5 Clinical Trial Readouts in Neurology to Look for in 2023


Take a look at 5 of the most-anticipated clinical trial data readouts expected in 2023 that neurology health care professionals should keep their eyes on.

Over the years, drug development has continued to boom throughout neurology, with record-setting amounts of funding and first-time disease-modifying therapies being introduced. There are several hundreds of ongoing trials assessing potential agents for patients with neurological conditions, all across different phases. With so much activity, keeping up with the latest findings can be difficult. Here are 5 clinical trials with expected data readouts in 2023 that NeurologyLive® will have its eye on.

Radiologically Isolated Syndrome: TERIS study (NCT03122652) of Teriflunomide

Christine Lebrun Frenay, MD, PhD, head of the department of neurology at the Centre Hospitalier Universitair de Nice

Christine Lebrun Frenay, MD, PhD

Patients with radiological isolated syndrome (RIS) present MRI features highly typical for multiple sclerosis (MS) without clinical symptomology suggestive of central nervous system (CNS) demyelination. Researchers have hypothesized that earlier treatment intervention may extend the time to the first acute or progressive clinical event resulting from CNS demyelination and reduce new radiological activity. For context, there are currently no disease-modifying therapies for RIS.

Later this year, data from the TERIS study assessing teriflunomide (Aubagio; Sanofi) in patients with RIS is expected to be reported. This multicenter, double-blinded 2-year study includes 125 patients with RIS who fulfil the 2009 RIS criteria. Similar to the pivotal ARISE study (NCT02739542), the primary outcome will be time to the first acute or progressive neurological event. Led by Christine Lebrun Frenay, MD, PhD, head of the department of neurology at the Centre Hospitalier Universitair de Nice, the study will also assess secondary outcomes such as change in number of new or enlarging T2 lesions, contrast enhancing lesions, T2-lesion volumes, and brain atrophy.1

This study is a sister study to ARISE, which evaluated the use of dimethyl fumarate (Tecfidera; Biogen) in patients with RIS. In ARISE, treatment with dimethyl fumarate resulted in significantly reduced the risk of first clinical demyelinating event, in both unadjusted (hazard ratio [HR], 0.18; 95% CI, 0.03-0.63; P = .007) and adjusted (HR, 0.07; 95% CI, 0.01-0.45; P = .005) Cox proportional hazards regression models, indicating the first ever disease-modifying effect in this patient population. Overall, dimethyl fumarate-treated patients had a risk reduction greater than 80% relative to placebo in the prevention of a first clinical event related to CNS demyelination.2

Duchenne Muscular Dystrophy: Phase 3 LELANTOS-2 study (NCT04632940) of pamrevlumab (FibroGen)

In June 2022, FibroGen announced it had completed target enrollment for its ongoing phase 3 LELANTOS-2 clinical trial of pamrevlumab, a first-in-class connective tissue growth factor (CTGF) inhibitor antibody, in patients with Duchenne muscular dystrophy (DMD). Initiated in March 2021 as a follow-up to the first phase 3 trial, LELANTOS-1 (NCT04371666), topline data is expected to read out sometime in mid-2023.3

Elias Kouchakji, MD, senior vice president of clinical development, drug safety, and pharmacovigilance at FibroGen

Elias Kouchakji, MD

Pamrevlumab, an agent that has received orphan drug, rare pediatric disease, and fast track designations from the FDA, is also in clinical development for other conditions such as idiopathic pulmonary fibrosis (IPF), locally advanced unresectable pancreatic cancer, and metastatic pancreatic cancer. In LELANTOS-2, 73 individuals with DMD, aged 6 to 12 years old, were randomly assigned to either intravenous pamrevlumab 35 mg/kg, dosed every 2 weeks, plus systemic deflazacort (Emflaza; PTC Therapeutics) or equivalent potency of oral corticosteroids; or matching placebo plus systemic deflazacort or equivalent potency of oral corticosteroids.

Elias Kouchakji, MD, senior vice president of clinical development, drug safety, and pharmacovigilance at FibroGen, said in a statement at the time of LELANTOS-2’s initiation, that kicking off the study "underscores our commitment to delivering a meaningful treatment for DMD, an area with a high unmet medical need," additionally highlighting that "Duchenne, the most common form of muscular dystrophy in children, is typically diagnosed by 2 to 6 years of age and progresses rapidly, resulting in the loss of independent motor function by the early teenage years."3

The company is expected to also announce data from its phase 3 clinical trial, ZEPHYRUS-1 (NCT03955146), assessing pamrevlumab in patients with IPF, prior to the data readout of LELANTOS-2. LELANTOS-2 will used ambulatory function assessment, defined as the change in North Star Ambulatory Assessment score from baseline to week 52 as its primary end point, while ZEPHYRUS-1 assesses change from baseline in forced vital capacity.

