JAKs of All Trades: What The Drug Class Means for Dermatology

With another year of the annual American Academy of Dermatology (AAD) meeting coming to a close, dermatologists from across the globe have had their fill of the most exciting cutting-edge research.

Late-breaking data, posters, and scientific sessions have highlighted the newest and promising therapeutics—some of which are on the cusp of breaking new ground. One of these therapies is the Janus Kinase (JAK) inhibitor class, which targets the JAK family of enzymes.

Interest in this drug class has long occupied research in the field—a reality that is reflected in the AAD VMX virtual offerings. Currently, the US Food and Drug Administrated (FDA) indications for JAK inhibitors have been limited to rheumatology and gastroenterology. But that may soon change in due time.

“It’s sort of mind-boggling how quickly this is moving forward,” Brett King, MD, PhD, of Yale School of Medicine, told HCPLive®. King led a virtual session at the conference titled JAK Inhibitors: The Next Frontier in Dermatology.

“Truly, these agents will change the landscape of treatment for these [dermatologic] diseases,” he continued.

And so, it can safely be said that JAK inhibitors will unlock new therapeutic pathways across the field. They may, in effect, change the tide for both diseases that already have FDA-approved treatment options (i.e., atopic dermatitis and psoriasis) and diseases that are yearning for a breakthrough (i.e., vitiligo and alopecia areata).

A Crash Course in JAKs

JAK inhibitors target the JAK-STAT pathway, a signal mediator for cytokines associated with psoriasis (IL-23), itch (IL-31), atopic dermatitis (IL-4, IL-13, 1L-31), alopecia areata (IFN-Y, IL-15), and vitiligo (IFN-Y, IL-15).

“What happens is binding of one of these cytokines to its unique receptor leads to dimerization of the receptor and activation of JAK enzymes in the intracellular space,” King explained in his presentation. Ultimately, this can lead to gene transcription and, therefore, disease manifestation.

“If we want to interrupt the activity of the pathogenic cytokines in order to make skin disease better,” King continued, “then we see with the JAKS an opportunity.”

As such, pathway activity can be inhibited through selective or widespread targeting of the JAK family: JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK 2). 

Peter Lio, MD, Clinical Assistant Professor of Dermatology & Pediatrics at Northwestern University Feinberg School of Medicine, spoke to HCPLive® on the potential behind this therapeutic mechanism.

“[JAKs] work incredibly quickly—on the order of hours to a few days—and they seem to have an effect that is clinically measurable” he said. “They seem to be among the most powerful treatments we’ve seen recently for some of these problems, where even refractory patients who failed other treatments seem to do well.”

Lio further compared the mechanisms of JAKs to biologics, noting the former’s ability to be administered as an oral or topical medication as opposed to an injectable.

The JAKs' Promise for Atopic Dermatitis

JAK inhibitors have seemingly made the most headway for atopic dermatitis, seeing abrocitinib, baricitinib, and upadacitinib on the docket for FDA approval. Over the past years, the FDA had approved and expanded indications for biologic dupilumab for patients down to the age of 6.

As King put it, these newer treatments—which come in either oral (abrocitinib, baricitinib, and upadaticinib) or topical (ruxolitinib) forms—can only “enrich” the dermatologist’s toolbox. 

After all, the plethora of data speaks for itself.

Pooled data presented at AAD VMX showed that investigative JAK 1/2 inhibitor ruxolitinib greatly improved metrics for skin clearance and patient-reported itch. At the same time, the findings showed an overall positive tolerability and safety profile.

An analysis of the phase 3 BREEZE-AD study, which compared baricitinib with placebo for atopic dermatitis, revealed rapid and significant improvements in disease presentation on the head and neck for patients with a baseline body surface involvement of 10-50%.

A late-breaking study indicated that induction with abrocitinib 200 mg as a monotherapy was highly efficacious. As such, >65% of patients achieved investigator global assessment (IGA) of 0 or 1 and at least 75% improvement in their disease presentation (EASI-75). 

Furthermore, the study also reported that most patients maintained response (whether on 200 mg or 100 mg) through week 40 of follow-up. Abrocitinib 200 mg in combination with a topical was also notably successful in recapturing response following a protocol-defined flare.

