5 Clinical Trial Readouts in Neurology to Look for in 2022

According to the National Institutes of Health’s clinical trials registry, more than 400 clinical trials of therapies designed to treat neurologic diseases are actively ongoing across phases 1 through 3 . Of those, more than 200 are in phase 3 development. Notably, many investigational therapies are addressing diseases with a high unmet clinical need, with either no currently available disease-modifying therapies or very limited options.

With so much activity in the clinical development pipeline, keeping up with the latest findings can sometimes be difficult. Here are 5 critical trials with expected data readouts in 2022 that NeurologyLive® will have its eye on.

Alzheimer Disease: Phase 3 GRADUATE 1 + 2 trials (NCT03444870 + NCT03443973) of Gantenerumab (Roche)

The GRADUATE program consists of 2 ongoing parallel, placebo-controlled, randomized, phase 3 studies evaluating the safety and efficacy of gantenerumab, an investigational anti-amyloid-ß antibody agent. The trials are expected to read out data in the second half of 2022, according to ganternerumab’s developer, Roche. Designed for the treatment of Alzheimer disease (AD), the drug received breakthrough therapy designation in October 2021, and, if approved, would become the first subcutaneous medicine for patients with the disease.¹

The dual trials include a combined 2000 participants who are being treated with a monthly target dose of 1020 mg. Participants will also have the option to have an optimized titration, which is aimed at maximizing exposure and minimizing dose interruption throughout the study period for better detection of a potential clinical benefit.

Diana Kerwin, MD, CPI

The agent has followed an interesting path to this point, headlined by a failed futility analysis in 2014 which led to a brief pause in dosing, followed by a failure to meet its primary end point the DIAN-TU-001 study (NCT01760005) in 2020. Despite this, there is still positivity surrounding the drug’s potential, especially given the regulatory path followed by Biogen’s anti-amyloid agent aducanumab. Data published in 2018 showed that over 36 months, gantenerumab reduced amyloid-ß plaques, with mean centiloid values of ­–4.3 (standard error [SE], 7.5), 0.8 (SE, 6.7)­ and 4.7 (SE, 8.0) in the SCarlet RoAD, Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups, respectively. This represented changes of ­–57 centiloids (SE, 10.3), –90.3 centiloids (SE, 9.0), and –74.9 centiloids (SE, 10.5), respectively.² Notably, SCarlet RoAD and Marguerite RoAD assessed significantly different doses of the therapy (105 mg and 225 mg/month, respectively).

"The GRADUATE 1 and 2 studies are evaluating the effect of a drug that has anti-amyloid effects to reduce the amyloid burden in the body. The study has been very well received by the patient community and participants as it provides an alternate administration with subcutaneous injections, or injections in the skin that will provide more flexibility for patients," Diana Kerwin, MD, CPI, president & founder, Kerwin Medical, and trial investigator, told NeurologyLive^®. "The data that will be released will provide further information about the reduction of amyloid and also effects on biomarkers and safety. With the results of every study, and the work of the scientific community and participants continue to further our understanding of Alzheimer’s and facilitate the development of promising therapies."

Duchenne Muscular Dystrophy: Phase 1b/2a Trial (NCT04906460) of WVE-N531 (Wave Life Sciences)

WVE-N531, the first drug candidate administered by intravenous infusion with PN chemistry for the treatment of Duchenne muscular dystrophy (DMD), is currently being evaluated in a phase 1b/2a clinical trial that includes 15 boys with DMD who are amenable to exon 53 skipping. Clinical data to enable decision-making on the next steps for the drug is expected to be generated throughout 2022.

The investigational agent is the first exon-skipping candidate from Wave to use its next-generation PN chemistry and will be assessed in up to 4 dose levels. Investigators will look at safety and tolerability of ascending doses, along with pharmacokinetics on muscle concentration and pharmacodynamics, shown by the effect on dystrophin expression.³

Laurent Servais, MD, PhD

In a preclinical study, WVE-N531 demonstrated dose-dependent increases of dystrophin production of up to 71% among patient-derived myoblasts in vitro. Treatment with an agent using the company's PN chemistry also led to 100% survival rate at 40 weeks in a cohort of double knockout mice, a severe and rapidly fatal in vivo model lacking both dystrophin and utrophin. In the same preclinical studies, mice treated with compounds designed with Wave's first-generation chemistry had a median survival of less than 12 weeks.³

"Restoration of meaningful levels of functional dystrophin protein in the muscles of boys with Duchenne muscular dystrophy will be critical for slowing disease progression. The preclinical data to date are very exciting as they suggest Wave’s new PN chemistry in WVE-N531 improves the pharmacokinetic profile of oligonucleotides while overcoming issues of poor intracellular access to muscle cells, prompting investigations in humans,” Laurent Servais, MD, PhD, professor of pediatric neuromuscular diseases, MDUK Oxford Neuromuscular Centre, and investigator in the WVE-N531 trial, told NeurologyLive^®. "Indeed, inadequate drug distribution and intracellular access have been largely responsible for limited success of previous exon skipping approaches to DMD, including with Wave’s prior suvodirsen program. As a trialist and clinician, I’m hopeful that these results will translate in the clinic and look forward to seeing the outcome of the trial."

