A plain language summary on indirectly comparing bleeding after valoctocogene roxaparvovec gene therapy to bleeding with emicizumab prophylaxis

Plain Language Summary: What is the study about? Hemophilia A is a genetic bleeding disorder that causes bleeding for long periods because of lower than normal levels of factor VIII (FVIII), a protein that is important for blood clotting. FVIII replacement therapy is the typical approach to manage bleeds, but new and improved therapies are becoming widely available. Prophylaxis with the medication emicizumab and gene therapy with valoctocogene roxaparvovec are two such novel treatments approved for use in adults with severe hemophilia A without inhibitors. Two separate clinical trials, HAVEN 3 and GENEr8-1, showed emicizumab and valoctocogene roxaparvovec reduced the frequency of bleeds when switching from FVIII prophylaxis. However, these therapies have not been directly compared in a clinical trial. Given important differences in the overall structure and people who participated in the HAVEN 3 and GENEr8-1 trials, a straightforward comparison of bleeding rates between trials would be inappropriate. Unanchored matching-adjusted indirect comparison (MAIC) is a method used to allow for comparisons across studies that are not exactly the same. What was the objective? This summary shares the results of a MAIC analysis between emicizumab and valoctocogene roxaparvovec using participant data from GENEr8-1 and published data from HAVEN 3. After balancing the baseline characteristics of the participants from each study to be more similar, the proportion of participants with zero bleeds and participants’ annualized bleeding rate (ABR) were compared. What are the key takeaways? After valoctocogene roxaparvovec gene therapy, a higher percentage of participants reported zero bleeds, and participants had lower ABRs compared with emicizumab prophylaxis. FVIII prophylaxis (as provided in the GENEr8-1 trial) and emicizumab were also compared, which found less bleeding occurred with emicizumab than with FVIII prophylaxis. What are the main conclusions reported by the researchers? While a single infusion of valoctocogene roxaparvovec provided better protection against bleeds than emicizumab prophylaxis, and emicizumab provided better protection against bleeds compared to FVIII prophylaxis, the limitations of the MAIC analysis as an indirect comparison should be considered when interpreting these results. Overall, these data provide important treatment information for health professionals and individuals with hemophilia A to consider for their treatment goals. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text.