DDW 2024 Posters Evaluate Safety, Efficacy, Impact of BMI on Zymfentra Use

Posters from Digestive Disease Week (DDW) looking at the ongoing LIBERTY-CD trial assessing Zymfentra, a subcutaneous infliximab product, compared with intravenous infliximab treatment in Crohn disease (CD) show the safety and efficacy of the product, as well as the impact of body mass index (BMI) on clinical outcomes. The conference takes place from May 18 to May 21, 2024, in Washington, DC.

Meta-Analysis Assessing Safety and Efficacy from LIBERTY-CD

The first study was a meta-analysis—including data from the LIBERTY-CD study—to investigate Zymfentra as a maintenance therapy or first-line therapy in comparison with other analysis for similar drugs in a similar population.¹

Zymfentra (infliximab-dyyb) was approved by the FDA in October 2023 and launched in March 2024. It was approved in the US as a novel biologic but is often considered a biosimilar or biobetter in international markets because the change in administration method utilizes Inflectra (infliximab-dyyb; known as Remsima in some markets), an infliximab biosimilar created by the same company (Celltrion). The product is approved for the treatment of CD and ulcerative colitis.

Given the expanding range of therapies and a lack of direct comparative evidence, a network meta-analysis of phase 3 randomized controlled trials (RCTs) was conducted to evaluate the efficacy of advanced CD therapies approved in Europe or the US. A systematic literature review identified studies evaluating maintenance therapies using intravenous (IV) or Zymfentra, SC adalimumab, IV or SC vedolizumab, SC ustekinumab, SC risankizumab, or oral upadacitinib in patients with moderate to severe CD who responded to induction therapy. Included studies were placebo- or active-controlled with 52 to 64 weeks of follow-up. Patients were biologic-naïve, receiving these drugs as first-line advanced therapy. The network meta-analysis synthesized clinical remission and endoscopic response rates using a frequentist random-effects model.

Nine RCTs (ACCENT I, LIBERTY-CD, CHARM, SEAVUE, GEMINI 2, VISIBLE 2, IM-UNITI, FORTIFY, U-ENDURE) were eligible, encompassing 14 treatment arms. SC infliximab 120 mg every 2 weeks (Q2W) demonstrated the highest risk difference (RD) vs placebo for achieving clinical remission (RD, 0.38; 95% CI, 0.23-0.53), followed by SC adalimumab 40 mg weekly (RD, 0.32; 95% CI, 0.17-0.48) and oral upadacitinib 30 mg daily (RD, 0.30; 95% CI, 0.08-0.53).

Endoscopic response data from LIBERTY-CD, FORTIFY, and U-ENDURE showed SC infliximab 120 mg Q2W also had the highest RD vs placebo for endoscopic response (RD, 0.39; 0.29-0.49), followed by SC risankizumab 180 mg every 8 weeks (Q8W) (RD, 0.37; 95% CI, 0.17-0.56) and SC risankizumab 360 mg Q8W (RD, 0.27; 95% CI, 0.06-0.48). The network meta-analysis indicated that Zymfentra 120 mg Q2W has a favorable efficacy profile in achieving clinical remission and endoscopic response as a first-line advanced therapy for maintenance treatment in patients with moderate to severe CD.

Impact of BMI on Clinical Outcomes Associated with Zymfentra Use

Another study looked at the role BMI may play in clinical outcomes associated with Zymfentra use in CD.²

Obesity and high levels of visceral adipose tissue are associated with lower response rates to IV infliximab. SC infliximab, a novel formulation, demonstrated superiority to placebo as maintenance therapy in patients with moderate to severe active CD in the phase 3 LIBERTY-CD study. Since SC infliximab is administered in a fixed dose regardless of BMI, it is important to assess its efficacy across different BMI categories. The post hoc analysis examined the association between BMI and the efficacy of SC infliximab therapy.

Data from LIBERTY-CD (NCT03945019) included 231 patients in the SC infliximab arm, categorized by BMI into underweight (BMI < 18.5 kg/m²; n = 27), normal (BMI 18.5-24.9 kg/m²; n = 133), overweight (BMI 25-29.9 kg/m²; n = 53), and obese (BMI ≥ 30 kg/m²; n = 18) groups. The coprimary end points at week 54 (clinical remission, defined as a Crohn’s Disease Activity Index [CDAI] score < 150, and endoscopic response, defined as a ≥ 50% decrease in Simple Endoscopic Score for Crohn's Disease [SES-CD] from baseline) and the change in CDAI score from baseline were evaluated by BMI subset. Correlations between BMI and CDAI score, SES-CD, or median trough level of infliximab (TLI), and the impact of BMI on week 54 TLI were also analyzed descriptively.

At week 54, there were no statistically significant differences in the coprimary end points or the change from baseline in CDAI score across BMI subsets, although trends showed decreasing rates of achieving these end points, change in CDAI score, and TLI with increasing BMI. Clinical remission rates were 63.0% (underweight), 66.2% (normal), 58.5% (overweight), and 44.4% (obese; P = .125).

Endoscopic response rates were 55.6% (underweight), 36.1% (normal), 41.5% (overweight), and 27.8% (obese; P = .207). Median changes from baseline in CDAI score were –227.3 (underweight), –212.9 (normal), –196.2 (overweight), and –204.5 (obese; P = .358). No significant correlations were found between BMI and CDAI score or BMI and SES-CD, while a weak but significant negative correlation was observed between BMI and TLI.

Additionally, there was a significant difference in median week 54 TLI across BMI subsets (17.0, 13.6, 9.3, and 6.6 µg/mL for underweight, normal, overweight, and obese, respectively; P = .007).

Although TLI varied significantly across BMI subsets, BMI did not have a statistically significant impact on week 54 clinical or endoscopic outcomes, likely due to the high TLI achieved with SC infliximab. The authors emphasized the need for larger and longer-term studies that include patients with higher BMIs and diverse body compositions.

References

1. Schreiber S, Danese S, Colombel JF, et al. Network meta-analysis to evaluate the comparative efficacy of advanced therapies as first line for maintenance treatment of adult patients with moderate-to-severe Crohn's disease. Presented at: DDW 2024; May 18-21, 2024; Washington, DC. Poster Mo1175.

2. Yarur A, Hanauer SB, Schreiber S, et al. Impact of body mass index on clinical outcomes and drug levels in patients with Crohn's disease receiving maintenance treatment with subcutaneous infliximab: a post hoc analysis of the LIBERTY-CD study. Presented at: DDW 2024; May 18-21, 2024; Washington, DC. Poster Su1755.