Jun 10, 2021

Biogen Wins Big! Now the FDA is Under Fire.

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Upshot

Biogen (NASDAQ:BIIB) received contingent approval on Monday (6/7/2021) for its controversial Alzheimer drug, aducanumab, a monoclonal antibody therapy for Alzheimer's disease. The FDA's decision to give aducanumab the green light under the Agency's accelerated approval pathway is the greatest step forward in Alzheimer's research in almost two decades, but it is also a highly controversial move that has left many clinicians and regulatory advisors scratching their heads. The efficacy of aducanumab, now marketed under the name Aduhelm, is hardly convincing, and the series of clinical trials that led Biogen to the FDA's doorstep casts further doubt on whether the therapy should be approved at all. Aduhelm is a monoclonal antibody therapy that functions by targeting the beta amyloid plaques that form in diseased brains and likely impair cognitive function. Researchers have known for decades that these amyloid plaques play some role in degenerative brain diseases (the "Amyloid Theory"), but multiple attempts by big Pharma to inhibit plaque formation has never resulted in an improvement in cognitive function (or slowing of cognitive decline).

Aducanumab met the same fate when it failed to meet the primary efficacy endpoint - an improvement in cognitive function as measured by the standard Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score, which be used to determine stage severity of Alzheimer's disease. Controversy surrounded Biogen's decision to halt their trials in March of 2019, given insufficient evidence that the drug would meet its primary endpoints, and then restart them a few months later. The company continued their Phase 3 pivotal studies for aducanumab in early 2020 and submitted their application for approval in August. The FDA's initial response was extremely positive, but in November a panel of 11 FDA advisors gathered together to discuss the nebulous results. It was conclusively determined that aducanumab's efficacy results were not convincing and, though the drug was safe to administer and clearly removes amyloid beta plaques, offers little to no benefit to the patient. Then, in a surprising twist of fate, the FDA granted approval in June of this year.

Why did the FDA go against the advice of their advisory committee? And what precedent does this decision set in Alzheimer's research and the drug approval process at large? Regardless of whether the medical community agrees on the clinical significance of Aduhelm, the FDA's actions will certainly have lasting consequences and affect the entire sector.

The Science

A contentious theory

The formation of beta amyloid plaques in the brains of patients suffering from Alzheimer's is a well-established biomarker of the disease, but their role in the pathogenesis of the disease is still not fully understood. There are many other changes that occur in Alzheimer's brains: vascular inflammation, neurofibrillary tangles, brain atrophy, chronic inflammation, and the formation of tau protein aggregates. Prior to Aduhelm's approval, there were only 5 treatments for Alzheimer's available. Three of these medications, Aricept (donepezil), Razadyne (galantamine), and Exelon (rivastigmine), function by increasing the levels of acetylcholine, a neuromodulator involved in memory formation and executive function. The fourth, Namenda (memantine), regulates glutamine signaling, important for information retrieval. The fifth approved treatment is a combination of donepezil and memantine, brand name Namzaric. None of these therapies target beta amyloid plaques, but researchers are convinced that inhibiting the formation of these protein aggregates will be the final panacea for the disease (the "Amyloid Theory" - https://www.nature.com/articles/d41586-018-05719-4).

An effective amyloid therapy has been elusive due to the difficulty in correlating a reduction in plaque formation with clinically-relevant improvements in cognitive function - many failed clinical trials have shown that even when beta amyloid plaques are cleared out there is no substantial improvement in brain function. Surely these plaques play an important role in the disease progression, but it has yet to be proven that Alzheimer's can be reversed by targeting them alone. So why did Biogen think that their monoclonal antibody therapy, which targets these same protein plaques, would result in any clinically meaningful improvement in patients?

Alzheimer’s Disease: Is a Dysfunctional Mevalonate Biosynthetic Pathway the Master-Inducer of Deleterious Changes in Cell Physiology? - Scientific Figure on ResearchGate. Major pathological hallmarks of AD are amyloid plaques and neurofibrillary tangles (B) that are absent in healthy brain tissue (A). Massive apoptosis occurs in later stages of the development of AD in the human brain (brain slices) (C). Sources: A and B: Google Images, BrightFocus Foundation

