A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial to Evaluate Efficacy and Safety of Lenabasum in Cystic Fibrosis

Cystic fibrosis is an autosomal recessive genetic disorder that affects
multiple organs, including the lungs, pancreas, liver, and intestine. Cystic
fibrosis is caused by one of many different disease-causing mutations in the
gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a
cyclic AMP-dependent chloride channel (Kunzelmann et al, 2013). Mutations in
CFTR on airway epithelial cells in CF lead to defective Cl- secretion and Na+
hyperabsorption by airway epithelia (Knowles et al, 1983). CFTR also are found
on cells of the immune system, such as neutrophils (Painter et al, 2006),
monocytes (Ettorre et al, 2014), and T cells (Shanshiashvili et al, 2012),
where loss of CFTR function leads to abnormal immune cellular function. In CF
patients, disease-causing mutations in CFTR lead to abnormally thick mucus
(Burgel et al, 2007) and aberrant immune responses (Cantin et al, 2015, Ratner
and Mueller, 2012).

The net result is a propensity in CF patients for recurrent infections and
over-exuberant, yet ineffective leukocyte recruitment, phagocytosis, killing,
and clearance of pathogens. The bioburden of bacteria in the lungs is high
with the microbiome skewed toward pathogens such as Pseudomonas aeruginosa (P.
aeruginosa). Chronic lung infiltration with neutrophils and release of
neutrophil elastase and other enzymes contribute to bronchiectasis and
pulmonary fibrosis, which are a major cause of morbidity and mortality in CF.

Abnormalities in innate immune responses that lead to chronic inflammation
contribute to the pathogenesis of CF (Hartl et al, 2012). These abnormalities
include a decreased ratio of pro-resolving to pro-inflammatory lipid mediators
(Karp et al, 2004, Ringholz et al, 2014a Ringholz et al, 2014b), increased
production of proinflammatory chemokines, such as interleukin (IL)-8 (Kim et
al, 2013, Wojewodka et al, 2014), abnormal cell surface expression of toll-like
receptors (TLRs), such as TLR5 (Simonin-Le Jeune et al, 2013), and enhanced or
impaired signaling through TLRs. The abnormalities of innate immunity extend
to functional disturbances in neutrophils (Ng et al, 2014), ineffective
bacterial uptake and subsequent killing by immune cells, reduced autophagy and
cellular apoptosis in phagocytes (Mayer et al, 2013), and decreased clearance
of apoptotic cells.
Among the abnormalities of innate immunity reported in CF is the inadequate
production of *Specialized Pro-resolving lipid Mediators* (SPMs) which are
molecules that initiate the physiologic process of resolution of inflammation.
The relative overproduction of pro-inflammatory lipid mediators to SPMs in CF
(Karp et al, 2004, Urbach et al, 2013, Ringholz et al, 2014a, Ringholz et al,
2014b) provides a mechanistic link to the failure of CF patients to resolve
inflammation.

In CF, the ratio of SPMs to pro-inflammatory mediators is disproportionately
low, tissue inflammation is excessive and persistent, pathogens are not
effectively cleared, and tissue fibrosis leads to irreversible loss of
structural damage to lungs. Of note, the ratio of a key SPM, lipoxin A4, to a
key proinflammatory lipid mediator leukotriene B4 is low in bronchoalveolar
lavage fluid of CF patients (Karp et al, 2004), even in the absence of
infection (Ringholz et al, 2014a). Lipoxin A4 is produced by lipoxygenase
interactions resulting from trans-cellular cooperation of neutrophils,
eosinophils, alveolar macrophages, platelets or airway epithelial cells, each
expressing different lipoxygenase enzymes, which act in sequence in lipoxin A4
biosynthesis (reviewed in Urbach et al, 2013). Normally, CFTR are expressed on
both neutrophils and platelets, and neutrophil-platelet interactions during
acute inflammation initiate lipoxin A4 production (Serhan and Sheppard, 1990).
Platelets from patients with CF produce about 40% less lipoxin A4 than healthy
subjects (Mattoscio et al, 2010). In addition, 15-lipoxygenase expression,
which is required for lipoxin A4 production, is reduced in CF (Ringholz et al,
2014a). In animal models of CF, mice deficient in CFTR have reduced production
of lipoxin A4 by neutrophils and platelets (Wu et al, 2014). Importantly, in
turn, lipoxin A4 increases CFTR protein expression (Yang et al, 2012).

