Dermatology, the branch of medicine dealing with diseases of the skin, hair, and nails, is perhaps the therapeutic area most well suited to topical and transdermal drug delivery, for obvious reasons. The global medical dermatology market is worth more than $20 billion (IMS Health), with the US accounting for about $7 billion. Within medical dermatology, there are many therapeutic areas; in the US, treatments for acne account for about 50% of sales (PHAST Integrated Monthly, March 2014).
One of the most commonly treated conditions in dermatology is acne. Most people have milder forms of acne as they go through puberty; however, some have more severe cases requiring medical help. A variety of oral and topical medications work to control acne. One particularly popular class of treatments, the retinoids, are derivatives of Vitamin A and are available in both oral and topical formulations.
Isotretinoin, an oral retinoid that was marketed as Accutane® by Roche, was a leading treatment that was removed from the from the US market in 2009 due to a series of lawsuits and safety issues. Accutane® achieved peak sales of about $750 million in the US and $1.2 billion globally. The current generic market for isotretinoin is estimated to be in the range of $500 million in the US. As a result of the safety issues associated with oral isotretinoin, a similar retinoid, tretinoin, was developed as a topical gel and cream. Initially marketed as Retin-A® by Ortho Dermatologics (a division of Janssen Pharmaceuticals, Inc), it is now promoted by Valeant and also available in a variety of generic forms. As a result of being administered topically, it has much milder side effects than oral isotretinoin. It can, however, cause significant irritation of the skin. Topical retinoids often cause an initial flare-up of acne and facial flushing.
Tretinoin is a drug most commonly prescribed by dermatologists for topical treatment of acne. However, it causes adverse skin irritation in many patients and consequently leads to a large number of those patients withdrawing from treatment. As a result, products often contain a less than optimal amount of tretinoin to reduce irritation but this leads to a decrease in efficacy as well. A new tretinoin formulation with the ability to deliver greater absorption of tretinoin, reduce irritation and dryness and limit systemic circulation should significantly increase the topical prescription retinoids market.
Previous studies conducted by Phosphagenics demonstrated a significant increase in the delivery of tretinoin into the skin, when formulated with TPM®, as well as substantially deeper penetration of the drug. The TPM®/Tretinoin Gel led to a 4-fold increase in total tretinoin absorption (p<0.05) and increased penetration (p<0.02) compared to Retin-A® with a 22-fold increase in penetration at the deepest skin layer analyzed using tape stripping (see chart below, n=10).
TPM®/Tretinoin Gel – Phase 1 Study Results
Despite significantly increasing the amount of tretinoin delivered, TPM® was able to reduce the amount of erythema and dryness compared to Retin-A® when evaluated with a Repeat Insult Patch Tolerance (RIPT) test after 3 weeks of application (see chart below, n=30, bars represent SEM).
TPM®/Tretinoin Gel – Phase 1 Study Results
In late 2014, Phosphagenics released results from a three month Phase 2 study that examined the efficacy of TPM®/Tretinoin Gel against Retin-A®. A total of 54 patients were recruited for the randomized double blind study at three trial sites in Australia and New Zealand. The study demonstrated that TPM®/Tretinoin gel was better than Retin-A® in treating inflammatory acne lesions, and also produced less erythema and dryness than Retin-A®. After two weeks of treatment with Retin-A®, the number of patients suffering erythema and dryness was significantly increased (p<0.05) and remained above baseline measures for 8-12 weeks of treatment. Treatment with TPM®/Tretinoin over the same period produced only a minor increase (not significant) in the number of patients with erythema and no increase in the number of patients reporting dryness. The small number of patients precludes a statistically significant difference between the formulations, but the results clearly support previous findings that the TPM® imparts a protective effect on the skin.
Another common dermatological condition is seborrheic dermatitis, an inflammatory condition affecting the scalp, face, and torso. Typically, it presents with flaky, itchy, and red skin. One of the causes of seborrheic dermatitis may involve an inflammatory reaction to a proliferation of yeast. Although multiple medications are available to reduce symptoms of the inflammatory reaction (e.g., itching, redness), there are limited antifungal treatments available. Ketoconazole is the only antifungal approved for seborrheic dermatitis that is available as a topical medication (foam and gel). It was marketed by J&J as Nizoral® prior to the entry of various generic products.
The global market for topical prescription antifungal products was about $2.6 billion in 2011, accounting for about 75% of the total antifungal market, making it the biggest market in dermatology. The market is forecast to grow to $3.4 billion in 2016, demonstrating a compound annual growth rate of 6.4% from 2011 to 2016 (Kalorama, Dermatological Drugs 2012).
Phosphagenics has formulated a TPM®/Ketoconazole Gel, with 3 months stability data available. The product is ready for Phase 2.