About Profervia^®

Aisa Pharma’s PROFERVIA^® is a repurposed oral pill being developed for the treatment of Secondary Raynaud’s, primarily in patients with Scleroderma, containing Cilnidipine, a new 4th generation calcium channel blocker that has never been approved in the United States or Europe.

Cilnidipine is approved for treating hypertension in several Asian countries but has never been studied or developed to treat Systemic Sclerosis or Raynaud’s previously. Cilnidipine is better tolerated and safer in its history of treating hypertension than the calcium channel blockers that are used off-label to treat Raynaud’s. Its safety record is well known in the Asian population with literally billions of doses in treating high blood pressure. The medical need to develop a treatment for Raynaud’s is clear because Raynaud’s has a severe impact on the quality of life of patients who develop the condition and there are no approved medical treatments. Raynaud’s in its various forms affects approximately 6% of the world’s population. Excitingly, cilnidipine has properties that distinguish it biologically from currently used calcium channel blockers and imply that it may be a better drug to treat Systemic Sclerosis and Raynaud’s than many other drugs.

Eligible for Market Exclusivity

Cilnidipine has never been approved by the US FDA for any indication, qualifying it as a new chemical entity (NCE). Aisa is evaluating cilnidipine in the RECONNOITER study program. NCE’s gain at least 5 years of market exclusivity in most countries, during which no competitors can be introduced to that country’s marketplace. This exclusivity runs in parallel to the 7-year exclusivity granted under the FDA’s orphan drug designation, which Aisa is applying for ( (10 years in European countries) and additional exclusivity is available with studies in the pediatric population. 9% of Scleroderma patients are diagnosed when children.

Profervia’s^® Mechanism of Action

Profervia® is a L and N selective calcium channel blocker, inducing vasodilating and venodilating effects and decreasing blood pressure in hypertensive patients, but not in normotensive individuals. US-approved CCBs primarily target L-channel receptors, but Profervia® has >50~500 X more activity at the N channel than these agents. This is key to its unique profile and benefits as the N channel is located throughout the body in the spinal cord, the kidney, the heart, on veins and on the endothelium (the inside of arteries). Various studies have demonstrated that in addition to its blood pressure lowering effect, cilnidipine has beneficial effects on kidney function, atherosclerosis, cardiac function, and nervous system (autonomic or non-voluntary) functioning. All of these body systems are adversely affected in patients with scleroderma.

Tadalafil works by inhibiting an enzyme, called PDE-V, that breaks down a chemical called cyclic GMP in the body, thus increasing it levels. The enzyme is located in various body locations including the vasculature and on platelets and by blocking it and raising cGMP levels, blood flow is increased by increasing another chemical called nitric oxide which results in dilation of arteries. Although PDE-V inhibitors are used principally for the treatment of erectile dysfunction, pulmonary hypertension and for benign prostatic hypertrophy, they are used as second line treatment for scleroderma and Raynaud’s.

In combining the two agents, PROFERVIA^® may demonstrate the beneficial effects of both. A previous study combining less effective and less well-tolerated calcium channel blockers with tadalafil showed a significant beneficial effect on Raynaud’s and skin manifestations in scleroderma patients.