Alzheimer's disease

After a slow start, the launch of Biogen’s prized drug for Alzheimer’s disease is picking up, which has given company leadership more confidence that it can both drive growth and compete with a rival medicine from Eli Lilly.

“We’re pretty convinced Leqembi is on the right path now,” CEO Chris Viehbacher said on a conference call with reporters.

Biogen’s development partner Eisai, which is spearheading Leqembi’s launch, had made optimistic predictions about the drug’s early launch trajectory. Biogen executives have been hesitant to second those estimates, noting that growth will depend on whether large, integrated healthcare systems adopt Leqembi.

Yet, if orders from these systems are any indication, Leqembi is on track to becoming a big product in the long-term, Viehbacher said. After an earlier setback, Eisai and Biogen also secured a long-awaited approval in Europe, a market some analysts believe could contribute about 20% of future sales.  

Until recently, Leqembi and Aduhelm — another drug developed by Eisai and Biogen — were the only Alzheimer’s therapies of their kind cleared in the U.S. They work by removing from the brain toxic clumps of a protein called amyloid beta. But that list lengthened with the approval of Lilly’s anti-amyloid medicine Kisunla.

Analysts have been debating which drug, Leqembi or Kisunla, will take the lead in a rapidly evolving market. Both come as intravenous infusions, and are specifically for Alzheimer’s patients in the early stages of the disease. There are key differences, however.

Data suggest Leqembi may be safer, while Kisunla is seen as more convenient since it’s administered every four weeks instead of every two. And because of the tests Lilly ran, patients can stop taking Kisunla once their amyloid levels drop below a certain threshold.

Biogen and Eisai believe a newer form of Leqembi they’ve been developing, an under-the-skin shot that’s also been approved, will help lift prescriptions and sales. Additionally, a large, late-stage clinical trial is evaluating Leqembi in people who have elevated amyloid levels but aren’t yet showing Alzheimer’s symptoms.

“Only Leqembi is really going to have the evidence base that covers that whole spectrum, from the early stage right through to maintenance,” Viehbacher said. Kisunla “is not going to be able to play into that.”

“Short term, we're going to see competition, certainly,” he added. “But I would also say that one of the biggest challenges to this launch has been building up the healthcare infrastructure. And so in a lot of ways, we actually welcome Lilly’s entry into the market, because [the] extra education that will happen with healthcare professionals will grow the market for everyone.”

Roche may seek an accelerated U.S. approval of its experimental Alzheimer’s disease drug trontinemab if the therapy continues to show in testing it can significantly lower levels of a protein linked to cognitive decline, executives said in a presentation to investors in late 2024.

The Food and Drug Administration has been willing to grant speedy approvals to Alzheimer’s drugs that can reduce the amount of sticky amyloid protein in the brains of people with the condition. Roche could lean on that precedent to seek an abbreviated approval path, as the company plans to look for an opportunity to get trontinemab to market before the final readout from a Phase 3 trial, said Hanno Svoboda, the drug’s lifecycle leader.

Two Alzheimer’s drugs, Eisai and Biogen’s Leqembi and the now-withdrawn Aduhelm, gained initial approvals based on their effects on amyloid, although the FDA rejected a similar request from Eli Lilly before eventually clearing Kisunla. Trontinemab began Phase 3 testing in 2025, and previous study results suggested it could clear amyloid more quickly than Kisunla.

Unlike trontinemab’s predecessors, the drug is designed to more easily slip past the blood-brain barrier, which could theoretically lead to more powerful and precise drug effects at a lower dose.

The drug’s apparently speedy effects could allow Roche to evaluate a potential “low-frequency, patient friendly” maintenance dosing regimen to keep amyloid levels from rebounding, Svoboda said.

The results also indicated trontinemab treatment led to lower rates than other drugs of an imaging abnormality called ARIA that indicates brain swelling.

Inside every human cell are thousands of snippets of genetic code that serve as the directions for creating proteins. And over the past four years, a small biotechnology company has been trying to prove that, by looking closely enough at this assembly of instructions, it can find new ways to treat diseases like Alzheimer’s, Parkinson’s and multiple sclerosis.

The company, Muna Therapeutics, now has a nod of confidence from one of the world’s largest drugmakers, after forming a collaboration with GSK that could ultimately be worth hundreds of millions of dollars.

