Kisunla (donanemab): BLA 761248

Aducanumab and lecanemab are amyloid-beta directed antibodies that received accelerated approval and traditional approval, respectively, and are indicated for the treatment of Alzheimer's disease, specifically patients with mild cognitive impairment (MCI) or mild dementia stage of disease.

For a summary of regulatory activity prior to the initial BLA submission for accelerated approval refer to the previous clinical efficacy review (Krudys, DARRTS 1/17/2023).

Because accelerated approval was never granted for the original submission, Study AACI is reviewed in the context of providing substantial evidence of effectiveness for traditional approval rather than simply verifying clinical benefit.

Study AACG, the relatively smaller Phase 2 study, was reviewed during the original submission for accelerated approval (Krudys, DARRTS 1/17/2023) and will only be briefly summarized in this review.

The clinical efficacy review for that submission recommended accelerated approval based on a finding of substantial evidence of effectiveness on a reasonably likely surrogate endpoint.

The applicant has provided substantial evidence of effectiveness to support accelerated approval.

The results of Study AACI demonstrate a reduced decline of approximately 20% to 30% on clinical endpoints in the combined population.

Statistically significant reduction in clinical decline in the Division's recommended endpoint, CDR-SB, was also demonstrated, with a treatment effect of -0.70 [-29%], p<0.001 in the combined population.

Statistically significant results favoring donanemab were observed for the multiplicity-controlled secondary endpoints ADAS-Cog 13 (-1.33 [-20%], p<0.001) and ADCS-iADL (1.70 [-28%], p<0.001), the two endpoints which comprise the iADRS.

This review will therefore focus on the results of Study AACI as an adequate and well-controlled large multicenter trial which can provide substantial evidence of effectiveness.

The purpose of this review is to evaluate whether the results of Study AACG and Study AACI provide substantial evidence of effectiveness to support the traditional approval of donanemab for the treatment of Alzheimer's disease.

Additional exploratory analyses were performed for iADRS and CDR-SB to determine whether subjects met a prespecified percentage of disease slowing at month 12 and month 18 based on the estimated placebo decline.

However, given the positive trends in treatment benefit and biomarkers for all subgroups, the review team recommends dosing in all ApoE ε4 genotypes, but describing efficacy and safety data in this subgroup to inform benefit-risk assessment.

Therefore, additional safety data would be needed to inform risk-benefit considerations in this population.

Please see the separate safety review by Dr. Branagan for considerations regarding a REMS.

The safety of donanemab was discussed at the meeting within the context of the benefit-risk assessment and within the context of whether subgroups of patients exist for whom the benefit-risk assessment would be more or less favorable.

The Agency has determined that there is not a need for a REMS.

The frequency of serious ARIA-E cases was 1% and serious ARIA-H microhemorrhage and ARIA-H superficial siderosis cases was less than 1%.

A postmarketing commitment to evaluate the long-term efficacy of dose cessation, including the potential need for maintenance dosing, is recommended.

At the time of this review, final labeling, enhanced post-market pharmacovigilance and post-marketing requirements (PMRs) were still under review.

In response to the CR and to support a traditional approval pathway, the sponsor has submitted the results of the Phase 3 confirmatory study, 15T-MC-AACI, to support the efficacy and safety of donanemab for the treatment of AD.