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

The phase 2 portion of the 2-part EMBOLD study, evaluating the safety and efficacy of ATA188, an investigational agent to treat patients with progressive multiple sclerosis (MS), is expected to readout results from an interim analysis sometime in 2022. ATA188, an allogenic T-cell immunotherapy, was shown to have a sustained clinical benefit over 39 months in an open-label extension (OLE) of the phase 1 trial in patients with progressive MS and may represent a potential option for a population that lacks disease-modifying therapies.⁴

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 recently published 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

Douglas Arnold, MD

"The MS community is very excited by a recent landmark paper demonstrated that EBV is the leading cause of MS.” Douglas Arnold, MD, neurologist, Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, and investigator in EMBOLD, told NeurologyLive^®. "This may be relevant to the preliminary results reported recently by the EMBOLD study showing that treatment with lymphocytes directed against EBV was associated with a remarkable change on MRI suggestive of repair of chronic MS lesions in patients who improved on this therapy. Trials are in progress to confirm these results."

Results from that OLE study showed that 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 Expanded Disability Status Scale (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). Overall, trends supported a correlation between increase in MTR signal and improvement in EDSS score as early as 6 months.⁶

Duchenne Muscular Dystrophy: EPIDYS Phase 3 trial (NCT02851797) of givinostat (Italfarmaco)

Italfarmaco is expected to read out topline data in June 2022 for its pivotal phase 3 EPIDYS clinical trial, which is assessing the efficacy and safety of givinostat, a histone deacetylase inhibitor (HDAC), for the treatment of DMD. After previously receiving pediatric disease designation, the investigational agent is being evaluated in a cohort of 179 boys with DMD in a double-blind, placebo-controlled study.⁷

By inhibiting HDAC activity, givinostat may help to activate muscle repair mechanisms to increase muscle regeneration, reduce inflammation, and reduce fibrosis. The first 50 patients randomized in the “in-target group” were treated for 12 months after which magnetic resonance spectroscopy (MRS) was used to measure muscle fat fraction (MFF) in the vastus lateralis muscle of the thigh. Investigators chose MFF as an objective end point because fat infiltration in these muscles is a characteristic of disease progression in patients with DMD.

Paolo Bettica, MD, PhD

Interim data from a prespecified analysis, released in April 2020, showed a lower muscle fat infiltration on MRS in patients treated with givinostat compared with those on placebo after 12 months of treatment. Previously, the drug showed positive results in a phase 2 setting as well, with investigators observing significant increases in the fraction of muscle tissue seen in posttreatment muscle biopsies and a reduction in the amount of fibrotic tissue.⁸

In February 2021, the company announced an update on the trial. At that time, Paolo Bettica, MD, PhD, chief medical officer, Italfarmaco Group, said, "We are very encouraged to see that the long-term study with givinostat continues to show a benefit in boys with DMD, which further supports its potential as a treatment. We have made significant progress despite the pandemic and instituted procedures to ensure the safety and well-being of all trial participants while being able to continuously provide access to the study drug, as well as to maintain the scientific validity and integrity of the trial."⁹

Alzheimer Disease: Phase 2b/3 Study (NCT03790709) of Blarcamesine (Anavex Life Sciences)

By mid-2022, Anavex Life Sciences is expected to release topline results from its ongoing phase 2/3b study evaluating blarcamesine, formerly known as ANAVEX 2-73, in patients with AD. The double-blind, placebo-controlled, 48-week clinical study is using the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) subscales as primary end points to assess the impact of blarcamesine on cognitive and functional measurements.¹⁰

Participants are randomized 1:1:1 to 2 different blarcamesine doses or placebo. In June 2021, the company announced that it had exceeded the enrollment target of 450 participants. Blarcamesine, an orally available agent, will also be evaluated on sigma-1 receptor (SIGMAR1) gene expression, a prespecified medicine biomarker. In a previously completed phase 2a genome-wide search study (NCT02244541), this gene expression correlated with direct measures of clinical benefit, cognition, and activities of daily living and function. This was the first such search for biomarkers associated with therapeutic response in AD. All told, the findings from that study were the basis of testing of potential selection markers for the ongoing phase 2b/3 trial.

