New Drugs, New Devices

By Ted Rosen, MD

The year 2017 saw many new drugs and devices introduced that show considerable promise for dermatology patients. A fast round-up of what was approved in 2017 (including one December 2016 entry) appears in Table 1.

Table 1.

Drug Brand Approval Date Indication/Area What’s New
Crisaborole Eucrisa® 12/14/16 Atopic dermatitis Good safety data, no limit on therapy duration, safe for use on face and eyelids, etc.
Dupilumab Dupixent® 3/28/17 For moderate-to-severe atopic dermatitis, approved for adults only, minimal adverse events
Guselkumab Tremfya® 7/13/17 Psoriasis Superior to adalimumab for achieving PASI75, PASI90, and PASI100 (44% achieved PASI100 at 24 weeks)
Brodalumab Siliq® 2/15/17 Similar results as guselkumab
Blue Control Device

 

7/13/17 Wearable blue light for psoriasis
Delafoxaciin Baxdela® 6/19/17 Antibiotic Fluorinated quinolone, wide spectrum
Ozenoxacin Xepi® 12/14/17 Non-fluorinated quinolone, cream for impetigo
Oxymetazoline Rhofade® 1/19/17 For persistent facial erythema of rosacea
Benznidazole Not branded 8/29/17 Chagas disease Oral agent to treat tropical disease
Avelumab Bavencio® 3/23/17 Merkel cell carcinoma New treatment for aggressive neuroendocrine cancer
Pembrolizumab Keytruda® 3/14/17 Hodgkin lymphoma Expanded indication for adult and pediatric Hodgkin lymphoma
H202 40% Eskata® 12/17/17 Seborrheic keratosis Topical solution, 40% solution most effective, 41.3% of lesions clear or near-clear
HZ/su Vaccine Shingrix® 10/20/17 Shingles vaccine May be more effective than current vaccine
Dignicap Cooling Cap 7/3/2017 Chemotherapy-induced alopecia 70% of chemotherapy patients expected to lose all of their hair retained at least 50% of scalp hair
DermaPACE device 12/28/17 Diabetic ulcers 48% of patients had >90% healing at 20 weeks

Note that trademarks and registered trademarks are the property of their respective owners.

 

The “libraries” of therapeutic options for many conditions are being expanded, such as the treatments for atopic dermatitis, psoriasis, and cutaneous cancers. With the wealth of new options comes the need to learn how to best deploy these new drugs and devices for use in our patients. A few highlights follow.

Crisaborole

Atopic dermatitis can be a lifelong condition and one that distresses patients by its appearance as well as by itching. Crisaborole, a nonsteroidal phosphodiesterase-4 (PDE-4) inhibitor, is indicated for patients with atopic dermatitis of at least two years duration. There is no skin atrophy, so it may be safely used on the face, eyelids, skin folds, and external genital areas. It is to be used twice a day and there is no limit on how long therapy may persist.1 See Figure 1 for atopic dermatitis patients treated with crisaborole by the author.

Atopic Dermatitis Crisaborole

Figure 1. Monotherapeutic regimen with crisaborole in an adult woman with atopic dermatitis.

 

Dupilumab

Dupilumab is indicated for moderate to severe atopic dermatitis in adults; it is a monoclonal antibody that works against subunit 4Rα of the interleukin (IL)-4 and IL-13 receptors. It reduced pruritus markedly compared to placebo and the once-weekly and twice-weekly regimens provided about equal effectiveness.2

Avelumab

Avelumab is an anti-programmed cell death (PD)-ligand (L)1 immunotherapeutic agent that has been approved for use in pediatric (≥ 12 years) and adult patients with metastatic Merkel cell carcinoma, an aggressive neuroendocrine cancer with high morbidity and mortality rates. Complete response occurred in 10/88 patients in a phase II trial and 19/88 had partial responses with median overall survival rates of 12.9 months.3

Cemiplimab

This anti-PD-L1 monoclonal antibody is used to treat unresectable locally advanced or metastatic cutaneous squamous cell carcinoma. It is not yet approved but early results hold great promise as the objective response rate in phase I was 46.1%. A phase II pivotal study is currently enrolling. The most commonly reported side effects are fatigue, arthralgia, and nausea.4

