On April 8, 2022 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, reported that data from Cohort A of its ongoing Phase 1/2 clinical trial of CFT7455, a novel degrader targeting IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL) (Press release, C4 Therapeutics, APR 8, 2022, View Source [SID1234611676]). The data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on Tuesday, April 12, 2022, at 9 AM CT by Sagar Lonial, M.D., FACP.

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"The early clinical data from the ongoing Phase 1/2 trial demonstrates that CFT7455’s differentiated pre-clinical profile, including enhanced PK and increased activity, has translated to the clinical setting," said Dr. Sagar Lonial, professor and chair, department of hematology and medical oncology, Winship Cancer Institute, Emory University. "Single agent CFT7455 has demonstrated preliminary evidence of clinical activity in a population of highly refractory and heavily pre-treated multiple myeloma patients. We continue to enroll patients in the ongoing clinical trial with the goal of providing a new treatment option for myeloma and lymphoma patients."

"We are encouraged by the early clinical observations and the potential of CFT7455 to be a next-generation therapy to treat multiple myeloma and non-Hodgkin’s lymphomas," said Adam Crystal, M.D., Ph.D., chief medical officer of C4 Therapeutics. "We believe this initial data highlights the ability of our TORPEDO platform to develop highly potent and selective degraders that have the potential to demonstrate deep and durable degradation of intended targets in the clinical setting. We will leverage the unique properties of CFT7455 to optimize its schedule and increase the therapeutic index as we progress to a recommended Phase 2 dose."

CFT7455 Phase 1/2 Clinical Trial
C4T designed CFT7455 to be highly potent and selective against its intended targets, IKZF1/3. The Phase 1/2 trial is designed to primarily investigate safety, tolerability, and anti-tumor activity. Secondary and exploratory objectives are to characterize the PK and pharmacodynamic profile of CFT7455. The Phase 1 portion of the study explores CFT7455 as a single agent in patients with relapsed or refractory (RR) MM and NHL, as well as in combination with dexamethasone in patients with RRMM. Following identification of a recommended dose(s) and schedule(s), the Phase 2 portion of the trial is expected to expand to the following four investigational arms: (1) in RRMM, single agent CFT7455; (2) in RRMM, CFT7455 combined with dexamethasone; (3) in peripheral T-cell lymphoma, single agent CFT7455; and (4) in mantle cell lymphoma, single agent CFT7455.

Cohort A, the first cohort in the clinical trial, explored CFT7455 as a single agent and enrolled five patients with MM. All patients in Cohort A were highly refractory and heavily pre-treated, having received a median of five prior lines of therapy (range of 4-14), including both lenalidomide and pomalidomide. The starting dose in the trial was 50 μg and all patients in Cohort A received single agent CFT7455 for 21 days of the 28-day treatment cycle. The data cut-off date was January 14, 2022. At the time of this data cut-off, two patients remained on therapy; however, these patients have since discontinued treatment.

Summary of Data from Cohort A:

Safety

Four patients received single agent CFT7455 at the starting dose of 50 μg per day. Two of these patients were dose reduced to 25 μg per day due to neutropenia, a known on-target toxicity associated with IKZF1/3 degraders.
The fifth patient enrolled at a starting dose of 25 μg per day based on the recommendation of the safety review committee.
Two dose-limiting toxicities (DLTs) were observed at the 50 μg per day starting dose, both consistent with on-target activity:
Grade 4 neutropenia lasting more than 5 days
A delay (more than 7 days) in initiating treatment in Cycle 2, in the setting of persistent Grade 3 neutropenia
No patient experiencing neutropenia had a concurrent infection or fever.
There were no serious adverse events reported and no adverse events resulted in death or treatment discontinuation.
Pharmacokinetics and Pharmacodynamics

CFT7455 was rapidly absorbed, with a plasma half-life of approximately two days. Accumulation of drug was observed up to four-fold by day 15 and achieved exposures at 50 μg that were equivalent to predicted highly active exposures based on pre-clinical studies.
CFT7455 demonstrated deep and durable degradation of IKZF1/3, as quantified by mass spectrometry, throughout Cycle 1.
Efficacy