Muna will analyze brain tissue samples from a variety of sources, from healthy individuals to Alzheimer’s patients to centenarians with and without cognitive impairment. The company will then use different technologies to determine where protein instructions are (or aren’t) in those tissues, with the goal being to identify and validate new targets for Alzheimer’s drugs. Once the companies are satisfied with the target, GSK will be in charge of taking the programs forward. 

The initial iteration of Muna formed in 2020 with help from Novo Seeds, the early stage life sciences investment arm of Novo Holdings, which is the controlling stakeholder in Novo Nordisk. It soon merged with another European startup, K5 Therapeutics, and in 2021 officially launched as a new version of itself. The combined company came equipped with $73 million from a group of investors that included Sofinnova Partners, Droia Ventures, Polaris Partners, Novo Holdings and the venture arm of Sanofi.

Muna’s CEO, Rita Balice-Gordon, said the deal represented a “pivotal moment” both in the biotech’s evolution and in “the broader Alzheimer's research landscape.”

For GSK, it’s another step into neuroscience — an area it abandoned more than a decade ago. Like some of its peers, the U.K.-based pharmaceutical giant has been slowly returning to brain drug development over the past few years. In mid-2021, it agreed to pay at least $700 million for rights to two drugs that a company called Alector had been testing against neurodegenerative diseases.

Later that year, GSK and the University of Oxford disclosed plans for a new center meant to find ways to development medicines faster and more successfully, with an initial focus on brain diseases like Alzheimer’s, Parkinson’s and ALS.

More recently, GSK partnered with a Flagship Pioneering-backed biotech to discover new drugs for Parkinson’s disease and another neurodegenerative condition. GSK, through its new venture investments arm, also helped fund a Switzerland-based biotech working on a potential medicine for Alzheimer’s.

Kaivan Khavandi, GSK’s head of respiratory and immunology R&D, said that his company sees Muna’s technology as being able to “determine the genetic and cellular basis of progression and resilience in neurodegenerative diseases.”

In an unusual reversal, key drug regulators in Europe said Leqembi, a high-profile medicine for Alzheimer’s disease, was worthy of approval, though only for patients less likely to experience a certain kind of concerning side effect.

Leqembi’s primary developer, Japan-based Eisai, submitted a marketing application to the European Medicines Agency in early 2023. After some delays, the agency later concluded that the drug’s safety risks outweigh its potential benefits. Chief among those risks was the “frequent occurrence” of a side effect known as “ARIA,” which can present as brain swelling and small-scale bleeding. 

Eisai appealed the EMA’s so-called negative opinion. The appeal process takes about four months and assigns different reviewers to assess the application. It’s also rarely successful for drug developers. Analysts at the investment firm RBC Capital Markets crunched the numbers and found that, over the past decade, the EMA’s main drug review committee has changed its mind only 20% of the time. 

But Leqembi beat the odds. The committee in late 2024 said it supported approval for patients with mild cognitive impairment or mild dementia due to Alzheimer’s, who have one or no copies of a gene believed to increase the risk of ARIA. According to Jefferies analyst Michael Yee, around 60% to 80% of the Alzheimer’s population in Europe fits that genetic profile. Yee also noted that Leqembi seems more effective in this type of patient, which may therefore help justify its price and reimbursement to European payers.

However, the recommendation still came with a caveat that measures be in place to reduce the risk of severe and symptomatic ARIA and “monitor its consequences in the long term.” The committee’s new opinion was adopted by the European Commission, which makes the ultimate verdict on what drugs receive marketing authorization in the EU, in April.

Eisai and its partner Biogen work together commercializing Leqembi, and initially hoped European regulators would clear the drug for a broader group of Alzheimer’s patients. Yet, even a narrower approval has been seen as a significant boost to sales. Abrahams has estimated that peak annual Leqembi sales would reach $8.3 billion, with 20% coming from the European market.

Leqembi is designed to combat Alzheimer’s by breaking up clumps of toxic proteins. These “amyloid beta” proteins have long been seen as a root cause of the disease, making them a prime target for pharmaceutical researchers. Kisunla, a recently approved product from Eli Lilly, also works on amyloid beta, as does another medicine from the Eisai and Biogen partnership, Aduhelm, though that drug was shelved following a series of commercial setbacks.

