,

Btobioinnovation.com 

Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com 

SPECIAL REPORT #21.23

Alzheimer’s disease treatments (Part 3)

In our report #21.18, we had indicated that: “It is possible to identify other trends flowing from the decision of the FDA to approve Aduhelm that may have lasting impact. Firstly, there will likely be rapidly more anti-amyloid-beta products coming for a regulatory review now that one product of this type has been approved”.

Less than three months later this prediction is already shown to be correct.

It started on August 17, 2021, when Eli Lilly announced a major executive leadership change and the creation of a dedicated neuroscience unit aimed at increasing Lilly’s focus on introducing breakthrough new medicines. Lilly had always hoped to file donanemab, its own beta-amyloid treatment, but was told at the time, by the FDA, that additional data would be required. A few weeks before Biogen’s Aduhelm was given an accelerated approval, Lilly’s management was considering conducting at least two more clinical studies in order to file donanemab in the US. Once the FDA had signalled that reduction of amyloid as a biomarker was an acceptable endpoint for Alzheimer’s disease treatment, Lilly rapidly shifted gears and went full speed to push the filing of donanemab with the already available data. On October 20, in their third quarter update, Anne White, senior VP of Lilly’s neuroscience unit, said that Lilly had begun a rolling submission of donanemab and was expecting to receive an accelerated approval before the release of the ongoing phase 3 data in 2023. She also indicated that Lilly had launched a head-to-head phase 3 study named TRAILBLAZE-ALZ 4 to show that donanemab was superior to Biogen’s aducanumab. “By clearing plaque faster and deeper, we believe… we have optimised the chances for showing compelling benefits in Phase 3” White said.

With the possibility to obtain an Alzheimer’s drug approval based on biomarker results, rather than the usual clinical endpoints, Biogen and Eisai on the one hand and Genentech and Roche on the other hand have also prepared FDA filling for their drugs.

On September 27, Biogen and Eisai, which have partnered since 2014 in the neuroscience field, announced that they begun the process of asking the FDA for accelerated approval for lecanemab, for which they have already received a breakthrough designation, and which works with a different mechanism from Aduhelm.  The application will be filed by Eisai, in a rolling fashion, and is based on results from a Phase 2 study of 856 patients with mild cognitive impairments that showed reduction of toxic brain plaques. It is not clear which is the exact dose of lecanemab the Japanese company is asking FDA to approve, but the 10 mg/kg dose was the one which delivered the best results. Eisai also indicated that they have already initiated a Phase 3 study in March 2019 and completed enrolment earlier this year with 1,795 patients. This ongoing study could serve as a confirmatory trial if the drug receives an accelerated approval.   

On October 8, Roche and Genentech announced that the FDA had granted breakthrough therapy designation for gantenerumab, almost five years after its pivotal clinical study was declared a failure and forced a temporary burial of the drug. Roche and Genentech are expected to complete two pivotal trials in late 2022 and receive a positive outcome from the FDA in less than a year from now.

Issues on pricing of these drugs will clearly be scrutinized by many observers, including politicians. The recent extremely slow launch of Adulhelm, with a stunning low number of $300 000 in third quarter sales is very far from an analyst consensus of $14 million. This setback is mainly due to the outrageously high price of $56,000 per year Biogen has set delays and even refusals on reimbursement by some payors.

It is more than of passing interest to note that none of the above-mentioned products will be available to European patients in a close foreseeable future. To the best of our knowledge neither Biogen, Eisai, Eli Lilly, Genentech or Roche are considering filing their drugs at the European Medicines Agency at this stage of their clinical development.

In our July issue we also stated:” Researchers may be emboldened to try new approaches which go beyond plaque destruction to examine biological features of Alzheimer’s disease.” It nevertheless came as a surprise when Alice Taubes and authors from the Gladstone Institute of Neurological Disease in San Francisco, from the University of California in Los Angeles and from the Icahn School of Medicine at Mount Sinai in New  York, published unexpected data, in the October 10 issue of Nature Aging. Their study, funded by NIH, based on experimental and real-world evidence, supports the repurposing of bumetanide, a long known oral loop diuretic agent, for the treatment of Alzheimer’s disease. The research team analysed information in databases of brain tissue samples and FDA approved drugs.  One of the most significant genetic risk factors for Alzheimer’s disease is a form of apolipoprotein E gene called APOE4. The team conducted computational drug-repurposing screen on more than 1,300 FDA-approved drugs. Five emerged with a gene expression, signature of interest. The most promising was bumetanide, a diuretic agent which has already been prescribed to millions of patients. The team validated the hypothesis by testing bumetanide in mouse models of Alzheimer’s disease and in induced pluripotent stem cell-derived human models. The neutralizing effects of bumetanide, which block the NKCC1 cation chloride co-transporter in the brain, was confirmed in both models. The team also performed a real-world model study in analysing electronic health record data sets from more than 5 million people and established two groups: adults over 65 years of age who took bumetanide and a matching group who did not take the fluid retention drug. The analysis was striking: subjects with the APOE4 genetic risk who took bumetanide had a 35% to 75% lower prevalence of Alzheimer’s disease compared to those not taking bumetanide. We are eagerly looking forward to reading the comments of the neurodegenerative scientific community regarding these findings.

Paris, October 29, 2021

This document has been prepared by btobioinnovation and is provided to you for information purposes only.  The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.