Celldex Therapeutics Scraps PN Plans After Barzolvolimab Phase 2 Miss

Celldex Therapeutics NASDAQ: CLDX said a Phase 2 trial of barzolvolimab in prurigo nodularis did not meet its primary or secondary endpoints, prompting the company to discontinue development of the drug in that indication while continuing to focus on ongoing late-stage urticaria studies.

Anthony Marucci, Celldex’s co-founder, president and chief executive officer, said the company was “disappointed” by the results, which showed barzolvolimab produced “profound systemic depletion of mast cells” but did not translate into improvements in itch or skin lesions for patients with prurigo nodularis, or PN.

“Unlike our intravenous Phase 1 study, this Phase 2 subQ study did not result in improvements in itch or skin lesions for patients, indicating that mast cells may not be the key pathogenic driver of symptoms in PN,” Marucci said.

Phase 2 Study Misses Itch and Skin Lesion Endpoints

Dr. Diane Young, Celldex’s senior vice president and chief medical officer, said the randomized, double-blind, placebo-controlled study enrolled 140 participants across six countries and 48 sites. Patients had moderate to severe PN and had either an inadequate response to prescription topical medications or were unable to use them for medical reasons.

Participants were assigned to placebo or one of two subcutaneous barzolvolimab dosing regimens: 150 milligrams or 300 milligrams every four weeks after an initial 450 milligram loading dose. The placebo-controlled treatment period lasted 24 weeks, followed by a 16-week follow-up period through week 40, with an option for an open-label extension.

The primary endpoint was the proportion of participants achieving at least a four-point improvement in the Worst Itch Numeric Rating Scale at 12 weeks. Young said patients entered the trial with a mean baseline score greater than 8 on the 0-to-10 itch scale.

“Patients treated with barzolvolimab did not have differentiated responses compared to placebo across either dose or at any of the time points,” Young said.

She added that key secondary endpoints, including an investigator assessment of skin lesions and a combined itch and lesion endpoint, also failed to show differentiation from placebo.

Company Points to Difference From Earlier IV Study

Celldex had advanced barzolvolimab into the Phase 2 PN trial after a small 23-patient Phase 1b study using intravenous administration showed positive signals in itch reduction and nodule resolution at the highest dose tested.

Young said the company is still reviewing the new data and plans to analyze biopsy samples in the coming months to better understand the discrepancy between the Phase 1b and Phase 2 results. She noted that the Phase 2 trial was larger and used subcutaneous administration rather than intravenous dosing.

“IV administration is associated with more rapid and higher drug concentrations relative to subQ,” Young said. “We can’t rule out that these differences may have contributed to the difference in outcome.”

However, she said both studies achieved profound decreases in circulating tryptase, a marker Celldex uses to assess mast cell depletion. Based on the current data, she said the company’s assessment is that mast cells may not be a key pathogenic driver of PN symptoms.

Safety Profile Described as Consistent With Prior Studies

Despite the efficacy miss, Celldex said barzolvolimab was well tolerated in the PN study and that the safety profile was consistent with prior trials. Young said the trial tested the highest subcutaneous exposure studied to date with the 450 milligram loading dose followed by 300 milligrams every four weeks.

The most frequently reported adverse events occurring in more than 10% of participants in any treatment group were hair color changes and nasopharyngitis, all of which were Grade 1 or Grade 2, Young said.

Young also discussed a serious adverse event reported by an investigator as treatment-related aseptic meningitis. Celldex disagreed with that assessment, and Young said the company’s conclusion was supported by the independent data monitoring committee. She said the patient did not have typical signs such as headache, neck pain or fever, had no neutropenia, and made a full recovery. Celldex believes the event was more consistent with neuroinflammation related to a viral infection and was not related to study drug.

The study also included one death from cardiac failure, which Young said was assessed as not related to treatment by the investigator, sponsor and data monitoring committee. The patient was a 73-year-old man with multiple cardiac risk factors and comorbidities at baseline.

In the question-and-answer session, Young said there were no cases of anaphylaxis in the study. She also said neutropenia occurred at a low incidence, below the 10% threshold shown in the company’s safety table, and all cases were Grade 1 or Grade 2 with no association with infection.

Focus Shifts to Urticaria and Other Programs

Marucci said Celldex will now direct resources to the rest of its pipeline, particularly three ongoing Phase 3 urticaria studies in chronic spontaneous urticaria, symptomatic dermographism and cold urticaria. The company expects to report top-line data from the EMBARQ chronic spontaneous urticaria Phase 3 studies in the September-October timeframe.

Celldex also said it expects Phase 2 data in atopic dermatitis late in the fourth quarter and plans to share more about broader life-cycle development plans for barzolvolimab later this year.

During the Q&A session, executives said they do not believe the PN outcome creates a read-through concern for the chronic spontaneous urticaria program, which they said is supported by robust Phase 2 data. Young said regular data safety monitoring committee reviews are ongoing in the Phase 3 CSU program.

Marucci said Celldex remains focused on barzolvolimab’s potential in mast cell-driven diseases and will continue reviewing lessons from the PN trial for barzolvolimab, CDX-622 and other pipeline candidates.

About Celldex Therapeutics (NASDAQ:CLDX)

Celldex Therapeutics, Inc is a clinical-stage biopharmaceutical company focused on the discovery and development of targeted immunotherapies for cancer and other serious diseases. The company's research platforms leverage novel antibody and vaccine technologies designed to engage the patient's immune system, with a particular emphasis on oncology and neurologic indications. Celldex's pipeline includes both monoclonal antibodies and biologic agents that seek to modulate immune responses or deliver targeted cytotoxic activity.

Among Celldex's lead product candidates is glembatumumab vedotin, an antibody–drug conjugate directed against the glycoprotein NMB (gpNMB) for the treatment of certain breast and skin cancers.

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