New Indications, Mechanisms Drive Second-Line Treatments

Patients with moderate to severe atopic dermatitis (AD) have seen the pipeline continue to expand and that 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 outcomes in patients.

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

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

Patients looking for maintenance options may also soon have a new possibility. Another novel treatment for AD under investigation is an autologous “microbiota replacement therapy.” An association between Staphylococcus aureus (S. aureus) and AD has long been recognized, and patients with AD are deficient in coagulase-negative Staphylococcus that has the capacity to produce antimicrobial peptides.

“Therapeutic bacteria have been used for gastrointestinal conditions (i.e., probiotics) and topical microbiota therapy is beginning to show hints of success,” said Hensin Tsao, MD, PhD, professor of dermatology and director, 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 one recent study³, researchers studied the use of autologous bacteriotherapy to treat S. aureus in patients with atopic dermatitis. Data showed a significant reduction of S. aureus count on treated skin compared to vehicle, clinically seen in the improvements of atopic dermatitis symptoms.

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

Bacteriotherapy would not likely be used as first line treatment in patients who have severe AD or who need immediate relief, Tsao added, however, they could potentially be useful as an adjunctive treatment or for maintenance.

Still in its fledgling stages, metformin is a novel treatment approach for nonmelanoma skin cancers (NMSCs) 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, researchers found that the use of metformin was associated with a lower risk of developing BCC, even at low doses. The hope is that the potential chemoprotective properties of the drug could be of therapeutic benefit for those patients at high risk for BCC.

“Although the results are encouraging, I think large trials need to be performed before thinking about metformin for BCC. Surgery for most BCCs is generally pretty straightforward but there are toxicities. It is possible that as we figure the mechanism of action for metformin’s effects, we can take advantage of the biological pathway and develop a more effective topical approach. For right now, hedgehog inhibitors such as vismodegib (Erivedge; Genentech, Inc.) and sonidegib (Odomzo; Sun Pharma) still have a role especially in advanced BCCs and metastatic BCCs,” Tsao said.

Looking forward on the shifting landscape of dermatologic therapy, Tsao said that with the explosion of new treatments, more head-to-head trials are needed to better define our choices when it comes to efficacy, safety and cost. According to Tsao, this is already being seen in the competitive psoriasis biologics world.

“As we approach the end of the sequencing phase of the Human Genome Project, I’d like to see better diversity in our population-based analyses so we can get a better sense of the true impact of genetics on disease biology in all races and ethnicities. Until now, most of the large genome-wide association studies have been performed in European cohorts; but that is slowly being rectified with some prospective concerted efforts. I’d like to see the Human Genome ‘Promise’ fulfilled medically. We’ve learned an inordinate amount of information that now needs to be harvested for medical gain,” Tsao said.

Disclosures:

Tsao is a consultant for Epiphany Dermatology (also MAB. stockholder) and LazarusAI, on the editorial boards for the Journal of the American Academy of Dermatology, Journal of Infectious Diseases, and International Journal of Oncology, and receives research funding from the Melanoma Research Alliance, Dept of Defense, and MGH donors.

References

1. Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, et al. Efficacy and Safety of Upadacitinib vs 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 decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland. J Am Acad Dermatol.2021 Jul;85(1):56-61. doi: 10.1016/j.jaad.2021.02.042. Epub 2021 Feb 19.