Pipeline Update: Status of Clinical Development for Multiple Sclerosis

The state of care for multiple sclerosis (MS) has evolved drastically in the last decade, with much of the development of disease-modifying therapy (DMT) shifting toward investigational agents that could potentially address progressive disease. Many in the clinical community have called for more attention to be given to this phase of MS, including the National Multiple Sclerosis Society and other organizations in the International Progressive MS Alliance.¹

Although there are DMTs available for progressive disease—including siponimod (Mayzent; Novartis) for secondary progressive MS (SPMS), ocrelizumab (Ocrevus; Genentech) for primary progressive MS (PPMS), and cladribine (Mavenclad; EMD Serono) for active disease in SPMS, among a few others—there remains a need for options to address progressive MS, including the accumulation of disability experienced by many patients. Additionally, a number of new developments are being evaluated for their potential to treat relapsing disease, with goals of furthering treatment personalization still benefitting from additional options for patients.

NeurologyLive has reported on a number of developments in the space and spoken with several experts in MS this year to track the progress being made to address the treatment needs of patients with progressive MS. Some of that development is detailed below.

Phase 3

IMU-838 (Immunic)

In July 2021, the FDA gave the go-ahead for an investigational new drug application (IND) for the phase 3 ENSURE program, which will evaluate IMU-838 in patients with relapsing-remitting multiple sclerosis (RRMS). Immunic also announced that a separate IND application for the supportive phase 2 CALLIPER trial of IMU-838 in patients with progressive multiple sclerosis has been cleared as well. The ENSURE program is comprised of 2 identical, double-blind, twin phase 3 trials, titled ENSURE-1 and ENSURE-2, designed to evaluate the efficacy, safety, and tolerability of IMU-838 in a 30-mg daily dose versus placebo in patients with RRMS. Approximately 1050 adult patients with active RRMS are expected to be enrolled in the studies and will be evaluated on time to first relapse as the primary end point. Both trials will run concurrently, with dosing of the first patient expected in the second half of 2021.²

Ublituximab (TG Therapeutics)

In June 2021, data presented at 7th Congress of the European Academy of Neurology from the ULTIMATE 1 (NCT03277261) and ULTIMATE 2 studies (NCT03277248) suggested that the investigational glycoengineered anti-CD20 monoclonal antibody significantly reduced annualized relapse rate (ARR) and MRI parameters compared to teriflunomide (Aubagio; Sanofi) in patients with relapsing forms of MS. The data will support a biologics license application (BLA) submission expected in the third quarter of 2021. Treatment with ublituximab resulted in an ARR of 0.076 in ULTIMATE 1 compared to 0.188 for the teriflunomide-treated group, representing a relative reduction of 60% (ARR ratio, 0.406 [95% CI, 0.268-0.615]; P <.0001). Similarly, in ULTIMATE 2, ARRs at 96 weeks were 0.091 and 0.178 in the ublituximab and teriflunomide groups, respectively, equating to a 49% relative reduction (ARR ratio, 0.509 [95% CI, 0.330-0.784]; P = .0022).³

Tolebrutinib (Sanofi)

The investigational orally available, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor is being assessed in a number of phase 3 trials, including the twin GEMINI 1 and 2 trials (NCT04410978 and NCT04410991), the HERCULES trial (NCT04411641), and the PERSEUS trial (NCT04458051). Additionally, a new phase 2a clinical trial paradigm for MS is underway, the design of which was presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021. It is evaluating the effects of tolebrutinib on 7-Tesla MRI paramagnetic rim lesions. Patients will initiate treatment with 60 mg daily while forgoing further anti-CD20 or other DMTs for the duration of the trial. The first cohort in the study will consist of 10 patients that are stable on anti-CD20 antibody therapy and within 3 months of their most recent dose.⁴

Evobrutinib (EMD Serono)

The investigational, oral, highly selective BTK inhibitor is currently the focus of 2 pivotal phase 3 trials in relapsing MS that are expected to conclude in September 2023. The trials—evolutionRMS 1 (NCT04338022) and evolutionRMS 2 (NCT04338061)—are multicenter, randomized, parallel-group, double-blind, double-dummy, active-controlled studies comparing evobrutinib and teriflunomide in adults with relapsing MS. Originally, the investigators intended to evaluate the study drug against interferon β-1A, but switched the comparator to teriflunomide after EMD Serono saw an opportunity to evaluate the drug in an even head-to-head comparison.

