On April 10, 2021 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a late-stage targeted oncology company, reported initial preclinical results evaluating its investigational synthetic lethal PRMT5 inhibitor in methylthioadenosine phosphorylase (MTAP)-deleted cancer models (Press release, Mirati, APR 10, 2021, View Source [SID1234577848]). Mirati’s internally discovered PRMT5 compound is the first to specifically target the PRMT5/methylthioadenosine (MTA) complex. This approach is designed to leverage elevated levels of MTA in cancers exhibiting an MTAP deletion and to selectively kill cancer cells harboring this genetic alteration. The results were presented today during a late-breaking minisymposium at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting [Abstract # LB003].

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Preclinical results showed that the Mirati PRMT5 compound bound selectively to the PRMT5/MTA complex and demonstrated a greater than 100-fold selectivity for MTAP-deleted cells compared with cells that do not exhibit this genetic defect in both proliferation and mechanistic assays. This selectivity for the PRMT5/MTA complex and MTAP-deleted cancer cells allows for the selective targeting of cancer cells while sparing healthy cells, which are also dependent on PRMT5 for cell growth and survival. In addition, treatment of MTAP-deleted tumor xenograft-bearing mice with the Mirati PRMT5 compound resulted in halted tumor growth and near complete reduction of symmetric dimethylarginine (SDMA), a biomarker of PRMT5 activity, at well-tolerated dose levels.

"We are proud to have a potential first-in-class therapeutic agent to specifically target the PRMT5/MTA complex in MTAP-deleted cancer cells," said James Christensen, Ph.D., executive vice president and chief scientific officer, Mirati Therapeutics, Inc. "Based on discoveries made by Mirati scientists, we have designed a novel approach to specifically bind to and inhibit PRMT5 in complex with MTA. With this approach, we are able to target MTAP-deleted tumors, which should result in an improved therapeutic index relative to known PRMT5 and MAT2A inhibitors."

About PRMT5 Inhibition in MTAP-deleted Cancers

PRMT5 is an enzyme critical to the survival of both healthy and cancer cells and is partially inhibited by MTA, which accumulates in MTAP-deleted cancers. The MTAP deletion is present in approximately 10 percent of all cancers and is the most frequently observed gene deletion event (MTAP/CDKN2A) across several cancer types. Cancers with an MTAP deletion, such as pancreatic, lung, and bladder cancers, are associated with a poor prognosis, representing a significant unmet medical need.

Activated PRMT5 is crucial for the regulation of cellular processes essential for cell survival, including regulation of RNA splicing, gene expression and protein translation. In MTAP-deleted cancer cells, the inhibitory cofactor MTA accumulates and binds to PRMT5. Mirati’s PRMT5 compound selectively targets the PRMT5/MTA complex in MTAP-deleted cancer cells while sparing healthy cells. The Mirati PRMT5 compound is advancing toward an Investigational New Drug (IND) filing in the first half of 2022.

On April 10, 2021 iTeos Therapeutics, Inc. (Nasdaq: ITOS), clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of highly differentiated immuno-oncology therapeutics for patients, reported a presentation featuring preliminary clinical data from 22 adult patients in the ongoing Phase 1/2a trial of its anti-TIGIT antibody, EOS-448, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, taking place virtually April 10-15 (Press release, iTeos Therapeutics, APR 10, 2021, View Source [SID1234577846]). The presentation highlights initial findings from the completed dose escalation monotherapy portion of the trial, indicating a favorable tolerability profile and early signs of clinical activity in advanced cancers.

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"We are pleased to share these data showing promising preliminary signs of clinical activity and a favorable tolerability profile with our anti-TIGIT antibody, EOS-448, in patients with advanced cancers," said Joanne Jenkins Lager, M.D., chief medical officer of iTeos Therapeutics. "The results support our excitement around TIGIT as a therapeutic target capable of harnessing the immune system to treat patients with advanced, difficult to treat cancers. We believe the depletion of TIGIT+ suppressive and exhausted cells shown at even the lowest tested dose provides evidence of engagement of the FcγR, and therefore the potential of EOS-448 to activate multiple immune mechanisms. Based on these encouraging results, we are enrolling a total of 40 patients in this study to evaluate the effects of EOS-448 within the tumor. We are advancing EOS-448 into the next stage of clinical development as both a monotherapy and in combination for the treatment of multiple indications, with the goal of improving outcomes for people with advanced cancers."