Responsiveness was measured based on International Myeloma Working Group (IMWG) criteria.
Three patients had best observed reductions in the difference of serum free light chain (dFLC) ranging from 41 percent to 78 percent. One patient had an increase of 56 percent in dFLC.
The patient who achieved a 78 percent reduction in dFLC did not achieve a partial response under IMWG criteria due to the presence of measurable plasmacytomas, which were assessed as stable.
Three patients had a best response of stable disease. Two patients had a best response of progressive disease.
Next Steps for CFT7455
C4T has completed modeling of the Cohort A data and believes alternative dosing regimens are expected to increase the therapeutic index by allowing time for adequate neutrophil maturation during the days off drug, with limited impact on efficacy. Patients are enrolling in Cohort B1, exploring CFT7455 as a monotherapy for RRMM, and Cohort C, exploring CFT7455 as a monotherapy for NHL. Cohorts B1 and C have a starting dose of 25 μg per day at an alternative dosing schedule. Each cohort will proceed with dose finding in parallel, with the goal of achieving a recommended Phase 2 dose in each of MM and NHL.

Investor Webcast Information
C4T will host an investor webcast today, Friday, April 8, 2022, at 2 PM ET, with Sagar Lonial, M.D., FACP to discuss the CFT7455 clinical data being presented at AACR (Free AACR Whitepaper). To access the call, please dial 866-374-5140 or 404-400-0571 and provide the conference ID: 66856580. The webcast can be also accessed under "Events & Presentations" in the Investors section of the company’s website at www.c4therapeutics.com. A replay of the webcast will be available on C4T’s website for 30 days following the event.

On April 8, 2022 Imvax, Inc., a clinical-stage biotechnology company developing personalized, whole tumor-derived immunotherapies, reported that data on the activity of the company’s tumor-derived immunotherapies in glioblastoma and other solid tumors at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 in New Orleans, La (Press release, Imvax, APR 8, 2022, View Source;utm_medium=rss&utm_campaign=imvax-presents-new-data-on-tumor-derived-immunotherapies-in-glioblastoma-other-solid-tumors-at-aacr-annual-meeting-2022 [SID1234611673]).

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"Imvax has developed a unique tumor-derived immunotherapy approach that we believe has potential to extend the promising results seen with cell-based therapies in blood cancers to the more challenging category of solid tumors. The data we are presenting at AACR (Free AACR Whitepaper) validates the transformative potential of our immunotherapeutic platform to multiple types of solid tumors," said John P. Furey, Chief Executive Officer. "We are eager to continue to advance programs in gynecological, liver, and other cancers, as well as to initiate our Phase 2b clinical trial in our lead indication, glioblastoma, later this year."

Platform applicability to solid tumors

Preclinical findings presented at the meeting support the applicability of Imvax’s platform to hepatocellular carcinoma and ovarian and other gynecological cancers. Utilizing murine models of those solid tumor types, researchers assessed survival and tumor burden of mice that underwent a tumor challenge after being pre-treated with Imvax’s tumor-derived combination therapy, consisting of tumor cells dosed with IMV-001, the company’s proprietary antisense component, and enclosed in a biodiffusion chamber (BDC). Control groups for each study were treated with saline filled BDCs. In all arms of the study, the BDCs were removed 48 hours after implantation, and the tumor challenge was then conducted 26 days later.

In the ovarian cancer model, 60% of IOV-001-treated mice were alive 58 days post-tumor challenge, compared to only 19% of mice in the control group (p=0.004). Circulating IFNγ was significantly higher in IOV-001-treated mice compared to controls on day 1 post-tumor challenge (p<0.001).

In the hepatocellular carcinoma model, 50% of IHV-001-treated mice were alive by 100 days post-tumor challenge; there were no survivors in the saline group beyond day 28 (p=0.004). Most of the long-term survivors had undetectable levels of tumors. At day 14 after tumor challenge, circulating IFNγ trended higher in mice treated with IHV-001, and PD1+ expression in both CD4+ and CD8+ T cell subsets was significantly lower (p=0.002) in those mice that would survive long-term.

Predictive model of glioblastoma patient response

Additional data presented at AACR (Free AACR Whitepaper) detail the creation of a predictive model of patient response to IGV-001 based on serum profiling. The model was created utilizing data from the Phase 1b study of Imvax’s IGV-001 product candidate. That study had previously reported a median progression-free survival of 17.1 months in newly diagnosed glioblastoma patients in the highest dose cohort treated with IGV-001, compared with 6.5 months in historical standard-of-care-treated patients (P=0.0025) (Andrews et al., Clin Can Res 2021).

