Phase 2 Trial of NM8074 in aHUS Patients Cleared to Open by FDA

Open-label study testing potentially safer, more targeted antibody-based therapy

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by Steve Bryson, PhD |

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NovelMed has been cleared to begin patient testing of NM8074, an investigational antibody-based therapy for atypical hemolytic uremic syndrome (aHUS) that is not expected to carry a risk of treatment-related infections.

The therapy candidate is designed to block the complement cascade — a part of the immune system that is overactive in aHUS patients — by a more targeted mechanism of action than that of approved complement-based treatments.

As a result, NM8074 has the potential to induce disease remission while allowing certain immune functions to continue, so patients might avoiding the life-threatening infections associated with current treatments.

The Phase 2 study (NCT05684159) will evaluate the therapy’s safety and efficacy at least 12 aHUS patients, ages 18–65, who are not using any complement-blocking treatments. Enrollment is expected to open soon.

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NM8074 designed to block alternative complement pathway in immune system

“The FDA’s [U.S. Food and Drug Administration’s] clearance of the Phase 2 clinical trial for aHUS, a rare disease, is an important milestone in the active life of NM8074,” Rekha Bansal, PhD, NovelMed’s CEO, said in a press release.

The complement system is a group of immunological proteins that, when activated, help the immune system eliminate disease-causing microbes. There are two major complement pathways: the classical pathway, which is triggered by antibodies binding to microbes, and the alternative pathway, which does not rely on antibodies.

In aHUS, the uncontrolled activation of the alternative complement pathway leads to low platelet counts, the destruction of red blood cells (hemolytic anemia), and increased blood clotting in small blood vessels (thrombotic microangiopathy, or TMA), particularly in the kidneys.

Soliris (eculizumab) and Ultomiris (ravulizumab) are approved complement-blocking therapies that prevent the cleavage of C5, a protein near the final step of the cascade process. However, these treatments block the complement cascade stimulated by both the classical and alternative pathways, which can compromise the immune system.

As such, patients using Soliris or Ultomiris are known to be at a higher risk of meningococcal infections, which can be severe, and must receive immunization at least two weeks before starting treatment.

NovelMed reports that NM8074 selectively binds to and blocks an active portion, or catalytic site, of Bb, a fragment of complement Factor B, which is part of the alternative complement pathway upstream of C5.

As a result, NM8074 has the potential to suppress the overactivation of the aHUS-related alternative complement without affecting the classical pathway. This means it may help in treating aHUS, while allowing patients to retain some essential immune functions.

“Our drug functions by binding Bb at its catalytic site and has no affinity for Factor B. As a result, the drug selectively blocks the alternative pathway (AP) without affecting the CP [classical pathway],” Bansal said. “We speculate that patients would not have to take the meningococcal vaccine in the future should the drug prove effective in the upcoming clinical trial of this rare disease.”

Potential therapy showed safety in early clinical trial

No safety concerns were reported in a Phase 1 trial (NCT05642546) evaluating NM8074, at escalating doses, in healthy volunteers, according to NovelMed.

Trial data confirmed the therapy completely blocked the alternative pathway, but not the classical pathway, a finding consistent with company data from laboratory tests. In addition, NM8074 blocked the formation of a complement cascade protein responsible for ongoing anemia in both Soliris and Ultomiris-treated patients.

“Based on our initial clinical data, it is clear that NM8074 could provide the selectivity and the specificity required for developing a novel biologic for the complete remission of thrombotic microangiopathy in patients with aHUS,” Bansal said.

The open-label Phase 2 study will enroll complement treatment-naïve adults whose disease is resistant to treatment or has relapsed, with signs of low platelets, hemolysis, TMA, and acute kidney damage. Eligible patients still are required to be vaccinated against meningococcus.

Administered by intravenous (IV) infusion, six patients will be treated with NM8074 at 20 mg/kg every two weeks over 85 days (almost three months; total of seven doses). Then, after a safety check, a second group of six enrolled patients will receive four weekly doses at 10 mg/kg, followed by 20 mg/kg doses every two weeks until day 85, for a total of nine doses.

The study’s primary goal is to determine whether NM8074 can induce disease remission, as assessed by changes in various related markers, including platelet counts, lactate dehydrogenase (LDH), kidney function, and other blood-based TMA features.

Secondary measures include assessing the time to complete TMA response, changes in blood clots, the total number of needed plasma infusions of exchanges, other markers of kidney function, and quality of life assessments.

Safety evaluations will begin after an initial dose is given the first three treated patients.

In addition to aHUS, NM8074 has the potential to treat a variety of disorders affecting the kidneys, eyes, nervous system, and blood, in which activation of the alternative pathway is their key driver.

“Given the role of the [alternative pathway] in multiple complement-mediated rare diseases, NM8074 has the potential to treat not only aHUS but several other complement-mediated diseases as well, where [alternative pathway] is the sole contributor of the pathological [disease] outcome,” Bansal said.