Six Neurology Drug Candidates to Watch in 2024: Clinical Updates and Pipeline Highlights

In 2023, the field of neurology witnessed a series of significant advancements. Qalsody, a new drug for ALS, was approved and launched, becoming the first FDA-approved treatment for ALS under the accelerated approval pathway based on biomarkers. Leqembi, the first fully approved Alzheimer's disease drug in 20 years, received FDA approval, advancing new drug development in the AD field. Zurzuvae, developed by Sage Therapeutics, was also approved as the first oral therapy for postpartum depression.

In 2024, the field of neurology will further unleash new potential. With a large number of promising drug candidates entering clinical trials, there will be some fresh and interesting clinical data emerging in the fields of neurodegenerative diseases and neuropsychiatry. Biospace has released six notable new drugs in the neurology field to watch in the first half of 2024, with their respective development companies set to announce a new round of mid-to-late stage clinical data.

1. Sanofi / Denali：SAR443820 / DNL788

Indications: Amyotrophic Lateral Sclerosis (ALS)

In the ALS field, Sanofi will announce the primary clinical results of the Phase II HIMALAYA trial for SAR443820/DNL788, a drug co-developed with partner Denali Therapeutics. Denali introduced SAR443820/DNL788 as a small-molecule inhibitor targeting RIPK1, a key signaling protein in canonical inflammatory and cell death pathways. Increased RIPK1 activity in the central nervous system is believed to lead to neuroinflammation and cell death, resulting in neurodegeneration.

The HIMALAYA trial employs a double-blind, randomized, placebo-controlled design. Part A of the trial has completed recruitment of 305 patients and will assess changes from baseline using the revised ALS Functional Rating Scale (ALSFRS-R) to determine disease progression. Part B of the HIMALAYA trial will serve as an open-label extension to comprehensively evaluate the Combined Assessment of Function and Survival (CAFS) score.

Currently, SAR443820/DNL788 for the treatment of ALS has received Fast Track designation from the FDA. Sanofi and Denali Therapeutics are also developing SAR443820/DNL788 for the treatment of multiple sclerosis, which is currently in Phase II clinical trials.

2. Intra-Cellular：Lumateperone

Indications: Major Depressive Disorder

Graig Suvannavejh, senior analyst of Mizuho Biopharma and Biotechnology Research, stated that Major Depressive Disorder (MDD) is a field worth watching in 2024. Among them, Intra-Cellular Therapies' Caplyta (lumateperone) for the treatment of severe depression will release Phase III clinical data.

Intra-Cellular's key asset, lumateperone, was approved in 2019 for the treatment of schizophrenia and received an expanded indication in December 2021 for the treatment of depressive episodes associated with bipolar disorder. Currently, Intra-Cellular is pursuing a third indication—MDD—and anticipates obtaining data from two Phase III clinical studies in the first half of 2024.

Lumateperone is an orally administered antipsychotic drug currently being evaluated in a three-part Phase III clinical trial for MDD. Studies 501, 502, and 505 are testing the drug primarily for the treatment of adult patients who have had an inadequate response to approved antidepressants. The primary endpoint of these studies is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after six weeks, while the key secondary endpoint is the change in CGI-S score over the same period. According to the January presentation, Intra-Cellular Therapies expects the primary data from Study 501 to be released in the first quarter of 2024, with the primary data from Study 502 following in the second quarter.

According to another Phase III trial reported in March 2023, lumateperone reduced the burden of depressive episodes in patients with MDD or bipolar depression with mixed features. Company executives stated that these data, along with the approval of lumateperone for the treatment of depressive episodes associated with bipolar disorder, "give us a certain level of confidence in the drug."

