New Drugs and Therapies for 2016: Foams

Drs. Neal Bhatia and Ted Rosen

Part 1 of an 8-part series on the large number of new topical and systemic medications that have become available or moved closer to approval in the last 12 months.

Patients love foams and several new ones entered the market during the past year.

Azelaic acid (AzA) for treatment of mild to moderate rosacea

Reduction in inflammatory lesions with AzA foam.

Reduction in inflammatory lesions with AzA foam.
AF, azelaic acid foam; V, vehicle
Draelos ZD, et al. Cutis. 2015;96:54-61.

AzA is used for the management of rosacea and a new 15% foam formulation (Finacea®) has been shown to be safe and effective for papulopustular rosacea (PPR). This new formulation was shown to be significantly superior to vehicle for the co-primary efficacy end points of treatment success according to investigator global assessment (IGA) and the nominal change in inflammatory lesion count from baseline to the end of treatment in patients with PPR (Figure 1). This new AzA formulation is also well tolerated and provides another option for patients with PPR that will help dermatologists match needs and preferences of individual patients and skin types with appropriate delivery modalities.

Calcipotriene 0.0005% and betamethasone dipropionate 0.064% foam

Percentages of patients achieving PASI 75.

Percentages of patients achieving PASI 75.
Cal, calcipotriene 0.0005%; betamethasone dipropionate 0.064%
Leonardi C, et al. J Drugs Dermatol. 2015;14:1468-1477.

A new foam formulation of calcipotriene 0.0005% and betamethasone dipropionate 0.064% (Enstilar®) was approved by the U.S. Food and Drug Administration (FDA) for the topical treatment of plaque psoriasis in December of 2015. It provides plaque psoriasis patients a new treatment option in an “elegant” vehicle that provides rapid relief from symptoms of this disease. In the pivotal phase III trial for Enstilar, over half of patients treated with the new foam were clear or almost clear according to IGA by week 4 (Figure 2). In addition, >50% of patients achieved PASI 75 with Enstilar. This foam was more effective than the ointment fixed combination of calcipotriene and betamethasone dipropionate as well as the individual components used alone in an additional phase IIa study.

Econazole 1% foam for Tinea versicolor in patients with skin type VI

Tinea versicolor is a common superficial fungal infection of the stratum corneum caused by lipophilic yeast of the genus Malassezia. The fungus interferes with the normal pigmentation of the skin, resulting in small, discolored patches that may be lighter or darker in color than the surrounding skin. Econazole nitrate is a broad-spectrum topical antifungal with activity against a variety of dermatophytes and yeasts. A new topical dosage form, econazole nitrate topical foam has been developed for treatment of interdigital tinea pedis and tinea versicolor and it has been shown to be effective for both indications.

Maui Derm 2016 Highlights: Concerns for Using Biosimilars in Daily Practice

J. Wu, MD

Are we following “first, do no harm”? Dr. Wu explained that non-medical switching of patients from originator products is already happening and it is affecting patients. Results from patients followed in Europe have indicated that patients with forced non-medical switches to biosimilars have more hospitalizations and emergency department and physician visits than patients continued on the originator product.

Extensive post-approval pharmacovigilance is required for biosimilars since short-term trials and small patient samples may result in failure to detect rare, but clinically important, adverse events.

Some experts support the view that a biosimilar is just “another lot” of the originator product, but much remains to be learned before this can be stated with confidence.

Maui Derm 2016 Highlights: Pre-clinical Characterization of Biosimilars

A. Blauvelt, MD

Before you consider a potentially less-expensive option, you need to understand exactly what you’re getting. A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. The wiggle room in the definition of these agents is in terms such as “highly similar” and “clinically meaningful”. What do they actually mean?

The pathway to approval for a biosimilar is very different from that of the originator molecule. Biosimilar development is focused on preclinical evaluation while that for the originator is concentrated on clinical trials.

Biosimilars are reverse engineered from the originator amino acid sequence to derive the DNA sequence. Biosimilars are identical to the originator for amino acid sequence, but that is all. Glycosylation (addition of sugars), protein folding, and other characteristics may be different. Glycosylation is critical since it is a key determinant of protein function and immunogenicity. Is there a risk associated with this? Time will tell.

Manufacturers want the “fingerprint” of the biosimilar to be as close as possible to the originator agent, but there is no criterion for close the match must be. There is a significant “degree of residual uncertainty” about biosimilars. Higher uncertainty will lead to a requirement for more supporting clinical data.

Maui Derm 2016 Highlights: Pharmaceutical Counterfeits – Are They in Your Practice or in Patient Hands?

