Ravulizumab Phase 3 Trial in ALS Discontinued Due to Lack of Efficacy


The long-acting C5 complement inhibitor, developed by Alexion and approved for atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria (PNH), failed to show an effect on ALSFRS-R score.

Gianluca Pirozzi, MD, PhD, senior vice president, and head, Development and Safety, Alexion

Gianluca Pirozzi, MD, PhD

Alexion Pharmaceuticals announced that it is discontinuing its phase 3 trial of the ravulizumab (Ultomiris) in amyotrophic lateral sclerosis (ALS), CHAMPION-ALS (NCT04248465). The decision was reached based on a recommendation from the Independent Data Monitoring Committee’s prespecified interim analysis which suggested that the trial be discontinued because of a lack of efficacy.1

Those enrolled in the study—target enrollment was 350 adults with sporadic or familial ALS—will discontinue treatment with ravulizumab and complete necessary follow-up visits, with the remaining data planned to be used to inform ongoing research. Otherwise, no new safety data were collected, with the overall safety profile maintaining consistency to prior study of the long-acting C5 complement inhibitor.

Study participants were randomized 2:1 to receive either ravulizumab or placebo every 8 weeks following an initial loading dose while remaining on their existing standard of care treatment for ALS. After 50 weeks, all patients were expected to enter the 2-year open-label extension phase of the study. The primary end point was the change from baseline in ALS functional rating scale-revised (ALSFRS-R) score, with secondary measures including ventilation assistance-free survival (VAFS), respiratory capacity, muscle strength, and neurofilament light chain (NfL) serum concentrations.2

"We are disappointed by this outcome and what it means for patients with this devastating disease. We would like to thank the entire ALS community as well as investigators and healthcare professionals who dedicated their time and expertise to this trial,” Gianluca Pirozzi, MD, PhD, senior vice president, and head, Development and Safety, Alexion, said in a statement.1 “We continue to be confident in the potential of targeting C5 for complement-driven diseases and remain fully committed to our efforts to serve the rare disease community.”

The State of ALS Therapeutic Development

Ravulizumab is not the only therapy this year whose development in ALS was found to be unsuccessful. In May, topline data from the ORARIALS-01 trial (NCT03491462) of arimoclomol, a heat shock protein amplifying drug, for the treatment of ALS revealed that the Orphazyme agent did not meet its primary or secondary end points of impact on function or survival.3

This news of CHAMPION’s discontinuation also comes despite the identified involvement of the complement system in ALS, including a strong suggestion that the C5a/C5aR1 axis, among others, is a potential target for therapeutics for the disease.4-7 Although the trial halt may put a theoretical hold on complement inhibition agent development for ALS, it does not mark the end of clinical development for the neuromuscular disease.

In 2021 alone, several promising investigational agents for ALS have made progress along the clinical pipeline, including ALS001, an investigational agent from Coya Therapeutics which was granted orphan drug designation for the treatment of ALS in early July.8 It is currently in an ongoing phase 2a trial (NCT04055623) that has an anticipated data readout later this year. Later in July, WVE-004, a stereopure antisense oligonucleotide from Wave Life Sciences aimed at treating C9orf72-associated ALS, began dosing in the phase 1b/2a FOCUS-C9 trial (NCT04931862),9 and just a few days after that, Cytokinetics announced the open enrollment for a new phase 3 trial, COURAGE-ALS (NCT04944784), to evaluate the efficacy and safety of its investigational agent reldesemtiv in patients with ALS.10 Earlier in the year, in May 2021, Amylyx announced the design of its phase 3 PHOENIX trial, a 48-week, randomized, placebo-controlled study of AMX0035.11

What's Next for Ravulizumab

Ravulizumab still holds a place in the market, despite this news. Previously known as ALXN1210, the Alexion product is current approved in the United States, Europe, and Japan for atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria (PNH), a pair of rare blood disorders caused by an overactivation of the complement system.

