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Clinical trials in neurodegeneration start a new page following aducanumab approval

BY SELINA KOCH, EXECUTIVE EDITOR

JUN 12, 2021 | 1:14 PM AEST

Biopharma executives in the Alzheimer’s field are delighted with FDA’s decision to grant accelerated approval to Biogen’s aducanumab. As the first biomarker-based approval for a neurodegenerative disease, the move cracks the door open to a shorter development path for everyone.

Though it will take time for additional biomarkers to be ready for use as surrogate endpoints, seven executives working in the Alzheimer’s field told BioCentury they are confident FDA’s approval of Aduhelm aducanumab from Biogen Inc. (NASDAQ:BIIB) marks a turning point for drug development in Alzheimer's and in neurodegeneration broadly.

“This is an inflection for Alzheimer’s treatment and a positive for drug development because it shows the flexibility FDA is willing to apply to neurodegeneration,” Carole Ho, CMO of Denali Therapeutics Inc. (NASDAQNLI), told BioCentury.

The decision set a precedent, signaling to the entire neurodegeneration field that FDA places high importance on the unmet need in these diseases, is willing to look past imperfect data and is ready to embrace biomarker findings in drug reviews.

After an 18-year hiatus, the decision has “supercharged” the field by reminding companies and investors that FDA approval in Alzheimer’s is possible, said Alzheon Inc. CEO Martin Tolar.

The approval also validates the biomarker-driven drug development strategy that has been gathering momentum in recent years at newcos and in pharma deals.

“We’re entering a new era of neurodegeneration clinical trials led by biomarkers, similar to where we’re at in cancer,” Howard Fillit, founding executive director and CSO of the Alzheimer’s Drug Development Foundation, told BioCentury.

Unanimously, the sources said Aduhelm’s approval will yield an array of benefits for Alzheimer’s drug development that far outweigh the complications to clinical trial design that will come from having a new, and somewhat burdensome, treatment option.
“Having a drug on the market will dramatically change care in a way that will generate natural history data on a scale that we couldn’t even imagine before.”
Carole Ho, Denali

Alzheimer’s companies working outside the amyloid hypothesis told BioCentury they do not expect to seek accelerated approval until their biomarkers have been broadly validated. β-amyloid reduction is likely only appropriate as a surrogate endpoint for amyloid-targeted therapies, they say, and they do not view FDA’s controversial acceptance of the endpoint as a sign the agency will lower its standards for other surrogate endpoints.

“Amyloid is a unique case,” INmune Bio Inc. (NASDAQ:INMB) CEO RJ Tesi told BioCentury.

But for Alzheon and other companies working on next-generation amyloid agents, Tolar argued it would be irrational not to try for accelerated approval. “All of us will seek accelerated approval now. Why would we not seek it? It will save huge time and cost.”
Alzheon dosed the first patient last week in a Phase III trial of oral β-amyloid inhibitorALZ-801, and has an 80+ patient biomarker study under way.

Andrea Pfeifer, CEO of AC Immune S.A. (NASDAQ:ACIU), agreed. “Our anti-Aβ vaccine will highly profit from this. We had already discussed a biomarker-based approach with the regulatory agency. Now the biomarker component of trials will be much more strongly supported than before.”

AC Immune’s ACI-24 is in Phase II testing. The company also created the anti-amyloid mAb crenezumab, which the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) is testing in a Phase II prevention trial.

Among the biomarkers that could extend the possibility of accelerated approval to more therapeutic mechanisms, neurofilament light chain (NEFL) was most cited as holding near-term promise, and unlike amyloid, NEFL could have broad utility across neurodegenerative diseases. KOLs are mixed on how soon tau will be ready for surrogacy.

ACCELERATING ALZHEIMER’S
Beyond simply having a new drug approved, FDA’s decision to base approval on a discordant, incomplete dataset plus biomarker data sends a powerful message that the agency is willing to be flexible in reviewing drugs for severe diseases with few treatment options. That’s been the case in oncology for years, but FDA is fragmented and its Office of Neuroscience had yet to embrace accelerated approval.

“Fundamentally, this is a step change in how the agency is talking about the severity of dementia. That was implicit before, but by changing the approval pathway it became explicit,” Jonathan Behr, a partner at SV Health Investors’ Dementia Discovery Fund, told BioCentury. Biogen is a limited partner in the Dementia Discovery Fund.