The Biogen Story

A tale of frustration

The legacy of aducanumab began in 2007, when Biogen licensed the worldwide rights to the drug from Neurimmune Holding AG, placing the fate of the drug and the future of Alzheimer's treatment in the hands of Biogen's team. The company began it's first Phase 1a study (a single dose of the drug) in Alzheimer's patients, titled "SAD", in 2011. The "SAD" study was a placebo-controlled trial in 53 patients with mild-to-moderate Alzheimer's disease with the goal of establishing the safety and pharmacokinetics Encouraged by the results, Biogen initiated a Phase 1b study (multiple doses are given to each patient) entitled "Prime" in 2013, followed by 2 other Phase 1 studies in different patient populations. The results were published in 2015 and 2016 and prompted the initiation of two Phase 2 studies entitled "Engage" (2015) and "Emerge" (2016). Both Phase 2 studies had identical designs, were placebo controlled, and had~1,650 participants each. "Engage" failed to meet its primary endpoint, but patients enrolled in "Emerge" who received high doses of aducanumab seemed to experience improvement in cognitive function. These intermediate results were promising and it was determined that treatment with a high dose of aducanumab reduced the cognitive decline of patients by 22% compared to placebo. These findings were further substantiated by a reduction in  beta amyloid plaque formation. All data indicated that "Emerge" was going to be a success and Biogen would have the first viable treatment for Alzheimer's in 20 years.

If it was easy, everyone would do it

In March of 2019, Biogen announced that it was discontinuing both the "Engage" and "Emerge" Phase 3 studies as well as the extended Prime Phase 1b trial. An independent data review committee determined that it was unlikely that the trials would meet their final efficacy endpoints, in contradiction to the intermediate data. Then, in a move that surprised the entire industry and had investors on the edge of their seats, the company declared that it will pursue approval for the "Emerge" trial. Apparently it had met its primary efficacy endpoint upon reanalysis of the data. Biogen claimed that a subset of patients that had received the high dose showed benefits on cognition, memory, language, and an overall improvement in daily living. The company began preparing their Biologic License Application (similar to an Investigational New Drug application, but specifically for biologic therapies) for submission in spring of 2020. In August 2020, the company submitted their BLA which included Phase 3 data from both Emerge (study #302) and Engage (study #301). The FDA's response was overwhelmingly positive, describing the data as "exceptionally persuasive", which sent Biogen's stock soaring. Not two days later (November 6, 2020), an independent advisory committee (which is composed of industry experts who's opinion is held in high regard with the Agency) opined and gave aducanumab the thumbs down... only 1 member voted "yes" for approval, with the remaining 10 members voting "no" (8) or uncertain (2). The stock plummeted, erasing all of the gains from week prior. The advisory committee deemed the evidence insufficient to suggest that aducanumab has any clinically-significant effect on improving cognitive decline. The FDA found themselves caught between a rock and a hard place. Historically, the Agency has rarely diverged from the advice of their advisory committees, agreeing with their recommendation 80% of the time (https://onlinelibrary.wiley.com/doi/abs/10.1111/1468-0009.12403) . Biogen's stock settled back down as investors eagerly awaited the FDA's final decision on approval.

On June 6, 2021, the FDA surprised everyone by granting aducanumab accelerated approval, sending Biogen's stock soaring to unprecedented levels and creating a tidal wave in the scientific and medical communities. A rift quickly formed between "pro approval" advocates and the (justifiably) skeptical. Why did the FDA grant a green light to a drug that was not conclusively effective?

The FDA's Justification

Risk-reward

Aduhelm (aducanumab) is the first approved Alzheimer's therapy to target the notorious beta amyloid plaques thought to be critical to the progression of the disease. When deciding on approval, the FDA must weigh the safety profile and probability/intensity of side effects against the anticipated clinical benefit. This risk-reward calculation is not straightforward and is influenced by the available treatments, severity of the disease, and political pressure to provide suffering patients with novel treatments that give them a chance at restoring their lives. Alzheimer's is, without a doubt, a crippling disease that affects over 6M Americans and has no treatment capable of reversing the progression of the disease. Alzheimer's destroys the lives of the afflicted and their loved ones; a tragic, slow decline into a shell of a person. The Alzheimer's Association and related patient advocacy groups have lobbied the Agency for years, and the FDA has been under pressure to provide patients with a new treatment.