Christopher U. Missling, PhD

Data from the phase 2a study and its extension (NCT02756858), published in April 2020, showed a treatment effect on multiple biomarkers at the end of a 57-week period. Among them included mean plasma concentration of blarcamesine (slope Mini-Mental State Examination [MMSE]: P <.041), genomic variants SIGMAR p.Gln2Pro (MMSE: P <.039; ADCS-ADL: P <.063) and COMT p.Leu146fs (MMSE: P <.039; ADCS-ADL: P <.063), and baseline MMSE score (slope MMSE: P <.015).¹¹

"A significant unmet need exists currently for Alzheimer disease patients worldwide given the lack of available adequate therapeutic interventions, and we are excited to have exceeded enrollment of this study for ANAVEX 2-73,” Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement in June 2021.¹⁰ “Given ANAVEX 2-73’s convenient oral route of administration we believe it has the potential to deliver broad clinical utility.”Blarcamesine has also shown positive benefit in treating Parkinson disease dementia, indicated by results from a proof-of-concept phase 2 study (NCT03774459). In that trial, the drug’s impact on increasing SIGMAR1 expression correlated significant with responses on primary and secondary end points.¹²

REFERENCES
1. Ad hoc announcement pursuant to Art. 53 LR: Genentech’s anti-amyloid beta antibody gantenerumab granted FDA breakthrough therapy designation in Alzheimer disease. News release. Genentech. October 8, 2021. Accessed January 26, 2021. https://www.businesswire.com/news/home/20211008005371/en/Ad-hoc-announcement-pursuant-to-Art.-53-LR-Genentech%E2%80%99s-Anti-Amyloid-Beta-Antibody-Gantenerumab-Granted-FDA-Breakthrough-Therapy-Designation-in-Alzheimer%E2%80%99s-Disease
2. Klein G, Delmar P, Kerchner GA, et al. Thirty-six month amyloid positron emission tomography results show continued reduction in amyloid burden with subcutaneous ganterenumab. J Prev Alzheimers Dis. 2021;8(1):3-6. doi:10.14283/jpad.2020.68
3. Wave Life Sciences announces initiation of dosing in phase 1b/2a clinical trial of WVE-531 in Duchenne muscular dystrophy. News release. Wave Life Sciences. September 29, 2021. Accessed January 26, 2022. https://www.biospace.com/article/releases/wave-life-sciences-announces-initiation-of-dosing-in-phase-1b-2a-clinical-trial-of-wve-n531-in-duchenne-muscular-dystrophy/
4. Bar-Or A, Pender MP, Hodgkinson SJ, et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis. Presented at ECTRIMS Congress; October 13-15, 2021; Poster P638.
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 26, 2022. 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. talfarmaco receives FDA rare pediatric disease designation for givinostat in Duchenne muscular dystrophy, announces completed enrollment in EPIDYS phase 3 trial. News release. Italfarmaco. October 9, 2020. Accessed January 26, 2022. https://www.biospace.com/article/releases/italfarmaco-receives-fda-rare-pediatric-disease-designation-for-givinostat-in-duchenne-muscular-dystrophy-announces-completed-enrollment-in-epidys-phase-3-trial/
8. Bettica P, Petrini S, D'oria V, et al. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2016;26(10):643-649. doi:10.1016/j.nmd.2016.07.002
9. Italfarmaco provides update on ongoing clinical programs with givinostat in oral presentation at XVII International Conference on Duchenne and Becker muscular dystrophy. News release. Italfarmaco. February 22, 2021. Accessed January 27, 2022. https://www.businesswire.com/news/home/20210222005359/en/Italfarmaco-Provides-Update-on-Ongoing-Clinical-Programs-with-Givinostat-in-Oral-Presentation-at-XVIII-International-Conference-on-Duchenne-and-Becker-Muscular-Dystrophy
10. Anavex Life Sciences announces exceeding of enrollment target for the precision medicine ANAVEX 2-73 (blarcamesine) phase 2b/3 clinical trial in patients with Alzheimer disease. News release. June 8, 2021. Accessed January 26, 2022. https://www.biospace.com/article/releases/anavex-life-sciences-announces-exceeding-of-enrollment-target-for-the-precision-medicine-anavex-2-73-blarcamesine-phase-2b-3-clinical-trial-in-patients-with-alzheimer-s-disease/
11. Hampel H, Williams C, Etcheto A, et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: analysis of the blarcamesine (ANAVEX2-73) phase 2a clinical trial. Alzheimer’s Dement. 2020;6(1):e12013. doi:10.1002/trc2.12013
12. Anavex Life Sciences announces ANAVEX 2-73 (blarcamesine) improved both primary cognitive and secondary MDS-UPDRS efficacy end points with significant biomarker correlation in placebo-controlled phase 2 clinical trial. News release. June 28, 2021. Accessed January 27. 2022. https://www.biospace.com/article/anavex-life-sciences-announces-anavex-2-73-blarcamesine-improved-both-primary-cognitive-and-secondary-mds-updrs-efficacy-endpoints-with-significant-biomarker-correlation-in-placebo-controlled-phase-2-clinical-trial/