When Biogen’s experimental treatment for amyotrophic lateral sclerosis (ALS) missed the main goal of a pivotal study last year, the drugmaker said further analysis could yield better results. Additional data now show that treatment over a longer period of time led to improvement on several measures of the neuromuscular disorder.

The latest clinical trial results were published Wednesday in the New England Journal of Medicine. The data lend additional support for the drug, tofersen, which has been submitted for FDA review and is expected to receive a regulatory decision in early 2023.

Tofersen is an antisense oligonucleotide, a type of drug comprised of small pieces of DNA or RNA. The Biogen drug addresses a subset of ALS patients whose disease is driven by mutations to the SOD1 gene. These mutations lead to abnormal versions of the SOD1 protein believed to contribute to motor neuron dysfunction and cell death. Tofersen is designed to bind to and degrade SOD1 messenger RNA, which in turn reduces synthesis of SOD1 protein.

The main goal of the randomized, placebo-controlled Phase 3 test of the drug was to evaluate ALS patients on various functional measures at 28 weeks. According to results reported last October, the observed patient improvement was not enough to show statistical significance. However, investigators at the time noted that the results showed reductions in SOD1 protein and neurofilaments, filaments found in neurons that are considered a potential biological indicator of neurodegenerative disease.

Biogen did not give up on the drug. In June, the company presented data analysis  in which the randomized study at 28 weeks was combined with an open-label extension study at 52 weeks. In that new 52-week analysis, Biogen reported slower declines in measures such as respiratory function and muscle strength in those who started on tofersen earlier—the patients who received the study drug at the start of the study compared with those who started on placebo and were switched over to tofersen at week 28 to begin the extension study. These are the results that are now published in the New England Journal of Medicine.

Timothy Miller, co-director at the ALC Center at the Washington University School of Medicine and the principal investigator of the tofersen clinical trial, said in a prepared statement that in addition to the lowering of SOD1 protein, the drug led to “substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process.” Miller added that looking at the results in the later time points in the open-label extension study show “meaningful clinical benefit.” The New England Journal of Medicine article notes that comparisons of earlier initiation of tofersen versus delayed initiation are still being evaluated in the extension stage of the clinical trial.

The 52-week data were part of Biogen’s submission seeking FDA approval. The FDA accepted that application in July, setting a Jan. 25, 2023 target date for a regulatory decision. At the time, the agency said it planned to convene an advisory committee meeting to discuss the application. The date for that meeting has not yet been set.

The published data for Biogen’s ALS drug come as an ALS drug from Amylyx Pharmaceuticals is making its way through regulatory review. Two weeks ago, an FDA advisory panel voted 7-2 in support of recommending approval of that company’s experimental ALS treatment, AMX0035. An FDA decision for the Amylyx drug is due by Sept. 29.

Meanwhile, another ALS drug developer, BrainStorm Cell Therapeutics, is taking a shot at FDA approval. Last year, the FDA called out Brainstorm’s analysis of its ALS drug, Nurown, saying that that in addition to missing the main clinical trial goal, the results fell did not show patient benefit. Nevertheless, Brainstorm said last month that it plans to seek FDA approval of its ALS therapy.

Photo: Adam Glanzman/Bloomberg, via Getty Images

0 comment
0 FacebookTwitterPinterestEmail

Money pile and medicine pills representing medical expenses

The latest–and perhaps final–blow to the once-promising Alzheimer’s Disease medication Aduhelm came when its maker, Biogen, said it will stop collecting data on patients who are using it. Biogen said this was a result of Medicare and Medicaid restricting coverage so severely that there would not be a substantial number of patients to follow. Even after Biogen cut its original price of $56,000 per year in half, there were very few takers for the medication, which aims to attack proteins some scientists have linked to cognitive decline, in both the public and commercial payer spaces.

Unless something changes, we will never know if this drug–or the more promising beta amyloid-directed monoclonal antibodies that are currently in late stages of development–   could help the thousands of Americans who suffer from Alzheimers. Many who did qualify for Aduhelm can also no longer get it, as Medicare and Medicaid will only cover it if patient data is collected–which is exactly what Biogen says it will quit doing.

Zooming out, there is a lot more at stake than Aduhelm: as more novel pharmaceuticals, including life-saving gene-therapies come to fruition, the danger is increasing that these medications will never actually reach those who need them, due to Medicaid, Medicare and others not covering their high costs.

But the door is opening to change; recently, a rule that restricted Medicare and Medicaid to setting just one price per drug, is supposed to go away; allowing the agencies to set a price range. This means that they could start more easily entering into value-based purchasing agreements for medications, where there is a linkage between pay and performance.

While it may be too late for Ahuhelm, such an arrangement could still be used for other more promising beta amyloid-directed monoclonal antibodies that are currently in late stages of development. This may be the only way to make sure these medications–and the patients they could help–are given a chance.

Currently, the Centers for Medicaid and Medicare Services, the federal program that runs Medicare and works with states to operate Medicaid programs, has stated that if approved by the FDA, the entire class of beta amyloid-directed monoclonal antibodies will be subject to restricted reimbursement like Aduhelm. For example, all accelerated approvals must undergo post-marketing clinical trials, analogous to the stringent requirements imposed on Aduhelm. And even beta amyloid-directed Alzheimer’s Disease drugs that go through the regular approval process must enter a “coverage with evidence development” protocol, which implies that post-approval collection of data in patient registries will be mandatory.

But all this does is place more obstacles in front of patients, and it doesn’t actually do anything productive with the data that would be collected.

On the other hand, value-based pricing would measure the cognitive decline or progress in Alzheimer’s Disease patients on the medication, and, accordingly, adjustments could be made to the acceptable price range of the product. Payers like Medicaid and Medicare could also receive reimbursement from pharma companies if the patients’ lives are not improved.