“FDA has lowered the bar for everybody. Now you can get approval on biomarker data plus a single study,” said Tolar, adding the decision “actually lowered the bar even further it because they granted the approval on data from an incomplete trial.”

“FDA has lowered the bar for everybody.”
Martin Tolar, Alzheon

Though most executives expect uptake of Aduhelm to be slow, particularly until reimbursement gets sorted out, they believe the therapy will be used. And because it’s the first drug that attacks the disease process rather than its symptoms, they say it will motivate more patients to seek an early diagnosis, which is the best time to intervene with candidate therapies.

“That is going to help in how we think about recruitment for trials,” said Denali’s Ho, who added that getting patients into the system early will have another benefit. “Having a drug on the market will dramatically change care in a way that will generate natural history data on a scale that we couldn’t even imagine before.”

None of the biotech executives are particularly concerned about Aduhelm usage complicating their companies’ clinical trials. Rather, they see opportunity for the drug to hasten the advent of combination trials, which everyone agrees are the future of Alzheimer’s care — yet another way the Alzheimer’s field may come to resemble cancer.

SPRINGBOARDING OFF ADU
With Aduhelm entering the market, the race is on to improve on the therapy with more convincing efficacy, less burdensome administration, and combination approaches. For the most part, industry leaders do not expect Aduhelm to get in the way of that endeavor.
Gene Kinney, CEO of Prothena Corp. plc (NASDAQRTA), likened the approval to the early days of HIV treatment. “You can look to a number of therapeutic indications where the first therapy approved is nowhere near where we are today. Think of AZT in HIV.”

“This is what we do,” said Kinney. “We develop new therapeutics that are meant to do better than the current treatments. In clinical trial designs, we contend all the time with marketed therapies.”

Prothena has a preclinical anti-amyloid mAb that Kinney says is “11-fold more potent than aducanumab.”

Denali and Biogen are developing a preclinical anti-amyloid therapy that uses Denali’s antibody transport technology to achieve much higher blood-brain barrier penetrance than a standard mAb. The approach may enable lower doses, which could avoid side effects and allow subcutaneous administration, which would be less burdensome than Aduhelm’s monthly IV infusions.

Alzheon’s ALZ-801 is oral, and because it stops formation of amyloid aggregates without removing existing plaque in vessel walls, Tolar thinks it will avoid the vasogenic edema of plaque clearing amyloid mAbs.

“In the future, you may get a 35% slowing in rate of decline with β-amyloid, and an autophagy drug adds another 10-20%, and neuroinflammation another 20%.”
Howard Fillit, Alzheimer’s Drug Development Foundation

Pfeifer said AC Immune’s vaccine against amyloid produces a polyclonal response against many forms of amyloid from small soluble species to plaques. “An agent which covers multiple toxic species may be more effective than a monoclonal antibody.”
None of the companies BioCentury spoke to believe it will become difficult in the near term to enroll patients who aren’t on Aduhelm, but Ho noted that as uptake grows companies have a couple of options for designing trials.

One approach, Ho said, is to treat Aduhelm as a background therapy that some patients will be taking and others won’t, and to simply make sure the numbers of those patients are balanced between arms. The other is to devise a combination trial in which all patients are on Aduhelm or on placebo depending on the arm. In the latter scenario, the company may need to pay for Aduhelm and may need to manufacture a placebo infusion version of the drug, she said.

ADDF’s Fillit said Aduhelm could speed up the transition to combination therapies, which is where the field is headed. “This is the first incremental step in whittling away at this disease. In the future, you may get a 35% slowing in rate of decline with β-amyloid, and an autophagy drug adds another 10-20%, and neuroinflammation another 20%. FDA has guidance on combination trials; companies will figure out the details.”

Despite the KOLs’ consensus that combination treatments will be needed for Alzheimer’s disease, companies have been reluctant to run combination trials, in large part because biomarker readouts for each agent would first have to be optimized separately.

"Without an approved therapy, combination trials are hard,” noted Ho. “The confirmation of aducanumab’s clinical benefit will take a long time, but the body of data suggests a confidence in the dose most likely to be beneficial; that takes out a major variable in combination trials. It’s complex when you think about having to test multiple doses of each therapy and combinations of doses.”

Very few Alzheimer’s combination trials have been run to date. Combining amyloid therapies with tau therapies is a near-term move the field could consider. Several anti-tau agents are in Phase II testing and could soon yield proof of concept.

