Amylyx provides hope in amyotrophic lateral sclerosis

Like in many neurodegenerative diseases, failure has been the norm for amyotrophic lateral sclerosis. But there could finally be some hope on the horizon in the shape of Amylyx’s AMX0035, which has been shown to improve function and survival in a phase II/III study, albeit modestly.

It is unclear whether another trial will be needed for approval, but privately-held Amylyx is preparing to go it alone. Meanwhile, pivotal data are due with Brainstorm Cell Therapeutics’ cell therapy NurOwn next month, and several other late-stage ALS studies are set to read out next year.

Combo approach

Amylyx executives are unperturbed by the potential competition. “We’re thrilled to see the pipeline as full as it is now,” one of the company’s co-chief executive officers, Josh Cohen, tells Evaluate Vantage.

In any case he believes that, should AMX0035 be approved, it will likely be used in combination with existing ALS drugs – and, potentially, other therapies that could get the go-ahead down the road. “This is a really tough disease; there might not be a single magic bullet.”

In the phase II/III Centaur trial, patients receiving AMX0035 were allowed to keep taking the approved ALS therapies riluzole and/or edaravone; indeed, 77% were on background therapy.

Last week, data were published from a long-term analysis of Centaur, showing that the mean overall survival in those treated with AMX0035 was 25.0 months, compared with 18.5 months among those who had originally been randomised to placebo. The difference was statistically significant, with a p value of 0.023.

The news came just over a month after Amylyx reported that Centaur had hit its primary endpoint, change in the ALS functional rating scale (ALSFRS-R). At six months there was a 2.32-point difference in ALSFRS-R between the AMX0035 and placebo groups (p=0.03). Higher scores on the 48-point ALSFRS-R, which measures daily activities such as walking and dressing, indicate better function.

However, the therapeutic effect looked modest, according to an accompanying editorial, and there are other reasons to be cautious about AMX0035’s chances: 19% of patients receiving AMX0035 dropped out owing to adverse events, most commonly diarrhoea, versus an 8% drop-out rate in the placebo group.

In addition, there was no significant difference between the treatment and placebo groups in a biomarker of neuronal injury, phosphorylated axonal neurofilament H subunit. This marker would be expected to decrease if AMX0035 prevents neuronal death, as is hoped.

Dr Sabrina Paganoni of Massachusetts General Hospital, the lead investigator of Centaur, admits that AMX0035 does not represent a cure for ALS. “We can’t completely stop or reverse ALS, but [AMX0035 is] certainly an improvement over what we have,” she tells Vantage.

Stopping neuronal death

She believes that AMX0035 could modify the course of ALS, however. The project is a combination of sodium phenylbutyrate, a histone deacetylase inhibitor that acts as a small-molecule chaperone, and taurursodiol, a bax inhibitor.

Both products are already used separately, the former to treat urea cycle disorders and the latter to help dissolve gallstones. Notably, a phase III academic trial of taurursodiol alone in ALS is set to yield data next year.

Sodium phenylbutyrate is designed to reduce endoplasmic reticulum stress, while taurursodiol targets mitochondrial dysfunction. The overall aim is to prevent the death of neurons – ALS is characterised by accumulation of unfolded proteins in endoplasmic reticulum, and dysfunction and slowing of mitochondria, “almost regardless of the original insult”, Amylyx’s other co-chief executive, Justin Klee, tells Vantage.

He says it is now up to regulators whether Centaur alone could support approval, or whether further studies are needed.

Either way, Amylyx plans to take AMX0035 forward in ALS without a partner. Mr Cohen reckons the company would only need 20 to 40 sales reps to market the drug, if approved, while Mr Klee adds: “ALS is a rare disease, but it’s well characterised. Patients are generally diagnosed and treated at centres of excellence at major academic medical centres.”

Amylyx is also testing AMX0035 in Alzheimer’s, with data from the phase II Pegasus trial due in early 2021.

ALS pipeline

As for the rest of the ALS pipeline, there have been some new additions since Vantage last looked at the space, although some projects have also fallen by the wayside, including Orion’s Simdax po, which flunked the Refals phase III trial in July (Biogen leads the way in renewed amyotrophic lateral sclerosis push, July 24, 2019).

Biogen is one of the few large groups to make a big push in ALS. Pivotal data with that group’s Ionis-partnered SOD1 inhibitor tofersen are due in the second half of next year, the group said in its third-quarter earnings presentation today.

The company has several phase I ALS projects, including two more from Ionis: BIIB078, an anti-C9orf72 oligo; and BIIB105, an anti-ataxin-2 oligo that entered the clinic this year. There is also BIIB100/KPT-350, an XPO1 inhibitor licensed from Karyopharm.

Another interesting approach in ALS is targeting complement: Alexion tooks its paroxysmal nocturnal hemoglobinuria therapy Ultomiris into phase III early this year, while UCB’s zilucoplan is being evaluated as part of the Healey ALS platform trial, an academic effort testing several potential ALS therapies at once.

Ultimately, various approaches might be needed to thwart ALS, Amylyx’s Mr Cohen and Mr Klee believe – either in combination, or with different therapies being targeted to different patients. Whether AMX0035 will become one of these options is now down to the FDA.