PhII failure in rare neurodegenerative disease? No matter, Biogen will motor on in Alzheimer's
Biogen’s fierce focus on disorders of the brain has hit another roadblock.
On Friday, the US drugmaker — which recently resurrected its amyloid-targeting Alzheimer’s drug, aducanumab — said its anti-tau drug, gosuranemab, failed a mid-stage study in patients with progressive supranuclear palsy (PSP), a rare brain disorder that results from deterioration of brain cells that control movement and thought.
Biogen, which licensed the monoclonal antibody from Bristol-Myers Squibb, said it is abandoning testing the drug in PSP patients, but will continue to investigate its use in Alzheimer’s patients with mild cognitive impairment, given differences in disease pathology, it said.
In patients with PSP, the build-up of tau typically occurs in the frontal cortex. While in Alzheimer’s, tau tends to accumulate in the hypothalamus and brain stem.
“It’s unclear what the precise implications are from the PSP failure – we’re sure Biogen will conduct in-depth analyses – but on the surface, it leads us to question the viability of targeting intra-cellular tau with an antibody. The basic premise behind the tau antibody approach is to prevent the “spreading” of tau from neuron to neuron, though as we understand it, at a given time point, very little tau is sitting outside of the cell, and most misfolded tau is pathogenic inside neurons,” Stifel’s Paul Matteis wrote in a note.
“Thus, we would view these data in PSP – which is theoretically an enriched indication for testing the tau antibody hypothesis – as also negative for the prospects of Biogen’s tau program in Alzheimer’s, given that the latter is more heterogeneous, and the same potential ‘antibody target access issues’ may also be a relevant challenge.”
Biogen did not offer much detail on the failed PASSPORT study, except to say gosuranemab had failed to induce a statistically significant improvement in the PSP rating scale at week 52 — the main study goal — and that it had also disappointed in key clinical secondary endpoints.
Expectations for the PSP program were already low, Credit Suisse’s Evan Seigerman wrote in a note.
“Tau targeting assets have so far been difficult to develop (AbbVie discontinued its program in PSP due to lack of efficacy). Despite evidence of CSF free tau suppression, it remains a challenge to prove how this translates into clinical benefit,” he said. “The company plans on continuing the development of ‘092 in Alzheimer’s disease ‘due to differences in disease pathology,’ but as we were with PSP have low confidence in the program.”
The gosuranemab study in Alzheimer’s patients, dubbed TANGO, has enrolled over 650 patients with an estimated primary completion date of May 2021, according to clinicaltrials.gov.
But the quest for treatments to prevent and treat Alzheimer’s, the most common form of dementia, is littered with failure. For long, researchers were partial to the amyloid hypothesis, which suggests that targeting beta-amyloid plaques that collect between neurons and disrupt cell function could make a material impact on the progression of the disease.
However, setback after setback seemingly put the nail in the amyloid coffin earlier this year after Biogen, one of the last flag bearers of the theory acknowledged their failure. But in a dramatic twist in October, Biogen indicated it had resurrected its faith in the amyloid theory, at least in a subset of patients, following a protracted period of data mining.
Meanwhile, researchers are also looking at tau. Initially, anti-tau therapies were focused on inhibiting kinases or tau aggregation, or on stabilizing microtubules (which help guide nutrients and molecules from the cell body to the axon and dendrites) — but most of these approaches have been abandoned due to toxicity or a lack of efficacy, or both. Scientists are now looking at developing tau-targeting immunotherapies.