Arimoclomol Prospective Study in Participants Diagnosed With Niemann-Pick Disease Type C

Arimoclomol Prospective Double-blind, Randomised, Placebo-controlled Study in Patients Diagnosed With Niemann-Pick Disease Type C

A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick disease type C (NPC). The purpose of this study is to assess the efficacy and safety of arimoclomol (compared to placebo) when it is administered as an add-on therapy to the participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat. The CT-ORZY-NPC-002 study has been expanded to include an open label paediatric sub-study including participants aged 6 to <24 months at study enrolment.

A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick disease type C (NPC). Participants must either 1) have completed Visit 2 (end of study [EOS]) of the CT-ORZY-NPC-001 study or 2) meet the eligibility criteria of this study including a requirement of stable treatment with miglustat for 6 months (if on miglustat therapy) prior to enrolment into the study. Aim: The purpose of this study is to assess the efficacy and safety of arimoclomol (compared to placebo) when it is administered as an add-on therapy to the participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat. Randomization: Participants will be randomized to receive placebo or arimoclomol (with an allocation ratio of 1:2). Pharmacokinetic evaluation (age below 12): To confirm the selected dose, participants less than 12 years of age will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before randomization and the start of continuous (multiple dosing) treatment. Early Escape Clause: In participants whose disease progression is too severe and/or too fast, the "early escape clause" will allow the Investigator to apply the escape route which implies that the participant can be treated with arimoclomol (as per blinded phase study schedule) and be followed up according to the study schedule or until the analysis of data from the controlled, 12-month blinded phase study period does not support the efficacy and/or safety of arimoclomol. Study duration: The duration of the blinded phase study period will be 12-months. Following this, all participants will be offered to continue into the extension phase of the study where every participant will receive arimoclomol and be followed up and attend site visits every 6 months until 60 months after randomization. The extension phase runs until arimoclomol has received Regulatory Approval or until the analysis of data from the controlled, blinded phase 12-month study period does not support the efficacy and/or safety of arimoclomol. The CT-ORZY-NPC-002 protocol has been updated to include a paediatric sub-study including new and naïve participants aged 6 to <24 months at study enrolment. Aim: The purpose of the paediatric sub-study, is to assess the safety and tolerability of 36 months of open-label arimoclomol when administered as an add-on therapy to the participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat. The Paediatric sub-study will run at the open sites participating in the main study. A total of 3-5 participants are planned to be enrolled. All participants will be treated with arimoclomol. Main Inclusion Criteria: Diagnosis of NPC1 or NPC2; NPC diagnosis confirmed by: Genetically confirmed (deoxyribonucleic acid [DNA] sequence analysis) by mutations in both alleles of NPC1 or NPC2, OR Mutation in only one allele of NPC1 or NPC2 plus either positive filipin staining or elevated cholestane triol/oxysterols (>2 x upper limit of normal). Males and females aged 6 to <24 months, with a cap of maximum 3 participants above 18 months Treated or not treated with miglustat; If a participant is on prescribed treatment with miglustat, the dose must have been stable for at least 1 month prior to inclusion in the paediatric sub-study If a participant has been discontinued from prescribed treatment with miglustat, they must have been discontinued for at least 1 month prior to inclusion in the paediatric sub-study The Legal Authorised Representative (LAR) has read and signed the Informed Consent Form (ICF) prior to any study-related procedures The LAR agrees for the participant to participate in all aspects of the trial design Main Exclusion Criteria: Recipient of a liver transplant or a planned liver transplant The Aspartate Transaminase (AST) and/or Alanine Transaminase (ALT) >3 x Upper Limit of Normal (ULN) for age and gender Renal insufficiency with serum creatinine level >1.5 x ULN Participants with known causes of active liver disease or prolonged icterus or malformation of organs other than NPC Participant was born before 37 weeks of gestation Participant weight <5 kg at study enrollment Participant is diagnosed with severe intra-uterine growth restriction Participant has severe neurological symptoms Participant has received or plans to receive a bone marrow transplant Arms and Intervention: 1 arm open label treatment with arimoclomol capsules 100 mg (dispersed in water) for oral administration (3 times daily). Doses: The dose in mL is based on the participant's weight in kg. Randomization: Open Label Pharmacokinetic: To confirm the selected dose, participants will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before the start of continuous treatment. Visit schedule time frame: Screening (V1); enrollment Week 1 (V2 baseline), Weeks 2 (V3), continuing visits at months 1 (V4), 3 (V5), 6 (V6), 9 (V7), 12 (V8), 15 (V8a), 18 (V9), 24 (V10), 30 (V11) and 36 (V12). Primary objective: Safety and tolerability Main Endpoint measures: Safety data: Adverse events (AEs); Vital signs; Hematology; Clinical chemistry Clinical status data: Clinical signs and symptoms captured through physical examination; Change from baseline in patient weight and height; Change in Bayley III score: Developmental delay scoring Imaging data: Changes from baseline in the size of the liver and spleen assessed by ultrasound

