Cyclosporine A (also ciclosporin, CsA) is a powerful polypeptide immunosuppressant drug that reversibly inhibits T-lymphocytes, most notably through targeting T-helper cells, and to a lesser extent, T-suppressor cells. CsA also inhibits lymphokine production and release including interleukin-2 (IL-2) or T-cell growth factor. This mechanism of action has provided useful in the prevention of allogeneic organ transplantation rejection, with specific utility in skin, heart, kidney, liver, and bone marrow transplantation. The drug has also been used to treat autoimmune diseases such as severe psoriasis, atopic dermatitis, rheumatoid arthritis, and to generate tear production in individuals with dry eyes.
CsA products in the U.S. include Sandimmune® (Novartis), available in soft gelatin capsules, oral solution, and injection, and Neoral® (Novartis), an improved version also available in soft gelatin capsules and as an injectable. Independent assessments of Sandimmune® and Neoral® show the later to offer improved pharmacokinetics and more consistent absorption (van Mourik ID, et al., 1999), but Neoral® still suffers from the same poor tolerability and side effects of Sandimmune®; and, both drugs have significant safety issues and contraindications that dramatically limit use in indications such as psoriasis, atopic dermatitis, and rheumatoid arthritis.
In terms of serious side effects, the FDA approved labels for Sandimmune® and Neoral® include warnings on nephrotoxicity, neurotoxicity, anaphylactic reactions, malignancies, and serious risk of life-threatening infections. The labels also include precautions on risk of hypertension, glomerular capillary thrombosis, and hypomagnesemia. There are several classes of medications that are contraindicated for use with CsA, including statins, anti-HIV medications, and other potent immune-suppressing agents like methotrexate. Less serious side effects include swollen or painful gums, headache, stomach pain, constipation, muscle spasms, tremors, shaking, and numbness.
Use In Dermatology
In the U.S., Neoral® is approved for the treatment of psoriasis. The label includes a bolded "Black Box" warning for many of the nephrotoxicity and neurotoxicity issues noted above, risk of serious infection, as well as a specific risk for the development of skin malignancies when used in combination with PUVA, radiation therapy, or methotrexate. The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain. The table below shows key adverse events and their frequency as seen in controlled clinical trials with oral systemic delivery of the drug.
This is a nasty drug! It's dangerous, and has potential very serious negative implications when taken systemically. The question is, "Why would anyone want to take this drug?" The answer is quite simple, it's incredible effective. For example, at 2.5 mg/kg/day BID, patients can expect to see improvement in clinical manifestations of psoriasis in as early as two weeks. The PASI-75 score, the percent of patients that see a 75% or greater improvement in the severity of their psoriasis, is an astonishing 79% at week 16. To put that in perspective, those results are 2.5X what a patient can expect to achieve on Celgene's Otezla® and 50-60% better than Pfizer's Xeljanz® at week 16. These results are similar, if not even better, than the injectable TNF-alpha drugs like Enbrel®, Humira®, and Remicade®. For example, Humira®, the market leader and best-selling biologic of all time, was approved based on a PASI-75 score of 71% at week 12.
Benefits of A Topical Formulation
In June 2015, Immune Pharmaceuticals (IMNP) entered into an agreement with Yissum for the exclusive licensing and development of a topical, biodegradable, nano-capsule formulation of cyclosporine A. The strategy is consistent with the company's goal of building a leading dermatology franchise focusing on acute autoimmune and inflammatory diseases. As a reminder, the company is currently studying its lead drug candidate, bertilimumab, in a Phase 2 trial for the treatment of bullous pemphigoid. Investors can read more information about this program >> HERE.
The concept for a topical formulation of CsA is quite simple - you get all the benefits of the powerful efficacy of the drug and avoid the primary systemic side effects such as nephrotoxicity, neurotoxicity, anaphylactic reactions, GI-related adverse events, and serious risk of life-threatening infections. It is a commercially validated strategy with many medications, including corticosteroids and non-steroidal anti-inflammatory drugs. In fact, topical formulations of CsA already exist, most notably, Allergan's Restasis®, which has been shown effective for the treatment of dry eyes (Perry HD, et al., 2008) and other ocular surface disorders (Tatlipinar & Akpek, 2005).
The topical nano-capsule technology and the application to CsA have been developed by the team of Professor Simon Benita, PhD, Director of the Institute for Drug Research and Dean of the School of Pharmacy at the Hebrew University of Jerusalem. Professor Benita pioneered an ocular nano-formulation of cyclosporine A called Novasorb®, approved for marketing in Europe for the treatment of severe keratitis associated with dry eye disease (Lallemand F, et al., 2012).
Professor Benita's work shows that CsA has been successfully incorporated in PLGA biodegradable nano-capsules and have developed stable topical formulations able to achieve therapeutic cyclosporine A levels in the targeted skin layers. The therapeutic effects of Nano-CsA have been confirmed in two different animal models, which investigators believe may support a potential topical alternative to the oral formulation (Neoral®) or Class I "superpotent" steroids such as clobetasol. In fact, Ex Vivo data (shown) below show that Nano CsA is as effective as clobetasol in reducing key inflammatory biomarkers such as IL-6 and IL-8.
I can see potential utility for a topical Nano-CsA in the treatment of both psoriasis and atopic dermatitis (AD). Formulations of CsA for veterinary use are on the market for atopic dermatitis, most notably, Atopica-Rx sold by Novartis. Research shows a topical nanotechnology formulation of CsA offers impressive results in dogs with atopic dermatitis (Puigdemont A, et al., 2013). The authors noted that after 21 and 45 days the lesion severity score in animals treated with CsA was significantly lower than at baseline (P < 0.01, both times). In contrast, the animals on topical placebo showed no significant improvement at days 21 or 45. The percentage of dogs with an effective reduction in pruritus at the end of the trial was 87.5% and 28.6% in the CsA and placebo groups, respectively. These results suggest that topical administration of CsA is effective in reducing the severity of skin lesions and pruritus in dogs with moderate to severe AD as soon as 3 weeks after starting treatment.
These are both rather large markets. Atopic dermatitis, also known as eczema, is a chronic inflammatory disease that results in itchy, red, swollen, and cracked skin. It is quite common in the U.S. According to the National Eczema Association, a substantial proportion of the population has either eczema - 31.6 million, or moderate to severe atopic dermatitis - 17.8 million. Mild to moderate psoriasis affects approximately 7.5 million Americans. Topical steroids are a common first-line medication for the treatment of both psoriasis and atopic dermatitis; however, excesses use can result in skin atrophy and striae.
For moderate-to-severe cases, a topical steroid may not be strong enough, forcing dermatologists to prescribe systemic immunosuppressants such as methotrexate or expensive biologic medications such as Enbrel® or Humira®. Oral medications such as Otezla® and eventually Xeljanz® are likely to gain sizable share ahead of the injectable biologic medications, but for localized moderate disease, topical treatment remains the desired choice for both patients and physicians. A topical Nano-CsA would provide a nice alternative to topical steroids when proven ineffective. Immune plans to file an Investigational New Drug (IND) application for Nano-CsA in 2016.