M. Gold, MD

Dr. Michael Gold explained the grim reality – There continues to be a huge global marketplace for fake toxins, fillers, and similar aesthetic products promising efficacy at cheap prices. Fraught with innumerable safety risks, and derived from uncontrolled and dubious production methods, many of these fake products contain toxic or at best utterly inert substances. These knockoffs can come in very realistic looking packages and are often “supported” by fake PI’s, websites, and seemingly legitimate journal references that turn out to be phony. The cheap products come from Eastern Europe and Asia. We should make sure our orders are direct from pharmaceutical companies and/or known, established and regulated distributors. Are we doing enough to educate patients and consumers who can easily find and buy these dangerous bogus products online?

New Toxins Coming
Ipsen, Galderma, and Alphaeon all have new neuromodulating toxins in later stages of development. While this provides more options with efficacy apparently similar to current modalities, it may create more confusion. We’ll stay tuned to monitor which is the best for our particular patient needs.

Filler Complications – Could You Cause Blindness?
The risk of blindness due to poorly placed injections has been well described and documented in literature. Consider carefully the underlying vasculature and anatomy (and the many variations and anomalies thereof) when using neuromodulators and fillers. Train staff to screen for and avoid causing an otherwise avoidable complication. Your practice should have protocols and supplies on hand to deal with complications expeditiously.

Maui Derm 2016 Highlights: Leaders in Industry

G. Martin, MD
P. Berns
T. Curran
J. Duffey

Pharma Industry Leaders Defend Against Biosimilars:

Industry leaders from AbbVie, Celgene and Anacor believe that they will able to defend current branded biologic products against biosimilars. AbbVie is expected to defend Humira against biosimilars in inflammatory diseases through 2022.

These industry leaders explained that cutting costs for branded drugs will not increase patient access. Drug price is not a primary determinant of access. Food for thought?

Prompt updating of guidelines to include important new therapies will aid negotiations with payers to improve patient access. Dermatologists are too slow in updating treatment guidelines. Can work on this via Maui Derm?

Manufacturers believe that appropriately delivered direct-to-consumer advertising provides useful and accurate information to patients and may even promote adherence to therapy.

Maui Derm 2016 Highlights: Psoriasis

B. Strober, MD, PhD
C. Leonardi, MD
J. Gelfand, MD
A. Blauvelt, MD
A. Kavanaugh, MD
L. Stein-Gold, MD

Newer Biologic Therapies Show Promise for Psoriasis Relief:

There has been increased focus on the IL-23/IL-17 in psoriasis and its treatment. IL-23 is upstream (targeted by tildrakizumab, guselkumab, and BI 655066), IL-17 is in the middle of the stream (targeted by ixekizumab and secukinumab), and the IL-17 receptor is downstream (targeted by brodalumab).

Efficacy of new targeted treatment options for psoriasis:

  • Gesulkumab has shown excellent efficacy with PASI 75 scores approaching 80%.
  • Tildrakizumab has demonstrated excellent efficacy in a phase II trial. PASI 75 scores in this study ranged from 75-80% for different tildrakizumab doses.
  • BI 655066 has demonstrated remarkable efficacy after a single treatment with 54% of patients achieving and sustaining PASI 100 for 9 months.
  • Secukinumab has demonstrated excellent efficacy (PASI 75 scores in >75% of patients) and a rapid onset of action (3 weeks for a mean reduction of in PASI scores).
  • Ixekizumab has also demonstrated very strong efficacy (>80% of patients achieving PASI 75) and has a very rapid onset of action. It is also numerically superior to adalimumab for the treatment of PsA.

The number needed to treat (NNT) is number of patients who need a specific treatment to gain one additional good outcome (e.g., achievement of PASI 75). The best NNT is 1, where every patient experiences a benefit with the treatment The NNT for achievement of patient achieving PASI 75 is about 1 for both secukinumab and ixekizumab. They are 1.7 and 1.4, respectively, for PASI 90; and 3.6 and 2.8 for achieving PASI 100. These values are far lower (better) than those for non-biologic synthetic agents or TNF inhibitors. These new therapies mean that clearance is an achievable goal for patients with psoriasis.

There are many well-established comorbidities of psoriasis, including cardiovascular and metabolic disease. There is also increased mortality in patients with psoriasis (a 5-year reduction in lifespan). Patients with psoriasis are 30 times more likely to have a cardiovascular event than to develop melanoma. Your patients with psoriasis should be carefully evaluated for these very common conditions

Emerging comorbidities of psoriasis include chronic obstructive pulmonary disease, asthma, and chronic kidney disease. It is important to understand the entire spectrum of disease in each of your patients with psoriasis and ask questions that can uncover depression that may result from this burden.

