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Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the Second Half of 2024
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Take a look at some of the most-anticipated clinical trials with expected data readouts in the second half of 2024 that researchers and clinicians in neurology should keep an eye out on.
As the field of neurology continues to advance, the second half of 2024 promises to be a pivotal period with the anticipated data readouts from several significant clinical trials. These trials, spanning a diverse array of neurological conditions, hold the potential to not only enhance our understanding of complex neurological diseases but also pave the way for innovative therapeutic approaches. From groundbreaking gene therapies to novel pharmacological interventions, the upcoming trial results are poised to influence clinical practice and patient outcomes profoundly. This article will provide an in-depth overview of these trials, highlighting their objectives, methodologies, and the potential impact of their findings on the future of neurology.
APOLLE4 Trial of ALZ-801 (Alzheon) for Alzheimer Disease
Alzheon’s pivotal phase 3 trial, APOLLOE4 (NCT0477022), a fully enrolled study of those with early-stage Alzheimer disease (AD), is expected to have topline data read out in the third quarter of 2024. The study, a randomized, double-blind trial comprised of 325 patients, is a follow up to a successful phase 2 biomarker study (NCT04693520), in which the therapy met its primary end point, demonstrating a statistically significant 31% reduction of plasma phosphorylated tau (p-tau)181 at 104 weeks.1
The study, supported by a $51 million grant from the National Institutes of Health, includes patients with 2 copies of the apolipoprotein e4 allele (APOE4/4 homozygotes), who make up approximately 15% of patients with AD. Over a 78-week treatment period, patients are assessed on changes in cognition, using the Alzheimer’s Disease Assessment Scale-cognitive subscale, as well as on secondary outcomes that evaluate aspects of function, activities of daily living, and neuropsychiatric symptoms.
In a recent update, the company announced patient dosing in an open-label extension of the phase 3 study, which adds an additional 52 weeks of observation for data collection. The second extension of the trial thus far, it will compile information on the safety of ALZ-801, as well as its effect on plasma biomarkers, hippocampal volume, cortical thickness, and cognitive effects at weeks 156 and 208.2
In its phase 2 biomarker study, investigators recorded no cases of amyloid-related imaging abnormalities for those treated with ALZ-801. Among safety concerns, the most commonly observed adverse events included COVID-19 infection, nausea, and decreased appetite. In total, 50% and 33% of patients with MCI and mild AD, respectively, maintained their Clinical Dementia Rating stage throughout treatment.
TrustTSC Trial of Marinus’ Ganaxolone in Tuberous Sclerosis Complex
Later this year, Marinus Pharmaceuticals is expected to announce topline data for TrustTSC, a randomized, double-blind, placebo-controlled study (NCT05323734) of ganaxolone (Ztalmy) as a treatment for patients with tuberous sclerosis complex (TSC). In a company update in April, Marinus noted that 85% of the study had been enrolled, with data to come in Q4. In addition, the company announced it was targeting a submission for a supplemental new drug application to the FDA for TSC in the first half of 2025 with priority review expected.3
TrustTSC consists of a 4-week prospective baseline period, defined as the first 28 days following screening, followed by a double-blind phase consisting a 4-week titration period and a 12-week maintenance period. It includes patients aged 1 to 65 who have a molecular confirmation of a pathogenic mutation in TSC1 or TSC2, as well as have a clinical diagnosis of definite TSC which includes 2 major features or 1 major feature with at least 2 minor features. Coming into the study, patients must have at least 8 countable seizures per month in the 2 months prior, and have inadequate seizure control, with at least 2 failed antiseizure medications.
Ganaxolone, an FDA-approved antiseizure medication, is a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. In addition to exhibiting antiseizure effects, it has anti-depressant and anti-anxiety impacts, and is generally safe and well tolerated. Ganaxolone is also currently being tested in the phase 3 RAISE study (NCT04391569) of patients with refractory status epilepticus (RSE) and RAISE II trial of patients with super RSE, with enrollment that was expected to complete this quarter.
REACH Study of Losmapimod in Facioscapulohumeral Muscular Dystrophy
Later this year, Fulcrum Therapeutics is anticipated to announce data from its phase 3 REACH study (NCT05397470) assessing its investigational agent losmapimod in patients with facioscapulohumeral muscular dystrophy (FSHD), a condition for which there are no approved treatments. The trial enrolled 260 patients with FSHD who were randomly assigned 1:1 to either losmapimod, administered orally as a 15 mg tablet twice a day, or placebo, over a 48-week treatment period.
The study’s primary end point is the absolute change from baseline in Reachable Workspace, while secondary end points include muscle fat infiltration, Patient Global Impression of Change, and Quality of Life in Neurological Disorders of the Upper Extremity. REACH also includes patient-centered assessments of healthcare utilization.
