PracticalDermatology

Christopher Bunick, MD, PhD, is on the frontlines of the drug development boom in dermatology. Dr. Bunick, an associate professor of dermatology at Yale University in New Haven, CT, is uniquely suited for this position as he also holds a PhD in structural biology and biochemistry.

“I really enjoy applying molecular-level insights to the field and asking questions about whether dermatology medicines really work; and if they do work, I dig deeper to see how they differ mechanistically from others in the same or different classes,” he tells Practical Dermatology. “I aspire to bring valuable mechanistic insight to the drug discovery process and connect that with how a drug works in terms of clinical efficacy and side effects.”

Dr. Bunick chatted with us about what’s new and exciting in the pipeline for a host of skin diseases.

What’s new in atopic dermatitis (AD) treatment?

Christopher Bunick, MD: In AD, the two big camps are biologics and JAK inhibitors. I think the use of traditional immunosuppressants is almost gone or extinct. The FDA has approved dupilumab (Dupixent) and tralokinumab (Adbry) for AD, and lebrikizumab is really close to market and has its own unique features. These biologics each have different mechanisms of action even though they work on highly related cytokine pathways to a degree. Patients who don’t respond to one may in fact respond well to another. Three JAK inhibitors are approved in AD: oral upadacitinib (Rinvoq), topical ruxolitinib (Opzelura), and oral abrocitinib (Cibinqo).

Are dermatologists using these medications?

Dr. Bunick: Five to 10 years ago, if you used methotrexate or cyclosporine to treat AD patients, you were taking great care of your patients. Now, we have JAK inhibitors approved in AD, but many dermatologists are scared to use them because of the imposed FDA boxed warnings. JAK inhibitors appear much safer than the traditional immunotherapies that we used to use, and that is really eye opening. This message needs to get out to help dermatologists feel comfortable using JAK inhibitors.

Are JAK inhibitors safe?

Dr. Bunick: Four-year safety data on upadacitinib was presented at the recent Revolutionizing Atopic Dermatitis (RAD) Conference. JAK inhibitors are proving to be very efficacious as well as safe in AD. There were no new safety signals after 4 years, and all the adverse event rates were low and didn’t increase from year 2 to year 3 to year 4. This is a game changer. They are not only safer than we thought but they are actually changing what we consider standard of care.

How so?

Dr. Bunick: In psoriasis, it’s no longer about achieving Psoriasis Area and Severity Index (PASI) 75. The standard of care is now PASI 90 and PASI 100 thanks to effective new treatments. JAK inhibitors and biologics are pushing the boundary of the Eczema Area and Severity Index (EASI). EASI 90 and EASI 100 should be the new standards of care in treatment and clinical trials.

What’s coming down the AD pipeline?

Dr. Bunick: Connect Biopharma is developing CBP-201, a human monoclonal antibody targeting IL-4Rα, for treatment of AD and asthma. Here, we have a molecularly refined receptor blocker with a unique biochemical mechanism of action that may have a higher efficacy threshold than cytokine blockers. The same can be said for Aslan Pharmaceutical’s eblasakimab targeting IL13Rα1. Companies in general are interested in a “Skyrizi-type” molecule for AD that achieves high efficacy with every 3-month dosing, which is less inconvenient and provides a longer duration of therapy for the patient.”

What about topicals in AD?

Dr. Bunick: I am really excited about a couple of topicals looming in AD. We have tapinarof cream, 1% (Vtama) and roflumilast cream 0.3% (Zoryve) already approved in psoriasis, but they are both likely to be approved for AD and seborrheic dermatitis in the near future. There are unique mechanisms of action for these drugs-tapinarof is an agonist of the aryl hydrocarbon receptor and roflumilast is a highly potent phosphodiesterase-4 (PDE4) inhibitor. Not all PDE4 inhibitors are the same. You can’t just say “I tried crisaborole (Eucrisa), and it didn’t work, therefore I won’t use another PDE4 inhibitor.” Roflumilast’s molecular design and inhibitory properties are distinct and make it highly effective, which I am presenting data on at the 2023 International Society for Investigative Dermatology (Tokyo) and World Congress (Singapore) meetings.

Is that true in other classes, too?

Dr. Bunick: Yes. The thing about a drug class, whether interleukin (IL)-17 or IL-23 or TNF inhibitors, for example, is that the unique molecular properties of each drug truly drive therapeutic differences. I enjoy uncovering these molecular properties that drive distinction within a class of drugs, whether unique epitopes, paratopes, binding sites, or bonding patterns. Linking these biochemical properties to drug efficacy or safety is important to providers and patients. It’s necessary to dig deeper within and between classes to find out what drives molecular differentiation. For example, it is not true to say you failed on one TNF inhibitor therefore you should not try another. We can see real and significant responses among different drugs even in the same class.

What’s going on in the rare skin disease space?

Dr. Bunick: Timber Pharmaceuticals is developing TMB-001, a topical isotretinoin that has been formulated using Timber’s patented IPEG delivery system for the treatment of congenital ichthyosis subtypes including X-linked or lamellar congenital ichthyosis.

It’s in phase 3 trials. It is a real miracle watching this medication work in patients. Getting this medication into the clinic will undoubtedly be a game changer for congenital ichthyosis patients. Palvella is developing a novel formulation of rapamycin for the treatment of pachyonychia congenita called PTX-022. Studies show it can reduce pain and help patients walk better. In 12 to 18 months, we will likely have two first-in-disease FDA-approved drugs for these rare skin diseases. Here, we have two established molecules with new cutting-edge vehicles. Hidradenitis suppurativa (HS) is incredibly inflammatory and multifactorial. It responds to some psoriasis medications, but most patients aren’t achieving the 90% response threshold with these medications. There is a real onus on industry and academia to find a therapy that gets HS patients to the 90% to 100% therapeutic thresholds.

Disclosure: Dr. Bunick has served as an investigator for Almirall, Timber, and Palvella; and a consultant for AbbVie, Almirall, Apogee, Arcutis, Eli Lilly, EPI Health/Novan, LEO Pharma, Novartis, Ortho Dermatologic, Pfizer, Sanofi-Regeneron, and UCB.