Inputs to the model included serum profiles of a number of cytokines as well as the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. An overall survival cutoff point of 21.9 months was used to dichotomize ‘good’ versus ‘poor’ outcomes. Utilizing a training subset of 10 patients, a classification decision tree was created. Applying this trained model on the full dataset (n=33) resulted in 93.9% correct classification of patients’ actual clinical outcomes. GBM-associated cytokines IL-8, IL-5, IL-6, and IL-13 were found to be key immune-correlates of patient outcomes. As these cytokines are known to correlate with tumor burden or prognosis, this observation further validated the utility of the model.

Imvax expects to utilize data from the upcoming Phase 2b trial of IGV-001 to further bolster the model’s predictive capabilities with the objective of identifying patient populations most likely to benefit from IGV-001 immunotherapy.

On April 8, 2022 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing potentially first-in-class therapeutics that combine both targeted and immune-mediated mechanisms, reported the presentation of two poster presentations at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting reporting new preclinical data that support the company’s preclinical TREX1 and clinical TPST-1495 programs (Press release, Tempest Therapeutics, APR 8, 2022, View Source [SID1234611671]).

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The first presentation reports on new preclinical data that support TPST-1495, a novel agent designed to specifically block the cancer-promoting EP2 and EP4 prostaglandin E2 (PGE2) receptors, further differentiating TPST-1495 from other approaches targeting the PGE2 pathway. The second presentation reports on proprietary inhibitors of TREX1, a cytosolic DNA exonuclease that inhibits activation of cGAS/STING in tumor and immune cells.

"As part of our diversified pipeline of innovative therapeutics, we reported the first preclinical data from our TREX1 program demonstrating the significant anti-tumor activity of our selective inhibitors. We believe TREX1 is the most promising approach to selectively activate the STING pathway broadly in metastatic disease with systemically administered, small molecule drugs," said Tom Dubensky, Ph.D., president of Tempest. "In addition, we presented preclinical data demonstrating that selective dual antagonism of both EP2 and EP4 prostaglandin receptors with TPST-1495 is a significantly superior approach to provide therapeutic anti-tumor benefit and activate human immune cell populations in vitro, as compared to either single EP2 and EP4 antagonists or NSAIDs. These data support the enthusiasm for our ongoing Phase 1 monotherapy and combination dose escalation and optimization study."

#1333: "Dual Blockade of the EP2 and EP4 PGE2 Receptors with TPST-1495 is an Optimal Approach for Drugging the Prostaglandin Pathway"

In vivo data demonstrated that monotherapy TPST-1495 significantly reduced tumor growth in mice via both T cell-independent and T-cell dependent mechanisms. The anti-tumor effect correlated with direct anti-proliferative effects on tumors in addition to increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and other anti-tumor myeloid and adaptive immune cell populations. Demonstrating its differentiated potency, therapy with TPST-1495 resulted in a significant survival advantage as compared to therapy with single EP2 or EP4 antagonists, or the NSAID celecoxib, in the APCmin/+ spontaneous colorectal cancer tumor mouse model. Additional data demonstrated that the administration of TPST-1495 resulted in near-complete restoration of immune function in human immune cell assays, reversing prostaglandin-mediated suppression of lipopolysaccharide stimulation-induced TNF-α production, even in the presence of elevated PGE2 concentrations in which single EP4 or EP2 inhibitors were not effective.

#2075: "Systemic Small Molecule TREX1 Inhibitors to Selectively Activate STING in the TME of Metastatic Disease"

The inaugural presentation for the TREX1 program summarized the approach to develop selective TREX1 inhibitor small molecules with picomolar potency. TREX1 inhibitors were profiled in various human and mouse cell-based assays, demonstrating that inhibition of TREX1 nuclease activity resulted in increased cGAS/STING pathway signaling and production of a reporter or interferon β. The anti-tumor activity of TREX1 inhibitors was evaluated in mice given sub-therapeutic doses of doxorubicin to effect double-stranded breaks in tumor cell DNA and induce the production of TREX1, resulting in significant anti-tumor efficacy and survival.

About TPST-1495

TPST-1495 is an orally available small molecule designed to block the cancer-promoting EP2 and EP4 receptors in the prostaglandin (PGE2) pathway, while sparing the homologous but differentially active EP1 and EP3 receptors. PGE2 signaling through EP2 and EP4 has been observed to enhance tumor progression through the stimulation of tumor proliferation, enhanced angiogenesis and suppression of immune function in the tumor microenvironment. Tempest has conducted head-to-head preclinical studies comparing TPST-1495 to single antagonists of EP2 and EP4 and observed significantly enhanced activity of TPST-1495 in both overcoming PGE2-mediated suppression of human immune cells in vitro, as well as significantly increased anti-tumor activity in mouse models of human colorectal cancer. Tempest is currently evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and possible anti-tumor activity of monotherapy and combination therapy TPST-1495 in a multicenter Phase 1a/1b dose and schedule optimization study in subjects with advanced solid tumors, with the potential to expand in indications known to be prostaglandin-driven, including colorectal cancer, or CRC, and in a tumor indication-agnostic, biomarker-selected cohort.

