Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C

A prospective, randomised, double-blind, placebo controlled therapeutic study in patients
with confirmed diagnosis of NiemannPick disease type C (NPC).

Patients must either 1) have completed Visit 2 (end of study [EOS]) of the CTORZYNPC001 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 patient's current prescribed
best standard of care; patient's standard of care may, or may not, include miglustat.

Randomisation:

Patients will be randomised to receive placebo or arimoclomol (with an allocation ratio of
1:2).

Pharmacokinetic evaluation(age below 12):

To confirm the selected dose, patients less than 12 years of age will undergo an arimoclomol
single-dose pharmacokinetic (PK) evaluation before randomisation and the start of continuous
(multiple dosing) treatment.

Early Escape Clause:

In patients 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 patient
can be treated with arimoclomol (as per blinded phase study schedule) and be followed up on
an annual basis until arimoclomol has received EU MA 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 patients will be offered to continue into the extension phase of the
study where every patient will receive arimoclomol and be followed up and attend site visits
at 18 months and 24 months (after randomisation) and then on an annual basis thereafter.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 patients 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 patient's
current prescribed best standard of care; patient's standard of 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 2-5 patients are planned to be enrolled. All patients will be treated with arimoclomol.

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

- If a patient 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 patient 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 patient to participate in all aspects of the trial design

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

- Patients with known causes of active liver disease or prolonged icterus or malformation
of organs other than NPC

- Patient was born before 37 weeks gestation

- Patient weight <5 kg at study enrollment

- Patient is diagnosed with severe intra-uterine growth restriction

- Patient has severe neurological symptoms

- Patient 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 patient's weight in kg.

Randomization:

Open Label

Pharmacokinetic:

To confirm the selected dose, patients will undergo an arimoclomol single-dose
pharmacokinetic (PK) evaluation before the start of continuous treatment.

Outcome measures:

Primary/Safety Outcome Measures

Collection of safety data:

- Adverse events (AEs)

- Vital signs

[Time Frame: Screening (V1), to week 1(V2 baseline), weeks 2, 4, 12, 24, 36, 48, 72, 96, 120
and 144 after baseline]

- Haematology

- Clinical chemistry

[Time Frame: Screening (V1), to weeks 2, 4, 12, 24, 36, 48, 72, 96, 120 and 144 after
baseline - V2]

Secondary Outcome Measures

- Clinical signs and symptoms captured through physical examination,

- Change from baseline in patient weight measured in kg

[Time Frame: Screening (Visit 1) to Baseline V2- 1 week after V1, 1, 3, 6, 9, 12, 15, 18, 24,
30 and 36 months after baseline]

• Change from baseline in patient height measured in meter

[Time Frame: Screening (Visit 1) to Baseline V2- 1 week after V1, 3, 6, 12 , 18, 24, 30 and
36 months after baseline]

- Change in Developmental delay scoring, using the Bayley III score

- Changes from baseline in the size of the liver and spleen assed by ultrasound

[Time Frame: Baseline, months 6,12, and 18 (Visit 2, 6, 8, 9)]

Inclusion Criteria:

EITHER NP-C patients who have entered the CTORZYNPC001 study and who have completed Visit 2
(EOS) of the CTORZYNPC001 study.

OR

NPC patients who did not enter or complete the CTORZYNPC001 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 patient 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 CTORZYNPC002 study;

o If a patient 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 patients 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 patients 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 patients of child-bearing potential) and for 3 months
after the last dose of IMP (for male patients 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 patient.

•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 patient'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 patients who have not completed the CTORZYNPC001 study, fulfilling any of the
criteria listed below:

- Patients 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 patients 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 patients;

- Severe manifestations of NP-C disease that would interfere with the patient's
ability to comply with the requirements of this protocol;

- Treatment with any IMP within 4 weeks prior to the study enrolment.