New Drugs and Therapies for 2016: Medical Devices

Drs. Neal Bhatia and Ted Rosen

Part 8 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.

Controlling bleeding:   XSTAT 30 dressing

According to the United States Army Institute of Surgical Research, 30-40% of civilian deaths by traumatic injury are the result of hemorrhaging. Of those deaths, 33-56% occur before the patient reaches a hospital. In December, 2015, the FDA cleared the use of the XSTAT 30 wound dressing, an expandable, multi-sponge dressing used to control severe, life-threatening bleeding from wounds in areas that a tourniquet cannot be placed in battlefield and civilian trauma settings. This expands the device’s indication from use by the military only to use in adults and adolescents in the general population.  XSTAT 30 is cleared for use in patients at high risk for immediate, life-threatening, and severe hemorrhagic shock and non-compressible junctional wounds, when definitive care at an emergency care facility cannot be achieved within minutes.  The dressing can be used for up to four hours, which could allow time for the patient to receive surgical care.

Dignicap cooling cap.

Dignicap cooling cap.
Cigler T, et al. Clin Breast Cancer. 2015;15:332-334

Chemotherapy-induced alopecia:  Dignicap® Cooling Cap

The Dignitana DigniCap® Cooling System was approved by the FDA in December, 2015 and it is indicated to reduce the frequency and severity of alopecia during chemotherapy in breast cancer patients in which alopecia-inducing chemotherapeutic agents and doses are used. It is a computer-controlled system that circulates cooled liquid to a head-worn cooling cap during chemotherapy treatment. The cooling action is intended to constrict blood vessels in the scalp, which, in theory, reduces the amount of chemotherapy that reaches cells in the hair follicles. The cold also decreases the activity of the hair follicles, which slows cell division and makes them less affected by chemotherapy. The efficacy of this system was studied in 122 women with Stage I or II breast cancer who were undergoing chemotherapy regimens that have been associated with hair loss. The primary endpoint was a self-assessment of hair loss by the women using standardized photographs at one month after the last chemotherapy cycle. More than 66% of patients treated with the DigniCap reported losing less than half their hair. The most common side effects of the cooling system include cold-induced headaches and neck and shoulder discomfort, chills, and pain associated with wearing the cooling cap for an extended period of time.

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.

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.