Summary of the Data Presented

The objective of the dose escalation portion of the ongoing EOS-448 trial, presented at AACR (Free AACR Whitepaper), is to evaluate primary objectives of safety and tolerability, and secondary objectives of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of EOS-448 as a monotherapy in patients with advanced solid tumor cancers. As of the data cut-off (December 31, 2020), the trial had enrolled 22 advanced cancer patients with solid tumors for whom no standard treatment was available. The patients received EOS-448 intravenously (IV) once every two weeks (Q2W) or once every four weeks (Q4W) according to their dose and schedule allocation. Doses of 20, 70, 200, 700 mg Q2W and 1400 mg Q4W were evaluated. Since the data cut-off for the AACR (Free AACR Whitepaper) poster, as of March 9, 2021, an additional 11 patients have received single agent EOS-448. In addition to the five dose levels which were described at AACR (Free AACR Whitepaper), patients have also received doses of 400mg Q4w and 700mg Q4w.

EOS-448 was generally well-tolerated at all tested doses in patients with advanced cancer. Preliminary evidence of clinical activity as a monotherapy, including a confirmed partial response in one pembrolizumab-refractory melanoma patient and disease stabilization in nine patients, was also observed. The most common treatment related adverse events were itching, infusion-related reactions, fatigue, rash and fever, and one treatment related serious adverse event, a grade 2 systemic inflammatory response, was observed. As of March 9, 2020, two additional treatment-related serious events have been reported: Grade 2 Systemic Inflammatory Response and Grade 3 infusion-related reaction.

PK assessments indicated a linear and dose-proportional response and PD assessments showed complete target engagement. Biomarker analyses showed evidence of FcγR engagement, as demonstrated by a reduction in suppressive immune cells and immune cells considered to be exhausted in the blood, including TIGIT+ regulatory T cells (Tregs) and TIGIT+ CD8 T cells, with only a slight reduction in the total CD8+ T cell count. A shift towards a more functional immune response was observed, with a two-fold increase in the ratio of CD8+ T cells to Treg and a four-fold increase in the ratio of CD8+ TIGIT- T cells to CD8+ TIGIT+ T cells.

"I am highly encouraged by these initial results from the EOS-448 trial, particularly the clinically meaningful response to treatment in the pembrolizumab-refractory melanoma patient," said Mario Sznol, M.D., professor of medicine and leader, Melanoma/RCC Disease-Associated Research Team, at Yale University. "The treatment of patients who develop resistance to checkpoint inhibitors is challenging in a number of tumor types, and these data give us hope that EOS-448 could provide benefit in adult solid tumor patients who don’t respond to or who progress on current checkpoint inhibitors."

The e-poster and abstract can be accessed on the AACR (Free AACR Whitepaper) conference website. The abstract and presentation details are as follows:

Title: Preliminary data from Phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancer
Session: Phase I Clinical Trials
Poster #: CT118
Authors: Tom Van den Mooter, et al.

The Company will host a conference call and webcast to provide an overview of the data on Monday, April 12 at 8:00 a.m. EDT. Details are as follows:

Participant Dial-In: (833) 607-1661
International Dial-In: (914) 987-7874
Conference ID: 2888301
Webcast: View Source

The abstract was posted online at 12:01 a.m. EDT on Friday, April 9 and the e-poster launched at 8:30 a.m. EDT on Saturday, April 10 on the AACR (Free AACR Whitepaper) conference website.

EOS-448 Further Clinical Development Plans
Based on these preliminary results, the Company plans to advance EOS-448 using combination trials in both checkpoint-naïve and resistant patients. These Phase 1b trials will assess the safety of EOS-448 in combination with pembrolizumab and in combination with iTeos novel agent inupadenant in patients with solid tumors, and as a monotherapy and in combination with an Immunomodulatory Drug (IMiD) in patients with multiple myeloma. Subsequent disease-specific Phase 2a trials are planned in patients with non-small cell lung cancer, head and neck cancer, melanoma, and myeloma. The Company is also planning for later-stage trials of EOS-448, including in combination with pembrolizumab.

