A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial to Evaluate Efficacy and Safety of Lenabasum in Diffuse Cutaneous Systemic Sclerosis

Systemic sclerosis (SSc) is a rare and serious disease and the deadliest of the
systemic autoimmune diseases (Bulpitt et al, 1993). The defining clinical
manifestation of SSc is fibrosis of the skin and internal organs. Clinical
manifestations include constitutional symptoms, skin thickening, restrictive
lung disease, pulmonary arterial hypertension, cardiac involvement including
arrhythmias, gastroesophageal reflux disease, gut dysmotility with
malabsorption and pseudo-obstruction, inflammatory joint and tendon disease
including contractures, myositis, Raynaud*s phenomenon, and digital ulcers
(Meier et al, 2012). The disease burden of SSc on day-to-day life is
significant with significant negative impact on quality-of-life and
patient-reported daily functioning.
Patients are commonly treated with systemic corticosteroids and
immunosuppressive drugs such as methotrexate and mycophenolate (Furst et al,
2012, Meier et al, 2012). No drugs specific for the treatment of SSc have been
approved by the FDA or EMA, other than for pulmonary hypertension secondary to
SSc or prevention of recurrent digital ulcers. Disease pathogenesis includes
chronic activation of the immune system, activation of fibrotic pathways, and
vascular damage. Lenabasum binds to cannabinoid type 2 receptors on activated
immune cells which triggers the production of specialized pro-resolving lipid
mediators, resulting in the resolution of inflammation, which is a
well-described physiologic process. Resolution returns inflamed tissue to
homeostasis without immunosuppression, including halting fibrotic processes.
Lenabasum has demonstrated beneficial activity in a human model of innate
immune responses and in human skin fibroblasts derived from patients with SSc.
Lenabasum has also shown beneficial activity in animal models of lung and skin
fibrosis in SSc, when administered prophylactically and in a therapeutic
manner. Lenabasum has been safety administered to ~250 subjects (both healthy
volunteers and in patients with serious inflammatory disease) to date, at a
total daily dose up to 240 mg, for a period of more than 12 months.

In the completed Phase 2 trial in SSc, lenabasum showed evidence of clinical
benefit as demonstrated by improvements in the modified Rodnan Skin Score, the
American College of Rheumatology Provisional Combined Response Index in diffuse
cutaneous Systemic Sclerosis score (Khanna et al, 2016), and multiple
physician-and patient-reported efficacy outcomes. The efficacy results support
the potential beneficial activity of lenabasum in this patient population.

Primary Efficacy Objective:
To evaluate the efficacy of lenabasum compared to placebo in the treatment of
SSc by assessing the American College of Rheumatology (ACR) Provisional
Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) at Week
52

Secondary efficacy objectives:
1. To evaluate the efficacy of lenabasum compared to placebo in the treatment
of diffuse cutaneous systemic sclerosis (SSc) by assessing change from Baseline
in the modified Rodnan skin score (mRSS) at Week 52.
2. To evaluate the efficacy of lenabasum compared to placebo in the treatment
of SSc by assessing the change from Baseline in the Health Assessment
Questionnaire-Disability Index (HAQ-DI) score at Week 52.
3. To evaluate the efficacy of lenabasum compared to placebo in the treatment
of SSc by assessing the change from baseline in FVC % predicted at Week 52.

Primary Safety Objective:
To evaluate treatment-emergent adverse events associated with lenabasum
treatment from Day 1 through Week 52

Secondary safety objectives:
1. To evaluate tolerability of lenabasum treatment and placebo treatment from
Day 1 through Week 52.
2. To evaluate changes in vital signs, weight, body mass index, physical
examinations, laboratory safety tests, ECGs,
and ARCI-M questionnaire associated with lenabasum treatment and placebo
treatment from Day 1 through Week 52.
3. To evaluate potential late-emerging adverse events (AEs) after
discontinuation of lenabasum treatment.
4. To evaluate long-term safety of lenabasum in OLE.

Biomarker objectives:
1. To evaluate the effects of lenabasum compared to placebo by assessing change
from Baseline in inflammation, fibrosis, and * smooth muscle actin positive
cells in histological examinations of skin biopsies at Week 52.
2. To evaluate the effects of lenabasum compared to placebo by assessing change
from Baseline in gene expression and gene pathways in skin biopsies at Week 52.

Pharmacokinetic Objectives
1. To evaluate the approximate trough concentrations of lenabasum at steady
state.
2. To evaluate the approximate maximum plasma concentration (Cmax) of lenabasum
after the first dose of lenabasum.
3. To evaluate metabolites of lenabasum.

This is a two-part, multicenter, Phase 3 study, assessing the efficacy and
safety of lenabasum in subjects with diffuse cutaneous SSc.
In Part A, subjects will be randomized to receive blinded study product
(lenabasum or placebo) for 52 weeks. After completion of Part A, consenting
subjects will begin open-label treatment with lenabasum (Part B). Subjects who
discontinue from Part A, and do not withdraw consent, or subjects that complete
Part A but do not consent to Part B, will be asked to participate in a two-year
safety follow-up.

Part A:
Subjects will be randomized centrally prior to or at Visit 1, with
stratification by three site locations [(1) United States, (2) Canada and
Europe and Australia, and (3) Asia] and SSc disease duration (* 24 months and >
24 months) in a 1:1:1 ratio to 1 of 3 treatment cohorts:
* Cohort 1: Lenabasum 5 mg twice per day (BID) (n = 118).),
* Cohort 2: Lenabasum 20 mg BID (n = 118).),
* Cohort 3: Placebo BID (n = 118).
Screening can occur up to 4 weeks before Visit 1. There will be a total of 11
study visits (Visits 1 * 11), which will occur at Day 1 and at the completion
of Weeks 4, 8, 14, 20, 26, 32, 38, 44, 48, and 52, respectively.