Lenabasum is a synthetic molecule that activates resolution of inflammation.
It is a preferential cannabinoid receptor type 2 (CB2) full agonist that has
12-fold greater affinity for CB2 than cannabinoid receptor type 1 (CB1) (Tepper
et al, 2014). Lenabasum shows little evidence of psychotropic activity at
likely therapeutic doses, because of limited ability to cross the blood-brain
barrier and reduced affinity for CB1.
There are two major CB receptor subtypes: CB1, mainly expressed in the central
and peripheral nervous system; and CB2, mainly distributed throughout immune
and hematopoietic cells, epithelial cells, fibroblasts, osteoblasts, skin
keratinocytes, and the peripheral nervous system (Rom and Persidsky, 2013).
CB2 is preferentially expressed on activated immune cells.

Lenabasum induces *class switch* of arachidonic acid metabolism from
proinflammatory lipid mediators to SPMs through effects on 15-lipoxygenase
(Zurier et al, 2009) and possibly other lipid metabolizing enzymes. Agonists
of CB2 are known to increase production of anti-inflammatory eicosanoids, such
as prostaglandin (PG) J2 and cytokines, such as IL-10 (Shanshiashvili et al,
2012). Further, CB2 agonists including lenabasum can induce apoptosis of T
cells (Bidinger et al, 2003, Singh et al, 2012), and fibroblasts
(Garcia-Gonzalez et al, 2009). Of direct relevance to treatment of CF,
endocannabinoids and synthetic CB2 agonists blunt inflammation, innate immune
responses and deposition of extracellular matrix, by:
* Inhibiting expression of TLR and nucleotide-binding oligomerization domain
(NOD)-like receptors and TLR signal transduction (Downer et al, 2011, Duncan et
al, 2013)
* Reducing production of early mediators of inflammation, including chemotactic
factors, such as IL-8 (Selvi et al, 2008) and proinflammatory lipids
* Inhibiting tissue infiltration with leukocytes, by inhibiting leukocyte
rolling and tissue infiltration (Mukhopadhyay et al, 2010), chemotaxis and
differentiation of dendritic cells (Adhikary et al, 2012)
* Reducing production of proinflammatory cytokines by these infiltrating cells,
including type 1 interferons, IL-1*, IL-6, tumor necrosis factor * (TNF*) and
IL-17 (Zurier et al, 2003, Parker et al, 2008, Selvi et al, 2008, Kong et al,
2014)
* Inhibiting accumulation of myofibroblasts, production of transforming growth
factor-* (TGF*), connective tissue growth factor, and extracellular matrix
components (Akhmetshina et al, 2009, Gonzalez et al, 2012, Börgeson et al,
2011, data on file)
*Class switching* of lipid mediators (Levy et al, 2001) to favor production of
lipoxin A4 and other SPMs would be expected to have therapeutic benefit in CF,
through effects on multiple pathologic pathways in CF. As examples, lipoxin A4:
* Enhances CFTR protein expression, at least in rat lungs (Yang et al, 2012)
* Decreases mucus thickness through effects on ion transport (Al-Alwani et al,
2014, Verrière et al, 2012)
* Increases airway epithelium integrity (Buchanan et al, 2013)
* Attenuates pulmonary fibrosis (Martins et al, 2009, Krönke et al, 2012).
Lipoxin A4 inhibits fibroblast proliferation (Wu et al, 2006) and TGF* receptor
type 1 expression and responses to TGF* (Brennan et al, 2013, Börgeson et al,
2011). Of note, high producer TGF*1 genotypes are associated with severe lung
disease in CF (Arkwright et al, 2000), TGF-* signaling and fibrosis are
markedly increased in CF (Harris et al, 2013) and TGF* may interfere with
therapies directed at correcting the processing defect in CFTR in CF patients
(Snodgrass et al, 2013).

