can be seen from Fig.16, at 3 months, male
patients show
lower proportion of eGOS levels 7 and 8 (Good Recovery) compared to female
patients,
reflecting more beneficial impact in female patients. At 6 months, male
patients show an
increase in proportion of eGOS levels 7 and 8 compared to 3 months. Female
patients show
an increase in Good Recovery from 3 to 6 months.
Fig. 17 shows the distribution of proportion of patients for the 8 eGOS levels
in Placebo and
Ronopterin-treated male patients with early and late infusion, with 179 male
patients (n =
179) being included. Fig.17A shows the proportion of patients for the 8 eGOS
levels in
Placebo and Ronopterin-treated patients at 3 months in male patients for early
infusion (< 12
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hours), Fig.17B shows the proportion of patients for the 8 eGOS levels in
Placebo and
Ronopterin-treated patients at 6 months in male patients for late infusion (>
12 hours), Fig.
17C shows the proportion of patients for the 8 eGOS levels in Placebo and
Ronopterin-treated
patients at 6 months in male patients for early infusion (< 12 hours) and Fig.
17D shows the
proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated
patients at 6
months in male patients for late infusion (> 12 hours). As can be seen from
Fig. 17, early
infusion (< 12 hours) is associated with an increase in proportion of male
patients with Good
Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated patients
from 3 to 6
months. Late infusion (> 12 hours) is associated with an increase in
proportion of male
patients with Good Recovery (eGOS 7 and 8) which, however, is less pronounced
compared
to Placebo-treated patients from 3 to 6 months. Overall, early infusion is
associated with
higher proportion of Good Recovery at 6 months in the Ronopterin-treated male
patients.
Fig. 18 shows the distribution of proportion of patients for the 8 eGOS levels
in Placebo and
Ronopterin-treated female patients with early and late infusion, with 44
female patients
(n=44) being included Fig.18A shows the proportion of patients for the 8 eGOS
levels in
Placebo and Ronopterin-treated patients at 3 months in female patients for
early infusion (<
12 hours), Fig.18B shows the proportion of patients for the 8 eGOS levels in
Placebo and
Ronopterin-treated patients at 6 months in female patients for late infusion
(> 12 hours), Fig.
18C shows the proportion of patients for the 8 eGOS levels in Placebo and
Ronopterin-treated
patients at 6 months in female patients for early infusion (< 12 hours) and
Fig. 18D shows the
proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated
patients at 6
months in female patients for late infusion (> 12 hours). As evident from Fig.
18, early
infusion (< 12 hours) is associated with an increase in proportion of female
patients with
Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated
patients from 3
to 6 months. Late infusion (> 12 hours) is associated with an increase in
proportion of female
patients with Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-
treated
patients from 3 to 6 months. Overall, early infusion is associated with higher
proportion of
Good Recovery at 6 months in the Ronopterin-treated female patients.
Pharmacolcinetic Results:
An exposure control was performed with samples collected after end of infusion
and 12 hours
after end of infusion. Due to the high sensibility of Ronopterin to oxidation,
no utilisable
values could be obtained for Ronopterin and, therefore, the first metabolite,
4-amino-
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dihydrobiopterin, was used as a surrogate The mean absolute concentration for
the first
metabolite of Ronopterin was 1071 ng/mL at the end of the infusion and 476
ng/mL 12 hours
later (56% elimination). The mean absolute value for the second Ronopterin
metabolite was
52 ng/mL at the end of the infusion and 37 ng/mL 12 hours after end of
infusion.
Safety and Tolerability Results:
Overall, the Ronopterin study treatment was well-tolerated and no significant
new safety
findings were seen in the study. A slightly higher number of adverse events
(AEs) and serious
adverse events (SAEs) were seen in the Ronopterin group compared to the
placebo groups.
However, the number of related AE/SAEs were low and comparable between the
groups.
The observed SAEs/AEs were expected for the patient population.
An increased ICP or e.g., intracerebral haematoma are normally classified as
an AE or SAE.
However, after TBI this and other pathophysiological responses of the brain
can typically be
expected and, thus, were recommended not to be considered as AE or SAE. The
apparent
increase in ICP increased compared to placebo (27 [23.9%] patients vs. 13
[11.7%] patients)
may be due to the over-reporting of some centres.
A higher number of renal AEs (11:3) and SAEs were observed in the Ronopterin
group
compared to the placebo groups; however, this was not unexpected for
pharmacodynamics of
Ronopterin and the population under study.
It will be readily apparent to a person skilled in the art that varying
substitutions and
modifications may be made to the invention disclosed herein without departing
from the
scope and spirit of the invention.
As used herein, the singular forms "a", "an", and "the", include plural
references unless the
context clearly indicates otherwise. Thus, for example, reference to "a
reagent" includes one
or more of such different reagents and reference to the method" includes
reference to
equivalent steps and methods known to those of ordinary skill in the art that
could be
modified or substituted for the methods described herein.
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All patents and publications mentioned in the specification are indicative of
the levels of those
of ordinary skill in the art to which the invention pertains. All patents and
publications are
herein incorporated by reference to the same extent as if each individual
publication was
specifically and individually indicated to be incorporated by reference.
The inventions illustratively described herein may suitably be practiced in
the absence of any
element or elements, limitation or limitations, not specifically disclosed
herein Thus, for
example, the terms "comprising", "including", "containing", etc. shall be read
expansively and
without limitation. Additionally, the terms and expressions employed herein
have been used
as terms of description and not of limitation, and there is no intention in
the use of such terms
and expressions of excluding any equivalents of the features shown and
described or portions
thereof, but it is recognized that various modifications are possible within
the scope of the
invention claimed Thus, it should be understood that although the present
invention has been
specifically disclosed by preferred embodiments and optional features,
modification and
variation of the inventions embodied therein herein disclosed may be resorted
to by those
skilled in the art, and that such modifications and variations are considered
to be within the
scope of this invention. The invention has been described broadly and
generically herein.
Each of the narrower species and subgeneric groupings falling within the
generic disclosure
also form part of the invention. This includes the generic description of the
invention with a
proviso or negative limitation removing any subject matter from the genus,
regardless of
whether or not the excised material is specifically recited herein. In
addition, where features
or aspects of the invention are described in terms of Markush groups, those
skilled in the art
will recognize that the invention is also thereby described in terms of any
individual member
or subgroup of members of the Markush group. Further embodiments of the
invention will
become apparent from the following claims.
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