Biogen touted an “unprecedented” drop in tau in a Phase 2 trial, backing the company’s decision to take diranersen to Phase 3 despite a missed primary endpoint and seemingly supporting the anti-tau approach.
The co-owner of one of two marketed anti-amyloid therapies, Biogen has long been a pioneer in the Alzheimer’s space. On Tuesday at the Alzheimer’s Association International Conference, the company presented detailed data from a mid-stage trial of its next candidate, showing that the tau-targeting antisense oligonucleotide can slow clinical decline in patients with the neurodegenerative disease.
“As a clinician, I am excited to see that we now can target successfully another core pathology of Alzheimer’s disease,” Szofia Bullain, vice president of Alzheimer’s disease and dementia clinical development at Biogen, told BioSpace prior to the presentation.
In the Phase 2 CELIA trial, a 60-mg dose of diranersen—discovered by Biogen’s longtime partner Ionis and licensed exclusively to the larger company—led to a 26% slowing on the Clinical Dementia Rating Sum of Boxes (CDR-SB) after 18 months, alongside a slowing of cognitive decline on several other scales, according to Biogen’s press release. The trial enrolled 416 patients with mild cognitive impairment due to Alzheimer’s or mild Alzheimer’s.
Diranersen missed the trial’s primary endpoint, which assessed statistically significant dose response for change from baseline on the CDR-SB, but Biogen underscored the fact that “CDR-SB results favored diranersen versus placebo across all studied doses.” Higher doses were not associated with greater slowing of decline, the company said.
Ionis Head of Development Holly Kordasiewicz said the CELIA study was designed as a dose-finding study to inform the Phase 3 trial, and “to show some of that initial proof of efficacy, so you can have some confidence going into that Phase 3 study.”
“The study hit all those objectives that it needed to hit on, even though it didn’t hit on that primary endpoint,” she told BioSpace ahead of AAIC.
Biogen reported the initial trial result in May, confirming then that it planned to take diranersen to Phase 3 regardless of the missed endpoint.
At AAIC, Biogen also revealed that diranersen is the first tau-directed therapy to demonstrate robust reductions in both CSF total tau (50–65%) and brain tau pathology, as measured by PET, across all studied doses in the trial. Bullain called the degree of tau reduction shown in CELIA “unprecedented.”
The connection between amyloid and tau is becoming clearer, experts told BioSpace last week, with amyloid indicating early signs of Alzheimer’s while tau accompanies cognitive decline.
Biogen’s presentation on diranersen was easily the hottest ticket at AAIC, which is being held this week in London.
The results are “key data that the field is looking to,” Laura Nisenbaum, interim Chief Science Officer at the Alzheimer’s Drug Discovery Foundation (ADDF), told BioSpace last week. “This is the first signal that we might be able to move beyond amyloid,” she added.
Analysts expressed cautious optimism following Biogen’s initial announcement. “Any new mechanism showing cognitive benefits in Alzheimer’s could be a big long-term win,” RBC Capital Markets told investors at the time, adding that Biogen’s “excitement” over the data “suggests there may be something here.”
BMO Capital Markets also saw positive signs. “We believe management body language suggests warranted enthusiasm for the asset, with data presentation likely providing more rationale for decision to move into phase 3 development,” the analysts wrote in a July 9 note following an investor meeting with the company. “While not perfect . . . we noted the rigor with which these data were interrogated by outside experts,” BMO added, recalling how Biogen’s head of development, Priya Singhal, had said, “These results are not by chance.”
In the Phase 3 study, Biogen will be looking for consistency in the results on a larger scale, Bullain said. “We would again look for robust target engagement, again pronounced impact on tau pathology measured by tau PET, and the same clinical benefits,” Bullain told BioSpace. “If we could replicate those numbers that we’ve seen in Phase 2, I think we certainly would be very happy.”
A history of FDA flexibility
Biogen is no stranger to pushing candidates forward despite failed trial endpoints—and the company has largely been successful. Before winning accelerated approval in January 2023 for their currently marketed Alzheimer’s drug Leqembi, the partners had a precursor: Aduhelm.
In 2019, Biogen and Eisai abandoned the program that would become Aduhelm—the first new Alzheimer’s drug in nearly 20 years—after a futility analysis indicated that two Phase 3 trials would not hit their endpoints. However, a few months later, Aduhelm was back. The partners reported that after a full analysis, one of the trials, the Phase 3 EMERGE study, had hit the primary endpoint at the highest dose, demonstrating a significant decrease in clinical decline. Aduhelm won accelerated FDA approval in June 2021 as the first drug to target an underlying cause of the disease.
Biogen and Eisai also overcame a negative vote by an FDA advisory committee—three members of which would ultimately resign over Aduhelm’s approval. It was essentially replaced on the market by Leqembi.
Two years later, Biogen again benefited from FDA flexibility when Qalsody was approved as just the fourth-ever treatment for ALS despite having missed its Phase 3 primary endpoint. Qalsody, an antisense oligonucleotide partnered with Ionis, was approved specifically for SOD1-ALS, a genetic form of the disease. In this case, the companies did have the support of an adcomm, which voted unanimously that the drug’s effect on a neurodegenerative biomarker could be a reasonable predictor of clinical benefit.
Experts who spoke with BioSpace agreed that earlier intervention is the key in Alzheimer’s.
“You’re going to want to intervene as early as possible as you can in the disease,” Kordasiewicz said. “We’re going to see that in the [Alzheimer’s] field. There’ll be early intervention, and we’ll keep going earlier and earlier.”
Ionis and Biogen have seen this benefit of earlier treatment with Qalsody, as well as with Spinraza—also fruit of the companies’ longtime alliance—in spinal muscular atrophy, Kordasiewicz said.
“With our ALS drug, there’s a portion of the patients who, if you go in early enough, it’s looking like there’s reports that they’re now doing better as well,” she added. Of diranersen, Kordasiewicz said, “It’s great to see this exciting mechanism come to fruition.”
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.