AstraZeneca's Alexion buy takes first hit as Ultomiris fails in rare neurodegenerative disease

Ultomiris
Industry watchers never settled on what to make of Ultomiris’ opportunity in ALS because the drug entered phase 3 without proof-of-concept data. (AstraZeneca/Alexion)

Bad news has struck first for AstraZeneca’s newly acquired Alexion rare disease franchise.

AstraZeneca has decided to cap a phase 3 trial testing C5 inhibitor Ultomiris in the rare neurodegenerative disease amyotrophic lateral sclerosis (ALS), the British pharma said Friday.

Alexion was previously expecting top-line readout in the first half next year, but an independent data monitoring committee has recommended that the phase 3 Champion-ALS be stopped early because Ultomiris had failed to show efficacy.

ALS is a fatal disease of motor neurons that can gradually paralyze patients until death. The average life expectancy from symptom onset is between two and five years, AZ says. Existing treatments may slow disease progression, but most of them are designed to help manage symptoms.

ALS represents a big unmet need, with about 15,000 diagnosed patients in the U.S. by Alexion’s estimate. Still, industry watchers never reached a consensus on Ultomiris’ overall market positioning.

RELATED: Alexion's Ultomiris notches myasthenia gravis win amid quest for 3rd Soliris use

Alexion figured Ultomiris’ mechanism of action, targeting the complement system, may reduce neuroinflammation and help ALS patients live longer. The idea had never been tested out in a proof-of-concept clinical trial before Alexion launched the phase 3 Champion-ALS study, SVB Leerink analyst Andrew Berens pointed out in a note to investors in December. With that, ALS has always remained an uncertain commercial opportunity for Ultomiris.

Ultomiris and its predecessor Soliris are the two most important marketed assets AZ scored with its $39 billion acquisition of Alexion. Ultomiris, thanks to its current indications to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, reeled in $701 million sales in the first half of 2021, up 48% year over year.

Beyond ALS, Ultomiris carries more favorable expansion odds in generalized myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD), where Soliris is already approved.

A phase 3 gMG trial already hit its goal as Ultomiris takers showed better improvement from baseline in a patient-reported score “with high statistical significance” over placebo, Alexion unveiled in mid-July, days before AZ officially wrapped up the merger. Readout from the NMOSD trial could come in the second half of 2022, according to Alexion’s latest R&D update in April.

Alexion’s complement franchise could reach $3.06 billion in global MG sales in 2025, and the NMOSD revenue could hit $1 billion that year, Piper Sandler analyst Christopher Raymond said in a February note. 

RELATED: Alexion's new blockbuster Ultomiris keeps gaining steam as $39B AstraZeneca deal looms

Meanwhile, Ultomiris’ failure in ALS is an ominous sign for UCB’s rival complement inhibitor zilucoplan. That investigational drug is currently undergoing phase 3 in a platform ALS trial dubbed HEALEY by Massachusetts General Hospital.  The study is also evaluating Biohaven Pharmaceuticals’ migraine drug Nurtec ODT, with data expected later this year or early 2022.

Other than those meds, Amylyx recently presented promising results from the phase 2 Centaur trial for AMX0035 on a physical functional scale called ALSFRS-R in ALS patients. The company has submitted an application with Canadian authorities and plans to file for approval with the European Medicines Agency. It’s running a phase 3 trial to support a potential FDA filing.

Meanwhile, Biogen recently found itself in a controversy over the compassionate use of its antisense ALS candidate tofersen. The drug is currently wrapping up a phase 3 trial for patients with SOD1 ALS. Biogen came under fire after it initially denied a patient access to the experimental drug outside its phase 3 program, which at the time had already closed enrollment. After a few weeks of public pressure, the Big Biotech said it would allow expanded access to the med starting in mid-July after the patients who had received placebo in the trial had a chance to switch over to the therapy.

A mutation in the SOD1 gene is estimated to only account for about 2% of all ALS cases.