Cancerous and Noncancerous Tumors

The vice president and head of regulatory affairs and market access at PellePharm in San Francisco, Alix Alderman is a resident of Kentfield, a town in Marin County, California. In her position with PellePharm, Kentfield native Alix Alderman played a role in attaining breakthrough therapy designation for patidegib topical gel to reduce the disease burden of persistently developing basal cell carcinomas in people living with Gorlin syndrome.

Alternatively referred to as nevoid basal cell carcinoma syndrome (NBCCS), Gorlin syndrome is a hereditary condition that can increase the risk of cancer and noncancerous tumors throughout the body. Individuals with Gorlin syndrome who develop cancer are typically diagnosed with basal cell carcinoma (BCC), usually with the first tumor appearance occurring during adolescence or early adulthood, with BCCs recurring and growing in increased number over time. While Gorlin syndrome can affect the entire body, it is most often associated with cancerous BCC lesions particularly on sun-exposed areas, such as the face, scalp, chest, and back.

Keratocystic odontogenic tumors (KCOTs) are the most commonly observed noncancerous tumors related to Gorlin syndrome. Left unchecked, these noncancerous tumors can result in health conditions such as facial swelling and tooth displacement as they spread throughout the jaw.

Individuals who have been diagnosed with Gorlin syndrome should thoroughly discuss their diagnosis and treatment options with a knowledgeable physician, as the condition can impact patients in radically different ways. BCCs are currently most commonly treated by surgical removal; standard excision or Mohs surgery on the face. For some, the diagnosis may result in zero tumors, while others will develop thousands of basal cell carcinomas over the course of their lifetime. Patidegib was designated as a breakthrough therapy based on the seriousness of persistently developing BCCs, dearth of any approved therapy to treat or prevent BCCs in Gorlin syndrome, and nonclinical and clinical data which suggested a potential for patidegib topical gel to address some of the community's unmet medical needs.

The Basics of Gorlin Syndrome

A senior biopharmaceutical executive in the San Francisco Bay Area, Alix Alderman resides in the Marin County census-designated place of Kentfield and works at PellePharm across the Golden Gate Bridge in downtown San Francisco. Alix Alderman's achievements with PellePharm include securing FDA breakthrough therapy designation for Patidegib, a topical gel therapy undergoing clinical trials for Gorlin syndrome.

Gorlin syndrome is a rare (1 in 31,000) genetic autosomal dominant disease that drastically increases the risk of developing multiple basal cell carcinomas (BCCs; skin cancer) among teenagers and adults. The disease also presents an increased risk of other tumors, including medulloblastoma of the brain, fibromas of the heart and ovaries, and other phenotypic abnormalities such as palmar pits on the hands and feet and keratocystic odontogenic tumors of the jaw bones.

Clinical researchers have found that Gorlin syndrome is primarily associated with a mutation in the PTCH1, PTCH2 or SUFU genes. All currently available BCC treatments cause pain, scarring and/or disruptive side effects. A global Gorlin syndrome community survey was conducted by the Gorlin Syndrome Alliance (US support group) in conjunction with the Gorlin Syndrome Group (UK support group) in late 2019-2020, with a total of 261 responders. This survey, the largest of its kind in this rare disease, revealed the significant physical burden of recurrent BCCs, with 48% of individuals reporting >50 BCCs on their face and 21% reporting over 200 BCCs to date. Forty-six percent reported >50 BCCs on their body, with 13% reporting more than 500 BCCs.

More than 50% of responders indicated that they are very or extremely burdened by the impact of BCC treatment (surgery or pharmacotherapy) on their physical appearance and mental well-being, and the healing time associated with BCC surgeries. This survey confirmed that the burden of multiple and recurrent BCCs is unrelenting in Gorlin syndrome and can have daily psychosocial impacts (anxiety, fear, frustration, depression) for the community. The investigation and development of new BCC treatments are desperately needed to improve the quality of life for people living with Gorlin syndrome.

Challenges Associated with Orphan Drug Development

A pharmaceutical executive based in Kentfield in Marin County, California, Alix Alderman has served as head of regulatory affairs/market access and vice president of PellePharm since 2017. Kentfield resident Alix Alderman’s drug development expertise include a pronounced focus on rare diseases and the orphan drugs used to treat them.

Briefly defined, the term “orphan drug” refers to a pharmaceutical developed for a rare disease and very small population; typically defined from a regulatory perspective as less than 200,000 patients in the US. Despite the small number of affected patients, these drugs are still be subject to clinical trials to determine a suitable benefit-risk assessment by FDA, compliance with orphan drug laws, and for reimbursement decisions by payers. The conditions that they treat are so rare that they are often simply not feasible to develop and commercialize under normal market conditions and can be priced highly, making reimbursement for a patient all the more critical.

Pharma’s Almanac Magazine lists technical challenges first on its list of problems in the world of orphan drug development. Because diseases that affect very small patient populations do not typically have a long history of scientific study, existing research provides limited assistance during the drug development process. This leads to informed risk-taking by developers to select trial endpoints and clinical outcomes assessments that are either novel or originally designed for studies in much larger patient populations, but nonetheless have a high probability of being informative and impactful based on very small numbers of trial participants. Close collaboration with FDA throughout the development process tends to be essential, as is early insight from payers. An understanding of the natural history of a rare disease and the spectrum of the disease can aid educating key stakeholders toward alignment on appropriate efficacy outcomes. Because orphan drugs are often complex in nature and require small production numbers, the manufacturing process can also present tremendous challenges.