About TREX1

Genetic evidence from human disease and mouse genetic knock-out studies identify the Stimulator of Interferon Genes (STING) pathway as a critical innate immune sensor for the development of immunity. Tumor cells can evolve to avoid immune recognition through inactivating the STING pathway by diverse mechanisms, indicating that it is important to generating tumor-specific immunity. Selective activation of the STING pathway may be achieved through targeted inhibition of TREX1, a cytosolic DNA exonuclease that modulates cGAS/STING signaling, which is overexpressed in tumor cells. Tempest is developing TREX-1 inhibitors with oral pharmacokinetics. In vitro and in vivo studies have shown that the company’s compounds enhance the activation of the STING pathway in DNA-stimulated human and mouse cells. Furthermore, preclinical results in several tumor models have shown synergies of its TREX-1 compounds with low doses of doxorubicin, demonstrating significant therapeutic anti-tumor efficacy and survival.

On April 8, 2022 Oncorus, Inc. (Nasdaq: ONCR), a viral immunotherapy company focused on driving innovation to transform outcomes for cancer patients, reported its presentation of preclinical data for both ONCR-021 and ONCR-788 in two e-posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, taking place April 8-13 in New Orleans, Louisiana, supporting the company’s selectively self-amplifying viral RNA (vRNA) Immunotherapy Platform (Press release, Oncorus, APR 8, 2022, View Source [SID1234611670]).

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"The preclinical data presented on ONCR-021 and ONCR-788 at AACR (Free AACR Whitepaper) are an important step forward for Oncorus’ novel approach of selectively self-amplifying vRNA immunotherapies formulated in lipid nanoparticles. We are incredibly pleased to see these vRNA drug candidates’ potent efficacy in preclinical tumor models, after intravenous administration of the nanoparticle formulation even in the presence of neutralizing antibodies," said Ted Ashburn, M.D., Ph.D., President and Chief Executive Officer of Oncorus. "These data further bolster our confidence in our vRNA platform’s ability to deliver the RNA genome of oncolytic viruses to tumors intravenously and to circumvent the common limitation of existing IV-administered oncolytic viral cancer therapies. We look forward to advancing this next-generation approach of selectively self-amplifying vRNA, furthering our goal of realizing the full potential of systemically active viral immunotherapies to transform outcomes for cancer patients."

Oncorus’ vRNA Immunotherapy Platform encapsulates the genomes of RNA viruses known to kill cancer cells within an LNP, producing a living oncolytic and immunostimulatory viral infection in the tumor to destroy cancer cells and stimulate the immune system. In preclinical studies, Oncorus’ IV-administered vRNA immunotherapies demonstrated efficacy in multiple tumor models, avoiding the challenges seen in previous studies incorporating IV administration of RNA-based oncology therapeutics.

In a poster titled, "ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer," Oncorus highlighted:

ONCR-021, Oncorus’ lead vRNA immunotherapy product candidate, is an LNP formulation of Coxsackievirus A21 (CVA21) vRNA, which encodes an optimized strain of CVA21.
ONCR-021 demonstrated greater in vitro and in vivo oncolysis compared to previously described CVA21 Kuykendall strain.
IV administration of ONCR-021 vRNA resulted in rapid initiation of viral replication, oncolysis and potent anti-tumor efficacy driven by CVA21 amplification in situ after delivery to tumor cells.
Preclinical data support the potential clinical development of ONCR-021 in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma based on viral tropism.
Oncorus plans to submit an investigational new drug (IND) application for ONCR-021 with the U.S. Food and Drug Administration (FDA) in mid-2023.

