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

A Phase I Study to Evaluate the Single and Multiple-dose Pharmacokinetics of Intravenous Trappsol Cyclo (HP-Beta-CD) in Patients With Niemann-Pick Disease Type C (NPC-1) and the Effects of Dosing Upon Biomarkers of NPC Disease

This research study is being conducted to find out whether Trappsol® Cyclo™, an experimental treatment for people with Niemann Pick disease Type C (NPC-1) is safe at 2 different dose levels and what effects it has on people who have this condition. NPC-1 is caused by a defect in the protein which is important for the transport of fatty substances like cholesterol out of cells. Without this protein, fats build up in the cells ultimately leading to organ damage. The way in which this experimental treatment works is not fully understood but laboratory experiments have shown that it can potentially remove cholesterol build up from the cells in people who have NPC-1. Approximately 12 patients will be asked to take part in this research study for up to 20 weeks (w) in total (including screening. treatment and follow-up). Recruitment is expected to take 6- 9 months.Patients who take part will receive treatment by an intravenous infusion every two weeks. The study will look at what the body does to the drug as well as what the drug does to the body by taking and examining blood and urine samples. A sample(s) of cerebrospinal fluid (CSF) will be taken by lumbar puncture during the first treatment dose and may be collected during subsequent doses. Liver and skin biopsy specimens will be taken to assess filipin staining. Cholesterol metabolism will be investigated in liver samples and splenic and hepatic elasticity will be assessed by ultrasound. Patients will also have their hearing tested, be asked questions by their doctor as well completing questionnaires to help assess any changes in their condition during treatment.This study is being sponsored and funded by CTD holdings Inc. It is planned to be run in the USA,.

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 to 9 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 or any uncertainty about their ability to give meaningful, informed consent (legal guardian may give consent with patient assent)
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