Disclosures Marc C. Patterson, MD, FAAN, FRACP - PowerPoint Presentation

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2. DisclosuresMarc C. Patterson, MD, FAAN, FRACPThe institution of Dr. Patterson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zevra Therapeutics. Dr. Patterson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Azafaros. Dr. Patterson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage. Dr. Patterson has received stock or an ownership interest from IntraBio. The institution of Dr. Patterson has received research support from Glycomine, Zevra, Idorsia, and Shire-Takeda. Dr. Patterson has received publishing royalties from publications relating to health care.

3. Evaluation of the Long-Term Effect of Arimoclomol in Niemann-Pick Disease Type C (NPC) - 48 Months Data from CT-ORZY-NPC-002Marc Patterson, MD1, Christine í Dali, MD2, Eugen Mengel, MD31Neurology, Pediatrics and Medical Genetics, Mayo Clinic, Rochester, MN, USA2Zevra Therapeutics DK, Copenhagen N, Denmark3SpinCS, Clinical Science for LSD, Hochheim, Germany

4. Niemann-Pick Disease Type CUltra-rare (1:100,000 live births1), autosomal recessive and fatal neurodegenerative lysosomal diseaseCaused by mutations in the NPC1 (95% of cases) or NPC2 genes2 Reduced NPC1 protein results in lysosomal dysfunction with accumulation of cholesterol in various tissues, e.g., the liver and brain2Characterized by range of progressive and disabling symptoms2, 3: Difficulties with walking, motor coordination, swallowing, speaking, and cognitive functionNo curative treatment – high unmet medical need1. Geberhiwot T et al. Orphanet J Rare Dis. 2018;13(1):50. 2. Vanier MT. Orphanet J Rare Dis. 2010;5:16. 3. Wraith JE et al. J Inherit Metab Dis. 2014;37(1):93-101.

5. ArimoclomolArimoclomol is an investigational, orally available small molecule that penetrates the blood-brain barrier1Potential mode of action2-5: Increases expression of lysosomal genes, including NPC1 Leads to overexpression of CLEAR genes and amplifies heat shock proteinsResults in enhanced cellular autophagy and improved lysosomal function Stabilizes lysosomes and facilitate NPC1 protein function Through these effects, arimoclomol leads to a reduction of aberrantly stored lipids61. Cudkowicz ME et al. Muscle Nerve. 2008;38(1):837-44. 2. Martina JA et al. Sci Signal. 2014;7(309):ra9. 3. Palmieri M et al. Hum Mol Genet. 2011;20(19):3852-66. 4. Sardiello M. Ann N Y Acad Sci. 2016;1371(1):3-14. 5. Settembre C et al. Science. 2011;332(6036):1429-33. 6. Data on file.

6. 5-Domain NPC Clinical Severity ScaleDisease-specific, clinician-reported outcome measure Allows quantification of disease severity and progression 5-domains (5DNPCCSS) focusing on core symptoms and extensively validated1-3: Ambulation Speech Fine Motor Skills SwallowCognition1. Patterson MC et al., Orphanet J Rare Dis. 2021;16:79. 2. Yanjanin NM et al., Am J Med Genet B Neuropsychiatr Genet. 2010; 153B(1): 132-140. 3. Evans W, et al. Orphanet J Rare Dis. 2021 Nov 18;16(1):482.

7. Data basis:NPC-001 trial1: observational, standard of care, prospectiveNPC-002 trial2,3: double-blind, randomized, with open-label extension of arimoclomol treatment, prospectiveASIS-01 cohort4: observational, standard of care, retrospectiveLiterature:Ory et al. 2017Yanjanin et al. 2010Cortina-Borja et al. 2018Discussion:NPC-001 and NPC-002 trial designProgression in untreated patientsProgression in arimoclomol treated patientsEffect of arimoclomol vs standard of care1. ClinicalTrials.gov ID: NCT02435030, EudraCT No: 2014-005194-372. ClinicalTrials.gov ID: NCT02612129, EudraCT No: 2015-004438-933. Mengel E et al. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. 4. Data on file

8. Clinical Efficacy Program - Arimoclomol in NPC PatientsNPC-0024 Year Open-Label ExtensionArimoclomol + Routine Clinical Care (N=41)n=26 patients from Arimoclomol double-blind armn=15 patients from Placebo double-blind arm06-14 (Baseline for roll over patients)Month:Randomization 2:1NPC-0011 Year Observational TrialScreening & EnrollmentVisit(N=36)Visit(N=31)Rollover(N=26)1 Year Double-blind PhaseArimoclomol + Routine Clinical Care (N=34)n=17 roll over patients n=17 new patients Placebo + Routine Clinical Care (N=16)n=9 roll over patients n=7 new patients 18243648600(Baseline for new patients)36912(Baseline for OLE)Primary Endpoint:Change in 5DNPCCSS score from Baseline at Month 12

