Processa Pharmaceuticals, Inc. (PCSA) Initiation Report

October 28, 2020 Processa Pharmaceuticals, Inc. Page 6 of 16 ALPHA SELECT LIST Institutional Research Other associated conditions include thyroid disorders, inflammatory bowel disease, sarcoidosis, and rheumatoid arthritis. Approximately 22,000 - 55,000 people in the US and more than 120,000 outside the US are affected by the more severe form of ulcerated NL (uNL). There is no standardized, effective therapy for NL and existing treatments are unsatisfactory for patients. Treatment is often guided by case reports and anecdotal evidence with variable results. First line options include topical, intralesional and systemic corticosteroids, particularly for recent lesions. Corticosteroids are actually contraindicated for inactive, atrophic lesions as they may exacerbate the condition and increase the risk of new ulcerations. The use of corticosteroids is primarily based upon clinical experience, as there are few data to support their efficacy. One retrospective review of 65 patients with NL included 22 patients treated with potent topical corticosteroids (regimen not specified), of which 1/3 had documented improvement. Other possible treatments include topical retinoids, topical calcineurin inhibitors, tumor necrosis factor inhibitors, cyclosporine, pioglitazone, hyperbaric oxygen, clofazimine, pentoxifylline and psoralen/UVA phototherapy. PCS499 The lead program is PCS499, an oral tablet of a deuterated analog of one of the major metabolites of pentoxifylline. Like pentoxifylline, PCS499 acts on multiple pathophysiologies that are important to NL, including inhibition of cytokines, decrease in blood viscosity, inhibition of platelet aggregation, anti-fibrosis and anti-inflammation. This ability to affect multiple biological pathways may provide a novel treatment solution for NL where other potential therapies have fallen short. However, gastrointestinal AEs related to pentoxifylline have limited the dose that can be taken, despite its efficacy in treating NL. PCS499 resolves this problem by metabolizing only to the active moieties of pentoxifylline. Therefore, it increases exposure to the efficacy-related metabolites and decreases exposure to metabolites causing AEs. Pentoxifylline is a xanthine derivative (often used in medicine for bronchodilator effects) that has been used in treating a wide range of inflammatory skin conditions, such as generalized granuloma annulare. Pentoxifylline improves microcirculatory flow and also has a potent anti-inflammatory effect that has been shown to modulate immune cell activity and inhibit pro-inflammatory cytokines, such as TNF-α, that induce granulomatous inflammation. Wee and Kelly (2015) have suggested that the early introduction of pentoxifylline in treating NL may prevent ulceration as well as the progression of irreversible atrophy and scarring. They found that NL lesions had a marked response to pentoxifylline treatment at a dose of 400 mg three times daily, without significant side effects. When pentoxifylline was prescribed at an early stage of NL, it reversed the inflammation and atrophy associated with the progression of disease. This is the first report demonstrating the near complete resolution of early stage NL lesions following pentoxifylline treatment. In a patient with uNL, pentoxifylline was effective in reversing progressive ulceration, although the underlying atrophic plaques persisted. There are other published case reports of successful use of pentoxifylline in treating both ulcerative (two patients) and nonulcerative (one patient) NL.