READ MORE: MRI Characteristics Reflect Specific MS Immunopatterns

Phase 2

CNM-Au8 (Clene Nanomedicine)

In February, also presented at the ACTRIMS Forum 2021, interim data from the phase 2 VISIONARY-MS trial (NCT03536559) suggest that Clene Nanomedicine’s investigational nanocatalytic agent demonstrates potential as a promoter of neurological improvement in patients with stable MS who are currently on DMT. The analysis showed that patients treated with CNM-Au8 with an Expanded Disability Status Scale (EDSS) score of 2.0 or higher experienced improvements equating to nearly 0.5 standard deviation (SD) above the baseline value for the most mildly affected patients, who were the comparator group, in the Symbol Digital Modalities Test (SDMT; P <.0001) as well as in Best Corrected Low-Contrast Letter Acuity (BC-LCLA; P = .0071). Additionally, improvements were observed in the 9-Hole Peg Test (9HPT) non-dominant (P = .0050) and in the Timed 25-Foot Walk test (T25W; P not significant).⁵

Autologous Mesenchymal Stromal Cells (NurOwn; BrainStorm Cell Therapeutics)

BrainStorm Cell Therapeutics announced that the company’s phase 2 trial evaluating NurOwn, which secrets neurotrophic factors (MSC-NTF) cells, met its primary end point of safety in the treatment of progressive MS, which was announced in March 2021. The 28-week, open-label trial (NCT03799718) enrolled 20 patients with primary and secondary progressive MS who were given 3 repeated administrations of NurOwn, each 2 months apart. A total of 18 patients were treated and 16 (80%) completed the study. Procedure-related adverse events (AEs) resulted in 2 patients discontinuing. There were no study deaths or AEs related to MS worsening. Efficacy outcomes were compared with a 48-patient matched clinical cohort from the CLIMB study. All told, 38% of patients who received the treatment showed at least a 10-point improvement in the 12-Item MS Walking Scale (MSWS-12) from baseline to week 28.⁶

Orelabrutinib (Biogen; InnoCare)

According to a July 2021 announcement, Biogen and InnoCare Pharma have entered into a license and collaboration agreement for the oral small molecule BTK inhibitor for the treatment of MS. The drug is currently being investigated in a global phase 2 study (NCT04711148) in patients with RRMS. The agent is a covalent BTKi with high selectivity and can cross the blood brain barrier, inhibiting B cell and myeloid cell effector functions in the central nervous system (CNS). By addressing the progressive biology of the disease, the companies believe orelabrutinib has the potential to slow disease progression and provide clinically meaningful benefit in all forms of MS.⁷

Phase 1

ATA188 (Atara Biotherapeutics)

Part 2 of a study evaluating ATA188 (NCT03283826) safety/tolerability, product kinetics, and biological and clinical effect in adults with progressive forms of MS is underway, with the design of part 2 of the phase 1, multicenter double-blind, placebo-controlled study was presented at the ACTRIMS Forum 2021. The study will evaluate the incidence of AEs, change from baseline in cerebrospinal fluid (CSF) immunoglobulin G index, change from baseline in clinical disability on expanded disability status scale, Timed 25-Foot Walk, and/or 9-hole peg test, ambulatory activity monitoring, cervical spinal cord volume and whole brain volume on MRI, the number of gadolinium-enhancing and new or enlarging T2 lesions on brain MRI scans. Other exploratory end points include assessment of potential biomarkers such as oligoclonal bands in CSF, the persistence of ATA188, and cytokine profiling in blood and CSF compartments.⁸

Non-RCT Assessments

Rituximab (Ritxuan; Genentech/Biogen)

In February 2020, the results of a retrospective observational study suggested that that treatment with rituximab has long-term effects on inflammatory disease activity in patients with MS after discontinuation or dose reduction.⁹ Currently, only 1 phase 3 clinical trial is ongoing with the agent, the NOR-MS study (NCT04121403), based in Norway, which is evaluating it alongside cladribine (Mavenclad; EMD Serono) and is currently recruiting patients.

The study showed a rarity in disease reactivation among patients with MS who discontinued treatment for any reason and that low-dose rituximab (<1000 mg yearly) is sufficient to maintain suppression of inflammatory disease activity. Among a cohort of 225 patients treated with rituximab, researchers observed no differences regarding the annualized relapse rates (ARRs) during full dose versus reduced dose or off treatment (0.02 vs < 0.01 and 0.02; P =.09). The study included patients with either relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS), with patients serving as their own controls by contributing patient-years on full dose, reduced dose, and off treatment.

Autologous Hematopoietic Stem Cell Transplantation (aHSCT)

A study published in Neurology in February 2021 suggested that aHSCT prevented disability worsening in the majority of patients evaluated with MS and produced a long-term disability improvement in patients with relapsing-remitting MS (RRMS). The observational, retrospective, multicenter cohort study found that the disability worsening-free survival rate was 85.5% (95% CI, 76.9-94.1) at 5 years and 71.3% (95% CI, 57.8-84.4) at 10 years in patients with RRMS. The disability worsening-free survival rate was 71.0% (95% CI, 59.4-82.6) at 5 years and 57.2% (95% CI, 41.8-72.7) at 10 years in patients with progressive MS.¹⁰