Therapeutic approaches to reduce inflammation in patients with CF have shown
clinical benefit, such as alternate-day corticosteroids and high dose ibuprofen
(Konstan et al, 2007), but adverse effects and other considerations have
limited their use. Alternative agents to reduce lung inflammation and
resulting fibrosis are needed. The development of new therapies that will do
this is a strategic priority for the Cystic Fibrosis Foundation.

Lenabasum is being investigated as a new therapy for CF because of its
potential to resolve inflammation and stop pro-fibrotic processes in CF.
Lenabasum triggers the physiologic process of resolution of inflammation. It
reduces levels of pro-inflammatory mediators and increases levels of SPMs
including lipoxins and resolvins in involved tissues. Lenabasum reduces
polymorphonuclear leukocyte infiltrates and improves bacterial clearance in the
lungs in a mouse model of infection-induced inflammation in CF. Similarly,
lenabasum reduces polymorphonuclear infiltration and pro-inflammatory mediators
while hastening bacterial clearance in a human model of infection-induced
innate immune response in the skin.

Primary efficacy objectives:
To evaluate the efficacy of lenabasum 20 mg twice per day (BID) compared to
placebo in the treatment of cystic fibrosis (CF) by assessing the rate of
pulmonary exacerbations (PEx) using primary definition of PEx.

Secondary efficacy objectives:
1. To evaluate the efficacy of lenabasum 20 mg BID compared to placebo in the
treatment of CF by assessing other efficacy endpoints
2. To evaluate the efficacy of lenabasum 5 mg BID compared to placebo in the
treatment of CF

Pharmacokinetic (PK) objectives:
1. To evaluate steady state plasma concentrations of lenabasum 20 mg BID and
lenabasum 5 mg BID at the estimated time of trough concentration after a dose
of lenabasum
2. To evaluate plasma concentrations of lenabasum 20 mg and 5 mg at the
estimated time of peak concentration after the first dose
3. To evaluate metabolites of lenabasum
4. To develop population pharmacokinetic models of lenabasum in Cystic Fibrosis
subjects

Safety objectives:
1. To evaluate safety of lenabasum 20 mg BID and lenabasum 5 mg BID treatment
and placebo treatment
2. To evaluate tolerability of lenabasum 20 mg BID and lenabasum 5 mg BID
treatment

This is a double-blind multi-center study to evaluate efficacy and safety of
lenabasum in subjects with Cystic Fibrosis
(CF). About 100 investigator sites in North America, Canada, Europe, Israel and
Australia. Approximately 415 subjects will be
eligable for enrollment in this study. Patients will attend a screening visit
where the following assessments will take
place in order to determine eligibility: Physician assessment of pulmonary
exacerbations (PEx)- which is called the
Antibiotic Use for Respiratory Signs and Symptoms Questionnaire
(AUR-Q),concomitant medication check,
contraceptive check, spirometry, CRISS and CFQ-R questionnaires, adverse
events, vital signs (consisting of systolic
and diastolic blood pressure (BP), pulse rate (P), respiratory rate (R), body
temperature (T), weight, height, and O2
saturation), common CF pathogens in sputum, ECG, biomarkers and laboratory
safety tests.

If the patient is eligible following these assessments they will be randomized
centrally to one of three treatment
groups* 5 mg twice a day (BID), 20 mg BID or placebo BID, in a 2:1:2 ratio.
Subjects who receive at least one dose of
study drug will be considered enrolled in the study.

