A Novel, Host-Directed Therapeutic for the Treatment of Sulfur Mustard Induced Lung Injury

PROJECT SUMMARY/ABSTRACT CMTx Biotech is a drug development company working to commercialize a pipeline of proprietary, non- antibiotic, chemically-modified tetracycline (CMT) compositions and formulations for the host-modulatory treatment of diseases with high unmet needs, including a proprietary, clinical-stage, orally-administered small- molecule drug candidate, incyclinide (CMT-3 / COL-3), as a medical countermeasure for the treatment of exposure to vesicants (blister agents) that may occur in chemical warfare, terrorism or industrial accidents. Vesicating agents, including distilled mustard (HD), mustard gas (H), mustard/lewisite, mustard/T, nitrogen mustard, sesqui mustard, and sulfur mustard, can cause moderate to debilitating injuries and pain to the eye, skin, and mucous membranes. The primary modes of exposure are through contact, inhalation and ingestion. Depending on the dose, route, and duration of exposure, toxic symptoms can range in varying degrees of ocular and dermal burns, blister formation, bronchospasm, dyspnea, pulmonary edema, bronchitis, and immune- and bone marrow suppression. Sulfur mustard is a human-made chemical warfare agent that causes blistering of the skin and mucous membranes on contact. Vesicating chemicals have been identified by the U.S. Department of Homeland Security (DHS) and the Department of Health and Human Services (HHS) as highly toxic chemicals of concern to public health security due to the devastating health effects of exposure. Unfortunately, no known antidote exists for sulfur mustard exposure. Treatment consists of removing sulfur mustard from the body as soon as possible and providing supportive medical care in a hospital setting or by trained emergency personnel. There remains a critical need for safe and effective medical countermeasures for the treatment of acute and chronic lung injuries caused by the inhalation of SM. The market for treatments specifically targeting sulfur mustard exposure is relatively limited to purchases by the U.S. Strategic National Stockpile and international equivalents. However, companies that secure FDA approval for a medical countermeasure (MCM) against certain chemical, biological, radiological or nuclear (CBRN) threats are eligible to receive a Priority Review Voucher (PRV), which allows the recipient to expedite the review of a future New Drug Application (NDA) or Biologics License Application (BLA) for a different product of their choice. PRVs can be sold or transferred to other companies, with an average value of approximately $100M. Our lead drug candidate is a pleiotropic matrix metalloproteinase (MMP) modulator which inhibits pathologically-excessive collagenolysis and resolves systemic inflammation. Safety of the compound has already been demonstrated in Investigational New Drug (IND)-enabling studies. The drug has been evaluated in several clinical trials for the treatment of diseases as disparate as AIDS-related Kaposi’s sarcoma, recurrent high-grade gliomas, refractory metastatic cancer, acne, rosacea and periodontitis. The Specific Aims of this STTR are (a) to demonstrate a dose-dependent survival benefit of incyclinide (25mg/kg, 50mg/kg, or 100mg/kg by oral gavage) in an established rat model of sulfur mustard (SM) inhalation with daily treatment initiated 24-hours post-SM exposure and continued for 28 days, and (b) to evaluate the effect of orally-administered incyclinide on the pathogenesis of SM-induced lung injury, pulmonary fibrosis and inflammatory biomarkers. Our long-term goal is to secure FDA approval for incyclinide as a safe and effective medical countermeasure for SM-induced lung injury. We anticipate that our drug candidate will improve survival and mitigate SM-induced lung injury in exposed rats, reduce SM-induced injury parameters as assessed through histopathology, as well as lung fibrosis and key inflammatory biomarkers. Successful completion of these studies will allow CMTx Biotech to (a) evaluate our drug candidate in non-rodent animal model of SM-induced lung injury, (b) prepare and submit a pre-IND meeting request and briefing document, and (c) scale-up production of the drug substance and drug product under current Good Manufacturing Practices (cGMP).