Additional results that month from a cohort of 20 patients with multiple clinical and radiological features predictive of aggressive MS revealed that treatment with aHSCT is safe and effective as a first-line DMT. At the last follow-up appointment, the post-transplant median Expanded Disability Status Scale (EDSS) score was 2.0 (range, 0-6.5), with only 1 patient not recording a change after treatment. EDSS score of 13 patients plateaued after the initial 6 months, whereas scores of 5 patients continued to improve beyond this period.¹¹

UCLA-Yuyu Pharma Candidate

The University of California–Los Angeles (UCLA) announced in Marhc 2021 that it is partnering with South Korean-based Yuyu Pharma in an effort to collaborate on the development—as well as the evaluation of safety and efficacy—of a novel treatment for MS. The project is being led by Rhonda Voskuhl, MD, Jack H. Skirball Professor of MS Research, and director, UCLA MS Program; and Michael E. Jung, PhD, presidential chair, Medicinal Chemistry, distinguished professor of chemistry and biochemistry, and associate dean for entrepreneurship and innovation, UCLA College Division of Physical Sciences. The collaboration came together through the efforts of UCLA’s Technology Development Group, which aims to bring the university’s research community’s innovations to the marketplace and is headed by Amir Naiberg, who serves as UCLA associate vice chancellor and the CEO and president of the Technology Development Group.¹²

REFERENCES
1. Zackowski KM, Freeman J, Brichetto G, et al. Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance. Mult Scler J. Published online March 15, 2021. doi: 10.1177/1352458521999970
2. Immunic announces FDA clearance to begin IMU-838 phase 3 ENSURE studies in relapsing-remitting multiple sclerosis and phase 2 CALLIPER study in progressive multiple sclerosis. News release. July 1, 2021. Accessed July 20, 2021. https://www.immunic-therapeutics.com/2021/07/01/immunic-inc-announces-fda-clearance-to-begin-imu-838-phase-3-ensure-studies-in-relapsing-remitting-multiple-sclerosis-and-phase-2-calliper-study-in-progressive-multiple-sclerosis/
3. TG Therapeutics announces presentation of data from the ULTIMATE 1 & 2 phase 3 trials of ublituximab in multiple sclerosis at 7th Congress of the European Academy of Neurology. News release. TG Therapeutics. June 18, 2021. Accessed July 20, 2021. https://www.biospace.com/article/releases/tg-therapeutics-announces-presentation-of-data-from-the-ultimate-i-and-ii-phase-3-trials-of-ublituximab-in-multiple-sclerosis-at-7th-congress-of-the-european-academy-of-neurology
4. Akinsanya J, Absinta M, Dargah-zade N, et al. Toward the use of paramagnetic rim lesions in proof-of-concept clinical trials for treating chronic inflammation in multiple sclerosis. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P126
5. Glanzman RL, Beadnall H, Barnett M, et al. VISIONARY-MS: Update to a Phase 2 clinical trial of catalytic gold nanocrystals, CNM-Au8, for the treatment of chronic optic neuropathy. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P050.
6. BrainStorm announces positive topline data in phase 2 study evaluating NurOwn as a treatment for progressive MS. News release. BrainStorm Cell Therapeutics. March 24, 2021. Accessed July 20, 2021. https://www.prnewswire.com/news-releases/brainstorm-announces-positive-topline-data-in-phase-2-study-evaluating-nurown-as-a-treatment-for-progressive-ms-301254709.html
7. Biogen and Innocare announce license and collaboration agreement for orelabrutinib, an innovative CNS penetrant BTK inhibitor for the potential treatment of multiple sclerosis. News release. July 12, 2021. Accessed July 20, 2021. https://www.globenewswire.com/news-release/2021/07/12/2261563/0/en/Biogen-and-Innocare-Announce-License-and-Collaboration-Agreement-For-Orelabrutinib-an-Innovative-CNS-Penetrant-BTK-Inhibitor-For-the-Potential-Treatment-of-Multiple-Sclerosis.html
8. Bar-Or A, Gamelin L, Ye W, et al. Phase I, multicenter, two-part study of ATA188, an open-label, dose-escalation and double-blind, placebo-controlled dose-expansion study. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P048.
9. Boremalm M, Sundstrom P, Salzer J. Discontinuation and dose reduction of rituximab in relapsing-remitting multiple sclerosis. J Neurol. doi: 10.1007/s00415-021010399-8
10. Boffa G, Massacessi L, Inglese M, et al. Long-term clinical outcomes of hematopoietic stem cell transplantation in multiple sclerosis. Neurology. Published online January 20, 2021. doi: 10.1212/WNL.0000000000011461
11. Das J, Snowden JA, Burman J, et al. Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with ‘aggressive’ multiple sclerosis. Mult Scler J Exp Transl Clin. Published online February 10, 2021.
12. UCLA forms research collaboration with Yuyu Pharma to advance MS treatment. News release. March 1, 2021. Accessed July 20, 2021. https://newsroom.ucla.edu/releases/ucla-yuyu-pharma-multiple-sclerosis-treatment