In July, ravulizumab was recommended for marketing authorization in the European Union (EU) for an expanded use indication that includes children and adolescents with PNH. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency offered its positive recommendation based on interim results from a phase 3 clinical trial, which were presented during the European Hematology Association 2021 Virtual Congress.12

1. Update on CHAMPION-ALS Phase III trial of Ultomiris in amyotrophic lateral sclerosis. News release. AstraZeneca; Alexion. August 20, 2021. Accessed August 24, 2021. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/update-on-ultomiris-phase-iii-als-trial.html
2. Alexion Announces Planned Initiation of Pivotal Phase 3 Study of ULTOMIRIS® (ravulizumab) in ALS. News release. Alexion. January 14, 2020. Published August 24, 2021. https://ir.alexion.com/news-releases/news-release-details/alexion-announces-planned-initiation-pivotal-phase-3-study
3. Orphazyme announces topline data from pivotal trial of arimoclomol in Amyotrophic Lateral Sclerosis (ALS). News release. Orphazyme. May 7, 2021. Accessed August 24, 2021. https://www.globenewswire.com/news-release/2021/05/07/2225216/0/en/Orphazyme-announces-topline-data-from-pivotal-trial-of-arimoclomol-in-Amyotrophic-Lateral-Sclerosis-ALS.html
4. Carpanini SM, Torvell M, Morgan BP. Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Front Immunol. 2019;10:362. doi:10.3389/fimmu.2019.00362
5. Parker SE, Hanton AM, Stefanou SN, Noakes PG, Woodruff TM, Lee JD. Revisiting the role of the innate immune complement system in ALS. Neurobiol Dis. 2019;127:223-232. doi:10.1016/j.nbd.2019.03.003
6. Woodruff TM, Lee JD, Noakes PG. Role for terminal complement activation in amyotrophic lateral sclerosis disease progression. PNAS. 2014;111(1):E3-E4. doi:10.1073/pnas.1321248111
7. Kjældgaard AL, Pilely K, Olsen KS, et al. Complement Profiles in Patients with Amyotrophic Lateral Sclerosis: A Prospective Observational Cohort Study. J Inflammation Res. 2021;14:1043-1053. doi:10.2147/JIR.S298307
8. Coya Therapeutics receives orphan drug designation from the FDA for ALS001, an autologous treg cell therapy, for the treatment of ALS. News Release. Coya Therapeutics. July 7, 2021. Accessed August 24, 2021. https://www.globenewswire.com/news-release/2021/07/07/2258942/0/en/Coya-Therapeutics-Receives-Orphan-Drug-Designation-from-the-FDA-for-ALS001-an-Autologous-Treg-Cell-Therapy-for-the-Treatment-of-ALS.html
9. Wave Life Sciences announces initiation of dosing in phase 1b/2a FOCUS-C9 clinical trial of WVE-004 in amyotrophic lateral sclerosis and frontotemporal dementia. News release. July 20, 2021. Accessed August 24, 2021. https://www.globenewswire.com/news-release/2021/07/20/2265597/0/en/Wave-Life-Sciences-Announces-Initiation-of-Dosing-in-Phase-1b-2a-FOCUS-C9-Clinical-Trial-of-WVE-004-in-Amyotrophic-Lateral-Sclerosis-and-Frontotemporal-Dementia.html
10.Cytokinetics announces start of COURAGE-ALS, a phase 3 clinical trial of reldesemtiv in patients with amyotrophic lateral sclerosis. News release. Cytokinetics. August 2, 2021. Accessed August 24, 2021. https://www.globenewswire.com/news-release/2021/08/02/2272729/35409/en/Cytokinetics-Announces-Start-of-COURAGE-ALS-a-Phase-3-Clinical-Trial-of-Reldesemtiv-in-Patients-With-Amyotrophic-Lateral-Sclerosis.html
11. Amylyx Pharmaceuticals presents trial design of global phase 3 PHOENIX study of AMX0035 in ALS at the European Network to Cure ALS (ENCALS) meeting 2021. News release. Amylyx Pharmaceuticals. May 12, 2021. Accessed August 24, 2021. https://www.businesswire.com/news/home/20210512005352/en/Amylyx-Pharmaceuticals-Presents-Trial-Design-of-Global-Phase-3-PHOENIX-Study-of-AMX0035-in-ALS-at-the-European-Network-to-Cure-ALS-ENCALS-Meeting-2021
12. Ultomiris recommended for approval in the EU by CHMP for children and adolescents with paroxysmal nocturnal haemoglobinuria. News release. AstraZeneca; Alexion. July 26, 2021. Accessed August 24, 2021. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/ultomiris-recommended-in-eu-for-children-with-pnh.html
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