On October 25, 2024 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported preliminary safety and antitumor data for RMC-9805, its RAS(ON) G12D-selective inhibitor, in patients with previously treated pancreatic ductal adenocarcinoma (PDAC) (Press release, Revolution Medicines, OCT 25, 2024, View Source [SID1234647424]). These initial results were presented during the late-breaking oral session at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona on October 25, 2024.

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"We are pleased to report the first clinical data for RMC-9805, our novel, oral RAS(ON) G12D-selective covalent inhibitor, which demonstrate encouraging initial safety, tolerability and antitumor activity evidenced by tumor regressions," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "While preliminary, these data bolster our belief that RMC-9805 has the potential to play a role in an emerging treatment paradigm for patients living with pancreatic cancer, both as monotherapy and in combinations. With today’s presentation, RMC-9805 becomes the third tri-complex compound from the Revolution Medicines pipeline to demonstrate clinical proof-of-concept, and it reaffirms our commitment to bringing novel RAS(ON) inhibitors to patients with RAS-addicted cancers."

The RMC-9805-001 Phase 1/1b study is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-9805 in patients with advanced solid tumors harboring a KRAS G12D mutation. As of the September 2, 2024 data cutoff date, 179 patients were treated with escalating doses of RMC-9805 (ranging from 150-1200 mg once daily (QD) and 300-600 mg twice daily (BID)). Study patients had received a median of two prior therapies (range 0-9) and all had previously been treated with standard of care.

As of the data cutoff date, RMC-9805 demonstrated an encouraging safety profile and was generally well tolerated across dose levels. For patients receiving 1200 mg of RMC-9805 daily (n = 99), the most common treatment-related adverse events (TRAEs) occurring in greater than 10% of patients were GI-related toxicities (nausea, diarrhea and vomiting) and rash that were primarily Grade 1 in severity and typically of limited duration. One Grade 3 TRAE of ALT elevation was reported, and no Grade 4 or 5 TRAEs were observed. Four patients (4%) experienced TRAEs that led to dose reduction and no patients discontinued treatment as a result of TRAEs. No dose limiting toxicities were observed and the maximum tolerated dose was not reached.

Preliminary efficacy was assessed in PDAC patients. At a candidate recommended Phase 2 dose of 1200 mg daily (20 patients at 1200 mg QD and 20 patients at 600 mg BID), patients who received a first dose of RMC-9805 at least 14 weeks prior to the data cutoff date achieved a 30% (n = 12) objective response rate (confirmed or pending), with a disease control rate of 80% (n = 32).

"Pancreatic cancer is the most RAS-addicted of all major cancers and the G12D variant is the most common RAS mutation in pancreatic cancer. No approved targeted therapies are available for these patients, making this an area of significant unmet need," said David Hong, M.D. of MD Anderson Cancer Center, principal investigator and lead author for the RMC-9805-001 presentation. "This is a challenging disease, but we observed a promising level of antitumor activity at generally tolerable doses in this Phase 1 study."

Investor Webcast
Revolution Medicines will host an investor webcast on Friday, October 25, 2024 at 12:00 p.m. Eastern Time / 6:00 p.m. Central European Standard Time to discuss the RMC-6236 and RMC-9805 monotherapy data in PDAC presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) ("Triple") meeting. To participate in the live webcast, participants may register in advance here. A live webcast of the call will be available on the Investors section of Revolution Medicines’ website at View Source Following the live webcast, a replay will be available on the company’s website for at least 14 days.

About Pancreatic Cancer and Pancreatic Ductal Adenocarcinoma
Pancreatic cancer is one of the most lethal malignancies, characterized by its typically late-stage diagnosis, resistance to standard chemotherapy, and high mortality rate. In the U.S., recent estimates indicate that in 2024, approximately 60,000 people will be diagnosed with pancreatic cancer, and about 50,000 people will die from this aggressive disease.

The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) and its variants, accounts for approximately 92% of all pancreatic cancer cases. Due to the lack of early symptoms and detection methods, approximately 80% of patients are diagnosed with PDAC at an advanced or metastatic stage. It is the most RAS-addicted of all major cancers, and more than 90% of patients have tumors that harbor RAS mutations. Metastatic PDAC remains one of the most common causes of cancer-related deaths in the U.S., with a five-year survival rate of approximately 3%.