BIOMARKER-BASED APPROVALS
Because no other biomarkers in the neurodegeneration field have amassed as much clinical data as amyloid, the executives do not expect Aduhelm’s approval to unleash an immediate flood of biomarker-based accelerated approvals.

Neuroinflammation company INmune Bio, which expects to start Phase II testing of Xpro1595 in the fourth quarter, is measuring several biomarkers of inflammation in its trial, but it does not anticipate seeking accelerated approval based on those markers. “To get approval we are going to have to ring the cognition bell. We’ll need one pivotal trial that shows improvement in cognition,” said Tesi.

XPro1595 is a biologic that selectively targets soluble and not membrane-bound TNFɑ to safety ameleorate neuroinflammation.

Though the next therapies that could be up for approval in Alzheimer’s disease target β-amyloid, which raises the prospect of accelerated approval, their Phase III trials are already well under way and won’t be influenced by the Aduhelm decision. The question that arises if the therapies produce equivocal data on their cognitive endpoints is whether FDA will approve them anyway based on amyloid reduction.

These next-in-line therapies are gantenerumab and crenezumab from Roche, donaneumab and solanezumab from Eli Lilly and Co. (NYSE:LLY), and lecanemab (BAN2401) from Biogen and Eisai Co. Ltd. (Tokyo:5483).

Behind these are anti-tau agents, but use of β-amyloid levels as a surrogate endpoint may not be appropriate for non-amyloid therapies. “No other therapeutic mechanisms have shown the level of amyloid reduction that anti-amyloid therapies have,” noted Ho.

Pfeifer agreed. She said AC Immune is developing multiple tau-targeting therapies of different modalities. “We’ve seen with our tau vaccine some inhibition of Aβ. We’re not exactly understanding why, but we’ve seen it. I don’t think that would classify Aβ as a biomarker for tau programs.”

According to Roche Global Head of Neurodegeneration Rachel Doody, tau biomarkers aren’t ready for prime time. “We don’t know enough yet about tau to say: how much tau should a person have? How does the measurement of tau with tracers reflect clinical benefit? So it’s at earlier stages.”

Pfeifer also believes tau biomarkers need more validation. “Right now, for a Phase III study, I think we are a bit behind in establishing tau as a surrogate marker.”

But she believes tau PET imaging will become an accepted endpoint much more quickly than β-amyloid PET imaging was, and that clinical data already exist that FDA could use to demonstrate correlations between tau reduction and cognitive benefit. In Biogen’s Phase III EMERGE trial, for example, phospho-tau correlated “extremely well” with cognitive outcomes, she said.

Considering there are multiple “tauopathies” besides Alzheimer’s disease, “I think tau biomarkers could become the standard for multiple indications and multiple therapies,” Pfeifer said.

Though blood-based biomarkers of β-amyloid and tau are starting to see use, Pfeifer thinks FDA will rely on PET imaging. “I do believe you will need to show tau pathology in the brain.”

The most-cited nominee for the next surrogate endpoint in neurodegeneration is NEFL, an abundant structural component of axons that is released as axons degenerate.

Rising NEFL levels signify active neurodegeneration and are therefore much closer to a readout of brain function than biomarkers of target clearance such as amyloid. Moreover, NEFL is not specific to any particular neurodegenerative disease, suggesting it could be an all-purpose tool.

“Neurofilament is an example of a biomarker with data from other diseases that could be used to support approval” in Alzheimer’s, said Ho. ”It hasn’t been in the label yet but many diseases have shown correlation between benefit and neurofilament,” including multiple sclerosis, spinal muscular atrophy, neuronal ceroid lipofuscinosis type 2 and other rare diseases.

Pfeifer said studies have shown NEFL and tau correlate with each other. “These two biomarkers as a couple are very strong. We are including both in our studies.”
FDA’s decision to approve Exondys 5 eteplirsen from Sarepta Therapeutics Inc. (NASDAQ:SRPT) based on dystrophin expression, before the marker had been correlated without functional outcomes, raises the question of whether the agency may do the same for programs that target genetic drivers of neurodegeneration, such as a therapy that targets SOD1 mutation carriers with amyotrophic lateral sclerosis (ALS) or targets HTT to treat Huntington’s disease.

Pfeifer does not think this is likely. “It’s a possibility but I still believe that at some point we would need clinical correlation.” Still, she said it’s not out of the realm of possibility. “The correlation could come from real-world data. So it could be a different approach like oncology, with additional data post launch. FDA is open to real-world data.”