9. NPC-002Arimoclomol + Routine Clinical Care (N=41)n=26 patients from Arimoclomol double-blind armn=15 patients from Placebo double-blind armNPC-0011 Year Observational TrialScreening & EnrollmentVisit(N=36)Visit(N=31)Arimoclomol + Routine Clinical Care (N=34)n=17 roll over patients n=17 new patients Placebo + Routine Clinical Care (N=16)n=9 roll over patients n=7 new patients Pooled untreated patientsPooling of NPC-001 and NPC-002 DB Placebo Patients Provides up to 2 Years of Observational (“Untreated”) Data

10. Pooling of NPC-002 DB and OLE Patients Provides Data for Arimoclomol Treatment of upto 4 YearsNPC-002Arimoclomol + Routine Clinical Care (N=41)n=26 patients from Arimoclomol double-blind armn=15 patients from Placebo double-blind armNPC-0011 Year Observational TrialScreening & EnrollmentVisit(N=36)Visit(N=31)Arimoclomol + Routine Clinical Care (N=34)n=17 roll over patients n=17 new patients Placebo + Routine Clinical Care (N=16)n=9 roll over patients n=7 new patients 4 Year Open-Label Extension1 Year Double-blind Phase18243648600(Baseline for new patients)36912(Baseline for OLE)Primary Endpoint:Change 5DNPCCSS score at Month 12Pooled arimoclomol-treated patients

11. Baseline Characteristics: Untreated and Arimoclomol Treated PatientsNPC-001/NPC-002NAge, mean (SD)Miglustat use,n (%)5DNPCCSS, mean (SD)Full NPCCSS excl. hearing domains,mean (SD)ASIS Score, mean (SD)Arimoclomol treated4911.6 (5.1)38 (77.6%)11.9 (7.0)20.8 (11.9)2.1 (1.7)Untreated4410.1 (4.8)36 (81.8%)9.6 (6.1) 17.0 (10.1)2.0 (1.7)ASIS: annual severity increment score; N: number of patients in cohort; n: number of patients with outcome; NPCCSS: NPC clinical severity scale; SD: standard deviation. 

12. 06121824304842366543210Estimated change from baseline 5-domain NPCCSSTime (month)Untreated patients on routine clinical care + miglustat 7MIGLUSTAT SUBGROUP06121824304842366543210Estimated change from baseline 5-domain NPCCSSTime (month)7FULL POPULATIONN=44Pooled untreated patients N=36Pooled untreated patients on miglustatDisease Progression in Untreated Patients – All patients and Subgroup on MiglustatUntreated patients on routine clinical care +/- miglustatLinear regression model, random slope and intercept. Shaded areas represent standard error.

13. Disease Progression in Untreated and Arimoclomol Treated Patients – All patients and Subgroup on Miglustat06121824304842366543210Time (month)7MIGLUSTAT SUBGROUP38353330292815162506121824304842366543210Estimated change from baseline 5-domain NPCCSSTime (month)7FULL POPULATION494441383534181831Arimoclomol# patients with observationUntreated: Linear regression model, random slope and intercept. Shaded areas represent standard error. Arimoclomol Treated: MMRM adjusted for baseline score and miglustat use. Error bars represent standard error. Estimated change from baseline 5-domain NPCCSSSafety observed during ongoing monitoring consistent with published profile.Patients +/- miglustat usePatients on miglustatUntreated Arimoclomol TreatedUntreated Arimoclomol TreatedUntreated44 patients contributed with datapoints36 patients contributed with datapoints

14. Disease Progression in the Untreated NPC-001/NPC-002 Cohort is Comparable to Other CohortsSourceNAge at baselineMean (range)Treated with miglustatDuration offollow-upYearsAnnual disease progression5DNPCCSSUntreated NPC-001/NPC-0024410.1 (2-18)a82%0.5-21.73ASIS-01 cohort ≤18 years1207.3 (1-17)80%1.7-71.66ASIS-01 cohort12813.2 (1-46)82%1.7-7 1.17bFull NPCCSS excluding hearing domainsUntreated NPC-001/NPC-0024410.1 (2-18)a82%0.5-22.88ASIS-01 cohort ≤18 years1207.3 (1-17)80%1.7-72.99ASIS-01 cohort12813.2 (1-46)82%1.7-7 2.14bOry et al. 201722110.7 (4-22)76%0.5-22.67Full NPCCSSOry et al. 201722110.7 (4-22)76%Unknown2.92Yanjanin et al. 201031812.9 (4-51)44%1 - >101.4bYanjanin et al. 201031914.7 (2-38)Not reported1 - >101.9ba Calculated using discrete age values at baseline. b Cohort includes wide age span. Adults usually have slower progression than pediatric patients. 1. Data on file. 2. Ory D, et al. Lancet 2017;390:1758-68. 3. Yanjanin NM, et al. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:132–140.  

15. Thank youIn conclusion, the data suggests long-term progression may be reduced in patients treated with arimoclomol for up to 48 months.The NPC-002 open-label extension trial completed this year with up to 60 months observation.Thanks to patients, families, caregivers, clinicians, hospital staff and patient organizations.

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