The US Food and Drug Administration on Monday approved the use of the experimental drug aducanumab for early phases of Alzheimer's disease -- despite an FDA advisory committee concluding last year that there is not enough evidence to support the effectiveness of the treatment.

The drug was developed for patients with mild cognitive impairment, not severe dementia, and intended to slow progression of Alzheimer's disease -- not just ease symptoms.

The FDA has not approved a novel therapy for Alzheimer's disease since 2003.

'We Have to Really Temper Expectations'

The FDA approved aducanumab, also known as Aduhelm, using its "accelerated approval" program, which allows for the earlier approval of a drug for a serious or life-threatening illness even though more study into the drug's benefits may be needed.

"There has been considerable public debate on whether Aduhelm should be approved. As is often the case when it comes to interpreting scientific data, the expert community has offered differing perspectives," Dr. Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research, said in Monday's announcement.

"At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward," she said, noting that the FDA ultimately decided to use accelerated approval and "concluded that the benefits of Aduhelm for patients with Alzheimer's disease outweighed the risks of the therapy."

Under accelerated approval, the drug aducanumab will still be studied. With this program, drug companies are required to conduct "post-approval studies" known as Phase 4 confirmatory trials to verify that treatments have clinical benefit. If the confirmatory trial does not verify the drug's benefit, then the FDA could remove the drug from the market.

"FDA will continue to monitor Aduhelm as it reaches the market and ultimately the patient's bedside," Cavazzoni said.

In November, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee was asked to vote on several questions about evidence of the drug's effectiveness. In response to a question about whether it was reasonable to consider data from one positive study as the primary evidence of aducanumab's effectiveness for the treatment of early Alzheimer's disease, none of the committee members voted yes -- 10 voted no and one was uncertain.

The committee's opinions were then left with the FDA as the agency mulled whether to approve the drug or pump the brakes.

"In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion," Cavazzoni said on Monday. "It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline."

The pharmaceutical company Biogen and its Japanese partner Eisai developed aducanumab, administered through intravenous infusion to treat early Alzheimer's disease. The drug was developed for patients with mild cognitive impairment, not severe dementia.

Dr. Richard Isaacson, director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian in New York, who had patients in the original aducanumab clinical studies, told CNN the drug targets the earliest symptomatic phase of the disease, called mild cognitive impairment due to Alzheimer's. Treatment of the pre-dementia period was the focus of the FDA's decision.

"We have to really temper expectations and explain to people that this drug is meant for the earliest symptomatic phases," he said. "It pains me to say this but if I have a severe Alzheimer's patient that can no longer speak or interact much with others and their family member is begging me to give them this drug, I won't be able to do it."

Controversy and High Price Tag

Aducanumab's road to FDA approval has been rocky -- and controversial.

In March 2019, Phase 3 clinical trials of aducanumab were discontinued because a futility analysis found the trials were unlikely to meet their primary goals at completion.

"The futility analyses showed the studies were most likely to fail," Isaacson said.

Several months later, Biogen announced that a new analysis, which included more patients, showed that those who received high doses aducanumab experienced a reduction in clinical decline in one trial.

The company noted in FDA briefing documents last year that patients treated with high-dose aducanumab showed 22% less clinical decline in their cognitive health at about 18 months -- meaning the progression of their early Alzheimer's disease slowed -- compared with those who received a placebo.

Results for some patients in another study supported those findings, as well.

"Now the messaging was like, 'Wait a minute. It worked, and it especially works if you pull all the high dosages from the two studies,'" Isaacson said. "Because it would take years to repeat a study, and considering the lack of available therapies to treat the pre-dementia phase, the company made an uncharacteristic decision -- to still apply to the FDA."

In July 2020, Biogen completed its submission to the FDA for a Biologics License Application for approval of the drug.

Since then, Alzheimer's disease researchers, doctors and patients have been waiting for the FDA's decision.

Some groups, including the nonprofit Public Citizen's Health Research Group, argued that the FDA should not approve aducanumab for treatment of Alzheimer's disease due to lack of evidence of its effectiveness.

In April, the nonprofit wrote a letter to US Health and Human Services Secretary Xavier Becerra asking the department's Office of Inspector General to investigate the "close collaboration" between FDA and Biogen regarding the company's application for approval of aducanumab.

There have also been concerns around cost.