Important Trends in 2017

  • The armamentarium of agents is building up, giving us more choices and likely improving treatment for patients
  • Many drugs are now being tested against active comparators—these head-to-head studies provide relevant and valuable clinical information (such as the study that showed guselkumab was superior to adalimumab in achieving PASI75, PASI90, and PASI100)
  • Indications may expand, for example, guselkumab is being investigated now for its potential utility in treating psoriatic arthritis

 

References

  1. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology. 2016;75(3):494-503.e494.
  2. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. The New England journal of medicine. 2014;371(2):130-139.
  3. Joseph J, Zobniw C, Davis J, Anderson J, Trinh VA. Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma. The Annals of pharmacotherapy. 2018:1060028018768809.
  4. Kaplon H, Reichert JM. Antibodies to watch in 2018. mAbs. 2018;10(2):183-203.

 

Oxymetazoline Hydrochloride 1% Cream for Rosacea

Oxymetazoline hydrochloride (HCl) cream, 1% (RHOFADE), an alpha-1A-adrenoceptor agonist and a partial agonist at the alpha-2 receptor, was approved in January of 2017 and is indicated for the treatment of persistent facial erythema associated with rosacea in adults. Nasal sprays containing a lower concentration of oxymetazoline HCl have been used off-label to treat rosacea for many years, and oxymetazoline hydrochloride (HCl) cream, 1% is the first approved treatment using this compound (Smith, 2017).

In two clinical trials, once-daily application of oxymetazoline hydrochloride (HCl) cream, 1% reduced persistent facial erythema associated with rosacea through 12 hours.  After 29 days of treatment, patients achieving clinical success at 12 hours were 15% vs 6% for placebo in one study and 12% vs 6% in the second trial (RHOFADE PI, 2017).

Oxymetazoline HCl cream, 1% is not the first adrenergic agent approved for the treatment of rosacea. Brimonidine topical gel, 0.33% (MIRVASO) is an alpha-adrenergic agonist indicated for the topical treatment of persistent facial erythema of rosacea in adults that has been available since 2013 (MIRVASO PI, 2016).

Which of these two preparations is a better choice for your patient?  There is no head-to-head comparison of these treatments, so it is hard to know. Combined assessment of results from different studies (for example, with network meta-analyses) has now become a fairly common approach for comparing treatments that have never been tested vs each other, but that has not been accomplished for these drugs.  A look at the labels for the two agents suggests that effect sizes for oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% are very similar, but that application site erythema may occur more often with bromocriptine gel, 0.33% than with oxymetazoline HCl cream, 1% (RHOFADE PI, 2017; MIRVASO PI, 2016).


References

MIRVASO (brimonidine) topical gel. 2016. Available at: http://www.galdermausa.com/PI/MirvasoPI.pdf

RHOFADE (oxymetazoline hydrochloride) cream, for topical use. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208552s000lbl.pdf

Obiltoxaximab: A Monoclonal Antibody for Cutaneous Anthrax

You should certainly hope that you will never have to use it, but it is still important to know about obiltoxaximab (Anthim), a monoclonal antibody administered by injection, that has been approved for treating inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs in adult and pediatric patients.

It is also approved for prophylaxis of inhalational anthrax when alternatives are not available or appropriate (Kaufman, 2016).

Why should dermatologists care? Because the most common type of human anthrax is the cutaneous form. Other forms of human anthrax (gastrointestinal, inhalational, or injectional) are rare (Kajfasz, 2014).

It is expected that the main use of obiltoxaximab is likely to be in the setting of bioterrorism, but it might also be effective for the rare patient in your practice with cutaneous anthrax.


References

Kaufman MB. Pharmaceutical Approval Update. P T. 2016;41:355-6.

Kajfasz P, Bartoszcze M, Borkowski PK, Basiak W. Retrospective review of the case of cutaneous anthrax-malignant pustule from 1995 in 15-year old girl. Przegl Epidemiol. 2014;68:657-9.

New Drugs and Therapies for 2016: Cosmetics

Drs. Neal Bhatia and Ted Rosen

Part 7 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.

