FDA Clears Phase 2 MoMeNtum Trial of DNTH103 in Multifocal Motor Neuropathy

Author(s):

MoMeNtum will evaluate the efficacy and safety of DNTH103, administered subcutaneously every two weeks over a 17-week period, followed by a 52-week open-label extension to collect additional safety and efficacy data.

Simrat Randhawa, MD

According to a recent announcement, the FDA has cleared Dianthus Therapeutics’ investigational new drug application (IND) for its phase 2 MoMeNtum trial assessing DNTH103, an investigational monoclonal antibody, in patients with multifocal motor neuropathy (MMN). Topline results for the double-blind, placebo-controlled trial are expected in the second half of 2026.¹

MoMeNtum, a global study, will assess the efficacy and safety of DNTH103 in 36 patients with MMN. Following determination of Ig dependency and responsiveness, patients will be randomly assigned to either placebo or DNTH103, delivered subcutaneously, every 2 weeks, for a 17-week period. After the initial treatment period, patients will have the opportunity to enter a long-term, 52-week open-label extension, where additional safety and efficacy data will be collected.

DNTH103 is a potent agent engineered to selectively target the classical pathway by inhibiting only the active forms of the C1s protein, a clinically validated complement target. It is enhanced with YTE half-life extension technology designed to enable a more convenient subcutaneous, self-administered injection dosed as infrequently as once every 2 weeks. In addition MMN, the therapy is being studied as a low-volume treatment option for patients with myasthenia gravis (MG) and chronic inflammatory demyelinating polyneuropathy (CIDP).

"Pre-clinical and clinical evidence support the classical pathway’s role in the pathology seen in MMN," Simrat Randhawa, MD, chief medical officer at Dianthus Therapeutics, said in a statement.¹ "DNTH103 is a potent and highly selective inhibitor of active C1s resulting in classical pathway inhibition, without inhibiting the alternative and lectin pathways that are critical in the defense against infection. The Dianthus medical team and our MMN steering committee are excited to investigate the potential benefits DNTH103 may bring to patients with MMN."

MoMeNtum will primarily evaluate safety and tolerability, but will also include other secondary end points such as time to intravenous immunoglobulin retreatment, time to relapse, and assessments of muscle and grip strength.

"There is a significant unmet medical need for a targeted biologic to treat patients living with MMN,” Hans Katzberg, MD, MSc, FRCPC, associate professor of neurology at the University of Toronto Prosserman Center of Neuromuscular Disease, said in a statement.¹ "Today, treatments for MMN are limited to intravenous or subcutaneous infusions of Ig, which can be both inconvenient for patients and difficult to tolerate. Treating MMN with an active C1s inhibitor, like DNTH103, has the potential to transform the lives of these patients."

Earlier this year, the company initiated its phase 2 MaGic trial (NCT06282159) of DNTH103 in patients with MG. The trial, which is expected to include 60 patients, evaluates the safety, tolerability, pharmacokinetics, and efficacy of the therapy in adults with the disease. Patients included will be randomly assigned to either low or high doses of DNTH103 or placebo over an 11-week treatment period, with dosing administered every 2 weeks.

More recently, at the 10th Congress of the European Academy of Neurology (EAN), which took place June 29-July 2 in Helsinki, Dianthus presented 2 posters highlighting preclinical and in vitro data of DNTH103 in disease models of generalized MG and CIDP. In the in vitro model of MG, serum from 3 AChR+ patients with MG were used, with fatigue index used as the primary end point. In comparison with another anti-C5 antibody, DNTH103 was shown to improve neurotransmission and muscle contract in the AChR+ MG model, providing further scientific rationale. In an additional assay, DNTH103 also maintained bacterial killing, potentially leading to a decreased risk of infection vs anti-C5 antibody.^2,3

Later this year, the company expects to initiate a phase 2 study of DNTH103 in patients with CIDP. In the CIDP model presented at EAN, DNTH103 was shown to have superior affinity and pharmacodynamic potency vs riliprubart (Sanofi), another investigational anti-C1 monoclonal antibody in development for CIDP. All told, DNTH103 consistently outperformed riliprubart when compared head-to-head across multiple in vitro experiments, including enzymatic assay, Weislab classical pathway assay in human serum, liposome lysis in human serum, and CH50 assay of RBC lysis in human serum.²

In an established in vitro model of CIDP containing 10% human serum, DNTH103 showed the ability to restore neuronal conduction velocity, further providing rationale for its development. Overall, the agent was shown to inhibit the classical pathway with the potential to be safer than less specific complement therapies that also block the lectin and/or alternative pathways. Authors concluded that DNTH103 has an extended half-life, and has the potential for patient-friendly, infrequent, low-volume, subcutaneous self-administration.³

REFERENCES
1. Dianthus Therapeutics Announces FDA Clearance to Initiate Phase 2 Trial of DNTH103 in Multifocal Motor Neuropathy (MMN). June 12, 2024. Accessed August 5, 2024. https://investor.dianthustx.com/news-releases/news-release-details/dianthus-therapeutics-announces-fda-clearance-initiate-phase-2
2. Vissing J, Peric S, Lewis LA, Stavenhagen J, Gokhale S. DNTH103, a potentially safer and more convenient novel therapy for generalized myasthenia gravis. Presented at European Academy of Neurology; June 29-July 2, 2024; Helsinki, Finland. EPR-118
3. Hatzberg H, Dysgaard T, Briggs C, et al. Preventing nerve damage in a CIDP model via sustained complement inhibition. Presented at European Academy of Neurology; June 29-July 2, 2024; Helsinki, Finland. EPR-243