On April 10, 2021 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing onvansertib to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, pancreatic cancer, and castrate-resistant prostate cancer, reported observations from its Expanded Access Program (EAP) of onvansertib in KRAS-mutated metastatic colorectal cancer (mCRC), featured in a virtual oral poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Cardiff Oncology, APR 10, 2021, View Source [SID1234577845]).

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Cardiff Oncology’s EAP has enrolled participants who failed or progressed on multiple lines of standard-of-care treatment and uses the same combination regimen (onvansertib 15 mg/m2 + FOLFIRI/bevacizumab) and dosing schedule as the Company’s ongoing Phase 1b/2 mCRC clinical trial. The median progression free survival (mPFS) of evaluable participants in the EAP is 5.6 months to-date, which represents an increase over the 2-3 months mPFS of historical controls1. 62.5% of participants had a greater than 50% decrease in KRAS MAF after one cycle of treatment and continue to show a durable response, having not yet reached the mPFS. Onvansertib has been well tolerated with no serious adverse events (SAEs) reported as of the AACR (Free AACR Whitepaper) cutoff date.

"The mPFS observed thus far is significantly better than what is expected and shows promise for improving overall prognosis in this patient population," said Dr. Manish R. Sharma, associate director of clinical research at START Midwest. "The Expanded Access Program has provided access to onvansertib for mCRC patients who are heavily pretreated and thus do not meet the stringent second line eligibility criteria for enrollment in Cardiff Oncology’s ongoing Phase 2 clinical trial."

Dr. Mark Erlander, chief executive officer of Cardiff Oncology added, "We are very pleased to provide access to onvansertib for mCRC patients with the greatest need for a new treatment option. It’s particularly gratifying to see many EAP participants benefit clinically from the addition of onvansertib to standard-of-care and improve from having progressive to stable disease or better."

Highlights from the AACR (Free AACR Whitepaper) presentation include:

Baseline Characteristics of Evaluable Patients (n = 20):

Evaluable participants received a median of 3 prior lines of therapy (range: 1-6)
15 of 20 (75%) evaluable participants received an irinotecan-based regimen as their last therapy prior to enrolling in the EAP
13 of 20 (65%) evaluable participants were progressing prior to enrolling in the EAP
Clinical Benefit:

Evaluable participants had a mPFS of 5.6 months (95% confidence interval: 2.7 months – median PFS not reached)
11 of 20 of participants evaluable for clinical benefit remain on treatment as of the AACR (Free AACR Whitepaper) cutoff date
Biomarker:

16 of 20 (80%) evaluable participants had a KRAS variant detected by droplet digital PCR (ddPCR) before beginning onvansertib treatment in the EAP
Participants with a greater than 50% decrease in KRAS MAF (n=10) after one treatment cycle had a significant increase in PFS (mPFS not reached) compared to participants who had a decrease in KRAS MAF of less than 50% (n = 6; mPFS of 2.6 months)
Tolerability:

Onvansertib in combination with FOLFIRI/bevacizumab has been well tolerated with no SAEs reported in participants as of the AACR (Free AACR Whitepaper) cutoff date
The virtual poster, "Expanded access program of the PLK1 inhibitor onvansertib for treatment of patients with KRAS-mutant metastatic colorectal cancer" is available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 e-poster website and is also posted on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

References

Bekaii-Saab et al., Clin. Colorectal Cancer, 2019
About the EAP for Onvansertib in KRAS-mutated mCRC

Sometimes called "compassionate use", expanded access is a potential pathway for a patient with a serious or life-threatening disease to gain access to an investigational drug for treatment outside of a clinical trial, particularly when no comparable or satisfactory alternative therapy options are available. The Cardiff Oncology EAP in KRAS-mutated mCRC is using the same combination treatment regimen (onvansertib 15 mg/m2 + FOLFIRI and bevacizumab) and dosing schedule as the ongoing Phase 1b/2 clinical trial and is intended for patients that have progressed on prior therapy and do not meet the second line eligibility criteria for enrollment in the clinical trial. The program has reached capacity and is no longer open to enrollment.

