Kesimpta FDA Approval Package (APPLICATION NUMBER: 125326Orig1s070)
-Kesimpta treatment reduced the relative risks of 3-month and 6- month confirmed disability worsening by 34.4% and 32.5%, respectively, as compared to teriflunomide. The pooled results from two adequate and well-controlled trials provided substantial evidence of efficacy that Kesimpta reduced the likelihood of accumulation of disability in patients with relapsing forms of MS relative to an active comparator with a significant effect on disability worsening.
-To support an indication for the treatment of relapsing forms of MS, clinical trials should demonstrate that a therapy is associated with a significant, clinically meaningful decrease in the frequency of MS-associated relapses, typically measured as an annual relapse rate (ARR). Some therapies approved for the treatment of relapsing forms of MS, including another anti-CD20 therapy, have also demonstrated an additional significant reduction of the accrual of disability over three-month or six-month observational periods.
-The applicant presents results from two adequate and well-controlled Phase 3 clinical trials as the basis of support for the effectiveness of ofatumumab for the treatment of relapsing forms of MS. These two efficacy and safety studies, Studies COMB157G2301 and COMB157G2302, were both randomized, double-blind, double-dummy, active-controlled studies comparing ofatumumab to teriflunomide treatment in adult patients with relapsing forms of MS. These trials were identical in design with the same primary efficacy outcome measure, ARR, along with the same secondary endpoints (3- month confirmed disability worsening, the number of gadolinium-enhancing T1 lesions, the number of new or enlarging T2 lesions, 6-month confirmed disability worsening, serum neurofilament light chain levels at 3 months, brain volume loss, and 6-month confirmed disability improvement) that were analyzed in a hierarchical analysis.
-A meta-analysis for the combined data (pooled from Studies G2301 and G2302) was prespecified for the key secondary disability-related endpoints, 3-month confirmed disability worsening, and 6-month confirmed disability worsening because the individual studies were not powered for these analyses. If both studies successfully rejected the null-hypothesis of the primary endpoint, disability-related endpoints could be tested at 1-sided significance level of 0.024 using the combined data from both studies, regardless of the outcomes of MRI- and neurofilament-related endpoints.
-Pooled Disability Outcome Findings As per prior agreement, the disability-related key secondary outcome assessments of disability at 3-month and 6-months were to be based on analyses of the pooled data from Studies G2301 and G2302 because each individual trial would not be adequately powered to provide individual study outcome analyses of these relatively small number of outcomes. 3-month Confirmed Disability Worsening (*see Table 11, page 31*)
-The time to 3-month disability worsening was statistically significant (p=0.002) in favor of Kesimpta treatment. Patients treated with Kesimpta had a lower rate of confirmed 3-month disability worsening as compared to patients treated with teriflunomide. Even though the individual studies were not powered for this endpoint, analysis of Study G2301 and G2302 individually yielded statistically significant results for the 3-month disability worsening endpoint (p=0.029 and p=0.036, respectively.) In prior clinical trials, teriflunomide reduced the confirmed disability progression at a 3-month interval relative to placebo; Kesimpta is therefore demonstrating superiority over a treatment that has a significant effect on disability progression in relapsing forms of MS.
-The biometrics reviewer confirmed the findings of the pre-specified secondary outcome analysis and several sensitivity analyses including a “worst-case” analysis in which Kesimpta-treated patients who discontinued from the study due to lack of efficacy were considered as having a confirmed 3-month disability worsening outcome (a risk reduction for ofatumumab vs. teriflunomide of 32.9%, p=0.004). The confirmed sensitivity analyses replicated the pre-specified analysis result, which is a significant effect on prevention of 3-month disability worsening in patients treated with Kesimpta.
-The time to 6-month disability worsening was statistically significant (p=0.012) in favor of Kesimpta treatment. Patients treated with Kesimpta had a lower rate of confirmed 6-month disability worsening as compared to patients treated with teriflunomide. Even though the individual studies were not powered for this endpoint, analysis of Study G2301 and G2302 individually yielded statistically significant results for the 6-month disability worsening endpoint for Study G2301 (p=0.022) but the result for Study G2302 was not significant (p=0.209). In clinical trials, teriflunomide reduced the confirmed disability worsening relative to placebo; in the pooled analysis, Kesimpta is therefore demonstrating superiority over a treatment that has a significant effect on disability worsening in relapsing forms of MS. The biometrics reviewer confirmed the findings of the pre-specified secondary outcome analysis and several sensitivity analyses including a “worst-case” analysis in which Kesimpta-treated patients who discontinued from the study due to lack of efficacy were considered as having a confirmed 6-month disability worsening outcome (a risk reduction for ofatumumab vs. teriflunomide of 29.6%, p=0.022). The confirmed sensitivity analyses largely replicated the pre-specified analysis result, which is a significant effect on prevention of 6-month disability worsening in patients treated with Kesimpta. (*See Table 12 (page 33) and Figure 3 (page 34)
-6-month Confirmed Disability Improvement The following table and figure, taken from the biometrics review, summarizes the time to 6-month confirmed disability improvement in both trials (*See Table 13, page 35). The analysis of confirmed disability improvement at 6-months was not statistically significant (p=0.094).