Progressive Multiple Sclerosis: Phase 2 EMBOLD trial (NCT03283826) of ATA188 (Atara Therapeutics)

With a lack of approved therapeutics for patients with progressive multiple sclerosis (MS), the demand for drug development remains significantly high. ATA188, an allogenic T-cell immunotherapy, has shown positive results in treating this patient group in a 2-part, phase 2 study called EMBOLD. When ATARA announced the completion of its planned interim analysis of EMBOLD in June 2022, the company noted that final data readout of the primary end point will occur in October 2023.4

Pascal Touchon, president and chief excutive officer of Atara

Pascal Touchon

Atara’s therapeutic targets Epstein-Barr virus (EBV)-infected B-cells and plasma cells in the central nervous system that may catalyze autoimmune responses and MS pathophysiology. A 2022 longitudinal analysis by Albert Ascherio, MD, DrPH, et al that included data from more than 10 million individuals added further substance to this long-held theory that EBV may be a leading cause for the disease.5

After completing the planned interim analysis, the target enrollment of 80 patients was achieved. The total enrollment was higher than initially expected as patients that were already in screening through the end of June 2022 were allowed to continue the enrollment process. Reviewed by an independent data and safety monitoring committee, this group believed that the 6-month interim end point was an inaccurate measure of the potential of the intervention, and thus recommended data on the primary end point at 12 months.4

"We look forward to completing the EMBOLD study as we aspire to demonstrate a potentially transformative profile for ATA188 in patients with progressive MS who have high unmet need and limited options," Pascal Touchon, president and chief excutive officer of Atara, said in a statement.

In an open-label extension of a phase 1 trial, the agent was shown to have a sustained clinical benefit that lasted over 39 months. All told, 7 of the 8 patients enrolled achieved sustained disease improvement (SDI) that was steady at all measured time points, with the most SDI driven by improvement on EDSS scores. For those with sustained EDSS improvement (n = 7), the magnetization transfer ratio for unenhancing T2 lesions was improved at 6 months (P = .0796), with significant improvement at 12 months (P = .0213) compared with those without sustained EDSS improvement (n = 15).6

Amyotrophic Lateral Sclerosis: HEALEY-ALS Platform Trial of SLS-005 (Seelos Therapeutics)

The HEALEY-ALS platform trial, approved by the FDA in 2020, is the first of its kind in patients with amyotrophic lateral sclerosis (ALS) and spans across 54 sites in the Northeast ALS Consortium in conjunction with the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston. One of the agents currently being assessed, Seelos Therapeutics’ SLS-005 (trehalose) is expected to have top-line data readout in mid-2023.7

Merit Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS, chief of the Department of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at Harvard Medical School

Merit Cudkowicz, MD, MSc

SLS-005 is a low molecular weight disaccharide that crosses the blood-brain barrier, stabilizes protein, and activates autophagy. That activation occurs through the activation of Transcription Factor EB, a key factor in lysosomal and autophagy gene expression. Seelos’ phase 2/3 trial, which used as the registered study in the platform trial, includes 160 patients with either familial or sporadic ALS. In the study, patients are randomly assigned 3:1 to either SLS-005 or placebo and evaluated on change from baseline in ALS Functional Rating Scale-Revised after 24 weeks.

In September 2022, the Sean M. Healey & AMG Center for ALS was awarded a grant from the National Institute of Neurological Disorders and Stroke to conduct an intermediate size expanded access protocol to evaluate the benefits of SLS-005. I am excited that the Healey & AMG Center is the recipient of the first ACT for ALS funding opportunity and look forward to launching the trehalose EAP,” Merit Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS, chief of the Department of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at Harvard Medical School, said in a statement at the time. "We are thrilled to bring broader access to this experimental therapy as we conduct the ongoing testing of trehalose in the HEALEY ALS Platform trial."8

Huntington Disease: Phase 1/2 Trial (NCT04120493) of AMT-130 (uniQure)

Later this year, uniQure is expected to read out data from its phase 1/2 trial assessing its gene therapy AMT-130 in patients with Huntington disease (HD), a disease that currently has no approved disease-modifying therapies or gene therapies available. Initial data from 4 patients included in the study, half of whom received the agent and half of whom experienced sham, showed that the agent was well tolerated at its lower dose of 6 x 1012 vg, without any serious adverse events (AEs) related to the treatment.9

Ricardo Dolmetsch, PhD, president of research and development, uniQure

Ricardo Dolmetsch, PhD

Months later, in June 2022, the company announced safety and biomarker data from 10 patients with early-stage HD enrolled in the low-dose cohort of the study. Six of the 10 enrolled patients received AMT-130, and 4 patients received an imitation surgical procedure. All told, the data showed that AMT-130 was well-tolerated, with no serious AEs. Two serious AEs of deep-vein thrombosis in the elbow in 1 patient and transient post-operative delirium in a second patient, were both resolved and deemed unrelated to treatment. Structural MRI also did not reveal any clinically meaningful safety findings in treated patients at 1 year of follow-up.10

At the time, Ricardo Dolmetsch, PhD, president of research and development, uniQure, said in a statement, "We are encouraged by this 12-month update of the patients enrolled in the low-dose cohort."

