sotigalimab (PYX-107)

Due to the unique epitope, it demonstrates superior activation compared to APX005M (S267E)...Furthermore, in humanized transgenic mice challenged with huPD-L1-expressing tumor cells, BA4415 induced superior anti-tumor activity. This novel anti-PD-L1/CD40 bispecific antibody holds potential for strong anti-tumor therapeutic efficacy by selectively restricting CD40 stimulation in tumors.

P1, N=42, Completed, Yale University | Active, not recruiting --> Completed | Trial completion date: Oct 2027 --> May 2024

P1, N=26, Active, not recruiting, Yale University | Recruiting --> Active, not recruiting

P1, N=32, Active, not recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Mar 2024 --> Sep 2024

P1/2, N=32, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P2, N=27, Active, not recruiting, Alexander Z. Wei, MD | Recruiting --> Active, not recruiting

These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.

P2, N=45, Terminated, Apexigen America, Inc. | Completed --> Terminated; Business decision (not due to safety reason).

P2, N=58, Active, not recruiting, University of Texas Southwestern Medical Center | Trial completion date: Nov 2023 --> Sep 2025 | Trial primary completion date: Nov 2023 --> Sep 2025

In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them.

Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options.

Trial Registration Related to trial #NCT03165994 Background Sotigalimab (sotiga) is an agonistic anti-CD40 monoclonal antibody that can stimulate anti-tumor immune responses...The high rates of clinical response with this treatment are associated with both pre-existing and treatment-induced T cell populations. Sotiga can therefore mediate the conversion of an immune-suppressive (‘cold’) to immune-activated (‘hot’) TME.

P2, N=44, Completed, Apexigen America, Inc. | Active, not recruiting --> Completed

Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.

P2, N=34, Completed, Apexigen America, Inc. | Active, not recruiting --> Completed | Trial completion date: Apr 2024 --> Feb 2023 | Trial primary completion date: Apr 2022 --> Nov 2022

D (75 mg/m2) + S (0.3 mg/kg) every 21 days is safe and tolerable in STS. Final analysis of the primary endpoint awaits further follow-up on recently enrolled patients. Subtype-specific analysis suggests improvement in median PFS for DDLPS over historical controls: 11.9 mos vs 4 mos (Stacchiotti S. Ann Oncol 2020; Livingston M. Sci Rep 2017).

P1/2, N=34, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=32, Active, not recruiting, Pediatric Brain Tumor Consortium | Recruiting --> Active, not recruiting

Recently, PRINCE, a randomized phase 2 clinical study, reported significantly improved 1-year overall survival (OS) for mPDAC patients treated with nivolumab and chemotherapy (nivo/chemo) compared to historical control but not for sotigalimab and chemotherapy (sotiga/chemo) or a combination of the three. Herein we demonstrate the value of both an unbiased approach, as well as the use of peptide level data for novel biomarker identification. We identify numerous proteins and peptides that have the potential to be used for better patient treatment stratification in the case of mPDAC and immunotherapy.

PRINCE is a ph1b/2 study evaluating gemcitabine (gem) and nab-paclitaxel (NP) ± sotigalimab (sotiga; CD40 agonist) ± nivolumab (nivo; anti-PD1) for pts with mPDAC (NCT0324250), where prophylactic GCSF use was prohibited. These analyses suggest that GCSF use may enhance the clinical benefits of chemo-IO in mPDAC. These potential benefits of GCSF usage warrant further evaluation in other chemo-IO trials as well as prospective evaluation in pre-clinical and clinical settings. Clinical trial information: NCT03214250.

P1, N=45, Recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Sep 2023 --> Mar 2024 | Trial primary completion date: Mar 2023 --> Sep 2023

Sotiga induced dramatic changes in the tumor microenvironment including increased frequency of activated T cells and APCs, and decreased frequency of Tregs. A distinct signature of T cell infiltration in baseline tumor biopsies was observed in patients who achieved a pCR versus those who did not, potentially identifying patients that may benefit from this novel treatment strategy.

Study treatment: carboplatin (AUC 2)/paclitaxel (PTX) (50 mg/m 2 ) weekly x 5 with radiation 5040 cGy plus up to 4 doses of sotiga 0.3mg/kg IV prior to Ivor-Lewis esophagectomy. Conclusions Sotiga combined with neoadjuvant chemoradiation for esophageal/GEJ cancers was generally well tolerated and achieved pCR rates in both AC and SCC that compare favorably to historical data and are promising for this treatment strategy. Additional evaluations of clinical outcomes (including DFS, OS) and immune-based biomarkers are ongoing.

P1, N=42, Active, not recruiting, Yale University | Recruiting --> Active, not recruiting | N=120 --> 42 | Trial completion date: Oct 2024 --> Oct 2027 | Trial primary completion date: May 2022 --> Nov 2022

P1, N=45, Recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Mar 2022 --> Mar 2023

We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

P2, N=44, Active, not recruiting, Apexigen, Inc. | Recruiting --> Active, not recruiting

Importantly, these immunologic changes were correlated with clinical response. Collectively, this combination therapy is well tolerated and has a notable clinical response rate, accompanied by broad innate and adaptive immune activation at both local and distant lesions.

P1/2, N=41, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Apr 2024 | Trial primary completion date: Dec 2021 --> Apr 2024

P1, N=150, Recruiting, M.D. Anderson Cancer Center | N=60 --> 150

P1/2, N=143, Completed, Apexigen, Inc. | N=400 --> 143

These results warrant further study of this combination in advanced, refractory melanoma. Trial Registration NCT03123783

P1, N=45, Recruiting, Pediatric Brain Tumor Consortium | Trial primary completion date: Sep 2021 --> Mar 2022

This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

This first in-human study of patients with anti-PD-1/PD-L1-resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.

P1/2, N=400, Completed, Apexigen, Inc. | Terminated --> Completed

PRINCE trial patients received gemcitabine/nab-paclitaxel with immunotherapy (I/O) agents (APX005M and/or nivolumab) . Baseline ctKRAS is significantly associated with OS and PFS in mPDAC in both independent cohorts . Further, early on-treatment ctKRAS clearance is strongly associated with improved PFS and OS, independent of baseline ctKRAS VAF . These data strongly support further investigation of ccfDNA as a biomarker of response and resistance to therapy.

In this ongoing, seamless ph1b/2 trial of gem/NP ± nivo ± APX005M in pts with mPDAC, antitumor activity was observed in all arms . 1° endpoint of 1-year OS > 35% was met when combining gem/NP with either nivo or APX005M; however, not the combination . Safety was manageable; consistent with ph1b .

The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

P1/2, N=400, Terminated, Apexigen, Inc. | Recruiting --> Terminated