FDA Grants AbbVie’s Upadacitinib Breakthrough Therapy Designation for AD
The FDA granted Breakthrough Therapy Designation for AbbVie’s investigational, once-daily oral JAK1-selective inhibitor upadacitinib (ABT-494) in adult patients with moderate to severe atopic dermatitis who are candidates for systemic therapy. This Breakthrough Therapy Designation is supported by positive Phase 2b results announced in September 2017. Upadacitinib is not approved by regulatory authorities and its safety and efficacy have not been established.
“Our history, scientific expertise and leadership in immunology drive our focus to develop new treatment approaches that address urgent and unmet needs,” said Michael Severino, MD, executive vice president, research and development and chief scientific officer, AbbVie. “Current treatment options for people living with atopic dermatitis are limited, and addressing these patient needs is important to us. We look forward to advancing upadacitinib into Phase 3 studies for atopic dermatitis soon.”
In the US, atopic dermatitis affects an estimated 28 million people of all ages, and can have a significant impact on the physical and psychosocial health of patients. AbbVie says it will present additional data from the Phase 2b trial at upcoming scientific congresses. Additional information on the clinical trials is available at clinicaltrials.gov.
Desmoplastic Melanoma May Be Highly Responsive to Anti-PD-1/PD-L1 Therapies
Patients with desmoplastic melanoma are more responsive to immune-activating anti-PD-1/PD-L1 therapies than previously assumed, Moffitt Cancer Center researchers report in Nature.
Pembrolizumab and nivolumab, which have been approved to treat melanoma, block the interaction between the proteins PD-1 and PD-L1. During cancer development, PD-1 and PD-L1 inhibit the immune system and allow tumor cells to escape detection and continue to grow. By blocking their interaction, immune-activating drugs restimulate the immune system to detect and destroy cancer cells.
Scientists previously believed that the tissue architecture of desmoplastic melanomas would reduce the ability of immune cells to infiltrate the tumor area and limit the effectiveness of immune-activating drugs. However, based on anecdotal reports of favorable responses, a group of researchers including Zeynep Eroglu, MD, Jane Messina, MD, and Dae Won Kim, MD, hypothesized that patients with desmoplastic melanoma may be more responsive to anti-PD-1/PD-L1 therapies than previously assumed, and explored this in the largest group of immunotherapy-treated desmoplastic melanoma patients studied to date.
They analyzed 60 patients with advanced/metastatic desmoplastic melanoma who were previously treated with a drug that targets either PD-1 or PD-L1. They discovered that 42 patients had a significant response to treatment. About half of these patients had a complete response in which their tumors entirely disappeared, and the remainder had a partial response, with significant reduction of their tumors. Seventy-four percent of patients were still alive more than two years after beginning treatment. This 70 percent response rate is one of the highest reported for anti-PD-1/PD-L1 therapies to date and is higher than response rates commonly observed in patients with other subtypes of melanoma (approximately 35-40 percent).
In a collaborative effort involving 10 US and international cancer centers, researchers confirmed that desmoplastic melanomas have high levels of DNA mutations, as they are highly associated with ultraviolet light DNA damage caused by sun exposure. NF-1 mutations were found as the most common driving genetic event. They also demonstrated that desmoplastic melanomas have the pre-existing immune cells and proteins necessary to mount an immune response against cancer cells. Desmoplastic melanomas also have high levels of immune cells called CD8 T cells that are critical for immune-activating drugs to be effective.
Cutera Introduces Juliet and Secret RF
Cutera has introduced two new devices to its laser and energy-based device offerings: Juliet and Secret RF. The North American launch of the Juliet laser represents Cutera’s first entry into the women’s health segment of the aesthetics market and offers patients a best-in-class alternative for improving sexual function and overall vaginal health. Secret RF is a fractional radiofrequency (RF) microneedling device that effectively remodels collagen, improves mild wrinkles, and diminishes scars.
Juliet is a minimally invasive, no-downtime treatment that utilizes Er:YAG laser technology to deliver two modes of energy to the vaginal area. The first mode stimulates the remodeling of collagen and the second mode stimulates the damaged tissue. Patients experience improved sexual function and an overall improvement in vaginal health.
Juliet treats burning, itching, dryness and painful intercourse in the vaginal wall typically associated with diminished estrogen production and post-partum changes. It is the ideal treatment option for women who have signs and symptoms associated with genitourinary syndrome of menopause. Additionally, women who have undergone breast cancer treatments or are interested in vaginal cosmetic improvements including tone and flexibility can benefit greatly from Juliet treatment.
The procedure takes approximately 10 minutes to treat internally and externally in a single session. Patients often feel and see improvement after the very first treatment, with optimal results seen after three treatments.
