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

Commentary

The Alzheimer’s puzzle isn’t yet solved.

The approval of Aduhelm (aducanumab) in June 2021, the positive results disclosed for donanemab in November 2022 and the accelerated approval of Leqembi (lecanemab) in January 2023, three drugs which reduce the amyloid plaque in the brain of Alzheimer’s patients, could trigger the belief that, after all these years, finally beta amyloid has proven to be the exclusive target to treat this dreadful neurodegenerative disease. This would be premature. There is still no consistent correlation between the reduction of amyloid plaque and the slowing down in patients’ cognitive function. To cite one expert: ‘we do not have the surrogate of amyloid established.’ The clinical outcomes for donanemab, the antibody treatment with the largest brain amyloid clearance at six months, will therefore be highly scrutinised.

Leqembi showed a reduction of 0.45 points in the rate of cognitive decline as measured by the Clinical Dementia Rating Sum of Bones (CDR-SB), an 18-point scale. How does one address patients and their caregivers on what to expect with a benefit representing an average of two weeks disease progression decline after 18 months of a biweekly intravenous treatment? “Eighteen months of treatment producing a difference of that minimal size is not the clinical benefit that patients are hoping for. This drug does not give anyone their memory back,” said Matthew Schrag, a researcher at Vanderbilt University in the US. The current clinical endpoints are measures of CDR-SB scores and the change in amyloid burden is assessed by a positron emission tomography (PET) scan, an invasive procedure to monitor disease progression. This is a lot to ask a patient to endure given the modest clinical benefit.

Furthermore, beta amyloid antibodies have been linked to a side effect called amyloid-related imaging abnormalities with brain oedema or effusion (ARIA-E). This needs to be monitored by magnetic resonance imaging (MRI) prior to treatment and again before the fifth, the seventh, and the fourteenth infusion. This is a procedure which involves a costly and stressful visit to a hospital for patients who may be frail.

From the point of view of a patient, the two recently approved treatments are far from being a panacea. In addition, they come at a yearly price of more than $25,000 which is unsustainable for most people.

Are the current poor clinical outcomes obtained with beta amyloid antibodies the best that one can expect? If cognition scores from 1,800 patients treated with donanemab are not substantially better, we will need to fundamentally reconsider this hypothesis.

Because of the high complexity of the brain, we believe that only approaches which embrace a holistic model for Alzheimer’s pathogenesis, where the neural system, the immune system and the vascular system are examined together will provide breakthrough therapeutic solutions. More scientists are now willing to start clinical studies where a beta amyloid pathway drug is combined with agents which restore synaptic plasticity, insulate neurons from injury, activate the microglial function and remove debris from Alzheimer patients’ brains. Unfortunately for the 55 million patients suffering from this disease, there is still a long way to go before ‘disease modifiers’ are available to significantly slow down or stop the progression of this disease.

Paris, February 18, 2023

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