This differs substantially from the approach of the Boston-based nonprofit Institute for Clinical and Economic Review and others who claim to embrace value-based pricing. Last year, ICER conducted a preliminary analysis of Aduhelm, extrapolating from clinical trial data. ICER concluded that a cost-effective price benchmark range would be between $3,000 and $8,400 per year for early-stage Alzheimer’s Disease patients, which is much lower than the current price of $28,000. But ICER’s assessment was not based on real world evidence beyond the clinical trials, as any true value-based pricing agreement would be.

Aduhelm’s ship has perhaps sailed, with the baggage of the FDA approval controversy, the recent departure of Biogen’s CEO and now the end of following patient data. Nevertheless, value-based arrangements could very much be in play for other beta amyloid-directed monoclonal antibodies, including Biogen/Eisai’s Lecanemab, Roche’s donanemab, and Roche’s gantenerumab–all currently in human trials.

Undoubtedly this would be a major undertaking, particularly logistically. And, getting Medicare and Medicaid to buy in won’t be easy. But, there’s precedent for the agencies wanting to pursue value-based agreements. The Center for Medicare and Medicaid Innovation has the authority to test models which modify Medicare payments for certain high-priced drugs.

And, to illustrate further, at the time of FDA’s approval of the CAR-T therapy Kymriah (tisagenlecleucel) in 2017 – indicated for acute lymphoblastic leukemia – it was accompanied by the announcement of a novel outcomes-based agreement with Medicare and Medicaid, in which those agencies would pay for Kymriah only if patients had responded to it by the end of the first month. Without disclosing why, Medicare and Medicaid quietly backed away from that agreement.

Maybe the substantial unmet need in Alzheimer’s Disease will trigger Medicaid and Medicare to consider alternative approaches to reimbursement. No one should pay for something that doesn’t work, including taxpayers—and those taking these medications. Value-based pricing prevents this.

Value-based pricing could have shown us with more certainty the real level of effectiveness of Aduhelm. Maybe it is worth paying something for; and value-based contracts are the only way to figure that out.

We are just at the beginning of a huge pipeline of drugs, including gene-therapies and other life-changing medications, for conditions long seen as incurable. Having a contract model where price is based on outcome data is the only way to make sure the people who really need these drugs get them–and only continue to take them if they work.

0 comment
0 FacebookTwitterPinterestEmail

Dementia or brain damage and injury as a mental health and neurology medical symbol with a thinking human organ made of crumpled paper torn in pieces as a creative concept for alzheimer disease.

In a meeting Friday, outside advisers to the Food and Drug Administration took a dim view of studies supporting what could be the first new drug for Alzheimer’s disease in nearly 20 years.

Over more than six hours, an 11-member advisory committee of outside experts raised numerous concerns about the data underpinning aducanumab, a drug developed in a partnership between Cambridge, Massachusetts-based Biogen and Japan-based Eisai.

In a final vote, 10 members of the advisory committee panel said the studies so far did not support the drug’s effectiveness, though FDA had argued otherwise in a presentation the panel. The 11th member registered an “uncertain” vote.  Though the vote is nonbinding, as is customary, FDA will consider the panel’s recommendations as the agency reviews the drug’s application for approval.

In a statement sent to MedCity News, Biogen’s CEO thanked patients and others for speaking at the FDA meeting. 

“Biogen thanks the many patients and advocates who shared their personal thoughts and experience at today’s Advisory Committee meeting, reflecting the significant unmet need for a treatment for Alzheimer’s,” said Michel Vounatsos said. “We appreciated the opportunity to share our data with the Advisory Committee, and we will continue to work with the FDA as it completes its review of our application.” 

Aducanumab  aims to slow the build-up of amyloid beta plaque in the brain, a key feature of Alzheimer’s disease. Previous therapies with the same goal have largely proven futile.

The drug from Biogen and Eisai appeared headed for the same dustbin in spring 2019. The companies halted a pair of clinical trials after it was determined they were likely to fail. The trials involved patients with mild cognitive impairment and dementia due to Alzheimer’s.

But the drug gained new life in October 2019 when Biogen unveiled data from the trials showing the drug appeared to work when taken in higher doses. 

Patients and caregivers acknowledged the drug may not be perfect. But they said it represented hope for people suffering from Alzheimer’s and a spur for continued research in the field.

One speaker – Dr. Stephen Salloway, an Alzheimer’s researcher and professor at the Warren Alpert Medical School of Brown University in Rhode Island – compared aducanumab to AZT, an early treatment for HIV/AIDS that eventually gave way to more effective drugs.

“We are at a critical juncture in Alzheimer’s disease,” Salloway told the panel, adding that patients and their families don’t have time to wait another four or five years for more clinical studies.

Other speakers said they had taken part in clinical trials for aducanumab and that it had helped them.

FDA staff also took a positive view of the drug. In materials prepared ahead of the meeting Friday, the agency described the study involving higher doses as being “highly persuasive and capable of providing the primary contribution to a demonstration of substantial evidence of effectiveness of aducanumab.”

Scientists on the FDA advisory panel were largely unconvinced. They recognized the urgent need for new treatments for the fatal disease, which afflicts 5.8 million Americans and has no cure. But they were concerned about the precedent if they approved a drug based on studies they deemed inconclusive at best.

“I think there’s a huge danger to approving something that turns out not to be effective. I think that danger is much, much greater,” said panel member Dr. Joel S. Perlmutter, a neurology professor at the Washington University School of Medicine in St. Louis.

Photo: wildpixel, Getty Images

Update: This story has been updated with comment from Biogen 

0 comment
0 FacebookTwitterPinterestEmail