“To me, this is an important study for clinical practice because it allows for—if you will—dose flexibility,” noted presenter Andrew Blauvelt, MD, MBA, of Oregon Medical Research Center. “You now have data about dose flexibility for abrocitinib in your patients with moderate to severe atopic dermatitis.”

As time has shown, the evidence for use of JAK inhibitors for atopic dermatitis continues to mount, and, in time, will allow them to solidify their formal place as viable, effective, and flexible treatment options.

The Promise Extends Beyond

Some of the most fascinating and exciting pieces of research to come out of this year’s premier dermatology conference were twin studies showing ruxolitinib cream’s potential for vitiligo— a pigmentation disorder that, to this day, has seen no FDA approved treatments on the therapeutic docket.

One study demonstrated that the topical cream applied twice daily was linked to significant improvements in total repigmentation on the face and body; the other study offered evidence for maintenance following treatment discontinuation following 104 weeks. 

In fact, all 3 patients on the highest dose of the cream had no loss of repigmentation.

“What we’re seeing is that many of the patients are holding that response through 1-6 months of follow-up,” commented David Rosmarin, MD, vice chair of Research and Education in the Dermatology Department at Tufts Medical Center, to HCPLive®. “So, that makes me really optimistic.”

Seemal Desai, MD, Clinical Assistant Professor of Dermatology, University of Texas Southwestern Medical Center, expressed a similar hope that the barren landscape for vitiligo may soon be of the past. 

“JAK inhibitors really represent an exciting new step in the frontier of treating vitiligo and autoimmune diseases,” he said. He pointed to the work being done with ruxolitinib in addition to other JAKs, such as tofacitinib.

“There are studies now being done on developing new JAK inhibitors for vitiligo,” Desai noted.

And yet, the robust work into JAKs continues beyond vitiligo. Baricitinib for alopecia areata, another autoimmune disorder without any FDA-approved treatments, is yet another unclaimed frontier eyed by dermatology.

Data from the phase 3 BRAVE-AA2 and BRAVE-AA1 studies support the efficacy of the JAK1 and JAK2 inhibitor for the treatment of such patients suffering from sudden hair loss. At week 36, patients with severe alopecia areata who received 2 mg or 4 mg of baricitinib demonstrated significant improvements in scalp hair regrowth compared to those randomized to placebo.

It may go without saying, then, patients who have long lived without hope can now look to the future of their care with slivers of optimism. There may just lie an opportunity in JAK inhibitors to reverse disease course and improve one’s quality of life.

Patients of color, especially, who uniquely suffer from these conditions may soon be offered novel therapies that can address their pigmentary/autoimmune/aesthetic complications.

The Big Picture

JAK inhibitors are certainly not the panacea, especially for those conditions that have long been untreatable. However, they represent a turning point in dermatology where clinicians and patients alike may now cling to hope for a further enriched therapeutic toolbox.

And yet, the work continues.

As of April 2021, a single JAK inhibitor has yet to be FDA-approved for any dermatologic disease. Research is ongoing in atopic dermatitis, psoriasis, vitiligo, alopecia areata, pruritis, sarcoidosis, and in many more conditions. And so, the aforementioned studies are certainly by no means exhaustive.

However, one need only glimpse at the robust work being done into JAK inhibitors—thanks to platforms like AAD VMX—to understand what may be coming next down the therapeutic pipeline.

And safety should not be forgotten. While studies have supported its general safety and tolerability in patients, King noted that these medications carry a black-box warning for cancer, infections, and blood clots while other types of therapeutics do not.

“This black box warning is going to be front and center of our minds as we’re thinking about bringing these medicines to our patients,” King said.

Nonetheless, he believed someday they will be able to overcome their safety concerns, noting biologic adalimumab’s popularity despite its black box warning. He also pointed to the JAK’s long-standing history.

“These medicines have been around now for 9 years in rheumatology and for the treatment of inflammatory bowel disease,” he continued. “We now have the experience of other doctors with large groups of patients to begin to give context to their risk and benefit profile.”

And while risk, safety, and efficacy continue to be explored for the JAK inhibitors, dermatology will continue to evolve and look for new mechanisms to ensure the skin truly has a fighting chance.