A Multicenter, Randomized, Double blind, Vehicle-controlled, Phase 3 Efficacy and Safety Study of Patidegib Topical Gel, 2%, for the Reduction of Disease Burden of Persistently Developing Basal Cell Carcinomas (BCCs) in Subjects with Basal Cell Nevus Syndrome

Basal cell nevus (Gorlin) syndrome (BCNS) is a rare autosomal dominant
heritable disease characterized by numerous phenotypic abnormalities, most
prominent among which is the development of numerous basal cell carcinomas
(BCCs) over a lifetime. Reports of its prevalence vary; the highest estimate is
1:31,000. The burden of BCCs varies among Gorlin Syndrome patients. In general,
Gorlin Syndrome patients have their BCCs treated as they become problematic
(i.e., at risk of invasion of vital structures such as eyes, nose, or ears,
become large enough that scarring will be particularly noticeable if treatment
is delayed, or become large enough off the face such that they are
uncomfortable, bleed). Thus BCNS patients typically are never free of BCCs; in
a trial of the effects of vismodegib vs. BCCs in Gorlin Syndrome patients,
Gorlin Syndrome subjects had an average of 27 BCCs present at baseline.
Although oral vismodegib can produce complete clinical clearing, once the drug
is stopped the BCCs recur.
Several topically-applied drugs are used in the treatment of BCCs. Some of them
can cure approximately 80% of the superficial subtype of BCCs, which generally
occur off the face, but they generally are not useful vs. nodular BCCs, which
are the more prevalent subtype, especially on the face. Prevention of BCCs so
far has been limited to admonitions to avoid sunlight, advice which is followed
infrequently by patients at risk of developing sporadic skin tumors, and which
has not been shown to produce a statistically significant reduction in BCC
incidence. Following identification of uncontrolled HH signaling as the driving
molecular abnormality in all BCCs, several anti-HH drugs have been developed
for oral treatment of BCCs. But because of annoying class-specific side
effects, most patients discontinue their treatment, and most/all of the
clinically and histologically cleared BCCs recur to the same size as before
treatment. Patidegib is a semi-synthetic small molecule and when given orally
has good therapeutic efficacy versus advanced BCCs but produces the same types
of adverse effects as do other systemic HH inhibitors. Patidegib Topical Gel,
2%, is manufactured with excipients generally accepted as safe, is stable in
the developed gel formulation, and can be applied to mini-pig skin without
irritation. Application of Patidegib Topical Gel, 2%, significantly reduces
murine BCC tumor size in vivo and reduces GLI1 biomarker expression in vitro in
human BCC tumor explants. PellePharm, Inc. is developing Patidegib Topical Gel,
2%, for the reduction of BCC burden in subjects with Gorlin Syndrome. This
trial will evaluate the ability of Patidegib Topical Gel, 2%, to reduce new
surgically eligible BCCs (SEBs) in subjects with Gorlin syndrome.

Primary Objective:
To assess the number of new BCCs in the 2 arms (Patidegib Topical Gel, 2%, and
Vehicle (placebo)) when applied twice daily to the face of subjects with Gorlin
Syndrome.

Secondary Objective:
To assess the safety and tolerability of Patidegib Topical Gel, 2%, in subjects
treated twice daily for 12 months

This is a global, multicenter, randomized, double-blind, stratified,
vehicle-controlled study of the efficacy and safety of Patidegib Topical Gel,
2%, applied topically twice daily to the face of adult subjects with Gorlin
Syndrome.
Subjects will be randomized (1:1) to receive either Patidegib Topical Gel, 2%,
or Vehicle for 12 months.
The assignment of subjects to the two groups will be stratified by gender, age
(>= or <60 years), and previous Hedgehog inhibitor (HHI) therapy.
Study duration is approximately 14 months: up to 45-day Screening period, 12
months active treatment, and 30-day safety follow up.
Number of subjects : Up to 150 subjects
All subjects who complete the Month 12/Exit Visit having demonstrated adequate
compliance with application of the Investigational Product (IP) without major
Protocol Deviations (PDs) during the study will be eligible for participation
in the open-label extension study.

Subjects will be randomized (1:1) to receive either Patidegib Topical Gel, 2%,
or Vehicle for 12 months to assess the number of new BCCs in the 2 arms
(Patidegib Topical Gel, 2%, and Vehicle) when applied twice daily to the face
of subjects with Gorlin Syndrome and the safety and tolerability of Patidegib
Topical Gel, 2%, in subjects treated twice daily for 12 months

In complete studies with the topical gel, the most common side effects were
muscle spasms and irritation at the application site (redness, itching,
pain/burning/stinging and hair loss at the application site).

The following risks may be associated with patidegib topical gel:
• the skin may become itchy, red, and/or dry when using this study gel.
• there may bepain/burning/stinging at the application site.
• The study gel may affect the quality and quantity of hair in areas where it
is applied.

The placebo may also cause side effects. The most important ones are:
• Itchy skin
• Red skin
• Dry skin

There is a risk of an allergic reaction:
• a rash
• a fast pulse
• sweating
• a feeling of dread
• swelling around the eyes and mouth
• swelling of the throat
• wheezing
• having a hard time breathing
• a sudden drop in blood pressure (making the patient feel dizzy or lightheaded)
• inability to breathe without assistance

Blood Draws
It may be painful when blood is drawn . Some people get dizzy or faint from a
blood draw. The patient could also get an infection, which is rare, or have
bleeding, redness, or bruising at the skin puncture.

Unknown Risks
Patidegib Topical Gel, 2% is an investigational treatment so there may be risks
and side effects that are not yet known.
There may also be unknown risks to an unborn child.