Losmapimod is a selective p38a/ß mitogen activated protein kinase inhibitor that has received orphan drug and fast track designations from the FDA. Earlier this year, data from the phase 2 ReDUX4 trial (NCT04003974) showed that the agent did not meet its primary end point, but did show improvements in structural and functional outcomes in those with FSHD. These results, published in The Lancet Neurology, helped inform the design and choice of efficacy end points for REACH.4
SHINE Study of CT1812 for Alzheimer Disease
At the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-July 1 in Philadelphia, Pennsylvania, investigators will present clinical efficacy results from the phase 2 SHINE study (NCT03507790) of CT1812, an investigational agent in development for Alzheimer disease (AD). CT1812 is an experimental orally delivered small molecule that penetrates the blood-brain barrier and binds selectively to the sigma-2 receptor complex. This receptor complex has been noted to be involved in the regulation of key cellular processes such as membrane trafficking and autophagy that are damaged by toxic interaction with amyloid-ß oligomers, oxidative stress, and other stressors.5
SHINE, a double-blind, placebo-controlled trial, includes approximately 144 patients with mild-to-moderate AD who are randomly assigned to either placebo or 1 of 2 doses of CT1812 (100 mg or 300 mg), for a 6-month treatment period. Supported by 2 grants from the National Institute on Aging of the National Institutes of Health, SHINE primarily looks at the safety of CT1812, as well as cognitive function, measured by the ADAS-Cog11, and biomarker evidence of disease modification.
In 2023, topline data from the phase 2 SEQUEL study (NCT04735536) showed that the agent met its primary end points for safety and tolerability, with positive, non-statistically significant impacts observed in underlying brain function. Over 4 weeks of treatment, patients on CT1812 experienced a numerical reduction in relative theta power to the period when they were on placebo. Although not statistically significant, these data indicated a positive impact on underlying brain function, which was further supported by nominally significant and directionally positive changes in AECc and alpha power.6
Phase 2 Trial of Interleukin-2 in Alzheimer Disease
Coya Therapeutics is expected to announce topline data from its phase 2 investigator-initiated, double-blind, placebo-controlled study of interleukin(IL)-2 later this summer. The trial, which features 38 individuals with mild-to-moderate AD, evaluates the efficacy and safety of low-doses of IL-2, otherwise known as COYA 302, at 2 different dosing regimens, in comparison with placebo. In the study, patients in the first cohort were randomly assigned to low-dose IL-2 for 5 consecutive days every 4 weeks while the second cohort was randomized to low-dose IL-2 for 5 consecutive days every 2 weeks.
The phase 2 study includes a 21-week treatment period, followed by a 9-week follow-up. In the study, investigators will observe changes in assessments of blood and cerebrospinal fluid biomarkers, neuroimaging, and cognitive function across different patient populations.7
EXPLORE44 Trial of AOC1044 in Duchenne Muscular Dystrophy
In the second half of 2024, Avidity Biosciences is expected to announced data from the 5 mg cohort of EXPLORE44 (NCT05670730), a phase 1/2 study assessing its investigational agent AOC 1044 in patients with Duchenne muscular dystrophy (DMD) amenable to exon 44 skipping. The study, a randomized, double-blind trial, is split into 2 parts.
Part A of the study assesses the effects of AOC 1044 in 5 single-dose cohorts of healthy volunteers, who were monitored for 4 months. Part B assesses the effects of AOC 1044 in 3 multiple-ascending dose-level cohorts of participants with DMD, dosed no more frequently than once every 6 weeks for 3 months, with 3 months of follow-up. The study primarily focuses on safety and tolerability, while also collecting data on pharmacokinetics, pharmacodynamics, and dystrophin protein levels.
In December 2023, the company announced topline data from the trial that showed AOC 1044 was safe among healthy volunteers and delivered 50-times greater concentrations of phosphorodiamidate morpholino oligomers (PMO) in skeletal muscle following administration. AOC 1044, a proprietary monoclonal antibody, binds the transferrin receptor 1 conjugated with a PMO targeting exon 44. At day 29, patients treated with a single dose of 10 mg AOC 1044 demonstrated statistically significant exon 44 skipping of up to 1.5% in comparison with placebo.8
Phase 2 Trials of SAGE-718 in Alzheimer Disease and Huntington Disease
Sage Therapeutics plans to report topline data from studies assessing SAGE-718, an investigational NMDA receptor positive allosteric modulator, from its phase 2 LIGHTWAVE study (NCT04602624) in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer disease (AD) and its phase 2 DIMENSION trial in Huntington disease (HD) cognitive impairment later this year.9 The company also noted that it plans to report topline data from SURVEYOR, another phase 3 study (NCT05655520) of patients with HD cognitive impairment, midway through this year.