Part B
Consenting subjects will be allowed to directly rollover from Part A into Part
B. To participate in open-label treatment, subjects should provide consent by
Visit 10 in Part A. The decision to participate in open-label treatment must be
made within one month of subject completion of Part A.
In Part B, all subjects will receive lenabasum 20 mg BID (open-label treatment)
and will be assessed at 15 study visits. Upon completion of treatment (Visit
15), subjects will be asked to return 28 days later for a Safety Follow-up
Visit. Subjects that discontinue Part B, except for those that withdraw consent
or are lost to follow-up, should be assessed at their time of discontinuation
(Early Termination Visit) and 28 days after the last dose (Safety Follow-up
Visit). Subjects that withdraw consent will be asked to complete the Safety
Follow-up Visit, but completion of this visit is not required.

2-Year Safety Follow-up
Subjects who discontinue from Part A (but do not withdraw consent) or choose
not to participate in the OLE will be asked to participate in a 2-year safety
follow-up. Subjects will be assessed for AEs at subject study product
discontinuation (either regularly scheduled visit or unscheduled visit) then by
telephone every 6±1 months for the duration of 2-years from their last dose,
unless Corbus discontinues the lenabasum development program. If a routine
visit for standard-of-care has been scheduled, AEs may be assessed at an
in-office visit in lieu of a telephone call.

In part A subjects will be allocated to receive either 5 mg IMP twice a day, or
20 mg IMP twice a day - or matching placebo. Which are both referred to as
Study Drug/IMP. Each subject will be treated with IMP during 12 months.

In part B all subjects will receive 20 mg lenabasum twice a day, during 24
months.

Lenabasum is an investigational medicinal product and has not been approved for
any indication, therefore, it is not guaranteed that enrolled subjects will
experience a clinical benefit from participation in this clinical study.
However, the potential for clinical benefit is supported by data obtained from
previously completed Phase 2 clinical trials in diffuse cutaneous SSc, and
Cystic fibrosis. In addition, the data from this study may have an indirect
benefit in that it will be used to further understand and characterize the
safety and potential clinical benefit of lenabasum and may therefore help other
SSc patients by contributing to medical research. The results of this study
are expected to provide further insight into the efficacy, safety, and
tolerability of lenabasum in patients with diffuse cutaneous SSc.

Prior to this study Lenabasum has been tested in approximately 250 healthy
volunteers and patients at doses ranging from 1 mg to 240 mg, with the length
of dosing ranging from a single dose to dosing for greater than one year. The
side effects seen in these studies were dose-related, which means they were
more likely to occur at higher doses of lenabasum. Of the subjects who took
total daily doses of 60 mg or less, side effects were less frequent and most
were mild or moderate in severity. In previous studies with lenabasum where
subjects received 40 mg or less of lenabasum no severe or serious side effects
related to lenabasum were reported.
Lenabasum has not been shown to adversely react with other drugs in previously
completed studies, therefore the expected risk of drug-drug interactions with
lenabasum is expected to be low.

As of 05 Mar 2019 data cutoff, 277 subjects have been treated with lenabasum in
7 completed clinical studies, of which, 2 studies have ongoing OLEs. Some SSc
subjects participating in the OLE are in their third year of dosing and some DM
subjects are in their second year of dosing. In addition, there are another 480
subjects exposed to lenabasum or placebo. 266 patients of these patients are
enrolled in the Ssc-002 study. As of the data cutoff for this Investigator*s
Brochure (IB), no study deaths or serious TEAEs related to study drug have been
reported in the study.

The potential burden and risk of participation in this study are not expected
to be different than other comparable clinical research studies.
In part A there are a total of 11 planned monthly visits plus screening. In
part B there are 15 visits and a follow-up safety visit. As the first visit of
part B is the same as the last in part A the total of visits for a subject
completing the study per protocol is 20. Every effort will be made to be
respectful of the subjects* time. The design of this study was developed based
on input from the US Food and Drug Administration and the European Medicines
Agency.
The number and amount of each blood draw, while more frequent than would be
associated with normal clinical care has been planned to keep the total volume
of blood drawn as low as possible (less than 150ml, including clinical
laboratory assessments and PK/metabolite sampling).
Twice during the study two 3 mm punch biopsy samples will be obtained from SSc
involved skin to assess changes in signs of inflammation and fibrosis and
protein product expression associated with inflammation and resolution. With
skin biopsies there is some risk of slight bleeding, bruising, tenderness or
pain at the biopsy site. A local anesthetic will be applied prior to the
procedure to reduce procedure associated pain. Punch biopsies are used in this
patient population during clinical care to assess disease progression.
At each study visit during part A and about every other visit during part B
subjects will be required to complete 7 to 11 questionnaires. To reduce the
burden associated with completing these questionnaires a tablet will be
utilized to collect subject responses electronically.
An electrocardiogram will be performed four times during part A and twice
during part B. Risk associated with this test is minimal, where localized skin
irritation from the gel pads is rarely seen.
Subjects will be required to perform spirometry at each study visit during part
A and 5 more times during part B. Spirometry may result in coughing, shortness
of breath, dizziness, and headache, which are temporary. Spirometry is
performed during normal clinical care to assess disease progression in patient
lungs.