On October 25, 2024 Rakovina Therapeutics Inc. (TSX-V: RKV) ("Rakovina" or the "Company"), a biopharmaceutical company committed to advancing new cancer therapies based on novel DNA-damage response targeting technologies, reported the presentation of its research on novel small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes at the 36th EORTC-NCI-AARC Symposium in Barcelona, Spain, on October 25, 2024 (Press release, Rakovina Therapeutics, OCT 25, 2024, View Source;utm_medium=rss&utm_campaign=rakovina-therapeutics-to-present-research-highlighting-small-molecule-bifunctional-inhibitors-of-parp1-2-and-hdac-enzymes-at-the-36th-eortc-nci-aacr-symposium-in-barcelona-spain [SID1234647423]).

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Rakovina’s novel class of bifunctional small molecule compounds, known as the kt-3000 series, has demonstrated potent dual inhibition of PARP1/2 and HDAC enzymes in preclinical studies. Compared to single-function inhibitors such as olaparib (PARP) and vorinostat (HDAC), dual-function kt-3000 compounds demonstrate greater potency against both HR-deficient and proficient cancer cells.

Based on these results, the Company intends to explore formulations of the lead compound, kt-3283, to support potential advancement to human clinical trials, while continuing to further medicinal chemistry efforts that refine properties of the class.

"The kt-3000 series represents a significant advancement toward overcoming treatment resistance to first-generation PARP-inhibitors. These bifunctional PARP+HDAC inhibitors could enable us to effectively address resistance in various cancers while minimizing toxicity associated with traditional combination therapies," said Rakovina Therapeutics Executive Chairman Jeffrey Bacha.

"We are excited to present our findings at the symposium and to continue advancing these promising compounds toward clinical development," he added.

Presentation Details:

Title: Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes
Presentation Date: October 25, 2024
Abstract Number: 338

On October 25, 2024 Purple Biotech Ltd. ("Purple Biotech" or "the Company") (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class therapies that overcome tumor immune evasion and drug resistance, reported new data regarding its tri-specific antibody platform, CAPTN-3, which were presented at the 36th European Organization for Research and Treatment of Cancer, National Cancer Institute, American Association for Cancer Research (AACR) (Free AACR Whitepaper) (EORTC-NCI-AACR) (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics (the "Triple Meeting") on October 25, 2024 in Barcelona, Spain (Press release, Purple Biotech, OCT 25, 2024, View Source [SID1234647421]).

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"CAPTN-3 is a novel technology platform allowing Purple Biotech to develop a variety of new tri-specific antibodies to address different targets on tumors and different mechanisms to treat cancer patients. Our Investigational New Drug (IND) enabling work is aimed to reach first in human clinical studies with our lead candidate IM1240 potentially by 2026," said Gil Efron, Purple Biotech CEO. "Development of this differentiated platform allows us to potentially offer partners and patients additional antibodies to treat different cancer types."

CAPTN-3 is a novel platform technology of conditionally activated tri-specific antibodies engaging both T cells and NK cells to target cancers expressing Tumor Associated Antigen (TAA) (aCD3xaTAAxaNKG2A) to induce a strong and selective immune response against the tumor. The addition of the NK engager aims to enhances the tumor-killing activity, providing a key differentiation for more sustained and potent anti-tumor effects. The anti-NKG2A arm also acts as a checkpoint inhibitor enabling simultaneous NK and T-cell activation. This scaffold is designed to be activated only at the tumor microenvironment (TME) to improve the safety profile and extend the therapeutic index. The capped-aCD3 is cleaved by multiple TME-specific proteases, increasing the likelihood of activation by various tumor types. To further extend the capped tribody half-life, human serum albumin is included. CAPTN-3 leverages a plug and play scaffold system providing a flexible design to easily swap and integrate various antibodies to target a wide range of diseases.

The platform’s lead compound IM1240 (aCD3xa5T4xaNKG2A) targets 5T4, a TAA expressed in a variety of solid tumors and which is correlated with advanced disease, increased invasiveness, and poor clinical outcome.

On October 25, 2024 PTC Therapeutics, Inc. (NASDAQ: PTCT) reported that on Oct. 23, 2024, the company approved non-statutory stock options to purchase an aggregate of 13,690 shares of its common stock and 20,250 restricted stock units ("RSUs"), each representing the right to receive one share of its common stock upon vesting, to nineteen new employees (Press release, PTC Therapeutics, OCT 25, 2024, View Source [SID1234647420]). The awards were made pursuant to the Nasdaq inducement grant exception as a component of the new hires’ employment compensation.