Safety

Aduhelm's safety is "well characterized in over 3,000 patients who received at least one dose of ADUHELM. The most frequently reported adverse event was radiographic detection of events termed Amyloid Related Imaging Abnormalities, or “ARIA.” ARIA (-E and/or -H) was observed in 41 percent of patients treated with ADUHELM 10 mg/kg compared to 10 percent of patients on placebo. Clinical symptoms were present in 24 percent of patients treated with ADUHELM 10 mg/kg who had an observation of ARIA (-E and/or -H), compared to 5 percent of patients on placebo. The most common symptom in patients with ARIA was headache. Other symptoms associated with ARIA included confusion, dizziness, visual disturbances, and nausea. Adverse reactions that were reported in at least 2 percent of patients treated with ADUHELM and at least 2 percent more frequently than in patients on placebo were ARIA-E, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, fall, diarrhea, and confusion/delirium/altered mental status/disorientation" (https://www.globenewswire.com/news-release/2021/06/07/2243019/0/en/FDA-grants-accelerated-approval-for-ADUHELM-as-the-first-and-only-Alzheimer-s-disease-treatment-to-address-a-defining-pathology-of-the-disease.html). Clearly there is a significant safety risk, but is it worth the potential benefit to patients?

Efficacy

The FDA's evaluation of efficacy was solely determined by the reduction in amyloid beta plaque formation, not an improvement in cognitive function (the clinically-relevant efficacy endpoint that all experimental treatments are evaluated against). This type of biomarker is considered a "surrogate endpoint", and serves as a molecular proxy for the drug's potential ability to actually treat patients in a clinical context.

"ADUHELM consistently showed a dose- and time-dependent effect on the lowering of amyloid beta plaques (by 59 percent [p<0.0001] in ENGAGE, 71 percent [p<0.0001] in EMERGE, and 61 percent [p<0.0001] in PRIME)" (https://www.globenewswire.com/news-release/2021/06/07/2243019/0/en/FDA-grants-accelerated-approval-for-ADUHELM-as-the-first-and-only-Alzheimer-s-disease-treatment-to-address-a-defining-pathology-of-the-disease.html).

The Agency decided that treating amyloid plaque formation a proxy for the drug's efficacy was sufficient to grant an accelerated approval, but Biogen will still need to complete another Phase 3 clinical trial to confirm that plaque inhibition has cognitive benefits. If that study fails, the FDA will almost assuredly rescind approval and Aduhelm will be pulled from the market. This conditional approval flies in the face of decades of regulatory standards, and may reduce the burden of proof for many more experimental treatments for debilitating diseases that have no effective treatments. It is critical that the unproven cognitive benefit of Aduhelm not be oversold... the drug does not reverse the progression of the disease, but may slow cognitive decline. Patients must be aware that the drug received and accelerated approval and the drug could be pulled at any time. Ultimately, Aduhelm's greatest value is intangible. Aduhelm represents hope. Perhaps the drug works particularly well for a subset of patients. Perhaps even a marginal attenuation in cognitive decline gives families a few extra years with their loved ones. We can only hope and pray.

“Today’s approval of ADUHELM is a transformational breakthrough in the fight to stop this horrible disease. After years of disappointment and despair, this decision offers new hope for many families and a trigger for future investment and innovation. Because ADUHELM was studied in people with early-stage Alzheimer’s disease, it will be important for our nation’s healthcare system—patients, providers and payers—to be ready for earlier detection, diagnosis and intervention in the treatment of the disease.”
~ George Vradenburg, Chairman and Co-Founder of UsAgainstAlzheimer’s
“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.”
~ Biogen CEO, Michel Vounatsos [1]
“I’m quite surprised. The most compelling argument for approval was the unmet need but that cannot, or should not, trump regulatory standards. It’s hard to find any scientist who thinks the data are persuasive. Unmet need is an important contextual factor but it’s not an evidentiary threshold.”
~ Caleb Alexander, a Johns Hopkins epidemiologist who served on the FDA’s advisory panel and voted against the approval of Aduhelm.
“For patients who qualify, I’m hopeful for them. Now we have a potential treatment for them that may modify the underlying disease course. But the largest responsibility for us is to educate patients and physicians as to what this means. This is not going to be penicillin for Alzheimer’s disease.”
~ Ronald Petersen, a neurologist who leads the Mayo Clinic Alzheimer’s Disease Research Center [2]

Economics of a Blockbuster Drug

Just how much does Biogen stand to profit?