On April 10, 2021 Kezar Life Sciences, Inc. (Nasdaq), a clinical-stage biotechnology company discovering and developing breakthrough treatments for immune-mediated and oncologic disorders, reported preclinical data on the company’s novel protein secretion program during two poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Virtual Annual Meeting (Press release, Kezar Life Sciences, APR 10, 2021, View Source [SID1234577844]).

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"The growing body of evidence generated by our team supports the strong therapeutic potential of inhibiting Sec61 and the protein secretion pathway as a way to generate novel therapies to treat multiple tumor indications," said Christopher Kirk, PhD, Kezar’s President and Chief Scientific Officer. "These data provide a robust scientific framework for identifying which tumor types might be the most sensitive to inhibition of the Sec61 translocon and the protein secretion pathway."

Kezar examined the activity of KZR-261, a small molecule inhibitor of the Sec 61 translocon, and a closely related representative molecule in hundreds of tumor cell lines. The objective was to compare drug activity and identify sensitivity to gene mutations and impact on gene expression levels. No single gene predicted the activity of KZR-261, consistent with the known impact of KZR-261 on multiple targets. However, representative gene modules identified through mechanism agnostic analysis were associated with sensitivity in tumor cells and show high overlap with key processes involved in protein secretion. Analyses of primary tumor and tissue expression datasets predict that many tumor types will be more sensitive than normal tissues and cells. Data from these analyses will inform selection of tumor types for study in future clinical trials.

Global proteomic profiling of protein secretion in tumor cells and non-transformed cells was also conducted. KZR-261 and the related molecules reduce expression of Sec61 clients, namely secreted and transmembrane proteins. In tumor cells, these compounds reduced expression of approximately 10% of Sec61 clients by at least two-fold. However, in non-transformed cells, KZR-261 inhibited the expression of less than 5% of measured Sec61 clients, many of which can be measured from clinical samples in future clinical trials.

Pending successful completion of drug product manufacturing, submission of an Investigational New Drug (IND) application is anticipated in mid-2021. A first-in-human Phase 1 study to evaluate the safety and anti-tumor activity of KZR-261 in patients with solid tumors is expected to commence shortly thereafter.

Details on Kezar’s poster presentations at AACR (Free AACR Whitepaper) are as follows:

Title: Prioritizing tumor types for clinical study of novel Sec61 inhibitors by searching for expression profiles of sensitive cell lines in tumor sample databases
Presenter/s: Eric Lowe, R. Andrea Fan, Henry W. B. Johnson, Christopher J. Kirk, Dustin McMinn, Yu Qian, Brian Tuch
Session: Genomic Profiling of Tumors – Abstract #2226
Date and time: Available on demand [8:30AM ET, Saturday, April 10, 2021]

Title: Quantitative proteomic profiling of novel anti-cancer small molecule inhibitors of Sec61: Mechanistic investigation and biomarker discovery
Presenter/s: Yu Qian, Jennifer Whang, Janet Anderl, Andrea Fan, Henry W. B. Johnson, Christopher J. Kirk, Eric Lowe, Dustin McMinn, Beatriz Millare, Tony Muchamuel and Jinhai Wang; Kezar Life Sciences
Session: Proteomics and Biomarker Discovery – Abstract #2816
Date and time: Available on demand [8:30AM ET, Saturday, April 10, 2021]

The posters are available in the "Our Science" section of kezarlifesciences.com.

About KZR-261

KZR-261, a novel, first-in-class protein secretion inhibitor, is the first clinical candidate to be nominated from Kezar’s research and discovery efforts targeting protein secretion pathways. KZR-261 is a broad-spectrum anti-tumor agent that acts through direct interaction and inhibition of Sec61 activity. The compound was discovered by Kezar through a robust medicinal chemistry campaign in which several scaffolds were progressed through the company’s proprietary platform evaluating Sec61 modulation. As a result, Kezar has established a broad library of protein secretion inhibitors. KZR-261 has demonstrated several encouraging properties that lead to its potential to be an anti-cancer agent for the treatment of solid and hematologic malignancies. An IND submission in solid tumors is expected to be filed in mid-2021.

