New Drugs – Maui Derm

Neal Bhatia, MD & Ted Rosen, MD

In this presentation from MauiDerm 2014, Dr Neal Bhatia, an Associate Clinical Professor at Harbor-UCLA Medical Center and Dr Ted Rosen, a Professor of Medicine at Baylor College of Medicine, bring us the latest information on drugs that are, or will be available to the practicing dermatologist.

Part 1

Neal Bhatia, MD

This information is extremely important, as dermatologists need to continue to stay up-to-date with regards to the new data and literature. As healthcare providers, it is imperative to pay attention to the serious drugs for a number of reasons, in that, many dermatologists are losing their skills and letting good medicine pass them by.

Apremilast

Apremilast is an inhibitor of PDE4 and is currently in phase III trials for a number of diseases, including ankylosing spondylitis, psoriasis, and psoriatic arthritis along with orphan status for Bechet’s disease. A published case report studying cutaneous lichen planus with apremilast (20 mg bid for 12 weeks then a four week holiday) (Paul et al. JAAD, 2013) demonstrated that 30 percent of the patients experienced a 2-grade improvement and all patients had some improvement. This is important because this data will help us to eventually learn the dose and how to titrate the drug. This study was; however, small in numbers, treatment time and dosages.

Apremilast was also studied in discoid lupus erythematosus (DLE). Remember that DLE is Th1 mediated and apremilast blocks the Th1 process by inhibiting the production of IL-12, 23 and Th-17. There is also subsequent suppression of the Th-1 and Th-17 profile. Eight patients started in the study and four patients finished the 85-day course. There were some gastrointestinal side effects and sensory neuropathy. (DeSouza et al. JDD, 2012) This indicates a need for larger studies.

Omalizumab

There is a lot of good data demonstrating that sub-cutaneous omalimuzab shows promising results for the treatment of chronic idiopathic urticaria with the treatment spaced four weeks apart. The best data was with the 300mg dose, whereby the patients received the four weeks and then were observed for 16 weeks. Most of the patients had very good severity scores as well as significant reduction. For patients with severe chronic urticaria who are done with antihistamines, cannot handle topicals, and do not know the triggers, omalizumab plays a promising role.

Dr Bhatia commented on the new treatments for onychomycosis and feels that we have a “flood year of antifungals this year.” What we need to know:

Naftifine 2% gel—data suggest that there is residual active drug available in the stratum corneum even up to 4 weeks after treatment
Luliconazole is approved for the treatment of tinea pedis
Efinaconazole and Tavaborole are not approved as yet—but the data for both medications show promise
Itraconazole 200 mg tablets with new dosing protocol—coincidentally around the time of the oral ketoconazole black box warning
Ketoconazole gel (Xolegel) for use on the face and Itraconazole tablets (Onmel) are back
Econazole Foam is coming and the data is encouraging with a new vehicle

In a Phase II study of luliconazole cream 1 percent for the treatment of interdigital tinea pedis, the researchers found that complete clearance was 26.8 percent and 45.7 percent in subjects in the two-week and four-week treatment group, two weeks post-treatment. The antifungal effect persisted several weeks post-treatment resulting in increased rates of mycologic and clinical cure. Four weeks post-treatment, complete clearance rates were 53.7 percent and 62.9 percent, respectively.

Niwano and colleagues looked at in vitro and in vivo antidermatophyte activities of luliconazole and found that it exhibited strong antifungal activity against Trichophyton spp with minimum inhibitory concentrations one to four times lower than lanoconazole or terbinafine. They also found that seven-day topical therapy (0.5% solution) was more effective than lanoconazole or terbinafine (0.5%) and luliconazole was the only drug that achieved complete mycologic cure with a three-day therapy.

Efinaconazole inhibits fungal lanosterol 14α-demethylase, which is involved in ergosterol biosynthesis at concentrations below minimum inhibitory concentrations. Efinaconazole is 4.8 times more potent than itraconazole in inhibiting ergosterol biosynthesis in T. mentagrophytes and is 7.3 times more potent than clotrimazole in C. albicans. Data on efinaconazole for toenail onychomycosis show favorable efficacy. The chart below demonstrates that you do not need occlusion to see any benefit with efinaconazole.

Tavaborole, representing a new class of anti-fungals, i.e., a novel boron-based compound, met all primary and secondary endpoints in the treatment of nail fungus when compared to ciclopirox lacquer in two studies and more importantly, demonstrated a negative culture of 87.0 percent vs 47.9 percent and 85.4 percent vs 51.2 percent, respectively. We will begin to see more and more phase III data in the near future.

Ketoconazole gel 2 percent has the same side effect precautions as oral products, on label, but these are doubtful. It’s important to remember that the brand name in some markets may be cheaper than the generic. Also of importance, rates of mycological cure and effective treatment (secondary efficacy endpoints) were observed in the Econazole Nitrate Foam 1% group relative to the Foam Vehicle in both phase 3 studies (P<0.001).

