AAIC: Biogen bolsters hopes for Alzheimer's pivotal push as anti-tau oligo slows cognitive decline

 You might need this, will your competent? doctor be ready?

Your risk of dementia, has your doctor told you of this?  Your doctor is responsible for preventing this! Is s/he willing to prevent this?

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

AAIC: Biogen bolsters hopes for Alzheimer's pivotal push as anti-tau oligo slows cognitive decline

Biogen's leading tau-targeting candidate has slowed cognitive decline across a suite of different clinical assessments, backing up the pharma’s decision to race the molecule into phase 3 development. In a closely watched presentation at the Alzheimer’s Association International Conference in London, Biogen shared results from the phase 2 Celia study of diranersen, an antisense oligonucleotide that blocks the production of tau by binding to its precursor mRNA. Tau is one of two proteins that become deformed and clumped in Alzheimer’s, with the other, amyloid beta, already successfully targeted by Biogen’s Leqembi and Eli Lilly’s Kisunla. The most drastic slowing of decline was seen in the 60 patients who had 60 mg of diranersen infused into their spinal fluid every six months, the lowest dose level tested in the trial. This strong showing by the low dose is why the trial previously failed its primary endpoint, which was based on a dose-dependent response to the drug. At the 18-month mark, patients in the 60 mg group topped placebo with 26% less decline on the Clinical Dementia Rating Sum of Boxes test, 42% on the cognitive subscale of the Alzheimer's Disease Assessment Scale and 50% on the Mini Mental State Examination questionnaire. These patients also showed 30% and 23% less decline, respectively, on two different measures that combine scores from these tests—the modified Integrated Alzheimer’s Disease Rating Scale and the Alzheimer's Disease Composite Score. Biogen’s head of Alzheimer’s clinical development Szofia Bullain, M.D., told Fierce in advance of the readout that it was “really reassuring” that the composite scores stack up to the individual tests.  “No matter how we look at this elephant, it always looks like an elephant,” Bullain said. However, diranersen was unable to demonstrate an improvement over placebo on a measure of daily functioning, a result that Bullain described as puzzling. “We have working hypotheses at this point,” Bullain said. “Maybe it's a function of time. We know it's a noisy endpoint, it's a care-partner reported endpoint—but we don't want to blame it on the endpoint.” Though the trial was not set up to compare diranersen with Leqembi and Kisunla, the experimental drug’s efficacy “was probably comparable to the existing drugs in some cases, maybe a little bit better on some metrics,” Lawren VandeVrede, M.D., Ph.D., a neurologist at the University of California, San Francisco and investigator in the Celia study, told Fierce. While VandeVrede cautioned that the results still need to be fully confirmed in phase 3, for diranersen developer Ionis Pharmaceuticals, the data are a vindication of the hypothesis that clearing tau tangles can hamper disease progression. “Given the quality of the data that we have to date, it is clear that modulating tau has a positive benefit on patients,” Holly Kordasiewicz, Ph.D., Ionis’ senior vice president of neurology research, told Fierce. Biogen and Ionis’ work on diranersen was powered by the duo’s previous successful collaboration on Biogen’s spinal muscular atrophy blockbuster Spinraza and Qalsody, a treatment for amyotrophic lateral sclerosis. Biogen secured the full license for diranersen from Ionis in 2019. The oligonucleotide “uses the same chemistry as our already proven technologies,” Kordasiewicz said. “Once you crack that code, then you can, at least for neuro, just run through all those targets and advance them.” Biogen plans to rapidly move diranersen into a phase 3 study, but Bullain told Fierce that despite the 60 mg dose’s phase 2 potency, the company hasn’t committed to a late-stage dose just yet. “This is too early to commit to one, but the 60 mg dose definitely distinguishes itself,” she said. 

A bright future

With the first generation of anti-amyloid antibodies on the market and next-gen molecules coming down the pike, tau always made sense to VandeVrede and other neurologists as the next logical focus for treating the devastating neurodegenerative disease. “The next target for me was always tau, the other protein that Dr. Alzheimer saw under the microscope,” VandeVrede said, referring to psychiatrist Alois Alzheimer’s 1906 description of amyloid plaques and tau tangles. But while amyloid plaques live outside of cells, tau tangles are found inside of neurons, making them difficult to reach. Previous antibody approaches have focused on tau as it moves between neurons, Kordasiewicz said, and so while they can stop tau from spreading, they can’t help clear it from the brain. Diranersen, on the other hand, blocks activity of the MAPT gene that codes for tau protein, preventing tau in all its forms from being created. With new tau production reduced, the brain can go to work clearing out the troublesome tangles, the Ionis neuro leader explained.

“Because you're not continuing to feed that pipeline, the natural homeostasis mechanisms can clear that existing tau pathology and lower those tau levels,” she said. “That's when you can start to see the benefits, which we've now seen in Celia.”

By targeting tau, diranersen also avoids the brain-bleeding side effect that has plagued Leqembi, Kisunla and Biogen’s defunct yet first-in-class Aduhelm.

But the experts Fierce spoke to don’t see diranersen, or any other tau-clearing drug, as a replacement for amyloid antibodies. Instead, all eyes are on the potential for combination therapies.

“I don't think it's like chicken or fish,” VandeVrede said. “I don't think you're choosing between two entrees here.”

“The response is incomplete with the amyloid targeting therapies, and the response seems to be predicated on the amount of tau that you have before you start the treatment,” the neurologist continued. While it remains to be seen how diranersen should be used in the clinic if it secures approval, VandeVrede is excited by the chance to attack Alzheimer’s through multiple pathways.

Kordasiewicz, too, finds the possibility of combinations enticing.

“In the future you very well could have amyloid beta antibodies [and] tau oligonucleotides working together to really combat both those key pathologies in the brains of these individuals,” she told Fierce.

For Biogen, though, right now is diranersen’s time to shine.

“We're laser-focused on diranersen as monotherapy,” Bullain told Fierce. “But of course, we understand we'll be launching into a world in which, hopefully, anti-amyloids are going to be the standard of care. So we are thinking about how to bring and maximize benefits to patients.”

While diranersen is the clear frontrunner, others are racing behind Biogen with tau-targeting candidates of their own. Voyager Therapeutics is using AAIC to share preclinical data for a small interfering RNA that is also meant to hinder MAPT mRNA, with plans to enter the clinic later this year. 

Meanwhile, Denali Therapeutics is going after both MAPT for tau as well as amyloid with molecules that can cross the blood-brain barrier by hitching onto iron receptors, building on the success of the recently approved Avlayah for Hunter syndrome. The biopharma’s CEO Ryan Watts, Ph.D., opened this year’s AAIC with a plenary address.