Biogen’s aducanumab is more likely to be granted conditional versus full FDA approval in Alzheimer’s disease (AD) based on recently presented data. The results presented in the Phase III EMERGE study need confirmation in order for the drug to not face a regulatory rejection.

Still, an expected advisory committee (AdCom) meeting vote will be split, and it is unlikely that the panel will be unanimous in their recommendations for aducanumab given the current data. Despite this caveat, high unmet needs in AD and patient advocacy group support would mean a rejection inviting much criticism for the FDA, creating an incentive for the agency to consider the conditional approval option.

The highly anticipated data for the 1,638-patient EMERGE (NCT02484547) study at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting on 4–7 December in San Diego, California revealed that aducanumab achieved a modest effect compared to some currently used AD treatments, meeting benchmarks investigators had previously said would be approvable. However, gaps in the data make a straightforward, non-conditional approval unlikely. But rejection is less likely considering patient support and that Biogen’s CTAD presentation strengthened impressions of EMERGE and adequately explained why the 1,647-patient ENGAGE (NCT02477800) Phase III trial in AD failed.

It remains to be seen if aducanumab could be accessible only to a restricted group of patients following a conditional approval. EMERGE’s data only showed efficacy signal in the mildest AD severity patients, and data on the apolipoprotein E4 (ApoE4) noncarriers still have not been revealed. This precludes expectations on whether patients outside of the presented data set can even access this treatment, they added.

Biogen announced it would file a Biologics License Application in 1Q20, and analyst reports have projected a timeline of 3Q20 for the AdCom meeting. Following CTAD, two analyst reports have put out optimistic sentiments, while two others have indicated low approval chances. Others have recommended waiting for the AdCom meeting to pan out for better approval impressions.

Two analyst reports estimated sales of $2.4bn–3.6bn by 2028, and Biogen has a market cap of $54bn. Biogen did not respond for comment.

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By GlobalData

Conditional approval an attractive compromise<

The EMERGE data at CTAD highlighted an approvable path, though confirmation would be needed, three investigators agreed. Given how long it would take to run another trial—EMERGE and ENGAGE took four years each to produce results—it would reflect very poorly on the FDA to dismiss the submission without compelling reason, the second investigator noted. The third investigator agreed, and noted that the CTAD presentation had addressed one of the biggest questions in the field on whether EMERGE’s efficacy would have been clinically meaningful.

However, the question remains whether the FDA would be amenable to a confirmatory trial after a conditional approval, or would it issue a rejection and request Biogen resubmit again after another trial that would be identical to EMERGE using the finalized protocol, the first investigator said.

This news service reported on 6 November 2019 that investigators said aducanumab could be approved even with a modest effect size, though that cannot be determined with just percentage scores and that baseline and raw score data were needed. Biogen had announced on 22 October that EMERGE turned out to be a positive trial that showed a 23% improvement in its primary endpoint of clinical dementia rating scale-sum of boxes (CDR-SB). The CDR-SB scale is commonly used in clinical trials to gauge drug efficacy.

The first two investigators noted that the 0.4-point lower decline than placebo (p=0.01) on CDR-SB corresponded with a modest effect size, and was comparable with some of the cholinesterase inhibitors (ChEIs) currently used for AD. Literature of ChEIs’ effect sizes at high doses suggested a median of about 0.28 (Rockwood, J Neurol Neurosurg Psychiatry. 2004 May; 75(5): 677–685), while calculations of aducanumab’s effect size from CTAD data is about 0.38. A third investigator agreed that aducanumab met the approvable effect size threshold of about 0.2–0.3, but added it is not feasible to compare effect sizes between aducanumab and ChEI literature due to different baseline patient characteristics.

The last approved drug for AD was memantine in 2003, now available as a generic, and there is a great need for new therapies beyond memantine and ChEIs, all investigators agreed. Conventionally, aducanumab not having met the two positive pivotal trials requirement would have been reason to issue a rejection, but the unmet need in AD and the compelling data in EMERGE alone would at least give the FDA pause to consider compromises, of which a conditional approval is an attractive, viable option, the second investigator said.

All three investigators agreed that the upcoming AdCom panel will be split, as the data is compelling enough to draw support in both camps. A unanimous recommendation for either decision is highly unlikely, they said.

Patient advocacy push, unanswered efficacy questions on patient subsets

It is not clear how much impact advocacy can have on pressuring the FDA to approve a drug, but aducanumab certainly has received much public attention, placing the FDA under additional scrutiny, the first and third investigator said. However, the third investigator pointed out the precedence of high unmet need in the disease space and strong patient advocacy eventually leading to conditional approval, despite weak submitted data, as for the case of Sarepta’sExondys 51 (eteplirsen). The therapy received accelerated approval in Duchenne muscular dystrophy conditioned with a confirmatory trial after the decision, despite its negative AdCom decision.

Given the FDA’s willingness to work with AD drug submissions that do not meet conventional standards, as indicated by a 2018 FDA guidance, the first investigator said he is hopeful for a favourable decision.

Washington, DC-based AD advocacy group UsAgainstAlzheimer’s would call for the FDA to expeditiously review the BLA upon its submission, said Chief Communications Officer Roger Lowe, though did not elaborate on plans. CTAD data and Biogen’s October presentation showed positive results, Lowe added.

Even if aducanumab were conditionally approved, the CTAD data did not address the ApoE4 noncarrier subset, prompting questions on label restrictions, all three investigators said. EMERGE had about 30% noncarriers, but there was no efficacy data or dropout rate on this subgroup, they said. The dataset does not provide strong evidence for efficacy or even safety for the noncarrier group, since non-carriers are hypothesized not to respond as well to beta-amyloid clearing strategies than carriers.

The dataset also does not speak to efficacy for patients with a disease severity beyond clinical dementia rating-global score (CDR-GS) 0.5—defined as very mild, the first and second investigators said. Of the 547 patients in the high-dose arm, only one patient had a baseline CDR-GS score of 1—defined as mild—which is insufficient to draw confidence for efficacy, they said. While the first investigator acknowledged that the trial is designed to recruit mostly very mild patients, it also leaves questions on how patients with CDR-GS scores of 1 or higher might fare with aducanumab. It is not clear however that an approval label would necessarily exclude patients who are not CDR-SB 0.5, though it could be possible payers might see the lack of evidence in the dataset as a motivation to set up access restrictions, the second investigator said.

by Shuan Sim in New York.

Shuan Sim is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.