Injectable Deoxycholic Acid

In April, 2015 the FDA approved deoxycholic acid (Kybella®), a treatment for adults with moderate-to-severe fat below the chin, known as submental fat. Kybella, a cytolytic drug, is identical to the deoxycholic acid that is produced in the body and which helps absorb fats. When properly injected into submental fat, the drug destroys fat cells. It is the only approved for the treatment of fat occurring below the chin (Figure 4). The safety and effectiveness of Kybella for treatment of submental fat were established in two clinical trials that enrolled 1,022 adult patients with moderate or severe submental fat. Results showed that reductions in submental fat were observed more frequently in participants who received deoxycholic acid vs placebo.

It is important to note that Kybella can cause serious side effects, including nerve injury in the jaw that can cause an uneven smile or facial muscle weakness, and trouble swallowing. The most common side effects seen with this new treatment are swelling, bruising, pain, numbness, redness and areas of hardness in the treatment area.

New Drugs and Therapies for 2016: Seborrheic Keratosis

Drs. Neal Bhatia and Ted Rosen

Part 6 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.

A-101

Seborrheic keratosis (SK) lesions are one of the most common skin tumors, affecting over 83 million people in the United States. While benign, these lesions are often cosmetically disturbing, may become symptomatic (irritated, pruritic, painful) or may be confused with more serious skin lesions. At presently, SK lesions are treated by cryotherapy, electrosurgery, curettage, or surgical removal. Each of these methods may be painful or can result in pigmentary changes or scarring at the treatment site.

A-101 is a topical solution of hydrogen peroxide and results from a phase II study that compared two concentrations of A-101 and placebo in 172 subjects with SK lesions indicated that it had significant efficacy in removing SKs and was well tolerated. Two phase III clinical trials will evaluate the safety and efficacy of A-101 in approximately 800 patients.

New Drugs and Therapies for 2016: Rosacea

Drs. Neal Bhatia and Ted Rosen

Part 5 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.

Brimonidine 3.3% gel

Rosacea is a chronic relapsing disease of the facial skin, characterized by recurrent episodes of facial flushing, persistent erythema, telangiectasia, papules, and pustules. At present, there is no effective treatment in primary care for the symptoms of flushing and erythema, and management generally consists of lifestyle advice and off-label use of drugs, such as propranolol or clonidine, which may cause significant side effects.

Brimonidine tartrate is a highly selective a2 adrenergic receptor agonist, with potent vasoconstrictive and vasostabilizing activity. Facial application of brimonidine tartrate reduces erythema through direct cutaneous vasoconstriction. Brimonidine tartrate gel (Mirvaso®) was recently approved for the symptomatic treatment of facial erythema of rosacea in adults. It is an aqueous gel that is applied to the face once every 24 hours, at any time that is suitable for the patient, for as long as facial erythema is present. Approval of Mirvaso was based on results from two randomized, vehicle-controlled phase III trials that included 553 patients. The primary efficacy end point was the ‘success rate’, defined as a 2-grade improvement on both the Clinician’s Erythema Assessment (CEA) and Patient’s Self‑Assessment (PSA) over 12 hours on days 1, 15 and 29. Results from these studies indicated that once-daily brimonidine 3.3% gel had a good safety profile and provides significantly greater efficacy vs vehicle gel for the treatment of moderate to severe erythema of rosacea.

New Drugs and Therapies for 2016: Hyperhydrosis

Drs. Neal Bhatia and Ted Rosen

Part 4 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.

BBI-4000

BBI-4000 (sofpironium bromide) is a new molecule that has been developed for the treatment of primary axillary hyperhidrosis (excessive underarm sweating). It is a “soft anticholinergic” that exerts it topical action and is rapidly metabolized into a considerably less active metabolite that reduces systemic side effects. Results from a phase IIb study of BBI-4000 were presented at the 2016 American Academy of Dermatology Annual Meeting. This 28-day trial evaluated the safety, tolerability and efficacy of three concentrations of BBI-4000 (5, 10, and 15%) versus placebo gel in 189 people with primary axillary hyperhidrosis. Study results indicated that BBI-4000 met its primary endpoint by successfully achieving a 2-grade improvement in the Hyperhidrosis Disease Severity Score (HDSS), in a dose-related fashion. At the maximum dose (15%), 38.3% of participants improved more than 2 points on HDSS at Day 29 vs 12.2% with vehicle. BBI-4000 also achieved a significant 1- and 2-grade improvement in a newly developed patient-reported outcome measure, the Hyperhidrosis Disease Severity Measure Axillary (HDSM-Ax).