The Secret fractional RF microneedling device, delivers heat into the deeper layers of the skin where targeted energy revitalizes, rebuilds, and firms up tissue, effectively remodeling collagen, improving mild wrinkles, and diminishing scars while leaving the outer layer of skin intact.
Used on all skin types, the Secret RF technology has customizable microneedle tips and two specialized handpieces to treat both the face and body. The non-surgical, in-office treatment typically takes approximately 15 minutes to complete. Many patients see improvement after the first treatment, with optimal results seen after three treatments.
Retin-A Micro Gel Microsphere 0.06% Now Available
Retin-A Micro (tretinoin) gel microsphere 0.06% is now available commercially to healthcare professionals. The FDA approved Ortho Dermatologics’ Supplemental New Drug Application (sNDA) for Retin-A Micro gel microsphere 0.06% for topical application in the treatment of acne vulgaris last fall.
Clinical data showed 98.7 percent and 94 percent of patients found Retin-A Micro to be tolerable.
In the prior 0.04% study, no severe irritation was reported at week 2, the typical peak of irritation, and only 1.3 percent (3/255) of subjects discontinued due to irritation.
In the prior 0.1% study no more than three percent of subjects reported severe irritation and only six percent (14/224) discontinued as a result.
Retin-A Micro (tretinoin) gel microsphere 0.06% features a unique microsponge delivery system technology that helps to control the release of tretinoin and improves photostability, even when used in conjunction with benzoyl peroxide. A pump delivery system also allows for controlled dispensing and consistent dosing.
Hologoic’s Cynosure Division Introduces TempSure Envi
Hologic’s Cynosure division is launching TempSure Envi—an FDA-cleared advanced radio frequency device.
TempSure Envi heats the deep layers of skin to regenerate collagen and improve the appear-ance of cellulite and wrinkles associated with forehead lines, frown lines, crow’s feet, smile lines and wrinkles on the chin. Treatments are safe for all skin types and require no downtime, lasting between 30 and 60 minutes based on the area treated.
TempSure Envi comprises Therapeutic Logic Control (TLC)—a system that links treatment time with target temperature, allowing for consistent treatment temperatures and high patient comfort levels. In fact, 99 percent of patients who participated in a Cynosure in-house study reported a pain-free treatment experience.
Cochrane Review: Biologics Trump Other Systemics for Pso
Biologics appear to be the most effective systemic medicines for achieving a chronic plaque psoriasis score of PASI (Psoriasis Area and Severity Index) 90, according to a newly published Cochrane Review.
Researchers culled the literature to December 2016 for randomized controlled trials that compared the efficacy and safety of conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and to provide a ranking of these treatments according to their efficacy and safety.
In all, 109 studies were included in the review (39,882 randomized participants, 68 percent men, all recruited from a hospital). The overall average age was 44 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most studies were placebo controlled (67 percent), 23 percent were head-to-head studies, and 10 percent were multi-armed studies with both an active comparator and placebo.
All of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90, the analysis shows.
In terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and conventional systemic agents. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents.
There were no significant differences between all of the interventions and placebo regarding the risk of serious adverse effects. Major adverse cardiac events, serious infections, or malignancies were reported in both the placebo and intervention groups. Nevertheless, the SAEs analyses were based on a very low number of events with low to very low certainty for just over half of the treatment estimates in total, moderate for the others. Thus, the authors note that results have to be considered with caution.
Considering both efficacy and acceptability, highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability, the study findings suggest.
Maui Derm: New Data Validates First IGA Scale for EBS Clinical Trials
Data from an evaluation of a completed Phase 2 study of diacerein 1% ointment (CCP-020) for the treatment of epidermolysis bullosa simplex (EBS) validate the first disease-specific Investigator’s Global Assessment (IGA) scale, Castle Creek Pharmaceuticals (CCP) reported at the Maui Derm meeting last month.
CCP recently announced the development of a novel five-point IGA scale for overall clinical assessment that defines EBS-involved skin as Clear, Near Clear, Mild, Moderate, and Severe based on the presence or absence of blisters and factors including blister size, erosions, crusting and erythema. The previous Phase 2 study of CCP-020 used blister count reduction as the primary efficacy endpoint, due to the absence of an instrument for clinicians evaluating the effects of pharmacological interventions on overall disease severity for people living with EBS.
To validate the new scale, investigators reviewed blinded photographs of affected body locations obtained from patients at each visit during the Phase 2 study. The primary endpoint was the proportion of patients with moderate to severe lesions who achieved treatment success, defined as an IGA score of 0 or 1 on a 5-point scale at week 16 of treatment with at least a 2-point reduction in the IGA score compared to baseline. Additional clinical endpoints included the proportion of patients with a 2-point reduction from baseline to week 16 and mean decrease in IGA score.
