A Response to “Letter to the Editor Regarding ‘Dupilumab Versus Lebrikizumab Demonstrates Greater Likelihood of Achieving and Maintaining Improvements in Efficacy Outcomes Using a Placebo-Adjusted Indirect Treatment Comparison’”

Dear Editor,

We appreciate the interest shown by Chovatiya et al. in our recent publication [1] and welcome the opportunity to address their methodological concerns. We respectfully disagree with several of their assertions and stand by our analytical approach. We also provide additional data that reinforce our conclusions.

Rand et al. previously conducted an unanchored matching-adjusted indirect comparison (MAIC) reporting comparable or better efficacy for lebrikizumab versus dupilumab [2]. However, several methodological issues were noted that challenged the robustness of this unanchored approach [3]. Thus, we performed an anchored, placebo-adjusted Bucher indirect treatment comparison (ITC), demonstrating that the likelihood of achieving and maintaining efficacy outcomes was higher for dupilumab versus lebrikizumab [1].

Response to Criticism of Week 16 Analysis (Induction Phase)

Chovatiya et al. argue that population differences between LIBERTY AD CHRONOS and ADhere preclude use of Bucher ITC for the week 16 analysis and that a population-adjusted MAIC is required. We agree that population-adjusted analyses are useful sensitivity checks; this is why we performed an anchored MAIC (see below). However, the primary rationale for the Bucher ITC remains valid for the following reasons.

First, the baseline characteristics between the trials were broadly comparable. As described in our publication [1], measures including mean Eczema Area and Severity Index (EASI), Peak Pruritus Numeric Rating Scale (PP-NRS), and Dermatology Life Quality Index (DLQI) were similar, and their standard deviations overlapped; where differences existed (e.g., higher proportion of Investigator’s Global Assessment [IGA 4] in CHRONOS), they would, if anything, probably bias against dupilumab (making IGA 0/1 harder to achieve in the dupilumab population) and thereby would not provide any observed advantage for dupilumab in our ITC.

Second, and importantly, we conducted an anchored MAIC adjusting LIBERTY AD CHRONOS individual patient data to match ADhere on age, gender, race, EASI, and IGA and presented these results at the International Society of Atopic Dermatitis (ISAD) 2025 Symposium [4]. The anchored MAIC efficacy results were consistent with our Bucher ITC, and all in favor of dupilumab, with statistically significant advantages for dupilumab versus lebrikizumab for EASI-75 (OR 2.81 [95% CI 1.27–6.24]) and PP-NRS Δ ≥ 4 (OR 4.74 [95% CI 2.09–10.76]) and numeric advantages observed for IGA 0/1 (OR 2.16 [95% CI 0.96–4.87]) and DLQI Δ ≥ 4 (OR 1.49 [95% CI 0.64–3.45]). The alignment of the anchored MAIC results with our Bucher ITC estimates provides empirical evidence that baseline population differences did not meaningfully impact the primary findings.

Together, these findings support the utility and validity of utilizing the anchored Bucher method for these indirect comparisons. The consistency between Bucher ITC and anchored MAIC results confirms that baseline differences were not clinically meaningful confounders. As recognized by the National Institute for Health and Care Excellence (NICE) and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) [5, 6], Bucher ITCs preserve the protection against bias offered by randomization, controlling both known and unknown confounders that are not treatment effect modifiers. In addition, Bucher ITCs rely on published data for a transparent analysis, whereas MAIC uses individual patient data that are not in the public domain, therefore preventing reproducibility of the analysis. Finally, our anchored MAIC, using the same methodology and covariate set advocated by Chovatiya et al., confirms the efficacy results in favor of dupilumab.

Response to Criticism of Week 52 Analysis (Maintenance Phase)

Chovatiya et al. contend that the withdrawal arms are not a “true” common comparator due to differential off-drug effects, citing higher maintenance rates in lebrikizumab versus dupilumab withdrawal arms (56% versus 30% EASI-75). We find fundamental issues with this reasoning.

First, the pharmacokinetic evidence does not support a differential off-drug effect at 36 weeks post withdrawal. Pharmacokinetic analyses demonstrate that dupilumab and lebrikizumab have comparable half-lives [7, 8]; consequently, no active substance would be detectable 36 weeks following the withdrawal of either dupilumab or lebrikizumab. This confirms that the withdrawal arms validly represent off-treatment status. The higher placebo response rates observed consistently across lebrikizumab trials (EASI-75 responses in placebo arms were 16% in ADvocate 1, 18% in ADvocate 2, and 42% in ADhere [9, 10]) probably reflect trial-specific factors rather than persistent pharmacological effects.

Second, methodological guidance supports an anchored approach. NICE and ISPOR explicitly state anchored comparisons are superior to unanchored approaches [5, 6]. The unanchored MAIC approach is known to be "subject to bias, even when all known prognostic factors are included," and should only be used when anchored comparisons are impossible [5, 6]. The recommendation from Chovatiya et al. for unanchored MAIC contradicts these established guidelines and represents a methodologically weaker approach.

Internal Inconsistency in the Critique

We must emphasize a fundamental contradiction in the arguments presented by Chovatiya et al. They simultaneously argue that baseline population severity differences preclude direct comparison between studies, dismissing the results of our comparative analysis, while also asserting that the maintenance effect of lebrikizumab is equal or superior to that of dupilumab, thereby making a cross-study efficacy claim. This logic inconsistency shows reasoning bias and undermines the validity of their arguments.

