On Monday, a 17-year drought in the Alzheimer’s drug world ended with the FDA approval of Biogen’s Aduhlem (aducanumab). The controversy behind the FDA’s decision was considerable, but it doesn’t seem to scare the drug developers who are now focusing on degenerative brain disease.
In a nutshell, Aduhelm’s approval came after conflicting results from clinical trials. In november 2020 an independent FDA advisory board did not recommend that the agency approve the drug, but in June, the agency still approved the drug through a fast-track approval program.
Aduhelm is now the first new treatment to tackle one of the underlying causes of Alzheimer’s disease: beta-amyloid plaques that build up in the brain.
The drug received the support of patient and industry groups (the FDA also Noted that the “need for treatment is urgent”, in a press release explaining the choice of the agency). Still, there have been a number of doctors who have expressed concern. A member of the expert committee who voted not to recommend Aduhelm’s approval in November has resigned since the announcement.
However, the inconsistency of science and the very public debate around Aduhelm’s endorsement does not seem to have stopped enthusiasm within the pharmaceutical industry. On the contrary, it could signal a new wave of additional treatments over the next few years, which will come on top of Aduhelm’s approval (however controversial that approval may be).
“This is great news for investors and for pharmaceutical companies working on new drugs,” says Alison ward, researcher at USC Schaeffer Center for Health Policy and Economics.
Historically, there have been a few factors that have made the development of an Alzheimer’s disease drug an uphill battle.
The first is a 17-year story of failure to bring a drug through clinical trials. Even Biogen’s clinical trials for Aduhelm were halted in 2019 because it was unclear whether they would meet their clinical goals (in fact, the trial’s target results). In fact, Aduhlem was approved on the basis of a “surrogate endpoint”, decline in beta-amyloid, and not the primary endpoint, cognitive function.
Trials for Alzheimer’s disease drugs have also been historically expensive. A 2018 article in Alzheimer’s and dementia: translational research and clinical interventions (a journal managed by the Alzheimer Association) estimated the cost of developing an Alzheimer’s disease drug to be around $ 5.6 billion. In comparison, the average investment required to bring a new drug to market is around $ 1.3 billion according to analysis of SEC files for companies that applied for FDA approval between 2009 and 2018 (although the median cost is around $ 985 million). Older estimates put the cost of bringing a drug to market at $ 2.8 billion.
For Alzheimer’s disease in particular, phase 3 trials are still largely sponsored by industry, but over the past five years, trials sponsored only by industry have decreases. Government grants and funding through public-private partnerships have been an igrowing share funds available.
Martin Tolar, the founding CEO of Alzheon, another company pursuing oral treatment for Alzheimer’s disease (currently in a Phase 3 clinical trial), says attracting other forms of funding was a challenge.
“It was impossible to fund anything,” he says. “It was impossible to interest Wall Street because everything was failing one after the other.”
He expects this recent Aduhelm endorsement to change that outlook significantly. Already, we are seeing increased interest in companies already in phase 3 clinical trials: after the FDA’s announcement, Eli Lilly actions, also conducting a phase 3 clinical trial, jumped 10 percent.
“I’ve probably had hundreds of talks, calls, bankers, investors, collaborators, pharmaceutical companies, etc.,” says Tolar. “Alzheimer’s disease is open for business.
With renewed interest and what appears to be a path for FDA approval, the environment for the next generation of Alzheimer’s drugs appears to be maturing. At present, there are approximately 130 Phase 3 clinical trials of Alzheimer’s disease drugs that are either completed, active, or being recruited.
Tolar sees the FDA’s decision, based on flawed data, as an “urgent signal” to approve new treatments that are imminent.
As Ward pointed out in a white paper on drug innovation in the classroom, “follow-up” drugs are becoming industry leaders, especially if they demonstrate greater safety or efficacy than the drug that first came to market. This, argues the document, suggests that drug approval could “pave the way” for more effective drugs in the future.
In the case of Alzheimer’s disease, it may not be a dominant drug, although others are approved, she notes. On the contrary, a set of new approved drugs can continue to complement each other.
“The way the medical community views AD [Alzheimer’s Disease] now it’s probably going to be a combination of drugs or a cocktail of drugs that combine to successfully delay progression, ”she says.
“If we are looking to treat AD with a drug cocktail, history suggests that it is individually approved drugs that come together to make these drug cocktails.”
There are still potential pitfalls to be aware of for future drugs. One argument is than with an approved drug available, it may be more difficult to recruit clinical trial participants, slowing the pace of drug discovery. In that regard, Ward argues that it will ultimately be overshadowed by patients who will now consider a potential diagnosis of Alzheimer’s disease now that there is something to treat it.
There is also the fact that Aduhelm’s costs are high (around $ 56,000 for one year of supply, most of which will be covered by health insurance), and the data remains questionable. These factors can push patients to other drugs, even if they are in clinical trials.
Additionally, there is the question of how well Aduhelm actually performs during the critical follow-up study mandated by the FDA as a condition of drug approval. Whether Aduhelm can really slow cognitive decline, as well as help treat beta-amyloid levels in the brain, remains questionable based on current data.
However, Tolar does not consider the results of this study to be particularly relevant because the industry will have evolved. Biogen CEO Michel Vounatsos said he might not share the results of this trial as long as nine years, although he noted that the company would try to provide data earlier.
“Then there will be better drugs,” predicts Tolar.
Tolar’s Phase 3 clinical trial just started this week and is expected to end by 2024.
Biogen and Esai will probably also have another drug ready for evaluation by then, as two Phase 3 clinical trials for another beta-amyloid antibody treatment called lecanemab are expected to be completed by 2024 and 2027.
The signal sent by Monday’s approval could be a path for future drugs, rather than an end in itself. The data is flawed, the costs high, and the controversy considerable, but the bandage has been ripped off.