On April 10, 2021 Elevation Oncology, a clinical stage biopharmaceutical company focused on the development of precision medicines for patients with genomically defined cancers, reported the presentation by its collaborators in the Marc Ladanyi lab at Memorial Sloan Kettering (MSK) of further preclinical data on the specific inhibition of NRG1 fusion-induced tumorigenesis and signaling by seribantumab, a HER3 monoclonal antibody, at the American Association of Cancer Research Virtual Annual Meeting 2021 (Press release, Elevation Oncology, APR 10, 2021, View Source [SID1234577841]). These data (Odintsov et al., 2021) in patient-derived xenograft (PDX) models of NRG1 fusion-positive pancreatic and cholangiocarcinoma build on earlier studies generated in lung and ovarian NRG1 fusion PDX models, recently published in Clinical Cancer Research, and further support the mechanistic rationale for the Phase 2 CRESTONE study for patients with solid tumors of any origin harboring an NRG1 gene fusion. The CRESTONE study is currently enrolling at sites across the United States.

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"Here we observed that NRG1 fusions activated HER3 and downstream signaling mediators such as AKT in a pancreatic cell line," said Igor Odintsov, MD, Research Fellow at MSK and lead author of the poster presentation. "Treatment with seribantumab was able to inhibit phosphorylation of the activated HER3 and AKT in the same cell line, and subsequent treatment of an APP-NRG1 fusion-positive pancreatic PDX model with seribantumab robustly inhibited tumor growth at clinically achievable doses."

Regressions were observed in all mice treated with 10 mg/kg BIW seribantumab, equivalent to a clinical dose of 2.6 g seribantumab in humans by allometric scaling. As in prior analysis in lung and ovarian NRG1 fusion PDX models, the pan-ERBB inhibitor afatinib was used as an active control in this pancreatic PDX model. No regression was observed in pancreatic PDX tumors treated with afatinib at 5 mg/kg QD.

NRG1 fusions have been identified in a variety of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, cholangiocarcinomas, and sarcomas. Current data suggest that NRG1 fusions are predominantly mutually exclusive with other known driver alterations and are therefore considered to be the primary driver of the tumor’s growth and proliferation.

"The rarity of competing oncogenic drivers in tumors driven by an NRG1 fusion presents a strong biological rationale for use of a targeted anti-HER3 monotherapy approach across tumor types. This approach is reflected in the design of our Phase 2 CRESTONE study as a tumor-agnostic study of monotherapy seribantumab with pre-defined exclusion of patients whose tumors harbor multiple actionable driver alterations," said Shawn M. Leland, PharmD, RPh, Founder and Chief Executive Officer of Elevation Oncology. "In rare instances when multiple actionable driver alterations are identified in the same tumor, we believe there may be a similar biological rationale for addressing each driver alteration through combinations of agents targeted to each individual alteration, rather than the traditional combinations with chemotherapy. We are excited to report early results from preclinical exploration of this hypothesis, and look forward to continued investigation of new treatment paradigms informed by comprehensive genomic profiling of tumors."

"We utilized an RBPMS-NRG1 fusion cholangiocarcinoma PDX model that also contained mutations in both ERBB4 and IDH1," continued Dr. Odintsov. "While treatment with monotherapy seribantumab or afatinib in this model produced mixed results, by applying a triple combination of seribantumab with afatinib to target the entire ERBB family, and AG-120 to target the IDH1 mutation, we were able to achieve regressions in the majority of tumors. This suggests that tumors harboring multiple oncogenic drivers may benefit from combination therapy that addresses the contribution of each genomic alteration in disease progression."

In totality, the data reported support the use of monotherapy seribantumab to treat GI and other cancers that are uniquely driven by an NRG1 fusion in the ongoing Phase 2 CRESTONE study. Patients and physicians can learn more about the CRESTONE study at www.NRG1fusion.com or on www.ClinicalTrials.gov under the NCT number NCT04383210.