Clinical and Mechanistic Context

Mechanistically, our findings are biologically plausible, given that dupilumab blocks both IL-4 and IL-13 signaling via IL-4Rα, whereas lebrikizumab only binds IL-13. The inhibition of both IL-4 and IL-13 signaling is likely to have a greater and more durable effect on the type 2 inflammation that drives atopic dermatitis [11]. This mechanism-based hypothesis is supported by multiple anchored indirect treatment comparisons, including the original Bucher ITC [1], the anchored MAIC validation [4], and network meta-analyses [12–14], all consistently demonstrating efficacy results in favor of dupilumab.

Conclusion

We stand by our Bucher ITC analyses, which (1) follow established NICE and ISPOR guidelines, (2) have been validated by anchored MAIC using the methodology advocated by Chovatiya et al., (3) demonstrate consistently favorable results for dupilumab versus lebrikizumab across multiple analytical approaches, and (4) transparently report all baseline characteristics and acknowledge limitations.

We appreciate this methodological discussion as it contributes to advancing rigorous comparative effectiveness research in dermatology.

Author Contributions

All authors contributed to writing (original draft preparation and review and editing): Sonja Ständer, Andreas Pinter, Firas G. Hougeir, Patricia Guyot, Yingxin Xu, Amy H. Praestgaard, Nick Freemantle, Ana B. Rossi, Gaëlle Bégo-Le-Bagousse, Zhixiao Wang, Kerry Noonan, and Mike Bastian. Conceptualization was performed by Gaëlle Bégo-Le-Bagousse, Mike Bastian, and Nick Freemantle. Methodology was developed by Gaëlle Bégo-Le-Bagousse, Yingxin Xu, Patricia Guyot, and Nick Freemantle. Validation was carried out by Gaëlle Bégo-Le-Bagousse, Yingxin Xu, Patricia Guyot, and Amy H. Praestgaard. Formal analysis and investigation were conducted by Yingxin Xu, Patricia Guyot, and Amy H. Praestgaard. Data curation was completed by Patricia Guyot, and visualization was performed by Gaëlle Bégo-Le-Bagousse. Supervision was provided by Gaëlle Bégo-Le-Bagousse, Kerry Noonan, and Mike Bastian. Funding acquisition was led by Gaëlle Bégo-Le-Bagousse. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.

Funding

This research was funded by Sanofi and Regeneron Pharmaceuticals Inc. No funding or sponsorship was received for publication of the article.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author, Mike Bastian, on reasonable request. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at https://www.vivli.org.

Declarations

Conflict of interest

Sonja Ständer declares receiving research grants from Almirall, Galderma, Sanofi, and Trevi Therapeutics; has been a consultant for AbbVie, Almirall, Amgen, BMS, Beiersdorf, Clexio, Galderma, Kiniksa, Klinge Pharma, KliRNA, P.G. Unna Academy, Pfizer, Sanofi, and Vifor; has served as an advisory board member for AbbVie, Almirall, Celldex, Galderma, Lilly, P.G. Unna Academy, Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, and Vifor; and has served as a speaker for AbbVie, Almirall, Amgen, Beiersdorf, Eli Lilly, Focus Insight, FOMF, GCI Health, Galderma, LEO Pharma, L’Oreal, MEDahead, Medicinske Tidsskrifter, Novartis, P.G. Unna Academy, Pfizer, Sanofi, STREAMED UP, touchIME, UCB, and Vifor. Andreas Pinter has been involved in clinical trials for AbbVie, Almirall Hermal, Amgen, Biogen Idec, BioNTech, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Galderma, GSK, Hexal, Janssen, Klinge Pharma, LEO Pharma, MC2 Pharma, Medac, Merck Serono, Mitsubishi Tanabe Pharma, MSD, Novartis, Pascoe, Pfizer, Regeneron Pharmaceuticals Inc., Roche, Sandoz, Sanofi, Schering-Plough, Tigercat Pharma, UCB Pharma, and Zuellig Pharma; declares receiving speaker fees from AbbVie, Almirall Hermal, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Galderma, Janssen, Klinge Pharma, LEO Pharma, Medac, Novartis, Pfizer, Sanofi, UCB Pharma, and Zuellig Pharma; and has received grants from AbbVie and Almirall. Firas G. Hougeir has been a consultant/speaker for AbbVie, Apogee, Eli Lilly, Galderma, LEO Pharma, Pfizer, Sanofi, and Regeneron Pharmaceuticals Inc.; and investigator for Apogee, Eli Lilly, Galderma, and LEO Pharma. Patricia Guyot, Amy H. Praestgaard, Ana B. Rossi, Gaëlle Bégo-Le-Bagousse, Kerry Noonan, and Mike Bastian are employees of Sanofi, and may hold stock and/or stock options in the company. Yingxin Xu and Zhixiao Wang are employees and shareholders of Regeneron Pharmaceuticals Inc. Nick Freemantle has received grants from Cure Parkinson’s Trust, European Union, Medical Research Council, and National Institute for Health and Care Research; consultancy fees from Abbott, Aimmune Therapeutics, ALK, AstraZeneca, Galderma, Gedeon Richter, Ipsen, Novo Nordisk, Sanofi, Thea Pharma, and Vertex Pharmaceuticals; and honorarium from Abbott Singapore.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.