Dianthus planning a 2024 trial of its complement inhibitor for CAD

Proof-of-concept study will test efficacy of DNTH103 in patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Dianthus Therapeutics plans to launch a proof-of-concept clinical trial of its therapy candidate DNTH103 in 2024 to test the efficacy of the complement inhibitor in people with cold agglutinin disease (CAD).

Data from the trial would be expected in the second half of next year.

Funding for the study will come from a planned merger between Dianthus and Magenta Therapeutics, a stem cell biology and drug development company. The merger is expected to support development of the new company’s therapeutic pipeline through mid-2026.

Cash obtained from each company, along with $70 million from healthcare investors, is estimated to provide a total of about $180 million toward the development program at the close of the merger, which is expected in the coming months. The merged company will use the Dianthus Therapeutics name.

“I’m delighted to announce this planned merger with Magenta, which comes at a pivotal moment in the evolution of our company as we advance our pipeline of next-generation complement therapeutics for people living with severe autoimmune diseases,” Marino Garcia, president and CEO of Dianthus, said in a company press release.

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DNTH103: a potentially more effective complement inhibitor

In CAD, a rare autoimmune disease, self-reactive antibodies attack and destroy red blood cells at low temperatures. The complement cascade, part of the immune system, is implicated in this process, and thus, it is the target of approved and experimental therapies for CAD.

Complement signaling involves three components: the classical, alternative, and lectin pathways. In particular, the classical pathway is implicated in CAD and other inflammatory or autoimmune diseases.

DNTH103 is an antibody designed to specifically block the active form of the complement C1s protein, which is responsible for initiating the classical complement cascade.

The complement cascade comprises several proteins that are usually in the inactive form while circulating in the blood. When activated by a trigger, they will activate each other like a chain reaction: the first activated protein activates the next, which activates the next and so on.

“Only a very small fraction of inactive complement proteins we have floating in our blood is activated at any given time,” Garcia said in a joint company webcast.

Enjaymo (sutimlimab), another C1s suppressor, is already approved for the treatment of CAD. But in contrast to Enjaymo, DNTH103 does not bind to inactive forms of the C1s protein, avoiding wasting the compound where it isn’t needed. That means that less of the medication is required to have a therapeutic effect, according to Dianthus.

Preclinical data indicated that DNTH103 could suppress antibody-induced red blood cell destruction with greater potency than Enjaymo.

Moreover, because DNTH103 specifically hones in on the classical pathway, it leaves alone the lectin and alternative pathways that are important for protecting the body against infections.

Other therapies under investigation for CAD, including APL-2 and eculizumab (marketed as Soliris for treating other autoimmune diseases), target components of the complement system that also cause the lectin and alternative pathways to be suppressed, potentially leading to unwanted side effects.

DNTH103 is also designed to be long-lasting in the bloodstream when self-delivered by patients as an under-the-skin (subcutaneous) injection. Given via a pre-filled pen, it would offer less frequent dosing and greater convenience for patients, the company noted.

An ongoing Phase 1 trial is evaluating the safety of single and multiple doses of DNTH203 in healthy adult volunteers. Its pharmacological properties and ability to suppress the complement cascade also are being assessed.

To date, 23 volunteers have been dosed in the trial, and data so far indicate that the treatment has favorable tolerability and pharmacological properties. 

A 300-mg dose, delivered via subcutaneous injection once every two weeks, is expected to safely surpass clinically-relevant thresholds of complement inhibition, according to the company.

Top-line results from that trial are expected in the second half of this year, which will support the launch of Phase 2 studies in people with a range of diseases, including CAD.

The objective for this study would be to provide proof-of-concept … [that] DNTH103 can potentially deliver similar clinical activity but in a much more convenient, lower-dose form than nonselective, high dose C1s inhibitors.

The Phase 2 trial in CAD will be open-label, meaning neither participants nor investigators will be blinded to the treatment that each person is given. No other trial details have been provided.

“The objective for this study would be to provide proof-of-concept … demonstrating that targeting the active form of C1s with a low-volume, potent antibody like DNTH103 can potentially deliver similar clinical activity but in a much more convenient, lower-dose form than nonselective, high dose C1s inhibitors,” Garcia said in the webcast.

Other planned Phase 2 trials of DNTH103 will involve people with other severe autoimmune conditions, including myasthenia gravis.

“Dianthus has made rapid progress in developing and advancing DNTH103 into the clinic where it has the potential to be a transformative classical pathway inhibitor for severe autoimmune diseases,” said Steve Mahoney, president, chief financial and operating officer at Magenta.