There was a significantly higher proportion of moderate to severe treated lesions that reached Clear or Near Clear status and at least a 2-point reduction from baseline, the study showed. The proportion of lesions treated with CCP-020 with only a 2-point reduction in IGA score also trended higher compared to control lesions. A greater mean reduction in IGA score from baseline to week 16 was achieved for lesions treated with CCP-020 versus control.
CCP plans to include the IGA scale in the analysis of the overall disease severity in patients with moderate-to-severe EBS in the ongoing Phase 3 DELIVERS study evaluating the safety and efficacy of CCP-020.
Research Elucidates LIGHT’s Role in AD
LIGHT, a member of the tumor necrosis factor (TNF) super family, directly controls the hyperproliferation of keratinocytes as well as the expression of periostin, a protein that contributes to the clinical features of atopic dermatitis and other inflammatory skin diseases such as scleroderma, report researchers from La Jolla Institute in California.
“Periostin is being used in the clinic as a marker for allergic diseases such as asthma as well as atopic dermatitis,” explains senior author Michael Croft, PhD, professor and head in the Division of Immune Regulation, in a news release. “The fact that LIGHT acts upstream of periostin and is controlling its production really reinforces the idea that this is potentially a very good clinical target for treatment of atopic dermatitis and other inflammatory skin diseases.”
A therapeutic antibody that neutralizes the activity of LIGHT successfully suppressed disease symptoms after they first appeared, suggesting that therapies based on blocking LIGHT may add a valuable treatment option for patients with severe eczema.
LIGHT is a cytokine primarily produced by T cells and exerts its function through two receptors, HVEM and LTbR.
In an earlier study, Rana Herro, PhD, an instructor in the Croft lab and lead author on both studies, had shown that LIGHT plays a key role in skin inflammation in scleroderma. But whether LIGHT signaling is also involved in other types of skin inflammation was unknown.
To find out whether LIGHT contributes to skin inflammation in atopic dermatitis, Dr. Herro used an experimental murine model for atopic dermatitis that replicates the human disease. Her experiments revealed that LIGHT-deficient mice only displayed minimal clinical symptoms compared to normal control mice. The same was true for animals that only lacked the LIGHT-receptor HVEM in keratinocytes, the predominant cell type in the outermost layer of the skin. “This is the important part of the study,” says Dr. Herro. ”Specifically deleting the receptor in keratinocytes was enough to abrogate disease.”
A closer look revealed that LIGHT stimulates the proliferation of keratinoyctes and thus the structural remodeling of the skin. It also showed that LIGHT strongly induces the expression of periostin. This protein is highly expressed in the skin of patients with atopic dermatitis and scleroderma, and animal studies have found it is essential for skin inflammation, although exactly how it functions is still being debated.
The researchers then went back and used an existing therapeutic antibody to block the interaction of LIGHT with its receptor, HVEM, after disease had already manifested. The antibody treatment suppressed inflammation and strongly reduced epidermal thickening. “Our findings suggest that therapies that block LIGHT signaling might halt atopic dermatitis in humans and maybe even reverse disease symptoms,” Dr. Herro says.
New Research Explains Why Women Who Have Been Pregnant Have Better Melanoma Outcomes
For decades, research has associated female sex and a history of previous pregnancy with better outcomes after a melanoma diagnosis. Now, a research team from Perelman School of Medicine at the University of Pennsylvania may have determined the reason for the melanoma-protective effect.
It’s related to a cellular protein called the G protein-coupled estrogen receptor (GPER). When GPER was activated and combined with anti PD-1inhibitor drugs in mouse cancer models, the therapy dramatically extended survival in all animals and eliminated the tumor in 50 percent of the mice.
The findings appear in the journal eLife.
Researchers say the key is GPER, a receptor found on melanocytes, which are pigment-producing cells in the skin. The receptor is normally activated by estrogen, levels of which are higher in females, especially during pregnancy. Activation of GPER likely explains why many women notice that many areas of their skin get darker during pregnancy. Previous research from the Ridky lab has shown the effects of GPER activation are totally different than the effects of classical estrogen receptor signaling, which is important in breast cancer. The team discovered that melanocytes do not even express the classical estrogen receptor, and that all estrogen effects were the result of GPER.
In melanoma specifically, once GPER is activated, the cancer cell becomes more differentiated. This means it divides less frequently, makes more pigment, and becomes more visible and vulnerable to the natural immune system. This makes it harder for the cancer to become resistant to immunotherapies.
