Amalyte’s second program is a novel approach to making topical PDE4 inhibitors with minimal systemic exposure and toxicity. PDE4 is a well-validated, high interest target, extensively studied at the molecular, pharmacological and clinical level, for a wide variety of inflammatory disorders. A major stumbling block in the development of PDE4 inhibitors is the potential for adverse effects, including nausea, emesis, headache and sedation that are characteristics of the drug class.
To circumvent the AE concerns, attempts are currently being made at several companies to develop “side-effect” free subtype-selective PDE4 inhibitors, or to develop inhibitors for topical administration at lower systemic exposure. Based on clinical and preclinical data, the effectiveness of sub-type selective inhibitors may be limited by their clinical potency when used at doses that have minimal effects on nausea and vomiting. Their utility for dermal applications, given potential low drug distribution, is even less certain. Concerning the existing topical strategies, it is well known that rolipram locally administered induces some adverse effects such as hyperalgesia, such that topical administration, particularly pulmonary delivery, may not provide the improvements in adverse effects required for a competitive product.
Amalyte's proprietary approach would eliminate the AE issues associated with PDE4 inhibitors for topical use. The medicinal chemistry approach is the result of a systematic review of the patent and scientific literature for the different classes of PDE4 inhibitors with chemistry targets based on strategies covering the proven pharmacophores, as well as targets based on structure-based drug design to contain unique scaffolds. Current work is directed at the medicinal chemistry optimization of lead compounds for selection of a clinical development candidate. Compounds will initially be developed for dermatitis and psoriasis, with later stage efforts focused on pulmonary conditions such as COPD and asthma.
Market Opportunity
Atopic dermatitis is a skin disorder characterized by intense itch, dry skin and redness. Often considered benign, it actually impacts very negatively on quality of life, sometimes more than psoriasis and diabetes. Elidel and Protopic, two new topical immunomodulators (TIMS) have demonstrated the opportunity and potential for new agents to enter the market. Both demonstrate good efficacy in dermatitis, and there have been no long term adverse events equivalent to the skin atrophy observed with long-term topical steroid usage, with systemic exposure to either compound very low with no accumulation in body tissue. However, the FDA recently issued black box warnings for both Elidel and Protopic over concerns about cancer risk based on information from animal studies, case reports in a small number of patients, and other information, resulting in their restriction as second-line agents for short-term and intermittent treatment of atopic dermatitis, at low doses and in children only over the age of two.
Based upon market studies and opinion leader interviews, there is a high level of unmet need in atopic dermatisis treatment for safer and more effective drugs for itch, particularly considering the restrictions placed on existing TIMS. About 40 million patients suffer from atopic dermatitis in the seven major markets. The late stage atopic dermatitis pipeline is empty and lacks innovation, and a gap in the market exists for effective non-steroidal therapies, left by Elidel and Protopic. A novel TIM agent such as a topical PDE4 compound lacking the safety concerns but with a differentiating mechanism of action and a better activity and side effect profile than topical steroids would represent a major opportunity in the dermatitis space.