-Conclusions on the Substantial Evidence of Effectiveness: Approval for Kesimpta (ofatumumab) for relapsing forms of MS is supported by efficacy findings from two adequate and well-controlled clinical trials, Studies G2301 and G2302. These studies demonstrated that Kesimpta treatment yielded consistent statistically significant reductions of over 50% (50.5% and 58.5%) in ARR relative to an active comparator. teriflunomide. A reduction of over 50% in ARR is a robust and meaningful outcome for a therapeutic to treat relapsing forms of MS; in these studies, a significant treatment effect on ARR is established relative to teriflunomide, an active comparator with its own significant treatment effect on ARR. The significant MRI findings in these two studies provide additional supportive findings for the primary clinical outcome analysis. With respect to the primary efficacy endpoint, these studies have provided substantial evidence of effectiveness for Kesimpta in the treatment of patients with relapsing forms of MS and a strong treatment effect on relapses. The disability assessment outcomes from Studies G2301 and G2302 support the conclusion that Kesimpta is superior to the active comparator with respect to reducing the likelihood of confirmed disability worsening. Various sensitivity analyses demonstrate that this effect on disability worsening is independent of relapse occurrences in the trial and is maintained through more conservative sensitivity analyses that assume worsening with missing final confirmation assessments. Drs. Rodichok and Ling note that the applicant’s methodology for calculating disability “worsening” at both time points differed from the conventions used for some historical assessments of confirmed disability “progression” in other development programs. Dr. Rodichok asked for, via an information request, an exploratory analysis from the applicant that utilized calculation methods excluding patient relapse visits as events that initiated or confirmed EDSS progression assessment and assumed patients with any worsening, but without confirmation of disability visits, had confirmed disability progression. The results of this exploratory analysis were confirmed by Dr. Ling and are discussed in the biometrics review. This confirmed disability progression analysis is conservative, even more so than the “worst case” scenario in the applicant’s sensitivity analyses, but the findings from this analysis remained significant for the 3-month confirmed disability progression endpoint (nominal p=0.012) and revealed a strong trend (nominal p=0.074) for the 6- month confirmed disability progression endpoint. Thus, the requested exploratory analysis of outcomes using this conservative approach were consistent with the applicant’s primary analysis and did not suggest that the applicant’s findings regarding disability worsening were driven entirely by relapses and absent confirmatory visits. Finally, the Division requested an analysis that allowed a clinical relapse to occur at the initiation of a disability progression, but excluded relapses that occurred within 30 days of a disability worsening confirmation visit for the 3- month disability confirmation endpoint. This analysis, verified by biometrics reviewer, again demonstrates a significant effect of Kesimpta on disability progression at 3 months (relative risk reduction of 34.9%, nominal p=0.002) in comparison to teriflunomide. The findings of this exploratory analysis are nearly identical to the prespecified primary analysis findings, and this analysis aligns with the Division’s current approach to disability outcome assessment. Thus, there is confidence that the robust treatment effect on disability progression from the applicant’s pre-specified primary analysis that is described in Section 14 of the labeling is comparable to the disability progression outcomes obtained in both historical and contemporary analyses, regardless of the differences in the definition of progression and how relapses were considered within the analytical methods. Furthermore, disability worsening or progression as an endpoint is considered to be a singular concept. A treatment effect that prevents an increase in disability as measured by EDSS over 3 months and 6 months represents only a difference in time of observed persistence, not an achievement of a treatment effect on two entirely unrelated, unique, clinically relevant outcomes. Achieving a significant finding on a single disability outcome, or both 3-month and 6-month outcomes, represents the same fundamental finding, that is, a relative prevention of a clinically relevant accumulation of disability over a quantum of time (*Underlining mine*)
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