After patient enrollment for the higher-dose level was briefly paused midway through 2022, the trial’s Data Safety Monitoring Board later recommended the company resume the trial. The reasons for the pause in this specific group were related to unexpected severe reactions shortly after the administration of AMT-130. After meeting with the DSMB, the company decided to pause enrollment to investigate the safety events and determine any mitigation steps. All unexpected safety events found in the 3 identified patients were fully resolved, allowing the DSMB to lift the pause.

1. Frenay CL, Siva A, Kantarci O, et al. Multicenter, randomized, double-blinded assessment of teriflunomide in extending the time to a first clinical event in radiologically isolated syndrome (RIS): the TERIS study. Neurology. 2017;88(16 supplement).
2. Okuda DT, Kantarci O, Lebrun-Frenay C, et al. Dimethyl fumarate delays multiple sclerosis radiologically isolated syndrome. Ann Neurol. Published online November 18, 2022. doi:10.1002/ana.26555
3. FibroGen Announces Completion of Patient Enrollment in LELANTOS-2, a Phase 3 Clinical Study of Pamrevlumab in Duchenne Muscular Dystrophy. News release. FibroGen. June 8, 2022. Accessed January 31, 2023. https://www.globenewswire.com/news-release/2022/06/08/2458555/33525/en/FibroGen-Announces-Completion-of-Patient-Enrollment-in-LELANTOS-2-a-Phase-3-Clinical-Study-of-Pamrevlumab-in-Duchenne-Muscular-Dystrophy.html
4. Atara Biotherapeutics announces completion of the ATA188 phase 2 EMBOLD study interim analysis in patients with progressive MS. News release. July 12, 2022. Accessed January 31, 2023. https://investors.atarabio.com/news-events/press-releases/detail/283/atara-biotherapeutics-announces-completion-of-the-ata188
5. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. Published online January 13, 2022. doi:10.1126/science.abj8222
6. Atara Biotherapeutics Presents New Magnetization Transfer Ratio Imaging Data and Two-Year Clinical Data from the Open Label Extension of ATA188 for Progressive Multiple Sclerosis at ECTRIMS 2021. News release. Atara Bio. October 13, 2021. Accessed January 31, 2023. https://www.businesswire.com/news/home/20211013005398/en/Atara-Biotherapeutics-Presents-New-Magnetization-Transfer-Ratio-Imaging-Data-and-Two-Year-Clinical-Data-from-the-Open-Label-Extension-of-ATA188-for-Progressive-Multiple-Sclerosis-at-ECTRIMS-2021
7. Seelos Therapeutics doses first patient in an open label Basket study of SLS-005 in amyotrophic lateral sclerosis in Australia and provides an enrollment update of its study on the HEALEY ALS platform. July 18, 2022. Accessed January 31, 2023. https://www.prnewswire.com/news-releases/seelos-therapeutics-doses-first-patient-in-an-open-label-basket-study-of-sls-005-in-amyotrophic-lateral-sclerosis-in-australia-and-provides-an-enrollment-update-of-its-study-on-the-healey-als-platform-301587454.html
8. Sean M. Healey & AMG Center for ALS awarded NINDS UO1 grant to support expanded access for trehalose (SLS-005). News release. Massachusetts General Hospital. September 30, 2022. Accessed January 31, 2023. https://www.massgeneral.org/neurology/als/news/healeyamg-awarded-ninds-uo1-grant
9. uniQure Announces Clinical Update on First Patients in Phase I/II Clinical Trial of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease. News release. uniQure. December 16, 2021. Accessed February 1, 2023. https://www.biospace.com/article/releases/uniqure-announces-clinical-update-on-first-patients-in-phase-i-ii-clinical-trial-of-amt-130-gene-therapy-for-the-treatment-of-huntington-s-disease/
10. uniQure announces update on low-dose cohort in phase 1/2 clinical trial of AMT-130 gene therapy for the treatment of Huntington’s disease. News release. June 23, 2022. Accessed February 1, 2023. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-update-low-dose-cohort-phase-iii-clinical
11. A message to the Huntington’s disease community from uniQure. News release. uniQure. November 2, 2022. Accessed February 1, 2023. https://hdsa.org/wp-content/uploads/2022/11/2022-11-02-Ltr-to-HD-Comm-Final.pdf
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