A study author said the data tips the scales in favor of benefit for AD patients.

A recent analysis reveals that upadacitinib, an oral Janus kinase 1 (JAK1) inhibitor, maintains its safety profile over a span of 5 years, aiding individuals with moderate-to-severe AD. 

The study, presented at the Revolutionizing Atopic Dermatitis (RAD) virtual conference, amalgamating data from three ongoing global Phase 3 trials—Measure Up 1, Measure Up 2, and AD Up—and focused on evaluating the efficacy and safety of upadacitinib in treating moderate-to-severe AD. These trials included adolescents and adults who received upadacitinib doses of 15 mg and 30 mg or placebos, alone or combined with topical corticosteroids, for a 16-week period. Patients continuing with upadacitinib entered a blinded extension for up to 260 weeks.

In the comprehensive analysis, a collective of 2,683 patients—2,154 adults and 529 adolescents—participated after receiving at least one dosage of upadacitinib, either 15 mg (1,337 patients) or 30 mg (1,346 patients). To determine the safety parameters, the study meticulously examined treatment-emergent adverse events of special interest (AESI) per 100 patient-years (PY) across the entire treatment duration. This method helped in normalizing data for varying follow-up durations.

Consistent Safety Across Timeframes

Significantly, the rates of AESIs for upadacitinib were similar between the 1-year and 5-year analyses. The figures for serious infections demonstrated minimal variance—15 mg: 2.3 (1 year) and 2.2 (5 years), and 30 mg: 2.8 (1 year) and 2.6 (5 years). Similarly, rates for other adverse events, including opportunistic infections, active tuberculosis, herpes zoster, non-melanoma skin cancer (NMSC), malignancy exhibited consistent trends across both doses and time intervals.

Lead study author, Christopher Bunick, MD, PhD, an associate professor of dermatology in Department of Dermatology and Program in Translational Biomedicine at Yale, emphasized the distinctive safety profile in adolescents.

“In adolescents, the incidence of adverse events, especially those of special interest, was markedly lower," he said. "There were no reports (a zero-incidence rate) of lymphoma, major cardiovascular events, venous thromboembolism, gastrointestinal perforation, or tuberculosis throughout both one-year and five-year observation periods. Moreover, the occurrence of other adverse events was extremely rare. Consistent with the general patient cohort, the safety profile of upadacitinib in adolescents did not reveal any new safety risks over time.”

Impact and Clinical Considerations

Highlighting the diversity and representativeness of the study population, which closely mirrors today's typical atopic dermatitis patient, Dr Bunick, noted, "Over half of the patients having at least one cardiovascular risk factor, more than 30% being tobacco or nicotine users, around 10% having hypertension, approximately 19% having a BMI over 30 kg/m², and about 20% of women taking oral contraceptives. Notably, not a single case of venous thromboembolism (VTE) was reported in this cohort, which underscores the drug's safety in a population that reflects real-world patients.”

Importantly, the analysis highlighted that upadacitinib, administered to both adults and adolescents, sustained low rates of serious infections (<3.0 E/100PYs) at both time points and doses. Dr. Bunick noted that this is what made the safety data for upadacitinib so special. 

"There were no new safety risks identified," he said. "In fact, the rates of serious adverse events, like malignancy, cardiac events, and thrombosis remained stable and rock-bottom low from 1 to 5 years. Importantly, this safety analysis is now the longest and largest safety study published on any approved advanced systemic therapy for atopic dermatitis. This provides reassurance on upadacitinib’s safety to dermatologists, other clinicians, and especially patients. The highest adverse event rate seen was for herpes zoster, ranging from 3.1 to 5.5 events per 100 patient years of medicine exposure; however, 5% or less of the patients in the trials had prior shingles vaccine. This suggests that dermatologists can intervene and reduce risk of herpes zoster associated with upadacitinib by encouraging shingles vaccination in their AD patients needing JAK inhibitor therapy.”

When asked about the impact of these findings on the current understanding of the benefit-risk profile of upadacitinib in managing moderate-to-severe atopic dermatitis and the implications for treatment guidelines or clinical decision-making, Dr.  Bunick said that the 5-year safety data now tips the scales in favor of benefit for AD patients. 

"This comprehensive dataset shows that the risk of serious adverse events for patients undergoing upadacitinib monotherapy—without the conjunction of other immunosuppressants or biologics—is low to exceedingly rare," he noted. "That said, continued shared decision making with patients, proper medical history intake, and proper clinical and laboratory monitoring should continue by dermatologists as for any medication being prescribed.”

Dr. Bunick emphasized that the long-term safety data for upadacitinib should be a crucial aspect of discussions about JAK inhibitors with patients. This information not only reassures dermatologists about the drug's safety profile but also aligns with its proven clinical efficacy. Network meta-analyses have consistently ranked upadacitinib as the most effective medication for achieving significant improvements in atopic dermatitis, measured by outcomes such as skin clearance (EASI-75 and EASI-90) and itch resolution (NRS ≥ 4 improvement). These data instill confidence in upadacitinib's therapeutic potential and its pivotal role in the management of atopic dermatitis.

Source: Bunick C, Chovatiya R, Guttman-Yassky E, et al. Long-term 5-year safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis including over 7000 patient-years of exposure. Abstract presented at: Revolutionizing Atopic Dermatitis (RAD) Virtual Conference; December 2023. Abstract 115-1000533.