5 Clinical Trial Readouts in Neurology to Look for in 2024

In the realm of neurology, drug development has experienced substantial growth over the years, marked by unprecedented funding and the introduction of inaugural disease-modifying therapies. Ongoing trials, numbering in the hundreds, are diligently evaluating potential agents for patients grappling with neurological conditions, spanning various phases of development. Amidst this prolific activity, staying abreast of the most recent discoveries can pose a challenge. Therefore, NeurologyLive® will be closely monitoring the anticipated data readouts from five clinical trials slated for 2024.

Myotonic Dystrophy Type 1: Phase 2 signal detection study (NCT04886518) of pitolisant (Harmony Biosciences)

Jeffrey Dayno, MD

Myotonic dystrophy type 1 (DM1) represents the 1 chronic neuromuscular disease with the most prominent sleep disorders, including excessive daytime sleepiness (EDS), sleep apneas, periodic leg movements during sleep, and REM sleep dysregulation. The sleep problems associated with DM1 occasionally resemble those observed in narcolepsy, which is associated with decreased levels of orexin in the cerebrospinal fluid.

In early 2024, Harmony Biosciences is expected to share the full dataset from its pivotal phase 2 signal biomarker detection study (NCT04886518) assessing pitolisant (Wakix) in individuals with mytonic dystrophy type 1 with EDS. The study features 30 individuals aged 18 to 65 years with DM1 who are followed through a 3-week titration phase, an 8-week stable dose period, and option open-label extension. In the trial, patients are randomly assigned 1:1:1 to high- or low-dose pitolisant or placebo.¹

In December 2023, the company announced topline data from the study, with results showing that pitolisant improved both EDS and fatigue over the 11-week treatment period. All told, patients on high- and low-dose pitolisant reported mean changes of –2.5 and –1.0 in Daytime Sleepiness Scale (DSS) the primary efficacy end point, in comparison with changes of –0.2 for those on placebo. On Epworth Sleepiness Scale (ESS), investigators reported mean changes of –4.88 for the higher dose pitolisant group vs –0.10 for placebo.

Dravet Syndrome: SWALLOWTAIL extension study (NCT04740476) of STK-001 (Stoke Therapeutics)

In July 2023, Stoke Therapeutics announced new positive findings from 2 ongoing phase 1/2a studies assessing its investigational antisense oligonucleotide STK-001 in children and adults with Dravet syndrome (DS). STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities.

Joseph Sullivan, MD

Dubbed MONARCH (NCT04442295) and ADMIRAL (2020-006016-24), the phase 1/2a studies were expected to be complete by the end of 2023 while the open-label extension, SWALLOWTAIL, is set to read out data in the first quarter of 2024.² SWALLOWTAIL only includes those who received a cumulative total dose of at least 30 mg of STK-001 in MONARCH and continued treatment with 30 mg or 45 mg doses every 4 months. Stoke is also expecting to announce end of study data for MONARCH and ADMIRAL in Q1 of 2024.

Combining available data from 45 patients who were treated with multiple doses (30 mg, 45 mg, 70 mg) in either MONARCH or ADMIRAL, findings showed that the greatest reduction in convulsive seizure frequency was among those (n = 11) treated with 2 or 3 doses of 70 mg in the ADMIRAL study. All told, investigators observed median reductions of 80% (n = 6) and 89% (n = 3) in the multiple-ascending dose (MAD) 70 mg cohort of ADMIRAL at 3 and 6 months postdose, respectively.

Preliminary data from SWALLOWTAIL, which included 26 individuals with DS, showed reductions in convulsive seizure frequency and substantial improvements in expressive and receptive communication, as measured by the Vineland Adaptive Behavior Scale-III, after 12 months. STK-001-treated patients also saw enhanced scores on Global Impression of Change as reported by caregivers and clinicians.

Friedreich Ataxia Cardiomyopathy: SUNRISE-FA study (NCT05445323) of gene therapy LX2006

SUNRISE-FA, an ongoing, dose-ascending, open-label trial, includes approximately 9 individuals with Friedreich ataxia (FA)-associated cardiomyopathy who are followed for a 52-week period. The study, which is expected to have data readout in early 2024, assesses the efficacy and safety of LEXEO's gene therapy LX2006.

R. Nolan Townsend

FA is a rare, autosomal recessive disease caused by a mutation in the autosomal frataxin (FXN) gene. Currently, there is no approved therapy that alters the progression of cardiomyopathy in FA, which is responsible for 59% of FA-related deaths. LX2006, administered as a one-time infusion, is designed to target the cardiac manifestations of FA by delivering functional FXN gene to promote the expression of the frataxin protein and restore mitochondrial function in myocardial cells.

The 3 cohorts of the trial will assess LX2006 in low, mild, and high doses, with safety, as demonstrated through treatment-emergent adverse events (TEAEs) and treatment-emergent serious events, as the primary outcome. Patients included in the trial are between 18 and 40 years of age, have a confirmed genetic diagnosis of FA, and met protocol specified ranges for antibodies and measures for FA cardiomyopathy. Those with uncontrolled diabetes, abnormal liver function, active infection of any time, and a contraindication to cardiac MRI, were excluded from the study.

The cardiac involvement seen in FA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and dilated cardiomyopathy. Dilated cardiomyopathy and arrythmia are associated with mortality in patients with FA, whereas hypertrophic cardiomyopathy is not.⁴

Trigeminal Neuralgia: Phase 2b LibraTN trial of NOE-101 (Noema Pharma)

Trigeminal neuralgia, a chronic pain condition that affects the trigeminal nerve and carries sensation from the face to the brain, is thought to affect 4-5 of every 100,000 people in the US annually. Associated with nerve injury or lesion, the condition is a form of neuropathic pain. NOE-101, developed by Noema Pharma, is a highly selective, potent, and cell-penetrant negative allosteric modulator of mGlu5 receptors, which has shown to be effective in controlling pain in animal models of neuropathic pain.