No drugs specifically target GPER, but researchers used a lab compound called G-1, originally developed by Eric Prossnitz, PhD, at the University of New Mexico Comprehensive Cancer Center, to stimulate GPER in mice, and then used anti-PD-1 inhibitors to treat the melanoma. The approach eliminated the tumors in half of all mice. The authors note that anti-PD-1 inhibitors, when used alone in mice with melanoma, extend survival modestly, but do not completely eliminate tumors, and no animals survive long-term.
Although researchers did not observe any toxicities from the compound in mice, though they say they plan further toxicity studies before hopefully moving on to human trials.
Adam Friedman, MD Awarded Innovations in Residency Training
The Journal of Drugs in Dermatology (JDD) awarded Adam Friedman, MD, FAAD with the Innovations in Residency Training Award at the recent Orlando Dermatology Aesthetic & Clinical Conference (ODAC) held in Miami. The award recognizes individuals who have fostered innovation and improvement in their residency programs, have increased emphasis on educational outcomes, and serve as exemplary role models for dermatology residents.
Dr. Friedman is the residency program director and director of translational research at the George Washington University School of Medicine. He is also deputy chair of the American Academy of Dermatology’s Poster Task Force, senior editor of the Dermatology In-Review online workshop and cram pack, and director of the Oakstone Institute Dermatology Board Review. Dr. Friedman is also a member of the Practical Dermatology® Editorial Board.
The award recognizes Dr. Friedman in particular for the educational program he developed at the GWU School of Medicine, Krazy Kodachromes, a three-hour, image-based review series attended live by dermatology residents in Washington, DC, and available on the JDD website: jddonline.com/krazy-kodachromes.
SkylineDx and Mayo Clinic to Collaborate on Development of Diagnostic Tests for Melanoma
SkylineDx and Mayo Clinic are working together to develop novel diagnostic tests to improve clinical decision making for melanoma patients.
SkylineDx will help Mayo Clinic to optimize and further develop an algorithm to identify risk factors associated with metastasis, originally discovered and developed by Mayo Clinic dermatologist Alexander Meves, MD, and his team.
The outcome of these molecular-based tests will help physicians target patients to appropriate treatment interventions. This meets the growing need for individual treatment and personalized medicine. Molecular testing can be performed on routinely collected biopsy tissue to determine the probability for metastatic spread with high accuracy.
The basis for this collaboration originated from the data and algorithm published in the peer-reviewed Journal of Clinical Oncology in 2015, in which Dr. Meves and his group worked to discover new molecular risk factors associated with sentinel lymph node (SLN) positivity in the primary melanoma.
Short Course Radiation Bests Longer Courses in Older Skin Cancer Patients
Shorter courses of radiation seem to be better than longer ones for older patients receiving treatment for basal and squamous cell skin cancers, a recent Penn State College of Medicine review suggests.
To reduce the risk of long-term damage, the standard approach to radiation therapy has been small, daily doses over the course of weeks. But this can be costly and inconvenient.
In a systematic review and meta-analysis, Nicholas G. Zaorsky, MD and colleagues looked at 21 international studies of radiation treatment for slow-growing skin cancers published between 1986 and 2016. The studies included almost 10,000 patients aged 62 to 84 years old who were followed up for anywhere from a year to more than six years post therapy.
Researchers found no difference in long-term cosmetic outcomes between shorter- and longer-course therapies. The most common types of long-term skin damage reported were discoloration and the appearance of spider veins. Skin cancer recurrence at the same site was rare among all the regimens, and there were no deaths related to treatments.
Based on this, the researchers recommend short courses of five, seven or 15 treatments— all adding up to around the same amount of total radiation exposure — for patients over 70 years old, especially if they have trouble traveling for treatments. Younger patients who are 60-70 years old can also consider these regimens, but they may live to see more skin damage from the treatments.
The meta-analysis has been published in Radiotherapy and Oncology.
FDA Approves Cosentyx Label Update to Include Scalp Psoriasis
The FDA has approved a label update for Novartis’ Cosentyx (secukinumab), the first interleukin-17A (IL-17A) antagonist approved to treat moderate to severe plaque psoriasis. The updated label includes Cosentyx data in moderate to severe scalp psoriasis—one of the difficult-to-treat forms of the disease. The label update, effective immediately, is based on the proven efficacy and consistent safety profile of Cosentyx from a dedicated Phase III scalp psoriasis trial.
The updated label addresses an important unmet need, according to the company. Scalp psoriasis can be challenging to treat with topical agents or phototherapy due to the presence of hair and other factors. Approximately half of all 125 million patients with psoriasis may suffer from scalp psoriasis. Read more about managing scalp psoriasis on p. 58.