In a poster titled, "Development of ONCR-788, a synthetic oncolytic virus based on Seneca Valley Virus for the treatment of neuroendocrine tumors," Oncorus highlighted:

ONCR-788, Oncorus’ second vRNA immunotherapy product candidate, encodes an optimized version of the Seneca Valley Virus (SVV).
Systemic IV administration of ONCR-788 led to potent anti-tumor efficacy, even in the presence of oncolytic virus neutralizing antibodies within the bloodstream.
vRNA delivery, viral replication, spread and lysis of tumor cells were observed after administration of ONCR-788.
Robust anti-tumor efficacy was observed across a diverse set of neuroendocrine tumor models, including tumor CDX and PDX xenografts, lung orthotopic and GEMM-derived models.
Enhanced T cell recruitment and activation, increased expression of PD-L1 on tumor cells and myeloid cells and M2 to M1 macrophage conversion were observed.
ONCR-788 in combination with an anti-PD1 resulted in improved anti-tumor activity as compared to ONCR-788 monotherapy.
Oncorus plans to submit an IND for ONCR-788 with the FDA following the IND submission for ONCR-021.

The posters presented at AACR (Free AACR Whitepaper) are available on the "Publications & Presentations" section of the Oncorus website at www.oncorus.com.

On April 8, 2022 OnKure, Inc., a clinical-stage biopharmaceutical company discovering and developing the next generation of oncology precision medicines, reported preclinical data demonstrating synergy between OKI-179, the Company’s oral Class I histone deacetylase (HDAC) inhibitor, and RAS pathway agents, including Pfizer’s MEK inhibitor, binimetinib, in RAS-mutated tumor models (Press release, OnKure, APR 8, 2022, View Source;utm_medium=rss&utm_campaign=onkure-therapeutics-announces-promising-preclinical-data-on-oki-179-in-ras-mutated-tumor-models-presented-in-a-late-breaking-session-at-aacr [SID1234611669]). The data will be disclosed in a late-breaking abstract during the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in New Orleans, Louisiana from April 8, 2022 to April 13, 2022.

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"The preclinical data highlighting our HDAC inhibitor’s synergy with RAS pathway agents are extremely promising, and based on the anti-tumor activity seen, strongly support the clinical development of this combination across multiple indications, including in cancer types less sensitive to RAS pathway inhibition alone," said Tony Piscopio, Ph.D., Co-Founder, President and Chief Executive Officer of OnKure. "OKI-179 has been designed to overcome the historic tolerability limitations of other HDAC inhibitors, supporting further development in rational combinations with other anti-cancer treatments. Since inhibition of the RAS pathway alone through MEK or BRAF inhibitors is often insufficient to drive tumor regression, it opens an opportunity for combination approaches with OKI-179, with the potential to establish this candidate as a backbone therapy for all RAS-mutated cancers."

The data, both in vitro and in vivo, showcase the potential of the synthetically lethal combination of OKI-179 and RAS pathway agents in treating RAS-mutated tumors. In cell-line derived xenograft models, OKI-179, binimetinib as a single agent, and binimetinib + encorafenib combination demonstrated tumor growth delay, but few regressions. OKI-179 combined with binimetinib in NRAS-mutated melanoma or combined with binimetinib + encorafenib in BRAF-mutated colorectal xenografts showed significantly increased regressions compared to either single agent following two weeks of dosing.

Jennifer Diamond, M.D., OnKure’s Chief Medical Officer said, "We plan to initiate the Nautilus trial, which will explore the combination of OKI-179 and binimetinib in advanced NRAS-mutated melanoma, and look forward to continuing to validate this synthetically lethal combination across cancer types in order to fully understand its potential as a therapeutic approach."

The poster presentation from the AACR (Free AACR Whitepaper) Annual Meeting is available on the "Publications" page of the Company’s website at View Source

About NRAS-Mutated Melanoma

Activating mutations in NRAS is the second most common oncogenic driver in melanoma, accounting for 20% of all melanomas. Tumors bearing NRAS mutations are more aggressive and are associated with poorer patient outcomes. Despite the prevalence of NRAS mutations and the severity of the resulting disease, treatment options for NRAS-mutated melanoma remain limited for patients who have disease progression following immune checkpoint inhibitor therapy, highlighting the significant unmet need.

About OKI-179

OKI-179 is a novel, oral Class I histone deacetylase (HDAC) inhibitor for the potential treatment of a wide range of solid and hematological malignancies. HDAC inhibitors have shown little activity in treating solid tumors, often due to poor tolerability, inappropriate dosing regimens, and a lack of stratifying biomarkers. OKI-179 is designed to have improved potency, selectivity, tolerability, as well as easy combinability to overcome the historic limitations of other HDAC inhibitors. This candidate has also shown a promising safety profile in advanced solid tumor patients, supporting potential combination studies in the future.