A key question is how to identify patients with psoriasis likely to develop psoriatic arthritis (PsA). A good question to ask patients with psoriasis is, “Do you have joint pain or other joint symptoms that you want to do something about?”

Tapering therapy is an attractive approach to patient management in patients with PsA and rheumatoid arthritis (RA), but there is some evidence that stopping medication and restarting after a flare may not regain the efficacy attained prior to the treatment holiday.

It is important to understand that patients’ and physicians’ evaluation of the impact of their disease are very different and patient reported outcomes (PROs) are very important for determining “how patients do”.

Variables that significantly affect patients’ response to disease include gender and the portion of the body surface affected by psoriasis. Women are more adversely affected by psoriasis than men and the head and face are the most important parts of the body for influencing the patients’ perception of their disease severity.

It is important to keep in mind features of therapy that can affect real-world patient adherence, Maintenance regimens that are less complicated enhance the potential for increased patient adherence and successful outcomes.

Maui Derm 2016 Highlights: Pediatric Dermatology

S. Fallon-Friedlander, MD
I. Frieden, MD
L. Eichenfield, MD
J. Treat, MD

Our faculty presented some fantastic insights into pediatric dermatology including:

Neonatal Herpes Simplex Virus – The Dark Side of the Force?

Neonatal herpes simplex virus (HSV) infection is rare occurring in 1/2000 – 1/5000 live births. HSV encephalitis and disseminated HSV are most concerning and difficult to detect clinically. Because of this, and the significant associated morbidity and mortality, we must have high index of suspicion these infections. HSV is the “Darth Vader” of pediatric dermatology. If there is any suspicion that a child is infected HSV, scrape, culture, and cover.

Eczema Coxsackium or Herpes Zoster?

Eczema “coxsackium” is a frequent reason for presentation of children in the dermatologist’s office. Be careful that it may mimic herpes zoster. Diagnosis may be made by polymerase chain-reaction (PCR) of blister fluid, or pharyngeal, or rectal swabs. Patients also have a high rate of onychomadesis (nail shedding).

Urticaria Multiforme (UM)

Patients with UM can be usually be effectively managed with antihistamines and do not require hospitalization or other therapy. UM occurs most often in infants and toddlers and it is characterized by annular urticarial and polycyclic morphology and a duration of individual lesions <24 hours. There are no mucosal blisters or erosions, but angioedema may be present.

Allergic Contact Derm. Is it Nickel?

Nickel is the most common cause of allergic contact dermatitis that we test for in our patients. Patients may be exposure to nickel via earrings, belts, snaps on pants, jewelry and even their laptop computers or iPads. Nickel reactions may also occur in patients with orthopedic devices. The American Academy of Dermatology (AAD) has noted that allergic contact dermatitis is on the rise and have emphasized that nickel should be avoided in the parts of piercings that are in contact with open skin. The rate of nickel release from a given alloy is the most important risk factor for nickel-associated allergic contact dermatitis.

The benefit of patch testing in patients undergoing arthroplasty is not clear. We are not sure what metals to test for or whether a positive patch test is a significant predictor of failure of the implanted device.

Atopic Derm. New Therapies, Communication Tips…And Peanuts?

We need to change our messaging to parents about treatment of their children with atopic dermatitis. Children need to be treated and many new therapies are becoming available. New agents are focused on blocking inflammation associated with activation of the TH2 pathway (e.g., interleukin [IL]-4, IL-5, and IL-13). It is now clear that atopic dermatitis is a disease of TH2-driven inflammation and impaired barrier function.

Peanuts? Recent studies suggest exposure of at-risk infants (positive for atopic dermatitis) to infants to peanuts decreases the probability of developing peanut allergy. These results may lead to a recommendation for peanut exposure to infants at elevated risk for development of this allergy.

Dupilumab, in particular, is viewed as a milestone in the treatment of atopic dermatitis, and it is being evaluated in children in studies being carried out in Europe. Other emerging therapies for pediatric atopic dermatitis include apremilast, crisaborole, OPA-15406 (phosphodiesterase type 4 inhibitor), dupilumab, and lebrikizumab.

Lesions and Port Wine Stains?

