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Who Lost When an FDA advisory board rejected Biogen’s Alzheimer’s drug aducanumab? (11/9 update)



By Mel Snyder, mel@pro-clinica.com


This morning, November 9, 2020, Biogen stock dropped from its $328 close the previous Friday to $230 on the news that an FDA advisory board voted 8-1 to reject the company’s drug aducanumab for Alzheimer’s disease - following a recent very positive internal FDA review. The following is an article I wrote in March 2019 when earlier trials suggested failure.



Failure struck more than Biogen last week when the company and its partners terminated its Phase 3 clinical trials of aducanumab for Alzheimer’s disease.


That failure meant everyone alive with Alzheimer's disease effectively received a death sentence. 


Aducanumab was the pharmaceutical industry’s most promising drug for people alive with Alzheimer's disease today. Its trial failure means they will die of, or with, that disease.


Medicine has hit a wall in treatments and cures. For 10 years, a team of researchers and nearly 3000 patients around the world had their hopes pinned on this Biogen drug. In a transgenic mouse model of Alzheimer’s disease, aducanumab was shown to enter the brain, bind to amyloid protein, and reduce soluble and insoluble amyloid protein in a dose-dependent manner.


Then, in patients with mild Alzheimer’s disease, a year of monthly intravenous infusions of aducanumab reduced brain amyloid protein in a dose- and time-dependent manner. That decline in amyloid protein was accompanied by objective slowing of clinical decline. The FDA granted aducanumab fast-track status through the regulatory process, confirming their assessment of its potential.


Development culminated in two global Phase 3 trials, ENGAGE and EMERGE, designed to evaluate the efficacy and safety of aducanumab in patients with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease dementia. 


Over that time, Biogen had spent $743 million on the biomolecule and its trials.


Then after all the time and money…


…futility analysis conducted by an independent data monitoring committee indicated the aducanumab trials were unlikely to meet their primary endpoint upon completion.

  • Imagine you’re a researcher for one of the three companies that collaborated on aducanumab – Neurimmune, Biogen and Eisai – and now, after 10 years, you discover that the drug that looked so promising in the lab, animal models and early trials was useless. You’ve invested 10 years of your professional lives in a colossal failure.

  • Imagine you’re an investor - in a single day, shareholders - including many Biogen employees - saw $17 billion wiped off the market cap of the company into which they sunk much of their savings.

  • But even worse – MUCH worse: Imagine your mom or dad is getting a monthly infusion for almost 2 years, knowing their disease may be progressing if they're unlucky enough to get the placebo, and perhaps blessed if they get the active new drug. You have hope.

Then you get a phone call from the investigator who’s been dosing and monitoring you – it’s over. There is no hope.


When a similar Roche drug failed in January, everyone was uneasy who'd invested their family and their careers and their savings in the Biogen drug. When the aducanumab study blind was lifted and the difference between active and placebo was determined to be non-significant, that determination struck a massive blow to more than just those who’d developed, tested, volunteered for the trials and invested in the companies.


But beyond them, it was a blow to the 50 million people worldwide alive with Alzheimer’s disease - a number that will almost double every 20 years, reaching 75 million in 2030 and 131.5 million in 2050. It's anyone's guess whether those 75 million - or even the 131.5 million - will see a cure in their lifetimes.


For an industry, too - this is a massive blow. The sticky clusters of a misfolded protein fragment called beta-amyloid in the photo above had been the target of virtually every global research study. When Biogen struck out, almost the whole effort to find an Alzheimer's cure struck out with them.


Where to, now? 


Around the world, researchers are going back to the basic research labs. Some see potential in targeting tau protein instead of amyloid. But billions will need to be invested on a restart - hopefully telescoped a bit by artificial intelligence and the cloud, and perhaps digital biomarker technology.


But after all the regret and disappointment declines in the labs and executive suites of Biogen and Eisai and Neurimmune – after the investors in Biogen console themselves in the fact that their stock hasn’t fallen to zero, we in pharma cannot lose sight of those for whom the pain and sadness of aducanumab’s failure will not end:


The millions of Alzheimer’s patients and their families worldwide for whom termination of the aducanumab trial means the abrupt end of hope for a cure in their lifetime.


References

Nature volume 537, pages 50–56 (01 September 2016) |BIOGEN AND EISAI TO DISCONTINUE PHASE 3 ENGAGE AND EMERGE TRIALS OF ADUCANUMAB IN ALZHEIMER’S DISEASE March 21, 2019 at 7:00 AM EDT

What the End of a Promising Alzheimer’s Drug Trial Means for One Patient in the Study. Time MARCH 25, 2019

https://www.alzforum.org/therapeutics/aducanumab

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melsnyder@gmail.com

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