Therapy for mucopolysaccharidosis II with an intravenous blood-brain barrier-crossing enzyme

WORLDSyposium2020Torayuki Okuyama Center for Lysosomal Storage Diseases, National Center for Child Health and Development, Tokyo, Japan
26-week results from a Phase 3 study in Japan suggesting significant efficacy against central nervous system and systemic symptoms
Overview of MPS II and JR-141
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Pathological accumulation of glycosaminoglycans in the lysosomes
a broad spectrum of symptoms, including CNS symptoms
Current ERT: ineffective for the CNS symptoms
the enzyme cannot cross the blood-brain barrier (BBB)
JR-141: anti-human transferrin receptor antibody fused IDS expected to cross the BBB
Phase I/II study: Marked reduction of HS concentration in CSF
after 3-week iv administration of JR-141
(Okuyama et al., 2018) JR-141
Anti-Human Transferrin Receptor Antibody
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Primary Endpoint Change in HS Concentration in CSF
Secondary Endpoints • Change in DS Concentration in CSF • Change in HS and DS Concentration in Serum • Change in HS and DS Concentration in Urine • Neurocognitive Testing • 6-minute Walk Test • Liver and spleen volumes • Adaptive Behavior Testing • Change in the Joint Range of Motion
Naïve Pts or
Demographics of the Pts enrolled in the JR-141-301 study
5 * Judged by medical monitor, based on the subject’s mutation, age, AE and other information(e.g. sibling’s phenotypes)
Characteristics N
ERT with idursulfase before the study Received (switched patients) 25
Not received (naïve patients) 3
Participation in JR-141-101 (Phase I/II study) Yes 10
No 18
Total 28
Positive interim results on primary endpoint up to week 26
decreased in all the patients (58.4±9.5 %)
CSF-HS Concentrations
Disease Severity and CSF HS Level at Baseline
7 The CSF HS is an appropriate biomarker that reflects disease severity
8 CSF HS increased during the idursulfase-treatment period
approx. 1 Y
idursulfase JR-141JR-141
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100%(17/17) severe patients showed AE stabilization or improvement 100%(8/8) attenuated patients showed DQ stabilization or improvement
Kyoto Scale of Psychological Development AE: Age Equivalence
Age group Worsened <-3M
Stabilized AE Change ±3M
>8 y (n=4) 0 4 0
Worsened <-0.5 SD
Improved >0.5 SD
Severe
Attenuated
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Age group Negative No-change Positive 0 to 2 y (n=2) 0 0 2
3 to 8 y (n=10) 0 1 9
> 8 y (n=6) 0 1 5
Behavioral Improvements in Severe Patients
- Vocabulary increase - Conversation or communication increase - Has resumed singing - Start counting numbers
ex)
- Has become calmer - Improvement of facial expression - Improvement of concentration - Smiled again
ex)
Age group Negative No-change Positive 0 to 2 y (n=2) 0 2 0
3 to 8 y (n=10) 0 5 5
> 8 y (n=6) 0 2 4
Language
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The HS and DS in serum were maintained in switched patients The HS and DS in serum rapidly decreased in naïve patients
Serum HS Serum DS
naïve patientsnaïve subjects patientspatients
Patient Adverse event term Severity Outcome Relationship to study drug
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Acute Respiratory failure Life- threating Death
Unrelated
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3 Pharyngitis streptococcal Hospitalization Recovered Unrelated
4 Right Chronic subdural hematoma Hospitalization Recovered Unrelated
No drug-related serious adverse events reported so far No patient has been withdrawn due to safety concerns
Serious Adverse Events (~November 2019)
Summary
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Positive interim results on primary endpoint up to week 26
CSF-HS decreased in all patients
• Most patients showed decrease to the level of attenuated patients
Developmental age was preserved or improved in all severe and attenuated patients at 26-week
Efficacy and safety on systemic symptoms were comparable to current ERT
Marketing authorization application of JR-141 is planned in Japan in this year
Global phase III study is under preparation in the U.S., Brazil and Europe
Acknowledgements
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• This study was sponsored by JCR Pharmaceuticals
Yoshikatsu Eto (Advanced Clinical Research
Centre & Asian Lysosome Storage Disorder Centre, Institute of Neurological Disorders)
• Institutions
Norio Sakai (Osaka University Graduate School of Medicine)
Motomichi Kosuga (National Center for Child Health and Development) Norio Sakai (Osaka University Hospital) Yoriko Watanabe (Kurume University Hospital) Hiroshi Mochizuki (Saitama Children’s Medical Center) Aya Narita (Tottori University Hospital) Hideo Sasai (Gifu University Hospital) Takashi Hamazaki (Osaka City University Hospital) Mahoko Furujo (National Hospital Organization Okayama Medical Center) Tomoko Matsubayashi (Shizuoka Children's Hospital) Kanako Yoshizaki (Kurashiki Central Hospital) Koichi Nakanishi (University of the Ryukyus Hospital) Isao Asakura (Fujieda Municipal General Hospital) Tohru Yorifuji (Osaka City General Hospital) Miori Yuasa (University of Fukui Hospital) Takanori Yamagata (Jichi Medical University Hospital) Koji Muroya (Kanagawa Children’s Medical Center) Toju Tanaka (National Hospital Organization Hokkaido Medical Center) Hiroshi Mitsubuchi (Kumamoto University Hospital) Ryutaro Kira (Fukuoka Children’s Hospital)
Therapy for mucopolysaccharidosis II with an intravenous blood-brain barrier-crossing enzyme (JR-141):
Overview of MPS II and JR-141
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CSF HS Levels through JR-141-101(Ph I/II) and JR-141-301 Studies
Kyoto Scale Developmental Assessment at Week 26
Behavioral Improvements in Severe Patients
Serum Concentrations of HS and DS
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