Some benign vascular lesions that will fade with time can look “scary” and should be managed conservatively. The International Society for the Study of Vascular Anomalies (ISSVA) classification will help you determine causes and even genetic mutations associated with uncommon/difficult-to-diagnose lesions.   http://www.issva.org/

The most important intervention of a child with Sturge-Weber syndrome is an ophthalmology examination. Recent data suggest that port wine stains without forehead involvement are not associated with glaucoma or evidence of central nervous system involvement. Early studies suggested that earlier laser treatment of port wine stains results in greater improvement, but more recent information has suggested that anesthesia in young children may result in impaired neural development. Results addressing this issue are conflicting, but there is still reason for concern.

Beware of “acquired” port wine stains. These are very rare and may actually be morphea.

Maui Derm 2016 Highlights: Dermoscopy Workshop

Ashfaq Marghoob, MD

A two-step dermoscopy algorithm can be employed for the assessment of skin lesions:

  • Step 1 is determination of whether a lesion is melanocytic or non-melanocytic and involves assessment of:
    • Network
    • Aggregated or peripheral rim of nodules
    • Streaks
    • Homogeneous blue pigment
    • Parallel pattern on volar skin
    • Pseudo-network system on the face
  • If the lesion has any of these features then, Step 2 is assessment with one of four algorithms:
    • Pattern analysis
    • The 7-point Checklist
    • The ABCD rule
    • The Menzies method
  • Diagnoses:
    • Nevus (reassure the patient)
    • Suspicious (biopsy, soft tissue myoepithelioma [STMM))
    • Melanoma (biopsy)
  • If the lesion is non-melanocytic, potential Step 2 diagnoses are:
    • Benign (dermatofibroma, seborrheic keratosis, clear cell acanthoma, hemangioma)
    • Malignant (basal cell carcinoma, squamous cell carcinoma)
    • If the lesion has no melanocytic or non-melanocytic features and no recognizable vascular pattern, reconsider melanoma:
    • Biopsy
    • Digital monitoring for STMM (but never for raised lesions)

Maui Derm 2016 Highlights: Pigmented Lesions

Hensin Tsao, MD, PhD
Ilona Frieden, MD
Ashfaq Marghoob, MD
Whitney High, MD, JD
Keith Flaherty MD

We should remember during examination and diagnosis that the number of nevi is a risk factor for melanoma. Especially when they vary in shape, size, and color. Literature supports the notion that the number of nevi (DN) can be (non-obligate) precursors to melanoma or (at least) that melanoma can arise in association with DN. However, 1-3% of new or changed lesions will be melanoma. Dermoscopy has provided a means for us to increase our sensitivity and specificity in the evaluation of new or changed lesions.

Spitz tumors:

These tumors are a particularly difficult issue for dermatologists and dermatologic pathologists. Spitz tumors may be classified as Spitz nevi (which are benign), spitzoid melanomas (which are malignant), and “atypical Spitz tumor” (a group of tumors whose biologic behavior cannot be accurately predicted on the basis of their histopathologic features).

At present there is no single marker or combination of markers that distinguishes an atypical Spitz tumor from spitzoid melanoma and diagnostic decisions must be made on the basis of assessments (e.g., comparative genomic hybridization, fluorescent in situ hybridization, and gene expression profiling) that are not definitive.

Immunotherapeutic agents for treatment of melanoma:

Yervoy (ipilimumab, targeted at cytotoxic T-lymphocyte-associated protein 4) and Opdivo (nivolumab, targeted at human cell surface receptor programmed death-1) have changed the landscape for treatment of melanoma. You might consider Opdivo as monotherapy should be the first choice for most patients and that addition of Yervoy should be reserved for later line switches or combination therapy due to its greater toxicity.

Long-term follow-up has indicated that Yervoy treatment results in long-term survival in about 20% of patients and it is yet to be determined whether other immune system-directed or other targeted therapies with superior short-term responses have such sustained efficacy.

Maui Derm 2016 Highlights: Cutaneous Oncology

George Martin, MD
Eggert Stockfleth, MD
Ted Rosen, MD
Brian Berman, MD, PhD

ALA PDT can be made “painless” by incubating ALA for 15 mins on the skin followed by 1-hour of blue light activation (BLU-U). AK clearance rates appear to be equivalent to conventional (but off-label) 1-hour ALA incubation PDT in a small scale split face study and clinical experience in over 120 patients.

AKs are a chronic disease. Consider a chemoprevention strategy that includes not only sunscreens, topical retinoids and Vitamin B3 (nicotinamide 500 bid) and the use of 3.75% imiquimod daily for 1 week, 2 weeks off then once weekly indefinitely. Immune stimulation over time limits AK recurrences during a pilot study.

Field therapy is an essential component of the treatment of patients with actinic keratoses (AKs), and the presence of these lesions is a biomarker for field cancerization (the combination of visible AKs and subclinical lesions).