In April 2024, topline data from the company's phase 2 PRECEDENT study showed that SAGE-718 did not demonstrate statistically significant differences vs placebo on the primary end point in patients with Parkinson disease (PD) who had MCI. After 6 weeks of treatment, those on SAGE-718 failed to distinguish themselves from placebo on the primary end point of Wechsler Adult Intelligence Scale Fourth Edition (WAIS-IV) Coding Test score. The trial, which randomly assigned 86 patients to either study drug or placebo, showed no between-group differences on other exploratory end points such as SCOPA-Cog. SAGE-718, also known as dalzanemdor, was well tolerated, with no new safety signals and treatment-emergent adverse events that were all mild to moderate in severity.
"We are disappointed by the results of the phase 2 PRECEDENT study given the significant burden of mild cognitive impairment on people and families affected by PD," Barry Greene, chief executive officer, Sage Therapeutics, said in a statement.9 "We are thankful for the patients and healthcare professionals who participated in this research. Although cognitive impairment is common in neurodegenerative disorders, the underlying pathophysiology and symptomatology in PD is distinctive, and these results do not necessarily predict results with dalzanemdor in other neurodegenerative conditions. We look forward to the topline data readouts from the phase 2 studies in HD and AD expected later this year."
Studies of DYNE-251 & DYNE-101 for Muscular Dystrophy
Dyne Therapeutics anticipates reporting data for multiple, higher dose cohorts from both the ACHIEVE (NCT05481879) and DELIVER (NCT05524883) trials assessing DYNE-251, an investigational therapeutic in development for Duchenne muscular dystrophy (DMD), and DYNE-101, an investigational antisense oligonucleotide (ASO) for myotonic dystrophy type 1 (DM1), respectively, in the second half of 2024.10 DYNE-251 consists of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a fragment antibody that binds to the transferrin receptor 1 (TfR1) which is highly expressed on muscle.
In May 2024, reported topline findings from the phase 1/2 DELIVER study continued to highlight treatment benefits of DYNE-251. All told, treatment with the agent once every 4 weeks for 6 months (Q4W) resulted in compelling impact on key disease biomarkers as well as functional improvements and favorable safety profiles. DELIVER consists of a 24-week multiple ascending dose (MAD) randomized placebo-controlled period, a 24-week open-label extension, and a 96-week long-term extension. The trial, which is designed to be registrational, enrolled ambulant and nonambulant males with DMD between the ages of 4 and 16 who have mutations amenable to exon 51 skipping.
Additional reports in May 2024 showed that topline data from the ongoing phase 1/2 ACHIEVE trial showed that treatment with DYNE-101 resulted in robust muscle delivery and dose-dependent, consistent splicing correction while also showing improvement in multiple functional end points and patient-reported outcomes among those with DM1. In the efficacy data, which includes 40 adults with DM1 enrolled in the randomized, placebo-controlled multiple ascending dose (MAD) portion of ACHIEVE, the therapy continued to demonstrate a dose-dependent splicing correction. Specifically, patients in the 5.4-mg/kg–Q8W cohort had a 27% mean splicing correction from baseline across a broad, 22-gene panel at 3 months, with all participants showing splicing correction.11
Phase 2 Trial of Dimethyl Fumarate for Friedrich Ataxia
According to a recent interview with Francesco Saccà, MD, PhD, an associate professor of neurology at the University of Naples, the phase 2 study assessing the use of dimethyl fumarate (DMF), an approved product for relapsing multiple sclerosis and psoriasis in Europe, in patients with Friedreich ataxia (FA), potentially anticipates some data, at least the primary and many of the secondary endpoints, by September or October of this year. Saccà also noted that potentially by the end of the year, investigators will close the entire analysis.
The study, which two sequential 12-week phases, assesses whether DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FA. FA, which is typically associated with several developmental features, is caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently ATP production abnormalities.12
"Dimethyl fumarate is also able to increase frataxin expression in FA in a specific way so that it's linked to the silencing of the gene. It enhances expression. There is a high chance that in patients with FA, we might even see a higher increase after dimethyl fumarate," Saccà told NeurologyLive in a recent interview.
