New indications and new mechanisms guide second-line treatments

Patients with moderate to severe atopic dermatitis have seen the pipeline continue to grow and this trend remains strong. Continued research has led to the development of new treatment options for patients with the skin disease, such as the monoclonal antibody dupilumab (Dupixent, Sanofi/Regeneron Pharmaceuticals, Inc), which has been shown to have significantly improved in patients.

The dawn of new JAK inhibitors such as upadacitinib (Rinvoq; Abbvie) for severe AD may be even more effective than dupilumab, providing this patient population with another safe and effective treatment option to help them eliminate their moderate to severe disease.

In a recent study1, researchers evaluated the efficacy and safety of upadacitinib compared to dupilumab in a large cohort of adult patients with moderate to severe AD and found that the oral JAK 1 inhibitor was more effective than dupilumab . Data showed that upadacitinib worked faster at baseline, but both agents converged to approximately 60-70% of EASI 75 (Eczema Area and Severity Index) at the end of the study at week 16 However, upadacitinib showed higher EASI 90 and EASI 100 with greater reduction in pruritus. The data showed only minor differences in the safety profile regarding serious adverse events, but larger studies are needed to confirm these findings.

Patients looking for maintenance options may also soon have a new option. Another new treatment for AD being investigated is an autologous “microbiota replacement therapy”. An association between Staphylococcus aureus (S. aureus) and Alzheimer’s disease has long been recognized, and patients with Alzheimer’s disease are coagulase-negative Staphylococcus which has the ability to produce antimicrobial peptides.

“Therapeutic bacteria have been used for gastrointestinal conditions (i.e. probiotics) and topical microbiota therapy is beginning to show signs of success,” said Hensin Tsao, MD, PhD, Professor of dermatology and director of the MGH Melanoma and Pigmented Lesion Center at Massachusetts General Hospital and professor of dermatology at Harvard Medical School, both in Boston, who recently spoke at the Maui Derm for Dermatologists 2022 meeting.2

In a recent study3researchers investigated the use of autologous bacteriotherapy to treat S. aureus in patients with atopic dermatitis. The data showed a significant reduction in S. aureus rely on treated skin versus vehicle, clinically observed in improvement of symptoms of atopic dermatitis.

“I think the viability of this approach will depend on several developments, including the efficiency and cost by which autologous bacteriotherapy can be generated. ‘Personalised’ therapies already exist in cancer vaccines, so I can imagine a day when “microbiome” therapies could be based on the genetic analysis of bacterial flora. It is also possible that they find a “universal” commensal organism that can be formulated rather than a personalized organism, which would make the more easily accessible approach,” Tsao said.

Bacteriotherapy would probably not be used as a first-line treatment in patients with severe AD or who need immediate relief, Tsao added, however, it could potentially be useful as an adjunctive therapy or for maintenance. .

Still in its infancy, metformin is a new therapeutic approach for non-melanoma skin cancers (NMSC) such as basal cell carcinoma (BCC). The oral antidiabetic drug is believed to have anticarcinogenic properties and is also known to inhibit the Sonic Hedgehog pathway. In a recent large population-based study3, the researchers found that metformin use was associated with a lower risk of developing BCC, even at low doses. The hope is that the drug’s potential chemoprotective properties could benefit patients at high risk for BCC.

“While the results are encouraging, I think large trials need to be done before considering metformin for BCC. Surgery for most BCCs is usually quite simple, but there are toxicities. It is possible that by understanding the mechanism of action of metformin’s effects, we can take advantage of the biological pathway and develop a more effective topical approach.At the moment, hedgehog inhibitors such as vismodegib (Erivedge; Genentech, Inc.) and sonidegib (Odomzo; Sun Pharma) still have a role, especially in advanced BCC and metastatic BCC,” Tsao said.

Looking forward to the changing landscape of dermatological therapy, Tsao said that with the explosion of new treatments, more head-to-head trials are needed to better define our choices for efficacy, safety and cost. According to Tsao, this can already be seen in the competitive world of psoriasis biologics.

“As we approach the end of the sequencing phase of the Human Genome Project, I would like to see better diversity in our population-based analyzes so that we can get a better idea of ​​the real impact of genetics on disease biology in all races and ethnicities Until now, most large genome-wide association studies have been performed in European cohorts, but this is slowly being rectified through “concerted prospective efforts. I would like to see the ‘promise’ of the human genome fulfilled medically. We have learned an inordinate amount of information that now needs to be harvested for medical purposes,” Tsao said.

Disclosures:

Tsao is a consultant for Epiphany Dermatology (also a shareholder of MAB) and LazarusAI, a member of the editorial boards of Journal of the American Academy of Dermatology, Journal of Infectious Diseasesand International Journal of Oncologyand receives research funding from the Melanoma Research Alliance, the Department of Defense, and MGH donors.

The references

  1. Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, et al. Efficacy and safety of upadacitinib compared with dupilumab in adults with moderate to severe atopic dermatitis: a randomized clinical trial. AMA Dermatol.2021 Sep 1;157(9):1047-1055. doi: 10.1001/jamadermatol.2021.3023.
  2. Fallon-Friedlander S and Tsao H. Dermatology in Review. Presented at: 2022 Maui Derm for Dermatologists; January 24 to 28, 2022; Maui, Hawaii.
  3. Nakatsuji T, Gallo RL, Shafiq F, Tong Y, Chun K, et al. Use of autologous bacteriotherapy to treat Staphylococcus aureus in patients with atopic dermatitis: a randomized, double-blind clinical trial. JAMA Dermatol.2021 Jun 16;157(8):978-982. doi: 10.1001/jamadermatol.2021.1311. Online ahead of print.
  4. Adalsteinsson JA, Muzumdar S, Waldman R, et al. Metformin is associated with a reduced risk of basal cell carcinoma: a population-based case-control study in Iceland. J Am Acad Dermatol.2021 Jul;85(1):56-61. doi: 10.1016/j.jaad.2021.02.042. Published online February 19, 2021.

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