HIMALAYA

A Phase 2 Multicentre, Randomized, Double-blind, Placebo-controlled, 3 arm Study to Evaluate the Efficacy, Safety and Tolerability of SAR443820 in Adult Patients with Amyotrophic Lateral Sclerosis Followed by a Long-term Safety Extension 

UK Chief Investigator

Dr Tom Lambert

Research summary

SAR443820 is an investigational drug that is being developed to slow down the disease progression of ALS. SAR443820 is a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor. RIPK1 is protein found within cells, involved in the regulation of inflammation, cytokine release, and cell death. Both preclinical and clinical studies have shown that RIPK1 is a key mediator of programmed cell death and inflammatory pathways in ALS. SAR443820, an inhibitor of RIPK1 that can penetrate the central nervous system, has the potential to modify the course of neurodegenerative processes and slow disease progression in patients with ALS. The purpose of this study is to see if the drug SAR443820 works to improve the symptoms of adults with ALS compared to a group receiving placebo (a dummy substance), with both groups continuing to receive their current treatment for ALS. Additional purposes of the study are to find out the pharmacokinetics (PK), and pharmacodynamics (PD) of SAR443820 and how safe and tolerable the drug is.

Inclusion / exclusion criteria

Key inclusion criteria:

• Male or female, 18-80 years of age (inclusive)

• Diagnosis of possible, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria

• Time since onset of first symptom of ALS ≤2 years

• Slow Vital Capacity (SVC) ≥60% of the predicted value

• Be able to swallow the study tablets at the screening visit

• Either not currently receiving riluzole or on a stable dose of riluzole for at least 4 weeks before the screening visit. Participants receiving riluzole are expected to remain on the same dose throughout the duration of the study

• Either not currently receiving edaravone or on the approved standard schedule of edaravone treatment. Participants receiving edaravone must have completed at least 1 cycle of treatment before the screening visit and are expected to continue edaravone treatment throughout the duration of the study

• Participants with a body weight no less than 45 kg and body mass index no less than 18 kg/m2

• Female participants with childbearing potential are eligible to participate if they are not pregnant or breastfeeding and agree to use adequate contraceptive method during study intervention period and for at least 32 days after the last dose of study drug

• Male participants must agree to use highly effective contraceptive method during the study period and for at least 92 days following their last dose of the study drug. Male participants must not donate sperms for the duration of study and 92 days after last dose of study drug

Key exclusion criteria:

• A history of seizure (history of febrile seizure during childhood is allowed)

• Having central IV lines, such as a peripherally inserted central catheter (PICC) or midline or port a cath lines

• With significant cognitive impairment, psychiatric disease, other neurodegenerative disorder (eg, Parkinson disease or AD), substance abuse, other causes of neuromuscular weakness, or any other condition that would make the participants unsuitable for participating in the study or could interfere with assessment or completing the study in the opinion of the Investigator

• History of recent serious infection (eg, pneumonia, septicaemia) within 4 weeks of the screening visit; infection requiring hospitalization or treatment with IV antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infection (such as tuberculosis) deemed unacceptable as per the Investigator's judgment

• With active herpes zoster infection within 2 months prior to the screening visit

• A documented history of attempted suicide within 6 months prior to the screening visit, present with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS ), or in the Investigator's judgment are at risk for a suicide attempt

• History of unstable or severe cardiac, pulmonary, oncological, hepatic, or renal disease or another medically significant illness other than ALS precluding their safe participation in this study

• Participants who are pregnant or are currently breastfeeding

• A known history of allergy to any ingredients of SAR443820

• Currently or previously treated with any strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers listed in Appendix 10 of the protocol within the specified washout period before the screening visit

• Received a live vaccine within 14 days before the screening visit

• Participants with concurrent participation in any other interventional clinical study or who have received treatment with another investigational drug (eg sodium phenylbutyrate and/or taurursodiol) within 4 weeks or 5 half-lives of the investigational agent before the screening visit, whichever is longer

• Participants who have received stem cell or gene therapy for ALS at any time in the past

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST ) >3.0 × upper limit of normal (ULN)

• Bilirubin >1.5 × ULN unless the participant has documented Gilbert syndrome (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)

• Serum albumin <3.5 g/dL

• Estimated glomerular filtration rate <60 mL/min/1.73 m2

Current status

Study completed

Locations

• Royal Stoke University Hospital

• Derriford Hospital, Plymouth

Information about study sites

Contact details

Stoke: Katrina Parkinson research@uhnm.nhs.uk

Plymouth: jonanderson2@nhs.net

Recruitment group(s)

Patients with MND

Recruitment target(s)

Up to 261 participants globally (8 participants in the UK)

Key dates

Recruitment open date: 18 May 2022

Recruitment end date: 14 June 2023 (earlier than planned - global recruitment target reached)

Funder(s)

Sanofi

Sponsor

Sanofi

Study design

Interventional, randomised controlled trial

Intervention (if applicable)

• Drug: SAR443820

• Placebo

Phase (if applicable)

2

Outcome measures

Primary outcome measures

• Change from baseline in the ALSFRS-R total score - Part A

• Combined assessment of the function and survival (CAFS) score - Part B

Secondary outcome measures

• Combined assessment of the function and survival (CAFS) score - Part A

• Change from baseline in slow vital capacity (SVC) - Part A

• Muscle Strength - Part A

• Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ5) - Part A

• Change from baseline in serum neurofilament light chain (NfL) - Part A

• Number of patients with treatmentemergent adverse events (TEAE) and Serious adverse event (SAE) - Part A

• Assessment of pharmacokinetic parameter -Plasma concentration of SAR443820 - Part A

• Combined assessment of the function and survival (CAFS) score - Part B

• Change from baseline in the ALSFRS R total score - Part B

• Time from baseline to the occurrence of either death, or permanent assisted ventilation (>22 hours daily for >7 consecutive days), whichever comes first - Part B

• Time from baseline to the occurrence of death - Part B

• Change from baseline in slow vital capacity (SVC) - Part B

• Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) - Part B

• Change from baseline in serum neurofilament light chain (NfL) - Part B

• Number of patients with treatment emergent adverse events (TEAE) and Serious adverse event (SAE) - Part B

• Assessment of pharmacokinetic parameter Plasma concentration of SAR443820 - Part B

Publications / Results reports

Links will be provided when papers are published.