In making its decision, the EMA’s committee pointed to clinical data showing the differences in ARIA rates among participants who had one or no copies of that risk gene, and those with two. In that former group, nearly 9% and 13% of those who got Leqembi experienced brain swelling and microbleeding, respectively, while the rates among those who got a placebo were 1.3% and 6.8%.

Among all the participants who got Leqembi, the rates of ARIA brain swelling and microbleeding were 12.6% and 16.9%.

As for effectiveness, the committee said the “benefits of Leqembi in the restricted population are in line with those seen in the broader population.” Regulators in the U.S., Japan, China and a handful of other countries have already approved Leqembi based on evidence that it slows the progression of Alzheimer's around 27% — an effect described as modest by some experts.

The Food and Drug Administration in May cleared a blood test that measures biomarkers to inform the diagnosis of Alzheimer’s disease.

Fujirebio Diagnostics received the 510(k) clearance, which the FDA said is the first of its kind, after showing its blood test is substantially equivalent to an existing diagnostic that uses samples collected through an invasive lumbar puncture, also known as a spinal tap.

Labcorp and Quest Diagnostics began selling laboratory-developed tests for the same biomarkers earlier this year. Executives at Eisai, the manufacturer of an Alzheimer’s drug, said on an earnings call that triage testing using blood-based biomarkers is “dramatically increasing.”

The presence of amyloid plaques in the brain is a sign that a patient with cognitive impairment could have Alzheimer’s, making PET scans the standard for diagnosis. Cerebrospinal fluid tests that compare the ratio of two proteins, pTau217 and beta-amyloid 1-42, can cut the need for PET scans, but the diagnostics rely on samples collected via a lumbar puncture. 

Blood tests could be more accessible and scalable than CSF diagnostics and PET scans. The approval of disease-modifying drugs such as Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla has increased interest in tests that can help physicians accelerate the diagnosis of Alzheimer’s.

Fujirebio, a Japanese diagnostics company, gave physicians a new testing option by securing 510(k) clearance for its Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio. The FDA cleared the test for the early detection of amyloid plaques associated with Alzheimer’s in people aged 55 years and older with signs and symptoms of the disease.

The blood test is substantially equivalent to a Lumipulse CSF test. Fujirebio compared the blood test to PET scans and CSF results in a multicenter clinical study of 499 plasma samples from adults who were cognitively impaired. 

Fujirebio found 91.7% of people who tested positive on the blood test had amyloid plaques by PET scan or CSF test result. The trial showed 97.3% of individuals with negative blood test results had a negative amyloid PET scan or CSF test result. The FDA said less than 20% of patients received an indeterminate Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio result.

“These findings indicate that the new blood test can reliably predict the presence or absence of amyloid pathology associated with Alzheimer’s disease at the time of the test in patients who are cognitively impaired,” the FDA said. 

To date, blood tests have been limited to triaging patients. People who test negative on a blood test are unlikely to have amyloid plaques and, as such, may be able to skip invasive CSF tests and expensive PET scans. Eisai identified regulatory authorizations, Medicare reimbursement and upcoming guidelines from the Alzheimer's Association as key steps toward the use of blood tests to confirm Alzheimer’s diagnosis.

“Alzheimer’s disease impacts too many people, more than breast cancer and prostate cancer combined,” FDA Commissioner Martin Makary said. “Knowing that 10% of people aged 65 and older have Alzheimer's, and that by 2050 that number is expected to double, I am hopeful that new medical products such as this one will help patients.”

Sanofi in May agreed to spend $470 million to take control of a young biotechnology company and its experimental drug for Alzheimer’s disease.

The French pharmaceutical giant invested $40 million into Vigil last June, and in exchange got an exclusive right to be first in line for deal talks if Vigil chose to license out its platform of small molecule drugs that amplify a protein called TREM2.

Neuroscience is one of Sanofi’s core “strategic” research focuses, alongside cancer, rare diseases and the immune system. Yet, in terms of product sales, it pales in comparison to those other three areas. Sanofi’s portfolio lists just one neurology drug, the multiple sclerosis therapy Aubagio, which last year accounted for less than 1% of the 41 billion euros in net sales recorded by the company’s biopharma unit.

