The U.S. Food and Drug Administration has approved the first new treatment for Alzheimer’s disease in almost 20 years, giving the go ahead for Biogen to develop the drug Aducanumab. This announcement has been met with rigorous debate over whether the treatment actually works.
Alzheimer’s disease
Alzheimer’s disease is an irreversible, progressive brain disorder that gradually destroys memory, thinking skills and the ability to carry out simple tasks. The condition is believed to occur when abnormal amounts of β-amyloid (accumulating as amyloid plaques) and tau proteins that accumulate in neurofibrillary tangles, form in the brain affecting neuronal functioning and connectivity. This results in progressive loss of brain function. The cause of most Alzheimer’s cases is still largely unknown, yet in 1-2% of cases genetic differences have been observed.
Despite the vast number of people affected by Alzheimer’s disease globally, the development of treatments for the condition is challenging. This is largely due to two major hurdles. The first is that researchers still do not know enough about the underlying biology of the disease. For example, researchers don’t know what regulates the build-up of β-amyloid and tau tangles in the brain. The second major hurdle is that drugs need to be able to cross the blood-brain barrier. This barrier prevents foreign substances from reaching the brain.
Alzheimer’s drug – Aducanumab (Aduhelm)
Yesterday, the FDA approved Aduhelm for the treatment of Alzheimer’s disease. This is the first drug to be approved for Alzheimer’s since 2003. It is also the first therapy that targets the underlying pathophysiology of the disease rather than just its symptoms. Aduhelm is a monoclonal antibody that targets amyloid beta plaques that form in the brains of Alzheimer’s patients. Since the approval announcement yesterday, shares of Biogen soared by 53% to a record $428 million.
Aduhelm clinical trials
Researchers evaluated Aduhelm’s efficacy in three separate studies, which represented 3,482 patients in total. The studies consisted of double-blind, randomised, placebo-controlled dose-ranging studies in patients suffering from Alzheimer’s disease. Patients receiving the treatment had a significant reduction of amyloid beta plaques, while the patients in the control arm of the study had no reduction of amyloid beta plaques.
These promising results supported the accelerated approval of Aduhelm by the FDA. Their approval is based on the surrogate endpoint of reduction of amyloid beta plaques in the brain. This is a hallmark of the development and progression of Alzheimer’s disease. The researchers quantified amyloid beta plaques using positron emission tomography (PET) imaging. This allowed them to estimate the brain levels of amyloid beta plaques in composite brain regions in areas of the brain expected to be widely affected by Alzheimer’s disease pathology compared to brain regions expected to remain untouched by such pathology.
The FDA made the decision to grant Aduhelm accelerated approval. This approval is designed to provide early access to potentially valuable therapies for patients with serious diseases where there is an unmet need for treatment, and where there is an expectation of clinical benefit despite some remaining uncertainty regarding that benefit.
Recognising that the existing clinical trials of the Aduhelm have provided incomplete evidence to demonstrate its effectiveness, the FDA now requires Biogen to conduct a new clinical trial. If this new trial, called a Phase 4 trial, fails to show the drug is effective, the FDA can rescind its approval.
Controversy surrounding Aduhelm’s approval
In March 2019, late-stage international trials of Aduhelm, which involved around 3,000 patients were halted by Biogen when analysis showed the drug, given in monthly infusions, was no better at slowing the deterioration of memory and thinking problems than a dummy drug. However, later that year, Biogen analysed more data and concluded that the drug did work, provided it was given in higher doses. It was found that a higher dose could delay cognitive decline by 22%, or about four months over a period of 18 months.
The announcement of the approval of this drug has been met with conflicting opinions. The Alzheimer’s Association welcomed the decision, hailing it as a new day of hope for Alzheimer’s disease. The charity’s president, Harry Johns, said he “fully supports” the decision calling it “a victory for people living with Alzheimer’s and their families”. Another charity, Alzheimer’s Research UK, have asked the Heath Secretary Matt Hancock to get the government to fast-track approval of the drug within the UK.
Meanwhile, John Hardy, a Professor of Neuroscience at University College London (UCL) said: “While I am pleased that aducanumab has received approval, we have to be very clear that, at best, this is a drug with marginal benefit which will help only very carefully selected patients”. Professor Robert Howard at UCL went further by calling the drugs approval a “grave error” stating that the FDA ignored data from the trial which showed no slowing of decline in cognition or function.
Although many doctors are doubtful of Aduhelm’s benefits, the FDA’s decision will also have ramifications in Alzheimer’s research beyond Biogen, especially for drug makers that have spent billions of dollars pursing amyloid treatments. Notably, shares in Eli Lilly, which is trialling its own amyloid-clearing drug, have jumped by 10% since the announcement.
Conclusions
Aduhelm provides a promising opportunity for the treatment of Alzheimer’s disease, and is an exciting breakthrough that has the potential to dramatically affect the lives of Alzheimer’s patients and their families. However, the drug still needs to be tested in Phase 4 trials, which could result in the drug being pulled from the market if the data fails to verify its clinical benefit.
Image credit: By Ildar Imashev – canva