Biogen announced on Monday that the wholesale cost of treatment with aducanumab -- which requires an infusion once every four weeks -- is about $4,312 per infusion, making the annual cost around $56,000 for a high dose.

"Biogen and Eisai are committed to providing access to ADUHELM for patients across a spectrum of financial situations," the company noted in its announcement. "For qualified, commercially insured ADUHELM patients, co-pay and infusion cost assistance programs may reduce out-of-pocket costs to as low as $0. Patients who are covered by Medicare through a Medicare Advantage plan have a maximum annual out-of-pocket cap."

In May, the Institute for Clinical and Economic Review released a draft report estimating that the drug should cost between $2,560 to $8,290 per year, and noted that "the evidence is insufficient to conclude that the clinical benefits of aducanumab outweigh its harms or, indeed, that it reduces progression" of Alzheimer's disease.

Other organizations, such as the Alzheimer's Association, have supported approval of the drug.

"This approval is a victory for people living with Alzheimer's and their families," Harry Johns, the association's president and CEO, said in a post on Twitter on Monday.
'The Infusion Gives Us the Basis for Hope'

For those with mild cognitive impairment and their families, the drug had given hope.

Jenny Knap, 69, has received infusions of the aducanumab drug for about a year now as part of clinical trials in two six-month stretches. She told CNN that she underwent treatment for about six months before the study was put on hold in 2019, and then continued treatment about six months ago.

"I can't say if I noticed it on a daily basis, but I do think overall, I'm doing much better in terms of looking for where my glasses are -- things like that," Knap said.

In 2015, when Knap was diagnosed with mild cognitive impairment, a clinical precursor of Alzheimer's disease, the signs of the condition were subtle, but they were there.

She often would misplace her glasses or she would repeat herself, forgetting conversations from moments ago, her husband, Joe Knap, said.

As these occurrences became more frequent, "we were aware that things were starting to slip through the cracks," Joe said.

Jenny visited the Cleveland Clinic's Lou Ruvo Center for Brain Health in Ohio for testing and received her diagnosis. Then a couple of years later, in early 2017, Jenny learned that she was eligible to participate in clinical trials for the Biogen drug aducanumab at the Cleveland Clinic. She signed up to volunteer -- and has been in the trial ever since.

"It turned out that for the first year and a half Jenny was in the placebo category," Joe said, which means she did not receive the treatment.

Now, every four weeks, with Joe by her side, Jenny receives aducanumab infusions at the Cleveland Clinic, which is about a half-hour drive from their home. Even though she just recently started treatment, Jenny said that she thinks it has been helping some, along with maintaining a healthy diet and exercising regularly -- she goes on 4-mile runs.

"Aducanumab's promise is to slow down the progression of the disease and not to improve the cognition. In her case, we did not appreciate any major decline," Dr. Babak Tousi, Jenny's doctor who led aducanumab clinical trials at the Cleveland Clinic site, wrote in an email to CNN.

"This treatment is very different than what we have had before. We have never had a medication that would slow down Alzheimer's disease progression," he said. "Current available medication such as donepezil or memantine only help modestly with the symptoms but do not slow down the disease's progression."

Jenny said that she has not experienced any noticeable side effects of the drug.

"At one point, it was a while back, there was evidence of some very slight bleeding in the brain. It was actually very low levels," Joe said about Jenny, but he added that doctors were not concerned.

On Monday, the FDA said patients must obtain a recent MRI before initiating treatment with aducanumab and MRIs before the seventh and twelfth infusions to look for brain abnormalities.

Tousi noted in his email that with continued treatment, "blood vessels may become leaky so fluid and red blood cells may leak out to surrounding area" and these "micro hemorrhages have been reported in 19.1% of participants of the trial who received" the maximum dose of treatment.

The trial was blinded so they did not know she was in the placebo group until recently. As the study went on, Joe said that she was later given the drug around August 2018 and continued until February 2019. Biogen suspended the trial in March 2019, but it then resumed last fall and Jenny began receiving infusions again.

So far, the infusions and maintaining a healthy lifestyle have given Jenny and Joe a more "upbeat" outlook on the future, Joe said. They were also happy to participate in the trial -- an effort to make a helpful difference in the lives of others.

"Before we got into the clinical trial, there was this fear of what lay ahead," Joe said. "The medical component of the infusion gives us the basis for hope. But then the exercise on a daily basis gives us immediate positives."