‘Pristine’ safety profile sets TYK2i apart from JAK ‘baggage’ in psoriatic disease, lupus
Click Here to Manage Email Alerts
In September 2022, the FDA approved deucravacitinib for moderate-to-severe plaque psoriasis, officially introducing tyrosine kinase 2 inhibition to clinics across the United States.
Hailed by its manufacturer as the first new innovation in oral plaque psoriasis treatment in a decade, deucravacitinib (Sotyktu, Bristol Myers Squibb) boasts, among other features, at least one potentially crucial advantage over its cousins in the larger Janus kinase-inhibitor family — fewer and less severe safety findings, and no black box warning.
!["My anticipation is that [deucravacitinib] will be approved in lupus, paving the way for other TYK2 inhibitors that are coming along," Philip J. Mease, MD, said.](/~/media/slack-news/rheumatology/misc/infographics/2024/rh0624mease_graphic_01.jpg?w=800)
“Up until the approval of deucravacitinib, the go-to drug for dermatologists was apremilast as an oral medication,” Roy M. Fleischmann, MD, a clinical professor in the department of internal medicine at the University of Texas Southwestern, told Healio. “With the studies showing that deucravacitinib is much more effective than apremilast, with less gastrointestinal toxicity and no black box warning, I suspect that dermatologists will prefer to use deucravacitinib rather than apremilast.”
This combination of an oral formulation, an improved safety profile over previous JAK inhibitors, and robust efficacy has brought significant attention to TYK2 inhibitors among rheumatologists.
Meanwhile, ongoing trials for the drug, and others in the TYK2-inhibitor class, may carry its success across specialties, from dermatology into rheumatology.
“Now we have a drug with a pristine safety profile with twice the effectiveness of its predecessors,” Philip J. Mease, MD, of the Swedish Medical Center and the University of Washington, in Seattle, said in an interview. “When I chat with key opinion leaders in dermatology, they were enthusiastic about deucravacitinib during the development phase and enthusiastic now that it is available.”
That enthusiasm is well-supported. In paper published in Nature Reviews Rheumatology, Morand and colleagues noted that TYK2 participates in signaling pathways downstream of type I interferons, interleukin-12, IL-23 and IL-10, and “elicits a distinct set of immune events” compared with JAK1, JAK2 and JAK3.
Given the involvement of these cytokines and signaling pathways in psoriasis, psoriatic arthritis, systemic lupus erythematosus and dermatomyositis, among other conditions, it is expected that TYK2 inhibitors could be approved for a wide variety of applications in the coming decade.
However, TYK2 inhibitors are not yet staples in rheumatology, at least in part because a full complement of comparison data are not yet available for the FDA to consider.
“We cannot discuss efficacy in the absence of head-to-head comparisons as there are not any head-to-head trials with JAK inhibitors or biologics,” Saakshi Khattri, MD, associate professor of dermatology at the Icahn School of Medicine at Mount Sinai, in New York, said in an interview. “The only head-to-head trial shows that deucravacitinib outperformed apremilast.”
However, more trials are coming. Encouraging phase 2 data for deucravacitinib in PsA and SLE have been published, along with findings for another TYK2 inhibitor, brepocitinib (Priovant Therapeutics), in PsA. These data may indicate a bright future for this class of medications.
‘No MACE, VTE or malignancy’
The study that launched deucravacitinib toward FDA approval was published in the Journal of the American Academy of Dermatology by Strober and colleagues. They compared deucravacitinib with placebo and apremilast in moderate to severe plaque psoriasis.
The analysis included 511 patients treated with deucravacitinib 6 mg daily, 254 patients treated with apremilast 30 mg twice daily, and 255 patients treated with placebo.
Results at week 16 showed that 53% of patients in the deucravacitinib arm reached the primary endpoint of at least a 75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75), compared with 39.8% of patients in the apremilast arm (P < .0001) and 9.4% of patients in the placebo group (P = .0004). Further data demonstrated that a Physician's Global Assessment score of 0 or 1 was reached by 49.5% of patients in the deucravacitinib arm vs. 33.9% for apremilast (P < .0001 for both) and 8.6% for placebo.
According to the researchers, continuous deucravacitinib treatment yielded continuous efficacy through week 52.
“The reason apremilast was chosen for a comparator for psoriasis trials was that apremilast had a surprisingly good run for a few years,” Mease said. “Though it was not well tolerated, it has a strong long-term safety profile.”
Given the results, Fleischmann stated he is cautiously optimistic that TYK2 inhibition with deucravacitinib could ultimately surpass the benefits seen by other medications targeting the JAK pathway, largely because of safety.
“It is too early to tell but so far there is a difference between the JAK inhibitors and deucravacitinib with respect to lab abnormalities, and so far no significant MACE, VTE or malignancy,” he said. “We will need to see the results in many more patients to see if this holds up.”
Those results are emerging not only in psoriasis, but in PsA and SLE, as well.
‘We are enthused’
In a paper published in the Annals of the Rheumatic Diseases, Mease and colleagues compared outcomes for two formulations of deucravacitinib — 6 mg daily and 12 mg daily — with those for placebo in a cohort of 203 patients with PsA. Results showed ACR20 response rates of 52.9% for the 6 mg group (P = .0134), 62.7% for the 12 mg group (P = .0004), compared with 31.8% for placebo at 16 weeks. In addition, both deucravacitinib doses bested placebo in various components of the Health Assessment Questionnaire-Disability Index, the Short Form-36 Physical Component Summary score and PASI 75.