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The inducement grants were approved by PTC’s Compensation Committee on Oct. 23, 2024, and are being made as an inducement material to each employee’s acceptance of employment with the company in accordance with Nasdaq Listing Rule 5635(c)(4).

All stock option awards have an exercise price of $42.48 per share, the closing price of PTC’s common stock on Oct. 23, 2024, the immediately preceding trading day. The stock options each have a 10-year term and vest over four years, with 25% of the original number of shares vesting on the first anniversary of the applicable employee’s new hire date and 6.25% of the original number of shares vesting at the end of each subsequent three-month period thereafter until fully vested, subject to the employee’s continued service with the company through the applicable vesting dates. The RSUs each will vest over four years with 25% of the original number of shares vesting on each annual anniversary of the applicable employee’s new hire date until fully vested, subject to the employee’s continued service with the company through the applicable vesting dates.

On October 25, 2024 IDEAYA Biosciences, Inc. (the "Company") reported clinical data from the Company’s Phase 1 expansion dose of IDE397 in patients with methylthioadenosine phosphorylase ("MTAP")-deletion urothelial cancer and non-small cell lung cancer ("NSCLC") in a late breaker abstract oral presentation at the 36th edition of the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium ("ENA 2024") in Barcelona, Spain (Press release, Ideaya Biosciences, OCT 25, 2024, View Source [SID1234647418]). The Company had additional poster presentations at ENA 2024 that highlighted preclinical data for the methionine adenosyltransferase 2 alpha ("MAT2A") and poly (ADP-ribose) glycohydrolase programs. IDE397 is the Company’s potent and selective potential first-in-class MAT2A inhibitor in Phase 2 clinical trials for the treatment of MTAP-deletion solid tumors.

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The interim Phase 1 expansion data for IDE397 in MTAP-deletion urothelial cancer and NSCLC demonstrated preliminary clinical efficacy and a favorable safety profile. The reported Phase 1 clinical data are based on 27 evaluable patients at the expansion dose of 30 mg once-a-day ("QD") of IDE397. The heavily pre-treated MTAP-deletion urothelial cancer and NSCLC patients, including ten urothelial cancer patients, nine adenocarcinoma NSCLC patients and eight squamous NSCLC patients, had a median of two to three prior lines of therapy, ranging from one to seven prior lines of treatment. Reported clinical efficacy and tolerability data are preliminary and based on investigator review from an unlocked database as of the data analysis cutoff date of August 22, 2024.

The Company reported an overall response rate of approximately 33% (one complete response and eight partial responses by RECIST 1.1 evaluation). Nine out of the nine responses have been confirmed, including four urothelial cancer patients (of which one was a complete response), three squamous NSCLC patients and two adenocarcinoma NSCLC patients. Two patients were confirmed after the data cutoff date. The Company also reported overall response rate by RECIST 1.1 evaluation by solid tumor type. For MTAP-deletion urothelial cancer patients, the confirmed overall response rate was 40%, or 4 out of 10 patients, for MTAP-deletion squamous NSCLC patients, the confirmed overall response rate was approximately 38%, or 3 out of 8 patients, and for MTAP-deletion adenocarcinoma NSCLC patients, the confirmed overall response rate was approximately 22%, or 2 out of 9 patients. As the Company previously disclosed in its Current Report on Form 8-K filed with the Securities and Exchange Commission on July 8, 2024, five confirmed responses were reported out of the 18 evaluable patients enrolled in the IDE397 Phase 2 monotherapy study. Further, there were zero non-evaluable patients reported as of the data analysis.

Additionally, multiple confirmed partial responses by RECIST 1.1 evaluation harbored genetic co-alterations, including MTAP-deletion and FGFR-TACC3 fusion in urothelial cancer patients and MTAP-deletion and KRAS G12D mutation in NSCLC patients.