Itraconazole (200 mg) (OMNEL) utilizes Metrex® technology which improves bioavailability. It is now available with a new dosing protocol, which is more convenient for patients. In one study, itraconazole (200 mg tablets) demonstrated statistically significant efficacy across all endpoints compared to vehicle at week 52 and was found to be noninferior to itraconazole 100-mg capsules at 52 weeks. The treatment duration of 12 weeks allows for 40-week follow-up. Remember that the nail grows out one tenth of a millimeter per day; therefore, every patient who is on any drug will not get a new nail for two hundred days. So, follow-up can be a slower process. The safety profile of Omnel is not statiscially different from that of itraconazole; however, there is a slight elevation in ALT.

Part 2

Dr Rosen continues the presentation with more dermatologic treatment advancements….

Pliagils (Lidocaine 7% + Tetracaine 7% Cream) is a topical, local analgesia for superficial dermatological procedures, such as filler injection, PDL or mild laser abrasion, and tattoo removal, which requires a longer application time. Pliaglis is self-occluding and forms a pliable peel. It is applied 20-30 minutes for most minor procedures and 60 minutes for more major procedures and is available in 30,60 and100gm tubes. A dosing chart is available pending on what area you are trying to anesthetize.

Sitavig (acyclovir 50mg Buccal) is indicated for recurrent oro-labial HSV. The Novel Lauriad® technology is a natural polymer derived from milk which adheres to the mucosa; therefore leading to high local drug concentration, but minimal blood levels. It is one tablet, applied within one hour of prodrome onset, on the upper gum at the incisor on the same side as the HSV lesion. After holding pressure for 30 seconds, the patient should allow the tablet to remain until it falls off (approximately six hours). Sitavig has shown to reduce the duration of an attack by 0.5 days based upon a randomized controlled trial of 775 patients.

Another advancement includes the approval of carbinoxamine maleate susp (Karbinal ER), which is a mildly sedating H1 antihistamine in an extended release formulation. It is used for the treatment of allergic rhinitis and conjunctivitis, uncomplicated urticaria, angioedema, and dermatographism. The advantages of this drug are that it is in a liquid form and there is infrequent dosing (2 times per day). It is also indicated for children as young as age two.

Vashe Skin and Wound Hydrogel, an aqueous-based, emollient containing, non-oily hydrogel, is a hypochlorous acid-containing material. It is intended to relieve pruritus, burning or pain from atopic, allergic contact and radiation dermatitis, as well as thermal burns. The drug maintains a moist environment, encourages autolytic digestion and prevents contamination. It works through the chlorination of histamine, leading to a less active derivative. It oxidizes many groups and subsequently directly and indirectly neutralizes the effects of cytokines, leukotrienes, alpha-1 antiproteinases, and cysteine proteases. This product is Aurstat with which you may already be familiar. It came from a partnership between PuriCore and Onset Dermatologics.

Old Drugs, New News:

Adapalene/BPO 1.2%/2.5% (Epiduo®)–Now FDA approved down to age 9
Desoximetasone 0.25% (Topicort®) –Now available as a spray
Ketoconazole 200mg tab (Nizoral®) –Severe limitations on use due to liver and adrenal toxicity, as well as drug interactions
Certolizumab pegol (Cimzia®) –Now approved for psoriatic arthritis, maybe psoriasis at some time in the future

Certolizumab Pegol (Cimzia®)

Cimzia is approved for the treatment of psoriatic arthritis (PsA) at 200mg sq QOW. A phase III, multi-center, randomized, double-blind, controlled trial (RAPIDTM-PsA study) looked at 409 patients with adult onset PsA. The loading dose was 400mg or placebo at baseline, week two and week four, followed by 200mg qowk, 400mg q4wk, or placebo qowk. Adverse events were found in 62 percent of the patients versus 68 percent (placebo). ACR 20, 50, and 70 response rates at weeks 12 and 24 were higher for each Cimzia dose group relative to placebo; however, patients treated with Cimzia 200mg every other week demonstrated greater reduction in radopgraphic progression at week 24. Patients treated with Cimzia 400mg every four weeks did not demonstrate greater inhibition of radiographic progression at week 24, compared with placebo-treated patients.

Overall, treatment with Cimzia resulted in improvement in skin manifestations in patients with PsA (62.2 percent to PASI 75). It is important, as dermatologists, to recognize that the safety and efficacy of Cimzia in the treatment of patients with plaque psoriasis has not been formally established and the use in psoriasis is off-label.

In conclusion, clinicians should pay special attention to the Nizoral FDA warnings published in July of 2013. (www.fda.gov) The FDA states that:

Oral ketoconzazole should not be used as first-line therapy for ANY fungal infection
Ketoconazole should be used only for the treatment of life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or not tolerated
Oral ketoconazole is no longer indicated for dermatophyte or Candida infections
Oral ketoconazole is not indicated for fungal infections of the skin or nails
It is contraindicated in anyone with liver disease

If you use this drug and there is any hepatotoxic event, that could cause a great problem as a practitioner.

In summary, the dermatology landscape is continuing to grow with promising new drugs for our patients and it is imperative to stay on top of the latest data.