Treating Alzheimer’s: regulatory hurdles in an anti-amyloid revolution

Leqembi (lecanemab-irmb) is a product that contains a monoclonal antibody directed to amyloid-beta. It is intended to reduce the formation of protein containing plaques in the brain which are associated with cognitive decline in Alzheimer’s disease. The US Food and Drug Administration (FDA) recently converted the accelerated approval of the drug, granted in January 2023, to a full authorisation on the back of data from pivotal clinical studies conducted by the marketing authorisation holder, Eisai¹. 

Accelerated approvals

The initial authorisation was converted in July 2023 after Eisai submitted the results of the pivotal CLARITY AD trial to the FDA. This study has been hailed as a breakthrough as the data show that Leqembi achieved a 27 percent reduction in the progression of Alzheimer’s, provided patients were treated early following the diagnosis of the disease.

Alzheimer’s is associated with neuronal organisational changes in brain. Amyloid beta plaques form in the brain prior to the development of further tangles of another protein called tau. While there is a growing acceptance that these proteins, and their presence in the brain, are not the trigger for the disease, but much more likely as the endgame manifestation of the Alzheimer’s cognitive decline progression, there is still hope that targeting these anomalies could have clinical benefits for sufferers. Lecanemab targets amyloid beta and was shown to reduce brain amyloid plaques in a dose dependent manner. This property of the drug was found by the FDA to justify accelerated approval in January 2023 as it was “reasonably likely to result in clinical benefit for patients”².

Developing Alzheimer’s therapies

Results from the CLARITY AD represent the first success of a medicine in treating the progression of Alzheimer’s. To appreciate the importance of these results, they should be seen in the historical context of the development of therapies since the discovery of the disease.

Many companies have tried and failed to develop Alzheimer’s medicines and the disease itself has been intractable in terms of bona fide treatments. Some medicines have been authorised to treat the symptoms of the progressive cognitive decline that accompanies the disease. Even then, there was a twenty-year gap between the authorisation of the last Alzheimer’s treatment and the 2021 authorisation of the anti-amyloid therapy Aduhlem (aducanumab), also approved by the FDA as an accelerated marketing authorisation. However, if anything, that approval only served to increase doubts in anti-amyloid therapies. The initial FDA accelerated marketing authorisation for Aduhelm has not, to date, been converted into a full marketing authorisation.

Learning from lecanemab: a breakthrough treatment

While the amyloid theory of Alzheimer’s progression has been around for some time, the data supporting the FDA accelerated authorisation of Aduhelm did not convince some agencies outside the US³. The European Medicines Agency (EMA) withdrawal report states that “although Aduhelm reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established. Results from the main studies were conflicting and did not convincingly show that Aduhelm was effective at treating adults with early-stage Alzheimer’s disease.”

This conclusion was based on the same data submitted to the FDA. However, the EMA expressed concerns around overall efficacy and, coupled with a concern raised over possible side effects presenting as brain abnormalities suggestive of swelling or bleeding on the brain, led the EMA to the view, following a re-examination process, that it would not recommend the approval of Aduhelm.

Even prior to the initial grant of its accelerated approval in 2021, high profile scientific journals carried articles questioning whether the FDA should rush to approve what turned out to be the first treatment approved for Alzheimer’s disease in 20 years⁴. Further criticism has been levelled at the interactions between the FDA and Biogen, the company marketing aducanumab, by investigations conducted by several US Congressional committees¹.

Approval of Alzheimer’s treatments

The future

In contrast to the controversy of the FDA’s actions over Aduhlem, data for Leqembi appears to illustrate a more conventionally positive picture for the benefit versus risk of anti-amyloid therapies. Outside the US, the EMA accepted the assessment of Leqembi on 26 Jan 2023, but it is not indicated to be under any form of accelerated assessment². Under a “usual” EMA assessment timetable, it is likely that Leqembi would not be authorised before Q2 2024. 

Given the clamour that has accompanied the approval of Leqembi in the US, it is also possible this could prompt the EMA to give it further consideration as a truly transformational therapy for high unmet needs and therefore provide justification to extend the use of the OPEN framework³. This is a relatively new multi-national collaborative project that aims to coordinate the review of important medicines across multiple jurisdictions more effectively to coordinate and align regulatory decision making. Interestingly, if Leqembi had been accepted on the EMA’s PRIME (PRIority MEdicines) initiative⁴ on the basis it was a medicine to treat a high unmet need, it would also have been eligible for the extended OPEN framework initiative announced by the EMA in July 2023.

The anti-amyloid revolution for Alzheimer’s

The validation of targeting amyloid could be given a further boost from results concerning another monoclonal antibody product, donanemab. Data has demonstrated similar, if not more promising evidence for its ability to slow the Alzheimer’s progression, compared to Leqembi. Eli Lilly published data from its TRAILBLAZER-ALZ 2 Phase III study that suggested donanemab could reduce the progression of early stage Alzheimer’s disease by around 35 percent⁵. 

These promising data from Phase III trials concerning lecanemab and donanemab have now shone a spotlight on diagnostic methods. These treatments are thought to work best when administered to patients as early as possible post-diagnosis. Hence catching Alzheimer’s and diagnosing the condition at an early a stage as possible has now become something of an imperative.

To conclude, the conversion of the accelerated approval of Leqembi looks set to drive fast-tracking and accelerated approvals of other promising Alzheimer’s therapies both in the US and wider afield. It is perhaps no coincidence that in January 2023, Lilly’s donanemab was rejected by the FDA for consideration under the accelerated approval. However, since publication of further clinical data for that drug, plus the conversion of Leqembi’s marketing authorisation, the EMA is reportedly considering donanemab for accelerated review⁶. If accelerated review is granted, this could lead to lecanumab and donanemab being authorised in close succession in 2024. This would be a welcome boost for Alzheimer’s sufferers in Europe. Based on recent regulatory activity, the age of anti-amyloid therapy for Alzheimer’s appears to have well and truly dawned.

About the author

Gareth Morgan is a life sciences partner at multinational law firm Pinsent Masons. He has decades of experience advising on patents, SPCs and regulatory exclusivities rights and has litigated in UK and EU courts. He advises clients on all exclusivity rights around pharmaceuticals and medical device products.

References

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