Processa Pharmaceuticals, Inc. (PCSA) Initiation Report

October 28, 2020 Processa Pharmaceuticals, Inc. Page 9 of 16 ALPHA SELECT LIST Institutional Research the number of active anabolites that make the drug effective. A Phase Ib study evaluating the combination of PCS6422 and capecitabine as first-line therapy for metastatic colorectal cancer (CRC) is expected to dose the first patient in December/January 2020. PCS6422 prevents DPD from rapidly metabolizing capecitabine into 5-fluorouracil (5-FU), thus extending the use/efficacy of capecitabine and reducing the metabolites that cause AEs. Associated AEs include neurotoxicity and HFS (observed in up to 60% of patients). HFS can affect daily living activities, quality of life, and requires dose interruptions/adjustments and even therapy discontinuation resulting in suboptimal tumor effect. DPD inhibitors prevent the formation of α-fluoro-β-alanine (F- bal), an inactive metabolite believed to be responsible for neurotoxic effects and HFS, as well as potentiate the antitumor activity of fluoropyrimidines by preventing their degradation. One dose of PCS6422 irreversibly blocks DPD activity for up to two weeks until DPD levels recover via de novo synthesis of the DPD enzyme. Thus, inhibition of tumor DPD will result in higher 5-FU intra-tumoral concentration and potentially better tumor response along with the decrease in F-Bal. PCSA acquired an exclusive, global license to develop and commercialize PCS6422 from Elion Oncology (private) in August 2020. Elion acquired the product from Fennec Pharmaceuticals (formerly Adherex Technologies) in 2016. The program was originally under development by GlaxoSmithKline (GSK). Elion was exploring the potential for the combination of PCS6422 with capecitabine as a treatment of advanced gastrointestinal (GI) tumors. Nonclinical efficacy data indicated that in colorectal cancer models, pretreatment with PCS6422 enhanced the antitumor activity of capecitabine without increasing toxicity. Several other xenograft animal models with human breast, pancreatic and colorectal cancer cells also demonstrated antitumor activity and PCS6422 significantly reduced the dose of capecitabine required to be efficacious. Elion met with the FDA in 2019 and agreed upon the clinical development program required for the combination of PCS6422 and capecitabine as first-line therapy for metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred. The FDA granted the program safe to proceed in May 2020 for a Phase Ib study, which will evaluate the safety and tolerability of several dose combinations of PCS6422 and capecitabine in advanced GI tumor patients, to be initiated in the first half of 2021. Administering most DPD inhibitors directly with 5-FU may decrease the antitumor effect of the 5-FU, which is the reason prior studies have been unsuccessful. Other DPD enzyme inhibitors (e.g. Gimeracil used in Teysuno approved only outside the US) act as competitive reversible inhibitors. These agents must be present when 5-FU or capecitabine are administered to inhibit 5-FU breakdown by DPD in order to improve the efficacy and safety profiles of 5-FU. Given the reversible nature of their effect on DPD, over time 5-FU metabolism to F-Bal will return, decreasing the amount of 5-FU in the cancer cells and decreasing the potential cytotoxicity on the cancer cells. Because PCS6422 is an irreversible inactivator of DPD, it can be dosed the day before capecitabine administration and its effect on DPD can last longer than the reversible DPD inhibitors and beyond the time 5-FU exists in the cancer cell. This dosing regimen of one day prior to 5-FU optimizes the potential cytotoxic effect and minimizes the metabolism of 5-FU. Prior to Elion’s involvement, GSK conducted two multicenter Phase 3 studies that failed to show non-inferiority in patients with colorectal cancer with PCS6422 administered in 10- fold excess to 5-FU. Unfortunately, PCS6422 was not administered early enough to irreversibly affect the DPD enzyme, thus the treatment produced less antitumor benefit than the control arm with the standard regimen of 5-FU/leucovorin (LV) without PCS6422. Later preclinical work suggested that when PCS6422 was present at the same time as and in excess to 5-FU, it diminished the antitumor activity of 5-FU, which supports PCSA’s proposed study design of clinically dosing PCS6422 several hours to a day before 5-FU to allow its clearance before the administration of 5-FU. Decreased antitumor activity through simultaneous dosing of PSC6422 and 5-FU was shown in later preclinical work and supports why the prior studies failed. Additionally, preclinical efficacy data from CRC models and xenograft animal models with human breast, pancreatic and colorectal cancer cells indicated that pretreatment with PCS6422 potentiates the antitumor activity of capecitabine and significantly reduces the dose of capecitabine required to be efficacious, which should consequently decrease additional dose-dependent side effects of capecitabine.