Early Data From Ionis/Biogen’s BIIB080 Keeps Tau Alzheimer’s Hopes Alive

While many other approaches have failed, Ionis and Biogen hope their novel oligonucleotide can stop toxic tau tangles forming in the brain.

Preclinical studies showed BIIB080 could prevent or even reverse Alzheimer's in transgenic mice - but the Phase I study did not examine clinical efficacy in humans.

While controversy around the US approval of Biogen’s beta-amyloid targeting Aduhelm rumbles on, its partner Ionis Pharmaceuticals has produced positive early-stage data from another Alzheimer’s candidate this time targeting tau, BIIB080.

Alongside beta amyloid, tau is the other key protein implicated in the disease, but over the years has seen similarly high numbers of failed drug candidates aimed at slowing or halting its misfolding and the formation of tau tangles.

Among these was a miss last month for another Biogen candidate, the monoclonal antibody BIIB092 (gosuranemab), in a Phase II efficacy study, with the company terminating its development. (Also see "Biogen Gives Up On Gosuranemab After No Benefit Seen In Alzheimer's Study" - Scrip, 18 Jun, 2021.)

But the approval of Aduhelm (aducanumab) has reinvigorated the whole field, and BIIB080 is just one of dozens of tau-targeting candidates receiving renewed attention (see table).

 

Clear Effects On Tau Levels

Ionis and Biogen have unveiled topline data from a Phase Ib placebo-controlled, multiple-ascending dose study showing that BIIB080/IONIS-MAPTRx met its primary endpoint of safety and tolerability in 46 patients with mild Alzheimer's disease.

The data were presented in a poster session at the 2021 Alzheimer's Association International Conference (AAIC) currently underway virtually and in person in Denver, CO.

The trial showed time- and dose-dependent lowering of tau protein in cerebrospinal fluid (CSF) over the three-month treatment period and sustained reductions during a six-month post-treatment period.

Reductions in total tau protein reached 49% in the high-dose group treated every four weeks and 42% in the group treated every 12 weeks. Similar reductions where seen in the levels of phosphorylated tau, a form of the protein which aggregates in the brain and is closely associated with a range of neurodegenerative diseases.

The study has now moved into an open-label long-term extension study comprising a 12-month treatment evaluation period and a four- or six-month post-treatment period. 

The Phase I study had no efficacy endpoints, but the partners have signaled they will take the candidate forward. Ionis’ chief scientific officer Frank Bennet added that antisense-mediated suppression of tau protein could be a feasible therapeutic approach for other tauopathies.

BIIB080 attracted attention in preclinical studies in MAPT transgenic mice, in which MAPT-targeted antisense treatment showed prevention and reversal of disease, along with tau-lowering in CNS tissues. These results are rarely seen even in animal studies, nevertheless the companies remain cautious about its potential.

BIIB080 differs from other tau-targeting candidates in being oligonucleotide, developed from Ionis’ antisense platform and delivered intrathecally. Ionis has had mixed fortunes with other intrathecally delivered antisense drugs from its pipeline so far – Spinraza (nusinersen) is a blockbuster in spinal muscular atrophy, but Huntington’s disease candidate tominersen failed in a Phase III study in March. (Also see "Roche Shelves Phase III Huntington's Candidate Tominersen" - Scrip, 23 Mar, 2021.)

The majority of other tau-targeting candidates in development are monoclonal antibodies, many of which block the creation of tau tangles which eventually result in the death of neural cells. BIIB080 works upstream of this process, by blocking the production of the tau proteins in the first place.

Aduhelm was granted US FDA approval based on its surrogate biomarker of reducing beta amyloid levels, which may have set a precedent for other Alzheimer’s drugs. However given the growing pushback against the regulator’s decision, Ionis and Biogen and other developers will still aim to generate clear clinical benefits in pivotal trials for other Alzheimer’s candidates.