Sanofi is trying to grow this pool with a few experimental medicines that have progressed to the later stages of development. One, frexalimab, is what Sanofi touts as a “pipeline-in-a-product” asset, since the company believes it has the potential to treat a range of illnesses, from MS to lupus to diabetes. Another, riliprubart, is being evaluated against “CIPD,” a rare disorder that harms the peripheral nerves, leading to arm and leg weakness.

A third, tolebrutinib, has been tested across different types of MS and is currently being considered for approval by the Food and Drug Administration, with a decision deadline set for late December. Sanofi got ahold of tolebrutinib through its $3.7 billion purchase of Principia Biopharma in 2020.

Notably, all of these medicines work by regulating the immune system, which is characteristic of Sanofi’s approach to neurology.

The Vigil deal follows this approach, too, as TREM2 alerts the brain’s resident immune cells to threats like the toxic “abeta” plaques that are a hallmark of Alzheimer’s. When this protein is impaired or loses its function, it can increase the risk of nerve cell injury, inflammation and death.

“TREM2 represents a compelling target at the intersection of immune dysregulation and neurodegeneration,” said Houman Ashrafian, Sanofi’s head of R&D.

The acquisition also supports Sanofi’s strategy of “leveraging our expertise in immunology” to solve health problems with “critical unmet need,” Ashrafian added.

In a note to clients, Stifel analyst Paul Matteis argued the timing of the deal was "interesting," given a TREM2-targeting drug from Alector and AbbVie had recently failed in a mid-stage study. That setback "significantly diminished enthusiasm for the target," according to Matteis, so while there were reasons to think Vigil's drug could fare better, "it was going to be hard to have conviction in this until we saw [Phase 2] data."

A key committee that helps decide what new medicines enter the European market changed its mind in July about a closely watched drug for Alzheimer’s disease, and put its support behind the therapy.

The reversal was a win for Eli Lilly, which developed the drug and had already secured marketing approvals in Japan, China, the U.K. and the U.S., where it’s sold under the brand name Kisunla. Lilly classified Kisunla as one of the new products that could even further grow the company, which has ballooned in value thanks to an emerging class of weight loss and diabetes treatments.

Analysts, too, have big expectations, predicting peak annual sales will reach into the billions. But for Kisunla to have a shot at such success, Lilly has had to convince healthcare regulators that the drug’s potential to slow down the progression of Alzheimer’s outweighs its known safety risks. Like two other Alzheimer’s medicines sold by Biogen and Eisai, Kisunla can cause swelling and small-scale bleeding in the brain — a slate of side effects collectively known as “ARIA.”

ARIA was a main reason why that key committee from the European Medicines Agency sided against Kisunla during its initial review of Lilly’s marketing application. The group highlighted, for instance, how clinical testing had found nearly 37% of participants given the drug experienced these effects, versus just under 15% of those on a placebo.

Reviewers did consider whether to recommend Kisunla for people who lack a certain gene believed to increase the risk of ARIA, but ultimately concluded there wasn’t enough supportive evidence to warrant authorization.

Following that rejection, which came in late March, Lilly said it would appeal the committee’s decision. While such tactics don’t often work out — an analysis from RBC Capital Markets found a reversal rate of just 20% over the past decade or so — there was reason to think the odds might be better in this case. That’s because Eisai had just won an appeal for its drug Leqembi, which had raised similar safety concerns with the EMA.

Lilly’s bet paid off, as the committee’s updated opinion was that Kisunla should be authorized as a treatment for early symptomatic Alzheimer's disease in certain adults who have one or no copies of that risk gene. The European Commission formally approved the therapy in September.

AbbVie acquired a young company with drugmaking technology from Johnson & Johnson and an experimental treatment for Alzheimer’s disease that’s in the first stage of human testing.

Aliada has a license to a technology J&J scientists created to get drugs across a kind of biological shield that protects the central nervous system. This “blood-brain barrier” is extremely selective about what molecules are allowed to pass through it, and has long been a major obstacle for brain drug developers. In recent years, large companies like Roche, Biogen and Eisai have licensed tools or medicines meant to overcome this obstacle.

AbbVie has marked neuroscience as a “key growth area,” and said in a statement that Aliada’s platform will “enhance discovery and development efforts” there. The technology functions somewhat like a Trojan horse, taking potential medicines that would normally be shut out from the nervous system and attaching them to “delivery molecules.” The carriers are designed to then bind to proteins that can ferry the cargo across the blood-brain barrier.

