COMBAT-ALS Trial Still Enrolling in North America

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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MediciNova is still recruiting adults with early-stage amyotrophic lateral sclerosis (ALS) for the COMBAT-ALS Phase 2b/3 clinical trial evaluating its investigational oral therapy MN-166 (ibudilast).

Patients are being enrolled at 19 sites across North America; more information about contacts and locations is available here.

“We continue to enroll patients in our ongoing Phase 3 trial in ALS,” Yuichi Iwaki, MD, PhD, MediciNova’s president and CEO, said in a press release regarding the company’s 2021 second-quarter financial and business update.

“And the European Patent Office recently issued a notice of intention to grant for a pending patent application which covers the combination of MN-166 (ibudilast) and riluzole for the treatment of ALS,” Iwaki added.

The latest European patent for the MN-166-riluzole combination for ALS, as well as similar patents issued in the U.S. and Japan, are expected to expire no earlier than November 2035.

Originally developed by Kyorin Pharmaceutical under the name ibudilast, the therapy also is approved in Japan for the treatment of asthma and post-stroke complications since 1989.

An orally available small molecule, MN-166 can cross the blood-brain barrier — the highly selective membrane that prevents circulating microbes and potentially harmful molecules from reaching the central nervous system (CNS, brain and spinal cord) — overcoming a common obstacle of CNS-targeted therapies.

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MediciNova licensed MN-166 from Kyorin in 2004 to develop and market the therapy for neurological conditions, such as multiple sclerosis and ALS, outside of Asia.

MN-166 is thought to reduce inflammation in the CNS, a known contributor to ALS progression, through several mechanisms, and to have neuroprotective effects.

It blocks the activity of four pro-inflammatory proteins — IL-1 beta, TNF-alpha, IL-6, and TLR4 — while potentially activating the anti-inflammatory signaling molecule IL-10. It also reduces the activation of microglia, the immune cells of the CNS that are overly active in ALS patients.

The therapy is thought to increase the production of neurotrophic factors that support the survival and growth of nerve cells, and was shown in cellular models to promote the clearance of toxic protein clumps that typically form in ALS patients.

MN-166 received fast track and orphan drug designations in the U.S. and orphan drug status in Europe for the treatment of ALS. These designations are meant to accelerate its development and regulatory review.

Results from a previous Phase 2 trial (NCT02238626) showed that MN-166, in combination with riluzole, significantly improved functional ability, quality of life, and survival, while delaying disease worsening, compared with riluzole alone.

Riluzole is a long-approved ALS therapy marketed as Rilutek, Tiglutik, and Exservan, depending on its mode of administration.

COMBAT-ALS (NCT04057898) is evaluating MN-166’s safety, tolerability, and effectiveness against a placebo in up to 230 adults, ages 18–80, whose ALS became evident within the past 1.5 years and who have a high level of function and near-normal lung function.

While the trial previously was designed to test MN-166, combined with a stable dose of riluzole, MediciNova changed its design and eligibility criteria so that the investigational therapy is assessed independently, and participants can continue to receive their standard ALS medications, including not only riluzole, but also Radicava (edaravone).

Participants will be assigned randomly to receive up to five oral capsules of either MN-166 (up to 100 mg/day) or a placebo, twice a day for one year. Those completing the randomized period will have the option to enroll in the study’s open-label extension phase, in which all will be given the experimental therapy for six months.

COMBAT-ALS’s main goal is to assess disease progression, measured through the ALS Functional Rating Scale-Revised. Secondary goals include changes in muscle strength, quality of life, functional activity, and survival, as well as safety measures.

“In collaboration with our ALS investigators Dr. Brooks and Dr. Oskarsson, we recently hosted a webinar for ALS patients and community members highlighting encouraging data reported to-date and the potential of MN-166 (ibudilast) to bridge a long-standing treatment gap without compromising safety,” Iwaki added.

Held in June, the webinar provided an overview of MN-166’s mechanism of action, the COMBAT-ALS study design, and results from the previous Phase 2 trial in ALS. It included presentations from Björn Oskarsson, MD, COMBAT-ALS’s lead investigator, and Benjamin Rix Brooks, MD, who led the first clinical trial of MN-166 in ALS patients.