JAK inhibitors look to overcome black box warnings in atopic dermatitis
Join Our Newsletter - Get important industry news and analysis sent to your inbox – sign up to our e-Newsletter here
X

Oral JAK inhibitors unlikely to be totally shut out in eczema by black box warning

By Reynald Castaneda 28 Sep 2021 (Last Updated September 28th, 2021 15:47)

Dermatologists point to several uptake openings for JAK inhibitors in moderate-to-severe eczema despite highly publicized side effect concerns.

Oral JAK inhibitors unlikely to be totally shut out in eczema by black box warning
The FDA has concluded that JAK inhibitors lead to an increased risk of serious heart-related events, enlarging these inhibitors’ pre-existing black box warnings. Credit: JHVEPhoto / Shutterstock.com

Need to know:

  • JAK inhibitors were expected to enter the moderate-to-severe atopic dermatitis (eczema) market earlier this year, but instead the class encountered multiple FDA regulatory delays. New FDA analysis show these inhibitors may lead to increased risk of heart-related events.
  • But dermatologists still see a window for JAK inhibitors to succeed in patients with moderate-to-severe eczema, owing to concerning safety issues mainly hinging on rheumatoid arthritis data.
  • Treatment breaks and close monitoring of patients is a way to reduce side-effect risk. Half of all moderate-to-severe patients will at least consider switching to new treatment options like JAK inhibitors in a bid to secure better symptom relief.

Black box warnings are likely to cloud JAK inhibitors’ uptake potential in moderate-to-severe atopic dermatitis (AD). Yet dermatologists noted this is unlikely to completely discourage colleagues and patients from at least considering this new weapon in the AD treatment arsenal.

This year was highly anticipated as it was expected to mark JAK inhibitors’ entry into the moderate-to-severe AD market. The frontrunner oral JAK inhibitors are AbbVie’s Rinvoq (upadacitinib), Eli Lilly/Incyte’s Olumiant (baricitinib), and Pfizer’s abrocitinib. The current reigning standard of care is Regeneron Pharmaceuticals/Sanofi’s biologic injection Dupixent (dupilumab).

Yet JAK inhibitors faced major US regulatory snags. These inhibitors had their PDUFA dates in AD delayed with revised timelines yet to be announced. Also, based on the FDA’s review of the class’s safety profile in rheumatoid arthritis (RA) and ulcerative colitis, for which they are already approved, the agency concluded JAK inhibitors lead to an increased risk of serious heart-related events, enlarging these inhibitors’ pre-existing black box warnings. “There is no question there will be a black box on all oral JAKs in AD,” Northwestern University Department of Dermatology chair Dr Amy Paller said.

“There is no question there will be a black box on all oral JAKs in AD.”

While a black box warning is expected in moderate-to-severe AD, dermatologists noted this does not mean JAK inhibitors would be completely shut out from the market. AD can be a debilitating disease and, in patients who need further relief not offered by Dupixent, they would be enticed to consider JAK inhibitors. In fact, cardiovascular disease (CVD) specific concerns in RA may not necessarily transpire in AD due to both diseases having completely different patient profiles, and safety concerns highly hinging on RA data.

With time, dermatologists will find ways to ease into prescribing JAK inhibitors in patients who need improvement from Dupixent. JAK inhibitor patients’ safety and efficacy will by closely monitored for at least 12 weeks, and then every three months for concerning side-effect signals. The potential for JAK inhibitors to improve upon Dupixent at certain points of treatment can be a valuable treatment strategy, although this might not be the most effective selling point especially if superior efficacy only happens short-term.

Label nuance key for uptake

Experts anticipate JAK inhibitors to eventually garner FDA approval in moderate-to-severe AD, though the class will have a tough time navigating the market due to its side-effect profile. The black box will a major obstacle for the class to gaining market momentum in AD, David Geffen School of Medicine dermatology assistant professor Dr Paul Yamauchi said.  In December 2020, this news service reported that challengers, including JAK inhibitors, could chip away at Dupixent’s dominance in AD via pricing. However, this approach is unlikely to be sustainable long-term as Dupixent’s price could be reduced to remain competitive.

While there are safety concerns, this does not mean JAK inhibitors will not be used at all. It will come down to what the FDA label would say, as there could be notable safety nuances among the inhibitors, Lausanne University Hospital dermatology professor Dr Curdin Conrad noted. While both JAK inhibitors Olumiant and Pfizer’s Xeljanz (tofacitinib) are approved in RA, Olumiant has a black box warning on thrombosis while Xeljanz does not. A Pfizer spokesperson said the FDA’s recent safety communications is specific to Olumiant, Rinvoq, and Xeljanz in their approved diseases.

Another label-specific detail that would suppress uptake is if JAK inhibitors were limited to patients who have progressed from Dupixent, Mount Sinai Beth Israel dermatology assistant professor Dr George Han added. This is not unprecedented: Olumiant’s current label requires inadequate response from TNF antagonist therapies, Wake Forest School of Medicine dermatology professor Dr Steven Feldman noted.

Issues may not extrapolate directly

Due to Dupixent’s favourable efficacy, only 10–20% of all moderate-to-severe AD patients may benefit from switching, Han said. These patients are also harder to treat, as they are in the severe end of the severity spectrum, he added. Yet, because it is already widely expected that JAK inhibitors would have a black box based on prior approvals, its uptake may not be as low as expected in AD, he explained. Severe AD is a debilitating disease and therefore some risk may be acceptable, University of Copenhagen dermatology professor Dr Jacob Thyssen noted. An AbbVie spokesperson said the company believes in Rinvoq’s risk-benefit profile.