Roopal Thakkar, AbbVie’s chief scientific officer, said that approach will strengthen the company’s research and development capabilities and should help in bringing forward “next-generation therapies for neurological disorders and other diseases where enhanced delivery of therapeutics into the CNS is beneficial.”

The Aliada deal also handed AbbVie a clinical-stage Alzheimer’s drug. A prevailing theory in Alzheimer’s research is the disease is caused, at least in part, by a toxic buildup of misfolded proteins. Aliada’s drug, known as ALIA-1758, is an antibody targeting a specific form of these “amyloid beta” proteins that are very stable and more prone to clumping together.

To Paul Matteis, an analyst at the investment firm Stifel, the deal is “interesting for a number of reasons,” one of which is that it “seemingly offers a vote of confidence in amyloid, just as sentiment in the space is reaching an all-time low.” He was specifically referring to Wall Street investors, who seem to have soured on anti-amyloid therapies after drugs like Aduhelm and Leqembi failed to meet lofty sales expectations.

Another intriguing aspect of the deal, according to Matteis, is it “arguably creates another formidable competitor” to Denali Therapeutics, which has a technology similar to Aliada’s. AbbVie’s acquisition reinforces “the value of brain delivery, broadly speaking,” the analyst wrote in a note to clients.

Findings from a large clinical trial strengthened the case that an experimental drug for cardiovascular illness could also be useful in combating Alzheimer’s disease.

The drug, known as obicetrapib, is designed to block a protein that regulates cholesterol levels. Three late-stage studies have shown patients treated with it experienced significant reductions in LDL — or “bad” — cholesterol. The drug’s developer, NewAmsterdam Pharma, disclosed near the end of last year data from the latest of those experiments, titled “Broadway,” which suggested obicetrapib may also offer some protection from heart disease-related complications like strokes.

In June, NewAmsterdam highlighted results from a pre-planned “sub-study” of Broadway focused on biological markers of Alzheimer’s.

There, the thinking is that obicetrapib’s lipid-lowering effects may safeguard neurons. Researchers believe high levels of LDL cholesterol in the brain contribute to the accumulation of amyloid and tau, the two proteins most closely linked to Alzheimer’s. And notably, the gene APOE4, which creates a protein that transports cholesterol throughout the brain, is the strongest genetic risk factor for the disease.

NewAmsterdam said the sub-study evaluated 1,727 patients, including 367 who carried the APOE4 gene. The main measure researchers looked at was a type of tau protein called “p-tau217.” Over a yearlong treatment period, levels of this protein diminished significantly across both the broader group and the APOE4 segment, according to NewAmsterdam.

Previously, the company ran a small, mid-stage study wherein 13 patients at the early stages of Alzheimer’s were given obicetrapib and followed for about six months. The experiment showed reductions in two cholesterol derivatives with ties to the disease.

The new findings differentiate obicetrapib from other drugs and “strongly support a potential preventive strategy for Alzheimer's disease,” NewAmsterdam’s CEO Michael Davidson said.

The outcome stoked excitement on Wall Street, too. Matt Phipps, an analyst at the investment firm William Blair, wrote in a note to clients that there are “clearly caveats to this analysis” since the sub-study wasn’t conducted in Alzheimer’s disease patients. Even so, taken together with the data from that smaller trial, his team thinks these latest results are “intriguing” and may ultimately provide “significant long-term upside” to NewAmsterdam’s stock price.

Jefferies analyst Dennis Ding echoed that idea in his own note. While investors have been “lukewarm” on the opportunity in Alzheimer’s because of the slow uptake of Biogen and Eisai’s products, “this could be an interesting call option over time” and might attract interest from strategic dealmakers.

Others were even more bullish. Roanna Ruiz, of Leerink Partners, argued that the Broadway results not only help obicetrapib stand apart from other oral drugs and “PCSK9s” — a separate, closely watched class of cholesterol-lowering medicines — but they also allow NewAmsterdam to “pursue the blockbuster Alzheimer's market.”

TD Cowen’s Tyler Van Buren went as far as to write the data suggest obicetrapib “can potentially be the first preventative therapy for Alzheimer's disease patients.”