Active dosing with study drug is 28 weeks. There will be 8 scheduled study
visits during active dosing with study drug,
labeled Visits 1-8. Visits occur at Visit 1 and at the completion of Weeks 4,
8, 12, 16, 20, 24, and 28 ± 1 week).
Subjects who complete Visit 8 on study drug will have a Safety Follow-up Visit
labeled Visit 9 at the completion of Week
32. All subjects who develop acute signs and symptoms of worsening lung disease
will be asked to return to the site
for evaluation at a Possible PEx Visit. Unscheduled Visits may be necessary to
assess the subject for safety purposes
unrelated to new respiratory symptoms or a PEx.

The following items will be assessed at all study visits: Physician assessment
of PEx (AUR
Questionnaire),concomitant medication check, contraceptive check, Spirometry,
CRISS questionnaires, BMI, Adverse
events, Vital signs (consisting of systolic and diastolic blood pressure (BP),
pulse rate (P), respiratory rate (R), body
temperature (T), weight, height, and O2 saturation) and Laboratory safety
tests. In addition, CFQ-R questionnaire and
Common CF pathogens in sputum will be completed at visits 1,5, 8 and possible
PEx visits. ECGs will be completed
at visits 1,5 and 8 only. Biomarkers for blood and sputum will take place at
Visits 1,2,5, 8 and possible PEx visits.
Plasma sampling for Lenabasum and metabolites will be completed at visit 1
before and 3±0.5 hours after
administration of first drug dose, at visit 2, 5 and 8 the sample will be taken
8 - 16 hours after the last intake of study
drug.

This trial includes analyses of time to and event rate of PEx. In this study, a
PEx is defined as a clinical event of new or
worsening pulmonary or systemic symptoms beyond normal day-to-day variation
that causes the physician to treat
with systemic antibiotics. There is no interim analysis planned.

Subjects will be allocated to receive either 5 mg IMP twice a day or 20 mg IMP
twice a day - or matching placebo. Both are referred to as Study Drug/IMP. Each
subject will be receive Study Drug for 28 weeks.

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 Cystic Fibrosis and diffuse
cutaneous SSc. 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
Cystic Fibrosis 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 Cystic Fibrosis.

Prior to this study Lenabasum has been safely administered to ~250 subjects
(both healthy and in patients with serious inflammatory disease), up to a total
daily dose up to 240 mg, and at dose of 40 mg/day for a period of more than 12
months.
Corbus were notified of 2 SUSARs originating from the US sites participating in
the JBT101-CF-002 study. The events reported were acute pulmonary exacerbation
(US-CORBUS-0037) and pulmonary exacerbation of cystic fibrosis
(US-CORBUS-0064). As of 05 Mar 2019, 480 subjects have been exposed to
blinded Lenabasum or placebo, including 223 subjects enrolled in CF studies. Of
those, 138 patients are enrolled in the CF-002 study. As of 02 Apr 2019, 14
and 10 (blinded) subjects experienced serious PEx in the CF-001 and CF-002
studies, respectively. In study CF-001, 14 subjects reported serious PEx; 8 of
whom received a dose of Lenabasum. The rate of serious PEx is currently
approximately 10.8% across both Corbus-sponsored CF studies, with study
JBT101-CF-002 remaining blinded, which is within the anticipated rate of
occurrence in the enrolled population. There were no SARs reported in other
Lenabasum trials to date and no significant difference in the rate of
infections between Lenabasum and placebo was identified in unblinded reported
studies.

Overall, lenabasum has been found to be well-tolerated in clinical studies
conducted to date with only mild or moderate adverse reactions observed. The
most common adverse reactions consistent with the pharmacological action of
lenabasum during placebo-controlled dosing has been dizziness in SSc and dry
mouth in CF study. Together, results from the preclinical safety, toxicology
and pharmacokinetic studies, efficacy studies in animal models of disease,
studies with human biomaterials, as well as safety and preliminary efficacy in
humans support a favorable benefit-risk profile of lenabasum. These data
justify its continuing investigation in clinical trials in rare and serious
autoimmune/inflammatory disorders, with significant unmet medical need, such as
Cystic Fibrosis.

