Biologics have been incorporated into current guidelines and clinical practice since the introduction of infliximab in 1998. The maturity of biologic therapies is exemplified by the expansion of real-world data and the evolution of biosimilars for infliximab (IFX) and adalimumab (ADA).
Indeed, some interesting chat comments pertained to the impact of lower costs of IFX and ADA biosimilars on access, including earlier and milder disease and flexibility of treating to target than has been possible in the U.S. where access is determined and limited by third-party payers. In addition, such improved cost structures would open the potential for economically feasible combination therapies with different mechanisms of action for refractory patients who have such dismal response rates to second-or third-line biologics.
The late-breaking “SEAVUE” study (775d) presented by Sands is the first head-head comparison of two biologic agents, ustekinumab (UST) and ADA, in patients with moderate-severe Crohn’s disease. (CD). The double-blind, double-dummy trial compared approved induction and maintenance doses for each agent over 1-year enrolling biologic naïve patients. In contrast to phase III trials with UST and ADA, the 386 enrolled patients had shorter-disease durations and lower Crohn’s Disease Activity Indices (CDAIs) and Simple Endoscopic Scores. The primary end-point was Clinical Remission at 52 weeks: achieved by 65% and 61% of UST and ADA patients. Numerically similar results with UST/ADA were also achieved for endoscopic remission and most other secondary end-points. Safety was numerically close for both agents, although more ADA-treated patients discontinued the trial related to adverse events versus UST (11.3% versus 6.3%); an overall 15% of UST-treated versus 24% of ADA-treated patients discontinued before week 52. The comparative efficacy and safety were similar over the one-year study, and results with both ADA and UST were better than reported in pivotal trials.
SEAVUE demonstrates the impact of treating CD earlier: to prevent disease transmural disease progression and avoid adverse "baggage" related to ineffective (aminosalicylates) or potentially toxic (steroids, thiopurines) conventional therapies. Imminent issues relate to currently shared decision making where the comparative SEAVUE results might lead payers to prioritize lower cost, less conveniently administered, therapies vs higher cost, somewhat better-tolerated options.
Regarding biosimilars, the Edinburgh IBD unit (Sialkvellas #610) presented experience with single and multiple switches of infliximab biosimilars that had “no negative effects in clinical outcomes at six months”. This addresses concerns regarding future multiple switches (de facto interchangeability) between approved biosimilar IFXs that may be “mandated” by third-party payers.
The multi-center, open-label LOVE-UC study presented by Vermiere (#456) assessed the efficacy, safety, and mucosal healing rates in early (UC< 4 years) vs late (UC> 4 years) treatment with vedolizumab and found “no difference in remission rates between early bio-naïve patients and late immunomodulator and bio-exposed patients”. Pugliese (#179) presented an Italian cohort of elderly (>65) vedolizumab-treated patients and reported 72% persistence at 12-months in bio-naïve patients and 52% for bio-exposed patients with an “acceptable” safety profile. Similarly, Weiss (Fr524) conducted a retrospective 568 patient cohort study of vedolizumab-treated IBD patients (UC and CD) from the VA Healthcare System divided by age (<65 vs >65) and reported similar rates of efficacy including steroid-free remission, IBD-related hospitalizations, and surgeries.
Real-world data were presented regarding UST for CD by Johnson (611) from a retrospective, multi-center consortium evaluating 1113 patients (90% with prior TNFi-exposure and 56% exposed to >2 biologics). Cumulative rates for clinical (40%), steroid-free (32%), endoscopic (39%), and radiographic remissions (30%) were reported through 12-months. Baseline albumin, prior TNFi exposure, and additional prior biologic exposures were associated with lower rates of responses while dose-escalation (“optimization”) was effective in 40% of patients not achieving remission with standard dosing. Cohen (#180) reported outcomes from the phase III UNITI studies to assess the impact of age at onset on UST outcomes and reported similar response and remission rates in adults treated with UST with pediatric and adult-onset CD (despite longer disease duration, higher CRP, and CDAI scores at baseline in the pediatric-onset group). Pregnancy outcomes in 39 patients treated with UST from UC and CD clinical trials were presented by Abraham (#178) who found no congenital anomalies and spontaneous abortion rates comparable to the U.S. population which were similar to Meserve’s (#613) large claims database with nearly 7500 expectant fathers exposed to biologics or immune modulators and found no association with increased risks of adverse birth outcomes6.
Regarding treat-to-target strategies, Schulberg (#459) described a randomized trial in CD patients with symptomatic strictures comparing high-dose ADA(160mg weekly for 4 weeks followed by 40mg every other week with a thiopurine (“therapy increase for continuing inflammation at 4 and 8 months) vs standard monotherapy dosing. More than half the intensive dosing patients were escalated further. The investigators reported improvement in 79% vs 64% at 12 months (p=0.17) (pre-stenotic dilation was not evaluated). Likewise, Pineton (#457) described an observational cohort of CD patients presenting with intra-abdominal abscesses treated with ADA after complete resolution of sepsis and abscess and found an initial 9% recurrence of abscesses. After 4-years the cumulative incidence rates of ADA failure was 54% and the intestinal resection rate was 25%. (Comparative data for patients treated with earlier surgeries and post-operative prophylaxis are not available.) Lastly, Danese (#105) assessed a treat-to-target strategy to optimize management of CD with UST in a phase 3b randomized trial comparing standard dosing to dose-escalation to 90 mg every 4-weeks for failure to improve after 16-weeks treatment. High rates of clinical response were seen in both groups but numerically higher proportions of patients achieved “endoscopic response” (>50% fall in SES-CD) in the treat-to-target cohort.
Overall, at DDW 2021 evidence continues to accumulate that earlier, effective treatment strategies and treat-to-target strategies (including dose-optimization) are more likely to translate into longer-term outcomes while current and forthcoming head-head trials remain gold-standards for comparative efficacy (vs hypothesis generating network meta-analyses). Expanding use of biosimilars is likely to provide greater access to earlier, more efficacious treatments and the potential for combining mechanisms to enhance efficacy.
Dr. Hanauer is a co-author, member of the steering committee, and consultant/speaker for Janssen Scientific Affairs, LLC
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