FDA Approval Is A Big Step But Alzheimer’s Drugs Face Other Hurdles

The breakthrough drug lecanemab captured considerable attention last November at the Clinical Trials on Alzheimer’s Disease conference when data revealed that it was successful in slowing cognitive decline brought on by the disease. As we outlined last December, it was a major step forward, advancing the argument that drugs targeting amyloid plaques in the brain could slow down or stop the course of the disease.

Seven months later, the US Food and Drug Administration has now granted full regulatory approval to the drug, branded as Leqembi and being sold via a 50/50 profit share by Biogen and Eisai. Meanwhile, Eli Lilly, building off promising Phase 3 clinical trial data for its competing drug donanemab said it would seek “the fastest path to traditional regulatory approvals.” That could mean full FDA approval sometime over the next 12 months.

But the path forward for novel therapies won’t be easy and even after being approved, there are still considerable challenges in getting them to patients promptly.

The Road to FDA Approval

Leqembi was granted accelerated approval by the FDA in January. However, due to controversy surrounding the approval of its predecessor Aduhelm, lecanemab did not receive Medicare coverage unless patients were enrolled in a randomized clinical trial. Nonetheless, the US Veterans Health Administration announced coverage for lecanemab in March, giving the Biogen-Eisai profit share an initial source of revenue.

Things continued to pick up for lecanemab in June when the Centers for Medicare and Medicaid Services announced that it will offer Medicare coverage of novel Alzheimer’s disease therapies that are granted traditional FDA approval, as long as providers participate in registry data collection efforts. Theoretically, the FDA's full approval of Legembi, now opens up coverage for those who are eligible, albeit with the standard deductible and 20% coinsurance.

Eli Lilly’s donanemab hasn’t had such an easy ride from a regulatory perspective. Shortly after the FDA issued accelerated approval for Leqembi, the agency denied donanemab the same status. This came with a specific request to provide data for at least 100 patients receiving donanemab for at least 12 continuous months. Due to the design of Lilly’s trial, paired with the efficacy of treatment, many patients had completed their course of therapy well before the 12-month mark. Eli Lilly has since reported Phase 3 trial results.

How the Products Stack Up

Excitement about the novel therapies is justified, given that both lecanemab and donanemab have met all primary and secondary endpoints in their pivotal trials with highly significant results. Both products showed a slowing of decline versus placebo at 18 months by 27% to 36%, depending on the measurement scale used and the population studied. Based on data that’s been published so far, clinical efficacy is comparable between the two.

A greater difference is observed in the safety profiles, where rates of swelling in the brain and cerebral microhemorrhages were considerably higher with donanemab. This is thought to be due to the mechanism of action targeting already-formed plaques instead of soluble precursors. Safety and potential side effects of new therapies will continue to be a focus for regulators, clinicians, and patients. The FDA added a black-box label to Legembi, stating that in rare cases it can cause bleeding in the brain.  

The dosing regimen represents the largest practical difference between the products. In its pivotal trial, donanemab was infused every four weeks until patients reached a predefined level of amyloid plaque clearance, representing a reduced treatment burden compared with dosing every two weeks for Leqembi. The Biogen-Eisai alliance is combatting this by testing both a reduced dosing frequency treatment maintenance phase and a subcutaneous formulation which could prove far more convenient for patients and caregivers in the future. Currently, Eli Lilly is holding out subcutaneous formulations for their next-generation product Remternetug, which is not expected to launch before 2026.

^{Footnote: ARIA-E: Amyloid-Related Imaging Abnormalities with Edema or Effusions; ARIA-H: Amyloid-Related Imaging Abnormalities as Hemorrhages or superficial siderosis; CDR-SB: Clinical Dementia Rating Scale – Sum of Boxes; iARDS: The Integrated Alzheimer’s Disease Rating Scale}

^{1. Efficacy results for donanemab shown refer to the intermediate tau population}

What’s Next?

While these therapies have seemingly overcome the biggest hurdle of all – demonstrating clinical efficacy – it will be a while until their use is truly widespread. We see three major barriers to uptake with the potential to frustrate patients, caregivers, clinicians, and manufacturers.

1. The indication is restricted to an early stage of the disease

According to the label, patients will be eligible for these therapies if considered to have mild Alzheimer’s disease or the prior stage known as mild cognitive impairment MCI. Diagnosis rates are lower during earlier stages of the disease, estimated at roughly 20% in the US for MCI, limiting the size of the population seeking treatment. Since Alzheimer’s is a progressive disease, patients may become ineligible if not diagnosed quickly at this early stage. Given the lack of efficacious therapies until now, primary care physicians are not in the habit of seeking rapid formal diagnoses for suspected cases. This will need to change to enable patients to access the required diagnostics and specialized care sooner.

2. Required diagnostic methods are complex

Diagnosed patients will become eligible for the new therapies once amyloid beta pathology is confirmed. In trials so far, this has involved either PET imaging or cerebrospinal fluid analysis, neither of which are widely available. PET imaging requires specialized equipment and radioactive tracers. The capacity of current imaging centers is likely to present a significant bottleneck to diagnoses. Most PET imaging worldwide is conducted for oncology indications, so an increased throughput of amyloid imaging will require both new routes for amyloid radiotracer supply and more trained professionals to interpret the images.

The currently accepted alternative to PET, CSF testing, involves an invasive lumbar puncture and is not common practice in the US. Blood tests are being developed which would offer greater convenience. The PrecivityAD blood test is already available in the US, and others are developing competing products, including Roche in collaboration with Eli Lilly. The accepted use of Leqembi or donanemab after a blood test alone would enable much faster uptake. For now, however, these tests do not offer the required specificity to provide acceptable proof of amyloid pathology.

On top of testing for amyloid beta pathology, the FDA’s black-box warning for Leqembi recommends genetic testing for ApoE ε4, given its association with an increased risk of adverse events. This will be another test that is not currently standard practice in the diagnosis of Alzheimer’s and will involve further healthcare professionals to provide genetic counseling.

3. Treatment places A considerable burden on patients, caregivers, and prescribers

At launch, both Leqembi and donanemab will be administered by intravenous infusion. This is typically carried out at an infusion center, where patients will need to visit every two weeks for Leqembi and every four weeks for donanemab. The capacity of existing infusion centers may hinder uptake and could complicate access to treatment where patients do not live nearby. The infusion takes approximately an hour, during which the patient is likely to be supported by a caregiver. On top of this, current recommendations for Leqembi state that an MRI should be repeated before the fifth, seventh, and fourteenth infusions to monitor for ARIA, with additional imaging possible if patients present with any symptoms suggestive of ARIA. This practical burden on patients and caregivers may deter patients from initiating treatment.

For clinicians, there will be administrative requirements related to treatment. CMS, for instance, requires data collection via registries. Collected data will include the drugs administered and results of imaging, cognitive, and functional tests conducted. The frequency of required reporting has not yet been specified, but this will lead to a considerable administrative burden which could restrict the volume of patients that prescribers can handle.

These barriers will need to be overcome to allow Leqembi and donanemab to realize their full blockbuster potential. In the meantime, we look forward to further developments in this emerging space as manufacturers look to improve safety and reduce treatment burden.

To learn more contact Matthew Weinstock, Senior Editor, Health and Life Sciences.