The potential burden and risk of participation in this study are not expected
to be different from other comparable clinical research studies. There are 8
planned weekly visits, plus screening and a possible Safety Follow-up visit,
labelled Visit 9, and every effort will b made to be respectful of the
subjects' time. The design of this study was developed on input from the US
Food and Drug Administration, Cystic Fibrosis Foundation, European Cystic
Fibrosis society and US and EU Co-Principal Investigators.

Blood and urine samples will be taken at all 9 visits and patients will be
asked to provide sputum samples, preferably spontaneously but induced where not
possible. Blood sampling may cause minor discomfort and occasionally may cause
bruising or inflammation of the place
where the blood was drawn. Only trained clinical staff and the medical staff
will perform the procedure. At each visit patients will be required to complete
3 questionnaires. To reduce the burden associated with completing these
questionnaires, a table will be utilised to collect subject responses
electronically. An electro cardiogram will be performed 3 times during the
study. Risk associated with this test is minimal, where localised skin
irritation from the gel pads is rarely seen. Subjects will be required to
perform spirometry at each study visit. 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.

The most common adverse reaction observed in reported lenabasum studies is
dizziness, often described as lightheadedness, that is usually mild and
transient. An individual subject should not receive any further study product
if any serious AE related to lenabasum occurs. To potentially reduce drop-out
rates from AEs or tolerability issues during the study, the treating physician
may choose to reduce the dose of study product by 1 capsule per day. This
decision should be discussed with the Medical Monitor for consensus prior to
instituting any reduction. The impact of any reduction in dose will be assessed
in sensitivity analyses of efficacy outcomes. AE monitoring will be carried out
at each visit. Additionally, subjects will be instructed to call study
personnel to report any abnormalities during the intervals between study visits
and to come to the site if medical evaluation is needed and the urgency of the
situation permits. An unscheduled visit will be made, if necessary, for medical
issues that arise between study visits.

Studies of human reproduction have not been performed with lenabasum. It is not
known whether lenabasum can cause foetal harm when administered to pregnant
women or whether it can negatively affect reproduction. Female and male
participants will be asked to use adequate contraception.If a female
participant becomes pregnant during the study, she will be instructed to inform
the trial doctor immediately. All participants who become pregnant during the
study will discontinue study drug and be removed from the study. The pregnancy
will be reported and the outcome reported, once known.

This study will include adolescent subjects with ages 12 to 17 years and body
weight * 40 kg. According to the Cystic Fibrosis Foundation 2015 Patient
Registry report, CF patients are at an increased risk of pulmonary
exacerbations increasing with age from adolescence to early adulthood,
therefore adolescents represent an important at-risk population for the planned
indication investigated in this study. The investigated doses of lenabasum 20
mg BID and lenabasum 5 mg BID that are proposed for the Phase 2 CF study,
predict systemic exposure (i.e., AUC and Cmax) of lenabasum in adolescents age
12-17 years to be similar to that in adults (refer to section 5.4.6 in IB). In
addition, the safety of treatment of adolescents with lenabasum at 20 mg BID is
supported by analyses of nonclinical studies of lenabasum pharmacology,
toxicology and metabolism (refer to section 4.2 in IB). All adolescent subjects
will be required to sign on both Assent Form and Parental ICF before they get
enrolled into the study.

Lenabasum is a Selective Cannabinoid Receptor Type 2 Agonist. Lenabasum has
shown low potential for abuse in
preclinical and evidence of psychotropic effects of the study product in
subjects is being tested in other ongoing trials
using the Addiction Research Center Inventory-Marijuana Test.