While many in the field of tau therapy rely on immunotherapies to remove neurofibrillary tangles from the brain, some focus on stopping tau production. In a poster shown at the Alzheimer’s Association International Conference, July 26-30 in Denver, Colorado, and online, Catherine mummery, University College London, Candice Junge, Ionis Pharmaceuticals, Carlsbad, Calif., And colleagues provided an overview of data from the very first trial of an antisense tau oligonucleotide in mild Alzheimer’s disease. In this Phase 1b trial, BIIB080, developed by Ionis in partnership with Biogen Inc., Cambridge, Massachusetts, did not cause any serious adverse events. It reduced both total tau and phosphotau-181 in cerebrospinal fluid by 30 to 50 percent. What this means for cognition remains unclear. A phase 2 trial is expected to begin in mid-2022.
- In the Phase 1 trial, tau antisense therapy appeared safe.
- BIIB080 reduced CSF tau levels by 30 to 50 percent.
- Phase 2 was due to start next year.
“This is a flagship study of human tau therapy” Adam boxer, University of California, San Francisco, told Alzforum. “This is the first to target the tau protein at the genetic level and shows that, in a small number of people for a relatively limited time, a significant reduction in the tau protein in CSF is safe and well tolerated.” Gil Rabinovici, also at UCSF, agrees, noting that “ASOs are a very promising potential approach to treating tauopathies.”
Antisense oligonucleotides correspond to specific extracts of mRNA, suppressing translation. They have experienced a revival, spurred in part by the endorsement of Ionis nurses for spinal muscular atrophy (November 2016 news; May 2018 conference news). ASOs are being tested for their therapeutic potential in neurodegenerative diseases, including AD (News August 2019).
For this Phase 1b study, researchers recruited 46 people aged 50 to 74 with mild AD from the UK, Canada, Germany, Sweden, Finland and the Netherlands. The diagnosis of AD was determined by an overall clinical dementia assessment score of 1, a mini-mental state examination score of 20 to 27, and amyloid CSF positivity.
Participants were randomized 1: 3 to receive placebo or BIIB080 at low, medium, and high doses. The researchers administered a drug or placebo by intrathecal injection every four weeks for three months, followed by a six-month monitoring period (see image below). One group received two high doses three months apart. After the monitoring period was completed, everyone began receiving ASO at their assigned dose every 13 weeks for another year with up to six months monitoring thereafter. This open-label (OLE) extension should end in early 2022.
Dosage and test. Participants received low (cohort A), medium (cohort B) and high (cohorts C and D) doses of BIIB080 over a three-month treatment period. This was followed by a six month sampling period. [Courtesy of Catherine Mummery, University of College London.]
The primary outcome was adverse events, while secondary outcomes included CSF tau and pharmacokinetics. No participant had serious adverse events and 43 completed post-OLE surveillance. Three-quarters of the placebo group reported at least one side effect, as did 94 percent of those who received the drug. Up to 30% of the treatment group experienced mild to moderate effects, such as headache, pain when injecting the drug, or post-lumbar puncture syndrome (see image below). The latter occurs if the perforated dura leaks the CSF, lowering intracranial pressure and causing a characteristic posture-dependent headache (Cohen et al., 1991).
Painful for some. A majority of participants in the placebo and treatment groups reported mild side effects, which the researchers attributed to the lumbar puncture procedure itself. [Courtesy of Catherine Mummery, University College London.]
Did the drug hit its target? Total levels of tau and phospho-tau181 in the CSF fell over time, dropping up to 35% in the low dose group and up to 50% in the high dose group eight weeks after the last dose (see image below). In those who received the high dose, the markers continued to drop over the next eight weeks, dropping a further 5%.
Other tau immunotherapies currently being tested, such as anti-tau antibodies, focus on the extracellular tau, stifling its spread and aggregation in the egg. In contrast, ASOs attack expression, which can negate tau levels inside and outside cells. “Shooting down all the tau is a more exciting and logical approach for me, given our uncertainty about the pathological isoform,” Mummery told Alzforum. The boxer agreed. “Even if the hypothesis that prion-like spread is important for tauopathies is not correct, genetic suppression of tau with ASOs will give us a much better idea of whether tau is at the heart of neurodegeneration,” he told Alzforum. Rabinovici noted that reducing all tau may make this approach applicable to multiple tauopathies, as each involves different oligomers and fibril conformations.
But what does lower tau levels in CSF mean clinically? At the moment, we don’t know. “The strong dose relationship shows a real biological effect, but the big question is whether this translates into clinical benefits,” Mummery told Alzforum. The anti-tau antibodies semorinemab and gosuranemab also lowered tau in CSF but had no clinical benefit in AD (May 2021 news; June 2021 news).
Ditto for Ionis ASO for Huntington’s disease. Tominersen, also known as HTTRx, halved the levels of mutant Htt in CSF, but provided no clinical improvement for patients. A Phase 3 trial ended in March (March 2018 news; company press release).
“Pathological mechanisms are unique among neurodegenerative disorders, so it is difficult to compare ASOs between indications,” Junge wrote to Alzforum. Rabinovici agreed. “The success of one ASO may or may not predict the success of others,” he said.
Although it’s still early days, Boxer is hopeful for BIIB080, noting that when he lowered the tau in the CSF of non-human primates, the tau levels also dropped in their seahorses, as judged by the post-mortem analysis (Jan 2017 news; DeVos et al., 2017). Mummery agreed. “The quality of the preclinical work is one of the reasons I am very excited about the potential of this drug,” she said.
Eric Reiman, Banner Alzheimer’s Institute, Phoenix, wondered how ASO affects other fluid markers. “Additional biomarker data, including for downstream neurodegenerative biomarkers such as NfL, and clinical data will be needed to clarify the disease-slowing effects of treatment,” he wrote to Alzforum (full comment below).
Rabinovici raised concern about how reducing tau low enough to see pathological changes is related to cognition. “With BACE inhibitors, we didn’t know that aggressive inhibition would accelerate cognitive decline until late stage trials, so how much is the reduction in tau too much? ” He asked.
A phase 2 trial of BIIB080 for mild AD is planned. “Although I have yet to see the protocol, trial sites have been approached to participate and we hope it will start by mid-2022,” Mummery told Alzforum. She believes the trial will include American and European sites. — Chelsea Weidman Burke
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[Lumbar post-puncture syndrome].
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DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM.
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Sci Transl Med. Jan 25, 2017; 9 (374)
Phase 1b study
company press release