“This was a successful phase 2 trial,” Mease told Healio. “Deucravacitinib showed benefit in various domains like arthritis, enthesitis, dactylitis and skin disease.”
However, unanswered questions remain.
“The key question is how effective it is in true axial psoriatic arthritis,” Mease said. “We do not know that yet.”
Mease suggested that the success of the TYK2 class overall is likely to inspire researchers to answer this question, but the data have yet to be seen.
There are data, however, for the drug in SLE.
In a paper published in Arthritis & Rheumatology, Morand and colleagues assessed the safety and efficacy of deucravacitinib in a cohort of 363 patients with active SLE from 17 countries. Treatment regimens included deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily or placebo. Results showed a placebo response rate of 34%, compared with 58% for the 3-mg formulation (OR = 2.8; P < .001), 60% for the 6 mg twice daily formulation (OR = 1.9; P = .02) and 45% for the 12 mg dose (OR = 1.6; P = .08). Other outcomes, including the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) 50 response, lupus low disease activity state (LLDAS) and joint counts, were all superior in the treatment groups compared with placebo.
Meanwhile, safety data demonstrated comparable rates across study groups, with no fatalities, opportunistic infections, tuberculosis, MACE or thrombotic events observed.
“From a mechanism-of-action point, it appears that TYK2 inhibition should work or prove efficacious in SLE,” Khattri said.
Indeed, TYK2 targets the IL-23 and alpha interferon inhibitory signal that is specific to lupus, according to Mease.
He added that the effect size in phase 2 trials in lupus was “better than anticipated.”
“We are enthused about getting involved in the phase 3 program,” Mease said. “My anticipation is that it will be approved in lupus, paving the way for other TYK2 inhibitors that are coming along.”
Fleischmann, although he counseled caution in lieu of the phase 3 data, shared some of this optimism.
“We will not know until the results of the phase 3 trials are available in SLE, but with the positive phase 2 in SLE and PsA, I expect that the phase 3 trials will be positive and therefore a treatment option for these diseases,” he said.
Looking ahead, Mease said he believes that dermatomyositis could also be an attractive target for TYK2 inhibition. As those trials get underway, all eyes are on other medications in the TYK2 class, including brepocitinib.
Free of JAK inhibitors’ ‘baggage’
In another paper published in Arthritis & Rheumatology, Mease and colleagues investigated the efficacy and safety of the TYK2/JAK1 inhibitor brepocitinib in patients with active PsA. The phase 2b trial included 218 patients overall. Results at week 16 demonstrated ACR20 response rates of 66.7% for the 30-mg daily dose (P = .0197) and 74.6% for the 60 mg daily dose (P = .0006), compared with 43.3% for placebo.
Further data showed that both brepocitinib doses bested placebo in terms of ACR50/ACR70, PASI75/PASI90 and MDA response rates through 52 weeks.
Regarding safety, the researchers reported 15 serious adverse events in 12 patients, with no fatalities or MACE.
“Brepocitinib was effective in all the relevant domains in PsA,” Mease said, adding that brepocitinib combines the TYK2 and JAK1 approaches. “This drug gives us more assurance in areas where JAK inhibitors are effective, like the axial spine. We would anticipate that it could also be effective in axial spondyloarthritis. A combination approach could offer broader cytokine inhibition.”
However, the combination with a JAK inhibitor does invite the possibility of a black box warning, which is why Khattri said she believes a pure TYK2 approach could be optimal.
“Although it is clubbed in the JAK family, TYK2 inhibition with deucravacitinib does not overlap with JAK inhibition, so it does not carry the safety baggage of JAK inhibitors,” she said.
The goal, instead, would be to add to the mechanism already provided by TYK2 inhibition.
“An IL-23 or TNF alpha inhibitor might not make sense, as TYK2 inhibitors target those cytokines,” Mease said. “In my view, it would make total sense to add a relatively safe compound that broadens the molecular reach.”
If there is one other potential concern with TYK2 inhibition that clinicians must consider, it is the possibility that it may make patients more susceptible to tuberculosis.
“The disadvantages are that it needs a TB test before starting, and some acne folliculitis that can be seen,” Khattri said.
Further investigation of such combinations and safety outcomes are necessary to sort out all this safety and efficacy information.
“Registries for various combinations have been established,” Mease said. “This will give ammunition for researchers to go to the FDA for approval.”
In the meantime, at least one TYK2 inhibitor is on the market, providing rheumatologists and dermatologists with a viable option for patients with psoriasis.
“We now have another oral option with another mechanism of action that was not available thus far,” Khattri said.
References:
Mease PJ, et al. Ann Rheum Dis. 2022;doi:10.1136/annrheumdis-2021-221664.
Mease P, et al. Arthritis Rheumatol. 2023;doi: 10.1002/art.42519.
Morand E, et al. Arthritis Rheumatol. 2023;doi:10.1002/art.42391.
Morand E, et al. Nat Rev Rheum. 2024; doi: 10.1038/s41584-024-01093-w.
Strober B, et al. J Am Acad Dermatol. 2023;doi:10.1016/j.jaad.2022.08.061.
Collapse
Read more about
Click Here to Manage Email Alerts