NPC1, Niemann-Pick Type C, Niemann-Pick, arimoclomol, lysosomal storage disorder, lysosomal storage disease, NPC2, NP-C

Participants less than 12 years received a single oral dose of arimoclomol capsule, based on participant's body weight, on Day 1.

Participants received arimoclomol capsules orally three times a day (TID) for 12 months. The dose was 31-124 mg arimoclomol base TID (equivalent to 50-200 mg arimoclomol citrate TID), based on participant's body weight.

Participants received matching placebo capsules (with regard to weight, appearance, smell, flavor etc.) orally TID for 12 months.

Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores

NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.

Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I) - Defined as Percentage of Participants Where the CGI-I Score Remains Stable or Shows Improvement (This Outcome Measure Was Considered Co-primary by the FDA)

The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. Responders were the participants with a score of 1 or 2 at Month 12.

Percentage of Responders in 5-domain NPCCSS - Defined as Participants Where the 5-domain NPCCSS Score Remains Stable or Improves as Compared to Baseline

NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. Stable was defined as a participant's total score for the 5 domains being the same at month 12 as at baseline. Improvement was defined as a participant's total score at month 12 being lower than at baseline.

Time to worsening was defined as the time until the participant reached the predefined minimal clinically important difference (MCID) of 2 points compared to baseline on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. The values reported per group are the 25th percentile Kaplan-Meier estimates and 95% confidence interval.

Worsening was defined as participants that have reached the predefined MCID of 2 points on their 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.

Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response)

The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify NPC disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major and eight minor domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). The total score is the sum of the score of each of the 17 domains and ranges from 0 to 61, with a high score indicating a more severe clinical impairment.

The 5-domain NPC Clinical Severity Scale (NPCCSS) focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.

The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). A higher score indicates a more severe clinical impairment.

The NPC Clinical Database (NPC-cdb) score aims to reflect the current clinical status of the participant. The NPC-cdb score represents both historical symptoms and a current status. The test consists of ten areas: visceral signs, development, motor function, ocular-motor abnormalities, seizures/cataplexy/narcolepsy, cognitive abilities and memory, behavioral and psychiatric abnormalities, speech, hearing, and abilities in daily life. The current status score is a severity-weighted sum of 72 symptoms considered as disease-relevant at the time of assessment. Each symptom contributes with a score between 1 and 5, the maximum score is 125. An increase in score reflects a reduction in the participant's abilities.

The EQ-5D-Y descriptive system includes 5 descriptive items: Mobility, self-care, doing usual activities, having pain or discomfort, and feeling anxiety or depressed. Each dimension has 3 levels: No problems, some problems, and a lot of problems. The change in the 5 individual items of the EQ-5D-Y per participant was explored by using the pareto principle at 6 and 12 months to show the number (%) of participants who felt: Better (better on at least one dimension and no worse in any other dimension), Worse (worse in at least one dimension, and no better in any other dimension)

The SARA included eight items reflecting neurologic manifestations of cerebellar ataxia. The test provides a direct and simple description of motor function in a participant. The test consists of 8 test items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. The total score of the 8 items ranges from 0 (normal cerebellar function) to 40 (not able to perform any of the test items).

The 9HPT test is a direct and simple measurement of fine motor coordination function, eye/hand coordination, and the ability to follow a simple direction. The 9HPT is a timed test in which nine pegs are inserted and removed from nine holes in the pegboard. Both hands are tested starting with the dominant hand. The time spent in completing the 9 HPT using each hand was recorded.

Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)

The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. A rating of 1 is considered normal, or with the least severe symptoms, a rating of 7 is extremely ill, or the worst symptoms. Scores thus range from 1-7 with lower scores indicating less severe disease.

Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)

The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement.

Inclusion Criteria: EITHER NP-C participants who have entered the CT-ORZY-NPC-001 study and who have completed Visit 2 (EOS) of the CT-ORZY-NPC-001 study. OR NPC participants who did not enter or complete the CT-ORZY-NPC-001 study but are fulfilling all of criteria listed below: ◦Diagnosis of NPC1 or NPC2; NPC diagnosis confirmed by: Genetically confirmed (deoxyribonucleic acid [DNA] sequence analysis) by mutations in both alleles of NPC1 or NPC2, OR Mutation in only one allele of NPC1 or NPC2 plus either positive filipin staining or elevated cholestane triol/oxysterols (>2 x upper limit of normal). Males and females aged from 2 years to 18 years and 11 months; Treated or not treated with miglustat; If a participant is under prescribed treatment with miglustat, it has to be under stable dose of the medication for at least 6 continuous months prior to inclusion in the CT-ORZY-NPC-002 study; o If a participant has been discontinued from prescribed treatment with miglustat, they must have been discontinued for at least 3 continuous months prior to inclusion in the CT-ORZY-NPC-002 study; Body mass index (BMI) Z score ≥ -2 SD (standard deviation) for age, according to the World Health Organisation (WHO) standards; Presenting at least one neurological symptom of the disease (for example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia); Ability to walk either independently or with assistance. Written informed consent (and assent if appropriate to local laws and regulations) prior to any study-related procedures; Willing to participate in all aspects of trial design including blood sampling (PK, blood biomarkers and safety labs), skin biopsies and imaging (ultrasonography of the liver and spleen); Ability to travel to the corresponding clinical trial site at the scheduled visit times for evaluation and follow-up; All sexually active female participants of child-bearing potential (post-menarchal) must use highly effective contraception during the study and until 1 week after the last dose of IMP. Highly effective birth control methods include: Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; and vasectomised partner. All sexually active male participants with female partners of child-bearing potential (post-menarchal) must use a condom with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of IMP. Sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the study and for 1 week after the last dose of IMP (for female participants of child-bearing potential) and for 3 months after the last dose of IMP (for male participants with female partners of child-bearing potential). The reliability of sexual abstinence needs to be evaluated by the Investigator in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. •Ability to comply with the protocol-specified procedures/evaluations and scheduled visits. Exclusion Criteria: Recipient of a liver transplant or planned liver transplantation; Severe liver insufficiency (defined as hepatic laboratory parameters, AST and/or ALT greater than three-times the upper limit of normal for age and gender (central laboratory assessment); Renal insufficiency, with serum creatinine level greater than 1.5 times the upper limit of normal (central laboratory assessment); Known or suspected allergy or intolerance to the IMP (arimoclomol or constituents); In the opinion of the Investigator, the participant's clinical condition does not allow for the required blood collection and/or skin biopsies as per the protocol-specified procedures; Treatment with any investigational drug during the study or in the 4 weeks prior to entering the study. This includes treatment with any investigational drug during the study in an attempt to treat NP-C; Pregnancy or breastfeeding; Current participation in another trial is not permitted unless it is a non-interventional study and the sole purpose of the trial is for long-term follow up/survival data (registry); For participants who have not completed the CT-ORZY-NPC-001 study, fulfilling any of the criteria listed below: Participants with uncontrolled severe epileptic seizures period (at least 3 consecutive severe epileptic seizures that required medication) within 2 months prior to the written consent. This includes participants with ongoing seizures that are not stable in frequency or type or duration over a 2 month period prior to enrolment, requiring change in dose of antiepileptic medication (other than adjustment for weight) over a 2 month period prior to enrolment, or requiring 3 or more antiepileptic medications to control seizures; Neurologically asymptomatic participants; Severe manifestations of NP-C disease that would interfere with the participant's ability to comply with the requirements of this protocol; Treatment with any IMP within 4 weeks prior to the study enrolment.

Patterson MC, Lloyd-Price L, Guldberg C, Doll H, Burbridge C, Chladek M, iDali C, Mengel E, Symonds T. Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale. Orphanet J Rare Dis. 2021 Feb 12;16(1):79. doi: 10.1186/s13023-021-01719-2.

Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Gronborg S, Harmatz P, Heron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsoe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, I Dali C. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. doi: 10.1002/jimd.12428. Epub 2021 Sep 7.