Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma.

PURPOSE: Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933). PATIENTS AND METHODS: INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS. RESULTS: In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%). CONCLUSIONS: INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.

Anti-CTGF Oligonucleotide Reduces Severity of Postsurgical Hypertrophic Scars in a Randomized, Double-Blind, Within-Subject, Placebo-Controlled Study.

BACKGROUND: Connective tissue growth factor (CTGF) levels are up-regulated in wounded skin and are thought to play a major role in scar formation. An antisense oligonucleotide targeting CTGF was evaluated in adult patients undergoing hypertrophic scar revision surgery, to determine effects on reducing the severity of subsequent scars. METHODS: In a randomized, double-blind, within-subject, placebo-controlled study, 23 female subjects (aged 28 to 55 years) with bilateral, symmetric, hypertrophic surgical scars of the breast underwent scar revision surgery. The resulting breast incisions were randomized to receive EXC 001 (5 mg/cm) or placebo injected intradermally at postsurgery weeks 2, 5, 8, and 11. Scar severity assessments were performed at weeks 12 and 24 by an expert panel using blinded photographs, and by physicians and subjects using a scar scoring scale, the Patient and Observer Scar Assessment Scale. An assumption of the design is that within-subject variance would be small and that whatever within-subject variance there was would be controlled through the randomization process. RESULTS: EXC 001 significantly reduced scar severity at both 12 and 24 weeks after scar revision surgery in all three measures (expert panel and physician Patient and Observer Scar Assessment Scale, p < 0.001; Patient and Observer Scar Assessment Scale, p < 0.003). CONCLUSIONS: This study provided positive preliminary data that intradermal injection of EXC 001 produced a significant reduction in severity of postsurgical skin scars, as measured by physicians, subjects, and an expert panel. This study provided evidence that suppression of CTGF could be a viable strategy for hypertrophic scar reduction therapy and that further study of the antisense oligonucleotide EXC 001 was indicated. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.