The Company also observed a disease control rate of 93%, including one complete response, eight partial responses and 16 stable disease by RECIST 1.1 evaluation, reflecting 25 of 27 evaluable patients with stable disease or better. Of the 27 evaluable patients, 15 are still on treatment and seven of the nine responses by RECIST 1.1 evaluation responses remain on treatment. The median duration of treatment has not been reached and is greater than 6.2 months. The median time to response is approximately 2.7 months. The median duration of response and median progression free survival data is still immature. Three urothelial cancer patients have been on treatment greater than 250 days, four squamous NSCLC patients on treatment greater than 200 days, and three adenocarcinoma NSCLC patients on treatment greater than 200 days.

The Company also reported a ctDNA molecular response ("MR") rate of approximately 81%, representing 17 of 21 reportable patients with 50% or greater ctDNA reduction and approximately 33%, representing 7 of 21 reportable patients, with a deep 90% or greater ctDNA reduction (several quality control failures of patient samples precluded the other patients from MR analysis). All 17 MRs were rapid occurring at the first ctDNA sample analysis.

The interim Phase 1 expansion data for IDE397 in MTAP-deletion urothelial cancer and NSCLC demonstrated a favorable adverse event ("AE") profile at the 30 mg QD expansion dose. Approximately 18% of patients experienced a Grade 3 or higher drug-related AE at the 30 mg QD expansion dose and no drug-related serious adverse events were observed. The Company observed no drug-related AEs leading to discontinuations. The Company anticipates that the favorable AE profile and dosing convenience of a 30 mg QD tablet has the potential to enable long-term dosing and combination development, including with MTA-cooperative PRMT5 inhibitors and topoisomerase payload antibody drug conjugates.

Additionally, the Company reported the first preliminary clinical case study of the IDE397 and Trodelvy (sacituzumab govitecan-hziy), Gilead’s Trop-2 directed antibody-drug conjugate, combination in MTAP-deletion urothelial cancer patients. The Company reported a partial response by RECIST 1.1 evaluation in a patient case report with a genetic co-alteration of MTAP-deletion and a FGFR3-TACC3 fusion, and rapid and deep first-evaluation molecular responses with ctDNA reduction of greater than 95% observed, that will be presented at ENA 2024. The Company is targeting to initiate the IDE397 and Trodelvy Phase 1/2 combination expansion in MTAP-deletion urothelial cancer in Q4 2024.

There are currently no FDA-approved therapies for patients with MTAP-deletion solid tumors, highlighting the unmet medical need. The priority MTAP-deletion solid tumor types for the IDE397 Phase 1/2 monotherapy program are urothelial cancer and NSCLC. MTAP-deletion prevalence has been reported at over 15% in NSCLC and over 25% in urothelial cancer, based on The Cancer Genome Atlas ("TCGA") database. The Company estimates that the MTAP-deletion annual incidence in the U.S. in NSCLC and urothelial cancer is approximately 48,000 patients, based on the 2024 Surveillance, Epidemiology, and End Results database. In addition, there are several potential expansion MTAP-deletion solid tumor types that are also being considered for monotherapy and combination development, including pancreatic, head and neck, gastric, and squamous esophageal cancer, among others. Based on the TCGA database, MTAP-deletion prevalence in pancreatic, head and neck, gastric, and squamous esophageal cancer represents an aggregate U.S. annual incidence of approximately 27,000 patients.

The Company has activated over 35 clinical trial sites globally in the U.S., Canada, Europe, and Asia Pacific to enable potential rapid enrollment for the IDE397 Phase 2 monotherapy expansion in MTAP-deletion lung and bladder cancer in its ongoing trial (NCT04794699). There is also an ongoing Amgen-sponsored Phase 1/2 trial of IDE397 and AMG 193 combination in MTAP-Deletion NSCLC (NCT05975073). The Company published at ENA 2024 preclinical combination efficacy data and the combination mechanistic rationale for IDE397 with clinical stage PRMT5 inhibitors, including BMS-986504 and AMG 193.

Next, the Company is enrolling a Phase 1 clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of IDE397 in combination with Trodelvy in MTAP-deletion urothelial cancer patients (NCT04794699). Pursuant to the Clinical Trial Collaboration and Supply Agreement dated November 29, 2023, the Company and Gilead retain the commercial rights to their respective compounds, including with respect to use as a monotherapy or combination agent. The Company is the study sponsor and Gilead will provide the supply of Trodelvy. IDE397 monotherapy or in combination with Trodelvy has not been approved by any regulatory agency, and the efficacy and safety of this combination has not been established.