What caused Roche's Huntington's drug tominersen to hit the skids in late-stage test? It's complicated, analysts say
Just last month, Roche hit the pause button on a Phase III test for Huntington’s hopeful tominersen after a data committee questioned its risk/benefit profile. Now, the drugmaker is conducting an autopsy to see what went wrong, but answers are in short supply.
On Tuesday, Roche presented follow-up data from tominersen that sought to provide some clue behind why the drugmaker halted its Phase III test. The answer? It’s complicated, Stifel analysts wrote in a note to clients Wednesday.
Last month, Roche hit the brakes on tominersen’s late-stage test after an independent data committee “made its recommendation based on the investigational therapy’s potential benefit/risk profile for study participants.”
Roche in-licensed tominersen, formerly known as IONIS-HTTRx, back in 2017 and had enrolled 791 patients in 18 countries so far in the Phase III GENERATION HD1 study prior to stopping dosing. The double-blind, placebo-controlled study tested tominersen in patients with manifest Huntington’s over 25 months, randomized to receive either a 120-mg dose of the drug every two months, a 120-mg dose every four months or placebo.
Full data showed that tominersen was trending worse than placebo in terms of improving patients’ symptoms and performed particularly poorly at higher doses. While the data were clear on why it was necessary to pause dosing, the underlying cause of why higher doses of tominersen performed so poorly is still unclear, Stifel analysts said.
There are four hypotheses, they said, on what could be driving tominersen’s lack of success, and those could have readthroughs for other candidates, including that the drug isn’t dispersing in the body properly, that it could be knocking down “good” Huntingtin protein, or that tominersen has specific toxicity concerns that make it unsuitable at higher doses.
The data on Tuesday, Stifel wrote, don’t really link any one of those causes to the drug’s performance — more likely it’s a combination of multiple factors. Take biodistribution, for example: “If biodistribution alone were the culprit here, we probably wouldn’t expect Tominersen to trend worse on all presented endpoints; we might even expect the drug to trend better on certain cognitive tests,” the analysts wrote.
The biggest readthrough for Ionis is for the rest of its antisense oligonucleotide drugs. If the problems that led to tominersen’s pause are also true of other ASO drugs, that could present a big problem for Ionis down the road, Stifel wrote, and a big opportunity for uniQure and its gene therapy, AMT-130, for Huntington’s.