3. Annexon Biosciences：ANX005

Indications: Guillain-Barré Syndrome

ANNEXON BIOSCIENCES is expected to announce key data from the Phase III clinical trial of its lead candidate ANX005 in the first half of 2024. ANX005 is being developed for Guillain-Barré Syndrome (GBS), a severe and potentially fatal autoimmune neurological disorder that can cause paralysis, neurodegeneration, and cognitive impairment. Currently, there are no FDA-approved treatments available for GBS.

GBS is caused by autoantibodies attacking peripheral nerves, triggering the complement cascade (C1q). ANX005 is designed to inhibit C1 as well as the entire complement pathway. It has currently received Fast Track and Orphan Drug designations from the FDA for this indication.

ANNEXON BIOSCIENCES noted in a press release that a Phase III study evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of ANX005 completed enrollment in 2023, with new data expected before July.

According to Annexon, in the Ib phase trial, ANX005 "demonstrated rapid and sustained improvement in muscle strength" as well as "improvement in neuronal damage and clinical function in GBS patients."

4. Wave Life Sciences：WVE-003

Indications: Huntington's Disease

Huntington's disease is one of the most challenging neurodegenerative diseases, but the pharmaceutical industry has not given up on developing new drugs for it. Wave Life Sciences, as one of the Biotechs, is striving to tackle this disease. The company is testing its core product WVE-003 in the Ib/IIa phase SELECT-HD trial. According to a company press release, Wave expects to share data from the 30 mg single-dose and multi-dose cohorts in this study in the second quarter of 2024 and conduct long-term follow-up.

Huntington's disease is caused by CAG repeats in the first exon of the huntingtin (HTT) gene. This mutation leads to brain cell death, resulting in a series of progressive cognitive, psychiatric, and motor symptoms, including involuntary twitching or writhing movements.

Wave Life Sciences CEO Paul Bolno once stated that WVE-003 is designed to preferentially reduce levels of mutant HTT (mHTT) protein by targeting a single nucleotide polymorphism called SNP3, which appears on the mHTT transcript. Bolno introduced that approximately 40% of adults with Huntington's disease are estimated to carry the mutation-associated SNP3.

Wave Life Sciences announced clinical data from SELECT-HD in September 2022, showing early signs of decreased mHTT in cerebrospinal fluid. The company reported that wild-type HTT [wtHTT] (the beneficial form of huntingtin protein) was preserved at both doses.

Last week, Wave Life Sciences released a preclinical study emphasizing the importance of preserving wtHTT biology. Bolno mentioned that the preservation of this protein "is also crucial for delaying disease progression." "These data represent the first repeat-dose evaluation of wild-type [huntingtin] preservation alongside mutant huntingtin knockdown."

For Wave, the anticipated results will also impact its existing collaboration agreement with Takeda, which has the option to co-develop and co-commercialize WVE-003.

5 and 6. Praxis Precision Medicines: PRAX-562 and PRAX-628

Indications: Epilepsy

Two key anticipated clinical data points in the epilepsy field come from Praxis Precision Medicines, specifically for its products PRAX-562 and PRAX-628. Both drugs were developed based on Praxis' Cerebrum small molecule technology platform.

Primary Results of Phase IIa Study of PRAX-628 in Patients with Photosensitive Reflex (PPR) Epilepsy Expected to be Released in the First Quarter of This Year. According to Praxis' update, the 15 mg cohort of the study showed "exceeding expectations" in terms of drug activity. New data is expected to be released after the completion of the 45 mg cohort.

PRAX-628 for Focal Epilepsy: A Next-Generation Functionally Selective Small Molecule Targeting Hyperexcitability of Sodium Channels in the Brain. Praxis stated that preliminary data shows the candidate drug to be "well-tolerated with potential therapeutic benefits" and capable of reaching effective concentrations within 24 hours.

Praxis Precision Medicines, Inc. is expected to announce the results of the Phase II clinical EMBOLD study of PRAX-562 in the first half of 2024. This study aims to evaluate the efficacy of PRAX-562 in treating pediatric patients with SCN2A and SCN8A developmental epileptic encephalopathy.