Aduhelm (aducanumab): BLA 761178

Dr. Krudys has also reviewed the evidence to support accelerated approval and concludes that reduction in brain amyloid as measured by PET is reasonably likely to predict clinical benefit.

In this setting, where the evidence supporting clinical benefit is strong but associated with the residual uncertainty conveyed by the clinical endpoint results of Study 301 (and the associated contribution of those results to the premature termination of both studies), Dr. Krudys concludes that the accelerated approval pathway is supported by the data.

The primary clinical review and the clinical pharmacology team's review have resulted in a conclusion that substantial evidence has been provided for the clinical benefit of aducanumab and both recommend standard approval.

Finally, a surrogate outcome for which there is substantial evidence of effectiveness, reduction in amyloid beta plaques on PET imaging, has been assessed in the aducanumab development program, and is reasonably likely to predict clinical benefit, as demonstrated in the reviews discussing the relationship of amyloid plaque reduction to clinical outcome.

When residual uncertainty exists about the clinical benefit of a drug, it is important to address that uncertainty, and accelerated approval provides an opportunity to address the uncertainty associated with a surrogate outcome that is reasonably likely to predict clinical benefit by requiring a post-approval study to verify the clinical benefit predicted by the effect on the surrogate.

As discussed above, he concludes that the accelerated approval pathway is supported by substantial evidence of the effect on aducanumab on reduction in amyloid beta plaques.

He also notes that the time- and dose-dependent effect of aducanumab on reduction of brain amyloid beta plaques observed across Studies 103, 301, and 302 meets the standard for substantial evidence of effectiveness in this context.

Despite the early termination of Study 302, Dr. Krudys considers the data submitted to be interpretable and capable of providing evidence for the effectiveness of aducanumab for AD.

In summary, regarding the evidence of effectiveness of clinical benefit, data from an early phase study (103) showed a notable dose-related numerical reduction in clinical decline relative to placebo for CDR-SB and MMSE, with nominal significance for both CDR-SB and MMSE at 10 mg/kg.

These additional findings of an effect on other critical aspects of Alzheimer's pathophysiology at doses of aducanumab associated with reduction in amyloid beta plaque and correlated with evidence of clinical benefit contribute to a reasonable likelihood that a lowering of amyloid beta plaque will result in clinical benefit.

OCP concludes that a larger reduction of brain amyloid is associated with less change on the CDR-SB (i.e., clinical benefit).

In its biostatistics review, the Office of Biostatistics (OB) within OTS provided documentation for its recommendation that substantial evidence of effectiveness had not been provided in the application.

Based upon this, I agree with the Office of Neuroscience that the benefit-risk balance for aducanumab is positive given the potential for important clinical benefit in the absence of treatment options that target the underlying disease, and with manageable risks, even considering the remaining uncertainty of clinical benefit.

Additional safety data would be helpful to inform risk-benefit considerations in this population.

Serious adverse events (SAEs) of ARIA in the placebo-controlled portion of studies 301 and 302 occurred in 2% (17/1105) of patients in the aducanumab 10 mg/kg group, compared with 0.2% (2/1087) of patients on placebo; SAEs occurred in 0.4% of patients with ARIA in the 10 mg/kg group.

To demonstrate the overlap of multiple types of ARIA in the same subject, I analyzed Study 302, and found all 8 patients with serious adverse reactions with ARIA experienced ARIA-E. Three of the patients also had ARIA-H superficial siderosis, 2 also had ARIA-H microhemorrhage, and 1 also had an ARIA-H cerebral hemorrhage.

As can be seen in Table 13, for patients allocated to the treatment arm of 10 mg/kg aducanumab, the risk for ARIA-E, ARIA-H microhemorrhages, and ARIA-H superficial siderosis is higher in ApoE ε4 carriers relative to noncarriers.

The Sponsor proposed a communication plan Risk Evaluation and Mitigation Strategy to mitigate the risk of ARIA.

If postmarketing clinical trials fail to verify clinical benefit or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 601.43(b), withdraw this approval.

If the confirmatory trial does not show that the drug provides clinical benefit, it could lead to removing the drug from the market.

The further study on the immunogenicity assay will inform any addition revision, if needed, is needed for the assay which will be used for testing clinical samples from the required confirmatory trial.