Open-Label Study of Nomlabofusp for FA
Larimar Therapeutics' also that it anticipates interim data from the OLE study assessing nomlabofusp, formally known as CTI-1601, among patients with FA in the fourth quarter of 2024.13 The study will initially assess daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver among patients with FA. The company plans to escalate the dose to 50 mg in the study after additional characterization of frataxin PD at the 25 mg dose. In May 2024, the FDA removed the partial clinical hold previously placed on the clinical program of nomlabofusp following the review of data from a phase 2 dose exploration study (NCT05579691).14
In the phase 2 study, results demonstrated that nomlabofusp, a novel protein replacement therapy aimed to address the root cause of FA through delivery of frataxin to mitochondria, was generally well-tolerated among participants throughout the 4-week treatment period. The treatment revealed a predictable pharmacokinetic profile and showed a dose-dependent increase in frataxin levels in skin and buccal cells. All participants with quantifiable levels at baseline and day 14 in the 50 mg cohort achieved frataxin levels in skin cells over 33% of the average level reported in healthy volunteers at day 14, and 3 patients achieved levels greater than 50% of the average healthy volunteer level.15
“We are very excited the FDA has removed the partial clinical hold on our nomlabofusp program following review of our phase 2 data. Helping patients with FA is our top priority and we appreciate the attention and thorough review by the FDA of all submitted data,” Carole Ben-Maimon, MD, president, and chief executive officer at Larimar, said in a statement.14 “Importantly, we are now cleared to dose escalate to the 50 mg dose in our ongoing open label extension (OLE) study which we plan to do following further characterization of frataxin PD at the 25 mg dose. The OLE study is evaluating the long-term safety as well as frataxin levels following daily administration of nomlabofusp and we look forward to interim data in the fourth quarter of the year.”
Studies of TSHA-102 for Rett syndrome
Taysha Gene Therapies is expanding 2 trials in light of the data. The company has lowered the minimum age in the adolescent and adult study to 12 years and moved up to a higher dose. Taysha is positioned to escalate to the higher dose in the pediatric study once it has initial safety data from the trial in adolescents and adults, something it expects to happen in the third quarter.16
In June 2024, Taysha announced positive data from its pivotal phase 1/2 REVEAL studies assessing TSHA-102, an adeno-associated (AAV)-based gene therapy for patients with Rett syndrome. All told, treatment with the therapy resulted in durable improvements across clinical domains in a small group of both adult and pediatric patients, including motor skills, communication/socialization, autonomic function, and seizures, in addition to demonstrating a safe profile.
Designed as a one-time lumbar intrathecal treatment, TSHA-102 aims to address the genetic root cause of Rett by delivering a functional form of MECP2 to cells in the central nervous system. Following an independent data monitoring committee review of safety data from the first high dose patient in the adolescent and adult trial, dosing for a high-dose cohort is expected to commence in third quarter of 2024.
"We are highly encouraged by the safety profile and broad clinical response observed across multiple domains in both the adult and pediatric patients with different genetic mutation severity treated with the low dose of TSHA-102," Sean P. Nolan, chairman and chief executive officer at Taysha, said in a statement."The longer-term follow up data indicate a durable response with sustained and new improvements across multiple clinical domains in both adult patients, and importantly, both pediatric patients showed initial improvements across consistent clinical domains, with early evidence of developmental gains following treatment with TSHA-102. We believe these improvements in adult and pediatric patients further reinforce the potential of TSHA-102 to be transformative for a broad range of patients with Rett syndrome."
Phase 2 CONNECT1-EDO51 Trial of PGN-EDO51 for Duchenne Muscular Dystrophy
PepGen anticipates reporting preliminary data from its phase 2, open-label multiple ascending dose (MAD) CONNECT1-EDO51 trial assessing PGN-EDO51, an investigational antisense oligonucleotide (ASO), for the treatment of individuals with Duchenne muscular dystrophy (DMD) amendable to an exon 51 skipping therapy, in mid-2024. The expected findings will include initial safety, exon 51 skipping, and dystrophin production data on 5 mg/kg PGN-EDO51 in approximately 10 male patients at least 8 years of age with DMD amenable to an exon 51-skipping approach.17
PGN-EDO51 had oligonucleotide tissue concentration and exon skipping assessed in a phase 1 trial that included 32 healthy adult males. All told, the trial met its primary end point, providing evidence that PGN-EDO51 was generally well tolerated at pharmacologically relevant doses. After 28 days of treatment, the majority of treatment-emergent adverse events observed were mild and resolved without any intervention.18
At the time of the announced results, McArthur said in a statement that, "We are particularly pleased with the high levels of exon skipping observed for PGN-EDO51 at 28 days. Exon skipping was higher on Day 28 than at Day 10, which we believe, in conjunction with our tissue concentration data, suggests both sustained drug exposure and pharmacodynamic effect. Furthermore, we believe that these results could signal the potential for the accumulation of exon 51 skipped transcript and dystrophin protein in muscle tissue with repeated doses of PGN-EDO51 in people living with DMD."19
