Dr Ricardo Rojo Cella is Executive Director at Pfizer, where he has worked since 2009. He received his MD at the Universidad La Salle, Spain, after which he obtained a Master’s degree in Neuroscience from the Universitat de Barcelona, Spain.
The Phase 3 JADE REGIMEN study (NCT03627767) was a 52-week study investigated abrocitinib, an investigational oral once-daily Janus kinase 1 (JAK1) inhibitor, in patients 12 and older with moderate to severe atopic dermatitis (AD) following response to initial open label induction treatment with abrocitinib 200mg. The JADE REGIMEN results build on the positive results from the JADE MONO-1 and 2 studies, demonstrating an even greater patient response to the drug than expected without the use of topical corticosteroids. Patients were randomised into one of three arms: 200mg, 100mg, or placebo. Both doses of abrocitinib met the primary endpoint, resulting in significantly fewer patients experiencing a loss of response requiring rescue treatment, or “flaring,” compared to those randomised to placebo. Both doses also met the key secondary endpoint of a larger percentage of patients maintaining an Investigator’s Global Assessment (IGA) response of clear or almost clear relative to placebo.
The JADE REGIMEN met its primary and key secondary endpoints
JADE REGIMEN is the fifth trial in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) global development program. Complete results from JADE MONO-1 (NCT03349060) were published in The Lancet in July 2020 , and the JADE MONO-2 trial (NCT03575871) published around the same time in JAMA Dermatology . Additional data from other studies in the JADE program will be available in the coming months, presented at the larger dermatological conferences.
In JADE REGIMEN, after achieving clinical response in the induction period, patients who continued on the higher dose of abrocitinib, 200mg, or switched to the lower dose, 100mg, had a significantly higher probability of not experiencing a flare compared to those on placebo through week 52 (81.1%, 57.4%, and 19.1%, respectively; P<0.0001 for both doses versus placebo). In addition, patients who continued on the higher dose of abrocitinib were significantly less likely to flare than those on the lower dose (p<0.0001). Patients on either dose of abrocitinib were significantly more likely to maintain an IGA score of clear (0) or almost clear (1) compared to placebo (P<0.0001 for both doses versus placebo).
The primary endpoint after treatment in the 12-week induction phase was the loss of response requiring rescue treatment among groups during the blinded treatment period up to 40 weeks. Loss of response requiring rescue treatment, or a “flare,” was defined as a loss of at least 50% of the Eczema Area and Severity Index (EASI) response at week 12 and an IGA score of 2 or higher (on a 5-point scale). The key secondary endpoint was the loss of response based on an IGA score of 2 or higher.
Out of 1,233 subjects enrolled, 798 (64.7%) responded during the initial 12-week induction period with abrocitinib monotherapy (200mg, once daily), a higher than expected responder rate compared to the monotherapy studies JADE MONO-1 and JADE MONO-2. Responder criteria was defined as achieving an IGA score of clear (zero) or almost clear (one), a reduction from IGA baseline of at least two points, and reaching an EASI-75 response compared to baseline.
No new safety signals were observed in the trial. Safety results showed that during the induction period 66.5% of patients experienced an adverse event and 1.6% experienced a serious adverse event. Following randomization, a higher percentage of patients receiving either the 200mg or 100mg dose of abrocitinib experienced adverse events compared to placebo (63.2%, 54%, and 45.3%, respectively). The percentage of patients who experienced serious adverse events were 4.9%, 1.5%, and 0.7%, respectively. More patients treated with abrocitinib discontinued from the study due to adverse events (6%, 1.9%, and 1.5%, respectively).
The safety profile of abrocitinib was essentially the same as for placebo with the exception of a 3.2% incidence of thrombocytopenia in patients on abrocitinib at 200 mg/day; no cases occurred in controls or patients on abrocitinib at 100 mg/day. Although venous thromboembolism has arisen as a potential concern in clinical trials of oral JAK inhibitors for rheumatoid arthritis, there were no cases in the recent JADE trials. A long-term safety extension study in JADE-MONO participants is underway.
The perceived unmet need?
Even though dupilumab has made a huge improvement for many patients with moderate to severe AD, there is still a large proportion of patients who do not respond to dupilumab or those with safety events that are bothersome enough to prompt patients to discontinue study drug. Being an injectable, dupilumab also has limitations for chronic patients, and there is no dosing flexibility. A good JAK-1 inhibitor like abrocitinib targets more cytokines than those that are touched by dupilumab, beyond interleukin (IL)-4 and IL-13 ,also targeting IL-31, IL-33, and TSLP, that have a direct impact in pruritis and skin inflammation .
Amelioration of T2I with abrocitinib?
We are still currently assessing whether type 2 inflammation is being directly modified by abrocitinib. We are testing the effects ex vivo on skin biopsies; these data will be important in defining the mechanism of clinical benefit that we have observed in the JADE program.
Longer-term immunosuppressive activity?
We acknowledge that a 12-week study is not informative to assess the benefit-risk of a therapy that is intended for chronic use. We designed JADE MONO-1 and -2 to be only 12 weeks for two reasons: one was the definite unmet need that there is, and secondly, is because when we evaluated our phase 2 data, we seemed to reach maximum efficacy after 8 weeks of therapy. In the interest of trying to reduce the burden of placebo in our population, we thought that 12 weeks was the most appropriate.
The next step forward is rolling out the data from the sister trials. The JADE COMPARE study has been submitted for publication in one major journal, and it should be published soon. The JADE REGIMEN study was an induction maintenance/randomised withdrawal study that will also inform prescribers and patients whether an induction maintenance regimen is a better option as opposed to continuous therapy. We completed our adolescent-only study (JADE TEEN) and the manuscript is being reviewed right now and it will be submitted to a dermatology journal also very soon. Atopic dermatitis patients will certainly benefit from having choices when requiring systemic therapy.
- Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, Bieber T, Thyssen JP, Yosipovitch G, Flohr C, Magnolo N, Maari C, Feeney C, Biswas P, Tatulych S, Valdez H, Rojo R. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020 Jul 25;396(10246):255-266.
- Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, Biswas P, Valdez H, DiBonaventura M, Nduaka C, Rojo R. Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020 Aug 1;156(8):863-873
- Crowley EL, Nezamololama N, Papp K, Gooderham MJ. Abrocitinib for the treatment of atopic dermatitis. Expert Rev Clin Immunol. 2020 Oct 8:1-8.
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