Most of the safety data surrounding JAK inhibitor use in inflammatory diseases is from RA, Thyssen said. And extrapolation of safety data from RA to AD may be misleading because they have different patient profiles, he added. Specifically, CVD risk factors are relatively less of an issue in AD patients compared with RA patients who tend to be older, inactive, overweight, and have a smoking history, he explained. The JAK inhibitors’ side effect might be the final trigger for CVD of pre-existing risk. AD patients are younger, more active and have fewer CVD risk factors, at least in EU patients, he said.

Strategies available to reduce risk

To potentially alleviate the side-effect risk of any drug in AD patients, they can be used with intermittent breaks, Thyssen said. Treatment can be paused, or the dose tapered, once the symptoms are controlled and then resumed once symptoms return, he added. This can also be done with JAK inhibitors since the effect kicks in so fast. Treatment breaks may benefit certain patients, like ones who have their symptoms controlled, as continuous dosing could increase risk of aberrant inflammatory pathways to emerge, Washington University School of Medicine dermatology associate professor Dr Brian Kim noted.

However, drawing hesitation for treatment breaks is that JAK inhibitors have a short half-life, meaning the treatment effect can dissipate quickly, Kim said. AD is a stable disease, compared with psoriasis where symptoms come and go, making AD less ideal for dosing breaks, he explained. Although, these inhibitors’ short half-life is an advantage if serious side effects do crop up, he added. Patients are very different: some need continuous treatment to obtain long-term disease control, while others can be treated intermittently, Thyssen noted.

Upon initiation with JAK inhibitors, patients can be observed for 12 weeks to check if there are safety issues, Kim said. And if symptoms improve dramatically, it will argue for longer-term use, he added. Clinicians would have to keep monitoring for side effects, with samples collected every three months for analysis, he noted. A Lilly spokesperson said it has an ongoing postmarketing program in RA to continue long-term safety characterization of Olumiant. This includes randomized and observational studies, as well as a completed long-term extension study. Regeneron and Sanofi did not respond to a comment request.

Patients more open to swap

JAK inhibitors would diversify available AD treatment options. Roughly 50% of patients will be happy to stay with Dupixent, with the other 50% likely to at least consider other options, Kim added. Dupixent efficacy can wane over time as disease pathways can change, Conrad noted. While Dupixent has a favourable side-effect profile, there are patients who may not tolerate it, Yamauchi said. Dupixent does not have a black box warning, but there is a general warning noting hypersensitivity, conjunctivitis, and comorbid asthma.

In the end, to convince clinicians to switch patients from biologics to JAK inhibitors may in some cases be challenging, particularly that the FDA has underscored black box warnings which could potentially be a class effect, Thyssen said. JAK inhibitors are approved in Europe; abrocitinib is marketed as Cibinqo in the UK. Yet there may still be uncertainty among doctors due to the heightened negative publicity of these side effects, Thyssen noted, adding JAK inhibitors are also a new treatment class in AD. In contrast, patients would be more open to switching for improved symptom relief, Conrad said, though Han cautions the number of patients who might be keen to switch should not be overstated.

Initial burst of superiority observed

As for JAK inhibitor efficacy, abrocitinib and Rinvoq are intriguing as both have head-to-head data versus Dupixent, which seem to suggest they can offer superior efficacy, at least at the start of treatment. In the Phase IIIb Heads Up study, 71% Rinvoq patients achieved the primary endpoint of at least 75% improvement in the Eczema Severity Index (EASI75) at week 16, versus 61.1% with Dupixent (p=0.006). Abrocitinib was also reported as statistically superior compared with Dupixent in the Phase IIIb JADE DARE trial, in a 30 August media release.

After several weeks, however, the hint of superior efficacy seems to disappear. In the Heads-Up study, the efficacy superiority of Rinvoq over Dupixent in the EASI75 endpoint is most profound at week 4, though the gap is much narrower by week 16. If the main selling point is superiority over Dupixent, this should be sustained long-term, Yale University School of Medicine dermatology associate professor Dr Brett King noted.

Noninferiority not necessarily a crutch

Since Dupixent established a high efficacy bar, particularly in the real world, JAK inhibitors having noninferior efficacy would still have value, King said. JAK inhibitors’ fast action would be valuable in people of colour who experience slower build-up to Dupixent’s full efficacy, Han added.

However, these head-to-head trials only used higher doses: only 30mg Rinvoq and 200mg abrocitinib were studied, despite the FDA review including 15mg Rinvoq and 100mg abrocitinib. If only the lower doses secure FDA approval due to side-effect concerns, then it would be challenging for JAK inhibitors to match Dupixent’s efficacy in the clinic, Han and King explained.

Efficacy does not seem to be a class effect among JAK inhibitors in AD, and so this would be a deciding factor among dermatologists, Kim said. Olumiant does not seem to be as potent as the other JAK inhibitors in AD, which seems counterintuitive as Olumiant targets both JAK1 and 2, while abrocitinib and Rinvoq are selective for JAK1, he noted, adding: “We still don’t know everything about JAK signalling.”