Biogen has priced a 12 month treatment course of Aduhelm at a whopping $56,000 per patient (5x what Wallstreet analysts expected). Aduhelm’s is labeled for all patients with Alzheimer’s, a surprising move considering that all of the clinical studies involved patient's with early-stage Alzheimer's. The drug must be received via IV infusion every month for the rest of the patient's life. The math is simple... if Aduhelm is used to treat only 25% of the 6M Americans suffering from Alzheimer's, then Biogen stands to make $84B yearly from Aduhelm in the US market alone (Biogen is currently seeking approval in the EU, CA, and Asia), making Aduhelm the largest drug in history. This dwarfs Biogen's top 10 selling drugs by an order of magnitude, which add ~$12B to Biogen's top line every year.  Given the fact that the overwhelming majority of Alzheimer's patients are on Medicare, the drug's extreme cost will be passed directly to the taxpayer. To put things in perspective, over $800B was spent on Medicare in 2019 (it's insane to think that Medicare expenditure on Aduhelm could represent over 10% of the entire budget!). The economics are almost too good to be true... and they likely will be significantly less favorable for Biogen due to pushback from Medicare and private insurers who will not cover the drug at its lofty list price. Will Washington allow Aduhelm to have such an impact on their Medicare budget, or will policy change cap the price they are willing to pay or limit the patients eligible to receive treatment? Very likely. And, of course, Aduhelm could be pulled from the market if it fails the ongoing study or performs poorly in the clinicl (see below). Regardless, Wallstreet bulls are having a field day, sending Biogen's stock soaring 55% to an all time high and adding $25B to their market cap on Monday (6/7/21) alone.

Lasting Consequences

The FDA under fire

The FDA's decision to fast-track Aduhelm has established a new, lower benchmark for approval. The FDA's stamp is seen as the gold standard around the world due to the degree of scientific rigor needed to advance experimental treatments through the Agency's regulatory process. Typically, two large-scale trials must clearly demonstrate clinical benefits that are worth potential side effects. Deviation from this standard will call into question the FDA's strength as the adjudicator of the pharmaceutical industry; they are betting their reputation on this one drug. The FDA's stutter stepping isn't a good look for the Agency, who should be adhering to the scientific process in making unbiased decisions. The Agency defends their decision based on the standards for accelerated approval, a designation often granted to cancer therapies to treat patients that have no other options, and is conditional on the drug's performance in the clinic. Aduhelm could get pulled from the market if 1) it fails to show clinical benefit to patients, 2) adverse events are reported that unfavorably skew the risk-reward profile, or 3) the drug fails the ongoing Phase 3 study that the FDA has required to gain full approval.

“This decision demonstrates that our regulatory system has been weakened... The FDA is the strongest thing we have going for us. One of the most important components of our biotech system is a strong regulatory agency. Strong does not mean needlessly rigorous, but it means that it adheres to scientific principles and honors the patients that it is there to serve.”
~ Luciana Borio, a former acting chief scientist at the FDA, said Monday after the agency’s announcement [3]

The sector at large

Unsurprisingly, lowering the bar for drug approval has bolstered investor confidence in the industry. Eli Lilly benefited the most, with their stock rising 12% and adding $20B to their market cap due to their advanced Alzheimer's treatement, donanemab. If the FDA holds fast with their decision to approve Alzheimer's treatments on the basis of their ability to remove amyloid beta plaques, and not demonstrate a clinically-meaningful endpoint, then Lilly will be held to the same standard. Results from a Phase 2 study released in March 2021 clearly showed this, with 68% of patients reporting no amyloid levels in 18 months of treatment. Theoretically, Lilly may be able to apply for accelerated approval immediately, although the FDA may require a larger Phase 3 study to confirm donanemab's ability to meet the surrogate endpoint. Aduhelm's approval may make it difficult for other Alzheimer's trials, as patients would rather take an approved treatment than sign up for a randomized, placebo-controlled trial. In any case, the FDA's decision opens the flood gates and it would be unsurprising if many more clinical-stage pharmaceutical companies apply for accelerated approval on the basis of promising, but not proven, efficacy results.

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. We examined the clinical trial findings with a fine-tooth comb, we solicited input from the Peripheral and Central Nervous System Drugs Advisory Committee, we listened to the perspectives of the patient community, and we reviewed all relevant data. We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.
~ Dr. Patrizia Cavazzoni, Director, FDA Center for Drug Evaluation and Research [4]

Quotations from Stat interviews:

[1] https://www.statnews.com/2021/06/07/fda-grants-historic-approval-to-alzheimers-drug-designed-to-slow-cognitive-decline/

[2] https://www.statnews.com/2021/06/07/fda-grants-historic-approval-to-alzheimers-drug-designed-to-slow-cognitive-decline/

[3] https://www.statnews.com/2021/06/07/by-approving-biogen-alzheimers-drug-fda-is-shifting-its-rules-that-is-a-giant-risk/

[4] (https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease)

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