Using this measure, 44.7% achieved a >2-point improvement at Day 29 in the 15% treatment group vs 19.5% for vehicle. Application site reactions were uncommon, were predominantly mild-to-moderate in severity, and resolved spontaneously. Treatment-related anticholinergic side effects were predominantly mild and transient and occurred in 11.2% of subjects randomized to BBI-4000.

New Drugs and Therapies for 2016: Atopic Dermatitis

Drs. Neal Bhatia and Ted Rosen

Part 3 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.

Approximately 18-25 million people in the United States suffer from atopic dermatitis, and 80-90% have mild or moderate disease. Patients suffering with the condition often try multiple treatments to treat their atopic dermatitis, yet many are not satisfied with the effectiveness of their medications.

Crisaborole 2% ointment

Proportion of patients achieving success in IGSA (clear or almost clear).

Proportion of patients achieving success in IGSA (clear or almost clear).

Crisaborole topical ointment, 2% is a novel, boron-based small-molecule phosphodiesterase (PDE) 4 inhibitor with anti-inflammatory properties. It has been evaluated in two phase III studies that involved more than 750 patients each. In these studies, patients were randomized to crisaborole or vehicle twice daily for a total of 28 days. Treatment was considered successful if on the 29th day a patient is gauged with an Investigator Global Severity Assessment (ISGA) score of 0 (clear) or 1 (almost clear), with a minimum improvement of two points from baseline. This outcome was achieved for about 33% of patients who received crisaborole and 17% of those treated with placebo (Figure 3). The most common side effects were pain at the application site and upper respiratory tract infections. A long-term study is being conducted to further evaluate safety with intermittent use of the medication for up to a year. If approved, crisaborole has the potential to offer physicians and patients a new, important therapeutic choice for treating mild-to-moderate atopic dermatitis.


 

Dupilumab

Dupilumab is a monoclonal antibody that blocks the actions of interleukin (IL) – 4 and IL-13. It is being developed by Regeneron and Sanofi for the treatment of atopic dermatitis and asthma. It has been evaluated in a 12-week phase IIa study and a 16-week phase IIb dose-ranging trial. Results from the 12-week study indicated that 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a ³50% reduction in the Eczema Area and Severity Index (EASI) score (EASI-50); and 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the IGA. Pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group vs 15.1% in the placebo group. Results from the dose-ranging study indicated that dupilumab 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, and 100 mg every 4 weeks were all significantly superior to placebo for decreasing EASI scores. The most frequent adverse event for dupilumab was nasopharyngitis.

New Drugs and Therapies for 2016: Oncology

Drs. Neal Bhatia and Ted Rosen

Part 2 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.

You may never prescribe these products, but you should still know about them.

Sonidegib

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation this pathway has been shown in a variety of human cancers, including, basal cell carcinoma (BCC). Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and other transcription factors. Sonidegib (Odomzo®) is an oral, selective SMO inhibitor approved by the FDA in July of 2015 for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who are not candidates for surgery or radiation therapy, or adults with recurrent laBCC following surgery or radiation therapy. Approval of Odomzo was based on results from the BOLT trial which indicated an objective response rate of 58% for patients treated with 200 mg Odomzo. The most serious risks with Odomzo are embryo-fetal toxicity and musculoskeletal adverse reactions including rhabdomyolysis.


Trabectedin

Soft tissue sarcomas (STSs) are a group of rare tumors that are often diagnosed after after metastases have developed. Doxorubicin either alone or in combination with ifosfamide has been used as first-line chemotherapy for advanced disease and high-dose ifosfamide, gemcitabine plus docetaxel, and dacarbazine have been employed for second-line treatment, albeit with little supporting evidence. Trabectedin (Yondelis®) is a synthetic, marine-derived alkylating agent derived from the Caribbean tunicate, Ecteinascidia turbinate and it was approved by the FDA for treatment of unresectable or metastatic liposarcoma and leiomyosarcoma in October of 2015. The efficacy of Yondelis for STSs was demonstrated by results from the TRUSTS trial and the most frequently reported grade 3/4 adverse events in this study were neutropenia and elevated hepatic transferases. Steroid pretreatment is effective for reducing hepatotoxicity with Yondelis, and steroids are now given routinely before administration of the drug. Further studies are ongoing to evaluate the efficacy and safety of combination therapy of Yondelis with other agents.


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.