IMBiologics' 'OX40LxTNF' Enters U.S. Phase 1b Trial – What Is Its Competitiveness?

By Sungmin Kim, BioSpectator
Published: June 10, 2025, 14:10 | Updated: June 10, 2025, 16:49

Navigator Medicines, a U.S.-based partner of Korea’s IMBiologics, has begun a Phase 1b clinical trial for the bispecific antibody targeting OX40L and TNFα, called 'NAV-240 (IMB-101)', roughly one year after acquiring exclusive global rights (excluding Asia) to the antibody. Two months after the licensing agreement with IMBiologics, Navigator officially launched, raising $100 million in Series A funding led by RA Capital Management and Forbion.

In March this year, Navigator disclosed the first-in-human Phase 1a trial results for NAV-240 at the American Academy of Dermatology (AAD 2025) meeting and began accelerating its development, selecting hidradenitis suppurativa (HS), a chronic inflammatory disease, as the first indication. The company believes NAV-240 could be developed as a once-monthly injectable treatment for HS.

Navigator is betting on the OX40L target and has also initiated development of a next-generation bispecific antibody with an extended half-life, ‘NAV-242’. Through this approach, the company aims to optimize drug exposure and dosage, providing differentiated treatment options for inflammatory and autoimmune diseases such as HS, Crohn’s disease, and ulcerative colitis. Additionally, Navigator is conducting preclinical development of the OX40L antibody ‘NAV-140 (IMB-102)’, also licensed from IMBiologics, and is discovering a new OX40L bispecific antibody ‘NAV-340’ (target undisclosed).

Globally, bispecific antibodies targeting both OX40L and TNFα are still in early development. Sanofi is currently the front-runner, having announced during its Q1 2025 earnings call in April that its nanobody ‘brivekimig’, targeting OX40L and TNFα, achieved the primary endpoint in a Phase 2 trial for HS.

Against this backdrop, Navigator announced on May 29 that it had administered the first dose of NAV-240 in a Phase 1b multiple ascending dose (MAD) trial involving healthy subjects. Interim results are expected to be released within the year.

In the Phase 1b trial, Navigator plans to administer NAV-240 to 24 participants across three dose cohorts, evaluating safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of repeated dosing. Based on these results, the company plans to initiate trials in patients with inflammatory and autoimmune diseases by the end of the year.

Tosh Butt, CEO of Navigator, stated, “This is a critical time for Navigator as we aim to make a positive impact for patients with difficult-to-treat autoimmune and inflammatory diseases. Our OX40L-targeted programs, including NAV-240 and NAV-242, aim to provide new treatment options in areas with high unmet needs.”

NAV-240 Phase 1a Trial Results – How Does It Compare to Sanofi?

TNFα is a well-known target in inflammatory diseases, effectively inhibiting type 1 inflammation mediated by Th1 cells across a broad range of indications. However, significant unmet needs remain due to limited efficacy in many patients.

OX40 and its ligand OX40L belong to the TNF receptor and superfamily, respectively. OX40L is expressed on antigen-presenting cells (APCs) and activated T cells, playing a key co-stimulatory signaling role essential for T cell responses. It is involved in a broad range of T cell responses including Treg, Th1, Tfh, Th17, and Th2.

Navigator expects that NAV-240, a ‘2+2’ structured bispecific antibody (OX40L antibody + TNFα scFv), will not only target TNFα involved in Th1 inflammation but also modulate type 2 inflammation. By regulating inflammatory cytokines and adaptive immune responses, the drug is expected to contribute to long-term immune homeostasis. The OX40–OX40L axis is a validated clinical target, with companies such as Amgen and Sanofi reporting positive results in late-stage atopic dermatitis trials.

In preclinical studies, IMBiologics demonstrated that the gene expression profiles of immune cells differed depending on whether NAV-240 (bispecific) or NAV-140 (OX40L antibody) was administered, suggesting that each mechanism may target different indications. NAV-240 is interpreted to primarily act in Th1/Th17-related diseases, whereas NAV-140 may be more effective in Th2-related conditions.

At AAD 2025, Navigator presented data from the single ascending dose (SAD) Phase 1a trial of NAV-240. This trial involved 40 healthy subjects receiving one of five doses (0.1, 0.3, 1, 3, 10 mg/kg) intravenously (IV), randomized in a 6:2 ratio against placebo (NCT06181786).

No serious adverse events or treatment discontinuations were reported. Only one subject in the lowest dose group (0.1 mg/kg) showed a possibly drug-related event, confirming the safety profile. NAV-240 demonstrated dose-dependent pharmacokinetics, and preliminary modeling predicts that once-monthly dosing will achieve serum trough levels above the target concentration in HS, which is known for high antibody clearance compared to other diseases like psoriasis.

HS is a chronic, progressive inflammatory skin disease characterized by painful and recurring abscesses and lesions, severely impacting quality of life. Current treatments include antibiotics, TNFα antibodies, IL-17 antibodies, and surgery. However, clinical response rates are low, and even FDA-approved Humira shows efficacy in only about half of patients, underscoring the need for more effective and longer-lasting treatments.

Sanofi Prioritizes Its Bispecific Antibody for HS

In a positive move, Sanofi revealed during its Q1 earnings that its TNFα x OX40L bispecific nanobody, brivekimig, met the primary endpoint in the HS OBTAIN Phase 2 trial (NCT06118099). Brivekimig is a 2+2 structured drug with an added albumin-binding domain to extend its half-life.

Key results showed that the drug produced clinically meaningful improvements in HiSCR50 and other efficacy endpoints in biologic-naïve patients. No new safety issues were identified after 28 weeks of dosing, with full data to be presented at a future conference.

Sanofi announced it would now prioritize development of brivekimig over its OX40L antibody amlitelimab, which failed to demonstrate similar efficacy in HS.

As part of its expansion strategy, Sanofi recently launched the T1D OBTAIN Phase 2 trial to assess brivekimig’s ability to preserve pancreatic beta cell function in newly diagnosed adult and adolescent type 1 diabetes patients (NCT06812988).

IMBiologics anticipates that IMB-101 (NAV-240) may become a best-in-class asset compared to brivekimig. The company stated, “Brivekimig, being a nanobody-derived molecule, showed immunogenicity in over 80% of subjects in Phase 1a. We expect IMB-101 to have competitive advantages in safety and dosing interval. Both preclinical and clinical results suggest that IMB-101 offers a broader therapeutic index.”

IMBiologics also expects to maintain a competitive edge with its OX40L-targeted antibodies.

Sanofi has been actively investing in amlitelimab as a follow-up asset to its blockbuster immunology drug Dupixent. It is currently focused on three indications within its OX40L portfolio. Amlitelimab, acquired through the $1.1 billion acquisition of Kymab in 2021, failed in a Phase 2 asthma trial this April, though efficacy was confirmed in eosinophil- and neutrophil-high subgroups. The company plans to continue into Phase 3 with a more targeted patient population.

The most advanced amlitelimab indication is atopic dermatitis, with two ongoing Phase 3 trials (COAST 1 and SHORE), and early efficacy data expected in the second half of this year. For HS, Sanofi has shifted its focus to fast-track development of its bispecific candidate, brivekimig.

IMBiologics expects to differentiate its OX40L antibody IMB-102 from amlitelimab based on epitope-driven mechanism of action. IMB-102 directly inhibits the OX40–OX40L interaction, while amlitelimab works by preventing OX40L trimer formation. In both in vitro and in vivo atopic dermatitis models, IMB-102 demonstrated higher inhibitory efficacy. Additionally, IMB-102 does not bind to homologous TNFSF proteins, indicating superior drug selectivity.