Biogen leads the amyotrophic lateral sclerosis hopefuls

Despite several recent late-stage failures, there is still a lot going on in the ALS pipeline.

Amylyx’s decision this week to pursue early US approval of its amyotrophic lateral sclerosis project AMX0035 put the focus back on a field that has seen more than its fair share of disappointment of late.

And, surprisingly, the mid-to-late-stage pipeline looks full, with many different approaches being tested. “I’ve been in the field for about nine years and, during that time, there’s never been as many trials and companies as there are today,” Amylyx’s co-chief executive officer, Josh Cohen, told Evaluate Vantage.

However, he added a note of caution: “I think it’s going to take a lot of shots on goal. We can’t expect every trial to succeed.”

Biogen and Ionis's push

The next attempt will involve Biogen and Ionis’s tofersen, which is being tested in Sod1-mutated ALS in the pivotal Valor trial, due to yield data this half. Biogen also has several other projects in phase 1: the anti-C9orf72 oligo BIIB078 and the anti-ataxin-2 oligo BIIB105, both also partnered with Ionis, and the exportin 1 inhibitor BIIB100, licensed from Karyopharm.

In addition, Ionis has a wholly owned candidate, ION363, which went into phase 3 this year.

Still, not all of the late-stage hopefuls are on solid ground. Cytokinetics has opted to take its contender reldesemtiv into pivotal development despite the failure of the phase 2 Fortitude trial. And that was after the company’s first-generation troponin activator, tirasemtiv, had already proven a dud.

Academic efforts

If troponin activation is not the way to go there are still plenty of other mechanisms being tested, notably in the academia-led Healey-ALS platform trial. The first few arms, involving UCB’s zilucoplan, Biohaven’s verdiperstat and Clene Nanomedicine’s CNM-Au8, are set to complete soon.

This year the trial added Prilenia’s priodopidine, and Seelos Therapeutics’ SLS-005 has also been selected, with dosing set to begin this quarter, the company said during its second-quarter results.

Zilucoplan is not the only complement inhibitor being trialled in ALS, the table below shows. This approach took a blow when the Champions-ALS trial of Astrazeneca’s Ultomiris was stopped last month owing to lack of efficacy.

Other recent flops have come from Orphazyme’s heat shock protein amplifier arimoclomol, Brainstorm’s autologous cell therapy NurOwn, and Orion’s Simdax po; an intravenous formulation of the latter, a calcium sensitiser, is used in heart failure.

Amylyx hopes for a quick approval in ALS, but might not be the only one. It could soon become clear whether some of the other shots on goal have managed to hit their target.

Selected ALS projects in mid-to-late-stage clinical development
Project Mechanism Company Trial details Note
Phase 3
Tofersen Sod1 antisense oligo Biogen/Ionis ValorAtlas in presymptomatic adults with Sod1 mutation Valor data due H2 2021; Atlas ends Aug 2026
Alsitek (masitinib) CD117, FGFR3 & PDGFR antagonist AB Science AB19001 Ends Dec 2022; study restarted in Aug 2021 after being suspended in Jun 2021
Reldesemtiv  Troponin activator Cytokinetics Courage-ALS  Ends Dec 2023
Jacifusen (ION363) Fused in sarcoma antisense Ionis NCT04768972 Ends Mar 2024
AMX0035 (sodium phenylbutyrate + taurursodiol) Histone deacetylase inhibitor + bax inhibitor Amylyx Phoenix not yet recruiting Amylyx plans US filing based on positive ph2 Centaur data
Phase 2/3
CuATSM  Copper-containing synthetic small molecule Collaborative Medicinal Development NCT04082832 Primary completion date Dec 2020 but still recruiting
Zilucoplan Complement factor C5 inhibitor UCB HEALEY ALS Platform Trial – Regimen A* Ends Oct (previously Mar) 2021
Verdiperstat Myeloperoxidase enzyme inhibitor Biohaven HEALEY ALS Platform Trial – Regimen B* Ends Oct (previously Mar) 2021
CNM-Au8 Elemental gold nanocrystals Clene Nanomedicine HEALEY ALS Platform Trial – Regimen C*; ph2 Rescue-ALS Healey C ends Oct (previously Mar) 2021; Rescue-ALS data due Q4 2021
Pridopidine Sigma-1 receptor agonist Prilenia HEALEY ALS Platform Trial – Regimen D* Ends Mar 2022
MN-166 (ibudilast/Ketas) Phosphodiesterase inhibitor Medicinova Combat-ALS Ends Dec 2023
Phase 2
PrimeC (ciprofloxacin + celecoxib Antibiotic/Cox-2 inhibitor & NSAID Neurosense Therapeutics NCT04165850 Ended Jan 2021
ALZT-OP1a (cromolyn + ibuprofen) Mast-cell stabiliser/NSAID Aztherapies NCT04428775 Ended Jul 2021
RT001  Synthetic omega-6 fatty acid Retrotope NCT04762589 Ends Sep 2021
BLZ945 CSF-1 inhibitor Novartis NCT04066244 Ends Sep 2021
PU-AD Heat shock protein 90 inhibitor Samus Therapeutics NCT04505358 Ends Dec 2021
ANX005  Anti-complement factor C1q MAb Annexon Biosciences NCT04569435 Data due 2022
3K3A-APC Activated protein C analogue ZZ Biotech NCT05039268* Ends Jan 2022
AT-1501 Anti-CD40L MAb Eledon Pharmaceuticals NCT04322149 Ends Mar 2022
Empaveli Complement factor C3 inhibitor Apellis Meridian Ends Sep 2022
Engensis  HGF gene therapy Helixmith  Revivals-1A Ends Dec 2022
Trametinib (SNR1611) Mek inhibitor Genuv Ph1/2, NCT04326283 Ends Dec 2022
WVE-004 C9orf72 antisense oligo Wave Life Sciences Ph1/2 Focus-C9; also includes pts with FTD Ends Feb 2023
RNS60  Oxygen nanobubbles Revalesio  NCT02988297 (nebulised version) Ends Dec 2023
Q-Cells Human glial restricted progenitor cells Q Therapeutics Ph1/2, NCT02478450 Ends Dec 2023
AL001 Sortilin inhibitor Alector/ Glaxosmithkline Not available First pt dosed Sep 2021
*Investigator-sponsored study. Source: Evaluate Pharma &

The table in this story has been updated to include Neurosense's PrimeC.

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