A phase 2b trial assessing NOE-101, dubbed LibraTN, is expected to have data read out in the first half of 2024.⁵ Dosing for the 24-week, prospective, double-blind, randomized-withdrawal, placebo-controlled study began in February 2022, weeks before the FDA authorized Noema's investigational new drug application (IND).

"The antinociceptive effect of NOE-101 is explained by its unique chemical and physical properties and its ability to block nuclear membrane mGlu5 receptors, the receptors overexpressed in chronic pain," Garibaldi said in a statement following the IND authorization. "Its efficacy is similar to the gold standard achieved by morphine and the non-opiate duloxetine, but with significant potential advantages in terms of side-effects and tolerance. The LibraTN study will help us gain further understanding of the efficacy of NOE-101 in patients with TN-associated pain."

Huntington Disease: Phase 1/2 Trials of AMT-130 (uniQure)

In December 2023, uniQure announced new 30-month interim data from its ongoing phase 1/2 trials assessing AMT-130, an investigational gene therapy for Huntington disease (HD). Results showed evidence of potential dose-dependent clinical benefit, as treatment with low dose resulted in a 0.39-point difference on Unified Huntington's Disease Rating Scale (cUHDRS) at 30 months and treatment with high dose resulted in and 1.24-point difference at 18 months.⁶

Edward Wild, PhD, FRCP

In the first quarter of 2024, uniQure noted that the company plans to begin regulatory interactions to discuss the data from both of the trials and potential strategies for ongoing development of AMT-130. Then in mid-2024, the company expects to present new data from the ongoing phase 1/2 studies of AMT-130, including additional follow-up data from treated patients. In its most recent data readout, the results were from a cut-off date of September 30, 2023, and did not include efficacy and biomarker data from the control patients who cross over to treatment.

Additional results from the readout showed that the therapy demonstrated a 0.95-points difference on Total Functional Capacity (TFC) at 30 months in the low-dose group and 0.49-points difference at 18 months in the high-dose (baseline values; low-dose, 11.9; high dose, 12.2). Additionally, patients on active therapy showed a 2.80-point difference in Total Motor Score (TMS) at 30 months in the low-dose and 1.70-point difference in the high-dose at 18 months (baseline values; low-dose, 13.3; high-dose, 12.1).

"The results from these phase 1/2 trials continue to be very encouraging as they show positive-trending, potentially dose-dependent signals across multiple key clinical and functional measures, in conjunction with further declines in NfL,” Edward Wild, PhD, FRCP, professor of neurology at University College London Queen Square Institute of Neurology, consultant neurologist at National Hospital for Neurology & Neurosurgery, and associate director of UCL Huntington’s Disease Center, said in a statement.

REFERENCES
1. Harmony Biosciences announces positive topline data from phase 2 signal detection study evaluating pitolisant in adult patients with myotonic dystrophy type 1. News release. Harmony Biosciences. December 7, 2023. Accessed December 8, 2023. https://www.prnewswire.com/news-releases/harmony-biosciences-announces-positive-topline-data-from-phase-2-signal-detection-study-evaluating-pitolisant-in-adult-patients-with-myotonic-dystrophy-type-1-302008352.html
2. Stroke Therapeutics announces positive new safety & efficacy data from patients treated with STK-001 in the phase 1/2a studies (MONARCH & ADMIRAL) and the SWALLOWTAIL open-label extension (OLE) study in children and adolescents with Dravet syndrome. News release. Stroke Therapeutics. July 25, 2023. Accessed December 21, 2023. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-positive-new-safety-efficacy-data
3. Lexeo Therapeutics announces completion of first cohort and dosing in second cohort in SUNRISE-FA, a phase 1/2 clinical trial of LX2006 for the treatment of Friedreich’s ataxia cardiomyopathy. News release. Lexeo Therapeutics. June 13, 2023. Accessed December 21, 2023. https://www.lexeotx.com/post/lexeo-therapeutics-announces-completion-of-first-cohort-and-dosing-in-second-cohort-in-sunrise-fa-a-phase-1-2-clinical-trial-of-lx2006-for-the-treatment-of-friedreichs-ataxia-cardiomyopathy/
4. Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V. Heart disease in Friedreich’s ataxia. World J Cardiol. 2019;11(1):1-12. doi:10.4330/wjc.v11.i1.1
5. Noema Pharma announces FDA investigational new drug authorization for phase 2b LibraTN study of mGluR5 inhibitor NOE-101 in trigeminal neuralgia. News release. Noema Pharma. February 14, 2022. Accessed March 8, 2022. https://www.globenewswire.com/en/news-release/2022/02/14/2384353/0/en/Noema-Pharma-Announces-FDA-Investigational-New-Drug-Authorization-for-Phase-2b-LibraTN-Study-of-mGluR5-Inhibitor-NOE-101-in-Trigeminal-Neuralgia.html
6. uniQure Announces Update on Phase I/II Clinical Trials of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease. News Release. Published December 19, 2023. Accessed December 19, 2023. https://www.globenewswire.com/news-release/2023/12/19/2798425/0/en/uniQure-Announces-Update-on-Phase-I-II-Clinical-Trials-of-AMT-130-Gene-Therapy-for-the-Treatment-of-Huntington-s-Disease.html