safimaltib (JNJ-6633)

P1, N=75, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jul 2024 --> Jul 2025

P1, N=226, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Oct 2023 --> Dec 2024

P1, N=45, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1 | Trial primary completion date: Nov 2023 --> Nov 2024

P1, N=75, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

P1b, N=75, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2026 --> Jul 2025

Furthermore, a MALT1 inhibitor (JNJ-67856633) showed efficacy in mature B cell malignancies from phase 1 studies (ref 1, 2)...SGR-1505 administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, demonstrates tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived and patient-derived xenograft models...Subjects with symptomatic or active CNS involvement, and other conditions or laboratory findings placing them at increased risk to the use of an investigational drug are excluded. SGR-1505 is initially dose-escalated using an accelerated titration design in cohorts of 1-6 subjects, and at higher dose levels using a conventional 3+3 design.

P1b, N=75, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Apr 2026

Preliminary data from this first-in-human MALT1 inhibitor (JNJ-67856633) phase 1 dose escalation study indicates that it has a manageable hematological and non-hematological safety profile. JNJ-67856633 hasdemonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with a higher ORR and is further explored in expansion cohorts.

P1b, N=45, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Nov 2023 --> Nov 2024

Preliminary data from this phase 1 dose escalation study of JNJ-6633 indicates it has a manageable hematological and non-hematological safety profile. JNJ-6633 demonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with higher ORR and is further explored in expansion cohorts.

Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.

BTK inhibitors have been widely studied in B-cell hematologic malignancies and 3 inhibitors, including the first-in-class BTK inhibitor ibrutinib, are currently approved. Conclusion The preclinical results confirm that JNJ-64264681 is a highly selective and potent BTK inhibitor and provide proof-of-concept for human trials in patients with B cell malignancies driven by the classical NF-κB pathway. JNJ-64264681 is currently in human clinical trials (NCT04210219 and NCT04657224) as single agent to establish dose and pharmacokinetics and to evaluate efficacy in combination with the first-in-class MALT1 inhibitor JNJ-67856633.

Taken together, the in vitro and in vivo data for JNJ‑67856633 and JNJ-64264681 suggest that combination therapy can increase the anti-tumor effect of the monotherapies and provide a more sustained response, offering strong support for clinical investigation of the combination of these two novel agents. A phase 1b combination study is scheduled to initiate.

In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM, and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocation, represent another attractive target for MALT1 inhibition.