Study of the Pharmacokinetics of Trappsol and Effects on Potential Biomarkers of Niemann-Pick C1 (NPC1)

The planned study has been designed as a Phase I, double-blind, randomised, multi-centre,
parallel group study based on information and data available from the administration of
Trappsol Cyclo via compassionate/named patient use in patients with NPC-1, and data on other
cyclodextrin products in the scientific literature.

The study is comprised of a screening phase of up to 4w a treatment phase of 12w and a 4w
follow-up The primary objective is to compare the plasma pharmacokinetics of single and
multiple doses of two different levels of IV Trappsol Cyclo. Secondary objectives include
investigation of the HP-β-CD effect of different doses of IV Trappsol Cyclo upon serum and
lymphocytic markers of cholesterol metabolism and evaluation of Trappsol concentrations in
the cerebrospinal fluid (CSF) following IV administration , evaluation of the impact of
treatment upon measures of neurological function including ataxia, aphasia and saccadic eye
movements, and the impact of treatment upon behavioral aspects of NPC-1.

It is planned to recruit a total of 12 patients to the study. Patients will be randomised 1:1
to one of the two dose levels (1500 mg/kg or 2500 mg/kg; six patients per dose level).
Treatment will be administered every two weeks by slow IV infusion over 8 hours at different
concentrations to achieve the proscribed dose levels. Patients will receive treatment for a
total of 12 weeks. Patients who withdraw prior to completion of the initial pharmacokinetic
and pharmacodynamic assessments will be replaced.

The design of the proposed study thus enables early assessment of potential biochemical
markers of response but allows for a sufficient dosing duration to enable the short-term
effectiveness of Trappsol in NPC to be assessed.

The maximum dose proposed for this study is below the maximum dose for which long term
clinical data is available in 2 patients (2800 mg/kg weekly for 3-5 years). Although
individual clinicians have not always utilized an escalating rate of infusion, the reports of
infusion related reactions in three patients suggest that this is an appropriate clinical
strategy to mitigate the risk of such events and is consistent with dosing administration for
other therapeutic agents. In the proposed study, treatment will be administered less
frequently than has been undertaken in compassionate use. This longer dosing interval is
supported by nonclinical data comparing the metabolism of cholesterol in non-human species
with that in man; although a once weekly dosing interval was initially studied in man based
on data in the mouse, HP-β-CD cholesterol metabolism/turnover in the mouse is 13-fold higher
than in man which, in NPC, likely translates into a 13-fold slower accumulation of
cholesterol in human cells compared with those of the mouse.Therefore, it is theorized that,
given the slower cholesterol metabolism in humans, the dosing interval could be much less
frequent in man than in mouse; however, based on what is known about cholesterol metabolism
in humans and the pharmacokinetic and pharmacodynamic effect of HP-β-CD in the mouse, a
dosing interval of 2 weeks in man is likely to be well within the therapeutic dosing interval
and also minimizes the amount of infusions required to be administered.

Inclusion Criteria:

1. Confirmed diagnosis of NPC-1 defined as one of the following

1. Two NPC-1 mutations on exome gene sequencing

2. One NPC-1 mutation and positive filipin staining (current or prior)

3. Vertical supranuclear gaze palsy [VSGP] plus either ≥ one NPC-1 mutation or
positive filipin staining and no NPC-2 mutations

2. NIH NPC Severity Score <30 and with no more than 4 individual domains with a score ≥
3.

3. Age range: 18 years upwards

4. At least one systemic manifestation of NPC disease defined as one or more of

1. Clinically detectable hepatomegaly and/or either ALT or AST outside the normal
range for the study laboratory

2. Clinically detectable splenomegaly

3. Impaired respiratory function due to NPC or a history of pneumonia in the last 12
months

5. Negative urine pregnancy test for females of child bearing potential

6. Written, informed consent

Exclusion Criteria:

1. The presence of NPC-2 mutations on exome gene sequencing

2. Previous receipt of cyclodextrin therapy within 3 months of baseline

3. Receipt of any of the following medications within 1 month of baseline: Coenzyme Q10,
curcumin, cinnamon, fish oil supplements, high dose vitamin D (>500
milli-International unit (mIU)/day), acetyl leucine, or gingko biloba

4. Concurrent treatment with any therapy indicated for the lowering of cholesterol such
as statins, fibrates, ezetimibe

5. Karnofsky score < 40

6. Inability to comply with the proposed protocol assessments

7. Concurrent medical conditions representing a contraindication to any of the study
medications

8. Grade 3 renal impairment or worse as indicated by eGFR< 60mL/min/1.73m2

9. Clinical evidence of acute liver disease including symptoms of jaundice or right upper
quadrant pain or INR >1.8

10. Involvement in another interventional clinical trial within the previous 6 months from
baseline

11. Weight <40 kg or >100 kg

12. Male patients and female patients of childbearing potential who are not willing to use
appropriate birth control (i.e. double barrier birth control) from enrolment until the
follow-up visit