Multicenter, open-label, single arm study to evaluate long-term safety, tolerability, and effectiveness of 10mg/kg olesoxime in patients with SMA

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disorder
clinically characterized by progressive muscular weakness and atrophy. In most
patients the disease results from homozygous deletion or mutation of the
survival motor neuron protein (SMN) gene SMN1 (Lefebvre 1995). Clinical
severity is inversely correlated with SMN2 gene copy number (Kolb and Kissel
2011).
SMA leads to predominantly proximal muscle atrophy and weakness and the
potential for medical complications. There is no effective pharmacological
treatment for SMA (Lewelt et al., 2012). Treatment is supportive with the goals
being to improve the patient*s quality of life and to minimize disability (Wang
et al., 2007).
Olesoxime (RO7090919, cholest-4en-3-one, oxime), is a cholesterol-like compound
identified through its survival-promoting activity on trophic factor deprived
motor neurons in culture. Olesoxime showed neuroprotective effects in four
animal models of motor nerve degeneration as well as anti-nociceptive and
neuroprotective effects in experimental models of painful peripheral
neuropathies induced by diabetes or chemotherapy. Olesoxime binds to proteins
that have been implicated in the formation or modulation of the mitochondrial
permeability transition pore complex. By binding to these proteins, olesoxime
may preserve essential mitochondrial functions such as calcium buffering in
stressed neurons, thereby reducing neuronal degeneration and death (Bordet et
al., 2010).
Seventeen clinical Phase 1, 2 and 2/3 studies were performed with olesoxime
including one Phase 2/3 double-blind study in SMA (Study TRO19622CLEQ1275-1):
849 healthy subjects and patients have been exposed to olesoxime.
Information on non-clinical pharmacology, non-clinical safety and clinical
experience can be found in the Olesoxime Investigator's Brochure (IB).

Main objective:
The main objective of this open-label, single arm study is to further
characterize the safety, tolerability and effectiveness profile of olesoxime in
SMA

The primary safety objective for this study is as follows:
To evaluate the safety of olesoxime in patients with SMA, focusing on the
nature, frequency, and severity of adverse events, as well as effects on
laboratory values, vital signs and electrocardiogram (ECG) parameters

The secondary objectives for this study are as follows:
To evaluate effectiveness of olesoxime compared to the natural history of
disease in patients with SMA, as measured by MFM D1+D2 and MFM Total scores,
and HFMS score.
To evaluate the disease associated medical complications and procedures in
olesoxime treated patients compared to the natural history of disease, focusing
on their nature, frequency of occurrence, and severity
To evaluate the disease course between last visit of the studies
TRO19622CLEQ1275-1 and TRO19622CLEQ1115-1, and baseline assessment in this
study, as measured by motor functional scales (e.g. MFM) and as measured by
nature, frequency, and severity of medical procedures.

The pharmacokinetic (PK) objectives for this study are as follows:
To investigate the pharmacokinetics of olesoxime in the target population using
Bayesian feedback analysis based on a population pharmacokinetic model (as
appropriate and permitted by the data).

The patient-reported outcome (PRO) objectives for this study are as follows:
To compare changes in Health Related Quality of Life and the relationship to
other measures of disease status (such as motor function scales), following
treatment with olesoxime versus the natural history of disease in patients with
SMA, as measured by PedsQL core, and neuromuscular sub-scales.
To assess health-related quality of life and conduct economic modeling using
the EQ-5D-5L.

CAREGIVER-REPORTED OUTCOME OBJECTIVES
The exploratory objectives for this study are as follows:
To assess caregiver related quality of life and conduct economic modeling using
the Caregiver resource use: Work Productivity and Activity Impairment:
Caregiver (WPAI:CG) and Caregiver generic health related quality of Life (Short
Form-36 questionnaire)

The exploratory objectives for this study are as follows:
To explore olesoxime treatment response of FVC in patients with SMA.
To evaluate the percentage of responders in patients with SMA, defined as
patients who did not have a decrease from baseline in MFM scores.
To investigate the impact of SMN2 copy number genes, transcripts and protein
involved in pathological pathways of SMA in patients with SMA on the safety,
pharmacokinetics, pharmacodynamics, and efficacy of olesoxime.
To explore olesoxime treatment response to levels of SMN2 mRNA and SMN protein
in blood.

This is an open-label, single arm study to further evaluate long-term
tolerability, safety and efficacy outcomes in patients with SMA who previously
participated in one of the following two clinical studies:
* Open-label Phase Ib, dose-ranged, single and multiple dose study to assess
safety and pharmacokinetics of olesoxime in 6-25 year old Spinal Motor Atrophy
(SMA) patients (TRO19622CLEQ1115-1), and
* Phase II/III, multicenter, randomized, adaptive, double-blind, placebo
controlled study to assess safety and efficacy of olesoxime in 3-25 year old
Spinal Muscular Atrophy (SMA) patients (TRO19622CLEQ1275-1).

The study will consist of Historical Data Collection, screening, treatment, and
safety follow up periods. The study will occur in approximately 23 sites in 7
countries in Europe. All patients who participated in the studies mentioned
above will be invited to participate in this study. The maximum number of
patients in this study will be 171.

Historical Data Collection
All patients who participated in TRO19622CLEQ1115-1 or TRO19622CLEQ1275-1 will
be asked to provide medical history and information of all relevant medical
procedures that occurred between the patient*s last study visit of
TRO19622CLEQ1115-1 or TRO19622CLEQ1275-1 studies and the screening visit of
this current study, including:
* Motor Function Assessment using any SMA validated motor function scale, such
as the MFM and HFMS;
* patient disability status as assessed during routine clinical visits, such as
Brooke or Vignos scales;
* any documented medical procedures and therapies related to the natural course
of SMA disease according to the opinion of the treating investigator.
The request to provide detailed medical history information will be documented
in a separate Informed Consent Form (please refer to Appendix 2 of the
protocol).
Patients (or their legal representatives) who decline to provide detailed
medical history information are still eligible to participate in the treatment
phase of the study.

Olesoxime will be given as 100 mg/mL oral suspension. The drug will be
administrated at 10 mg/kg once a day with food in the evening, throughout the
study, either orally or via gastric tube with food.

The clinical formulation is a powder and solvent for preparation of an oral
suspension. The drug product will be supplied by Roche. Final investigational
medicinal product (IMP) kits will be delivered as one box containing one amber
glass bottle containing 7.5 g olesoxime powder and one amber glass bottle
containing sesame oil. The powder will be constituted on first use to yield a
homogeneous suspension containing 100 mg/mL of olesoxime in sesame oil. IMP
will be administered in mL at a dose of 10 mg/kg with suitable oral devices.
For more information please refer to the Investigator*s Brochure, the pharmacy
manual, and the patient*s instruction for use.

During clinical development of olesoxime, 849 healthy volunteers and patients
have been exposed to study drug. Olesoxime has shown to be well tolerated at
all tested dose regimens including co-administration with riluzole or
beta-interferons. To date, there are no identified risks with olesoxime therapy.
Based on efficacy data from the completed trials and based on the safety
findings observed to date, the sponsor considers the benefit-risk balance to
have remained positive for the continuation of the development program with
olesoxime.