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 SQZ Biotechnologies (NYSE: SQZ), a cell therapy company developing novel treatments for multiple therapeutic areas, reported preclinical data from its next generation SQZ APCs, enhanced APCs or eAPCs, and the potentially broader applicability of the platform at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting (Press release, SQZ Biotech, APR 10, 2021, View Source [SID1234577860]).

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"One of the advantages of the Cell Squeeze technology is the ability to simultaneously engineer multiple functions in cells, the underpinning of our SQZ eAPC program. With this next generation program, we are aiming to achieve the benefits of combination therapies that can drive powerful immune responses within a single multiplexed cell therapy," said Howard Bernstein, MD, PhD, chief scientific officer of SQZ. "Our vision is to incorporate additional functionality and new antigens to the foundation we are establishing with our lead SQZ APC program. The eAPC and KRAS data presented at AACR (Free AACR Whitepaper) provide preclinical examples of how we could potentially extend our impact across indications and help more patients."

SQZ eAPCs build on the power of the SQZ APC platform, which is focused on producing robust and specific CD8 T cell activation through efficient MHC-I antigen presentation. By delivering multiple mRNA into cells in a single squeeze, SQZ eAPCs are designed to further enhance T cell stimulation and boost immune-signaling that would otherwise require combinations with additional immune-oncology agents. In addition, the mRNA-based cargo facilitates presentation of a broader range of tumor epitopes, which could expand the addressable HPV+ patient population. The eAPC platform offers the opportunity for application across oncology and infectious diseases.

Highlights from the SQZ eAPC preclinical data shared at AACR (Free AACR Whitepaper) (Posters 1525 and 2626) include:

Enhancement of the quality and quantity of CD8 T cell activation by SQZ eAPCs through incorporation of CD86, membrane bound IL-2 (mbIL-2), and membrane bound IL-12 (mbIL-12), leveraging multiplexed delivery of mRNAs encoding each component
mbIL-2 and mbIL-12 mRNA delivery via Cell Squeeze led to surface expression of the cytokines in all measured human PBMC subsets (B cells, T cells, NK cells, and monocytes) and resulted in functional IL-2 and IL-12 signaling
CD86, mbIL-2, and mbIL-12 mRNA delivered alone or in combination increased antigen-specific CD8 T cell responses as much as ten-fold
Multiplexing CMVpp65 and influenza M1 mRNA antigens with signal 2/3 mRNAs enhanced the potency of SQZ APCs – inducing stronger antigen-specific CD8 T cell responses for infectious disease
Co-squeezing E6 and E7 mRNAs drove antigen-specific CD8 T cell activation regardless of HLA haplotype, which could significantly broaden the addressable HPV+ patient population and potentially eliminate the need for HLA screening
Cell Squeeze mRNA delivery stimulated memory CD8 T cells across various antigens and HLA haplotypes
SQZ is leveraging the cargo flexibility of its Cell Squeeze technology to pursue additional tumor targets. SQZ APCs have demonstrated the ability to elicit specific KRAS G12D and G12V CD8+ T cell responses in both animal models and in human cells.

Highlights from the SQZ-APC-KRAS preclinical data shared at AACR (Free AACR Whitepaper) (Poster 1524) include:

SQZ APCs engineered with KRas G12D and G12V peptides, both alone and multiplexed, generated specific and robust CD8 T cell responses against the target mutations
KRAS G12D and G12V make up over half of all KRAS mutations, with approximately 100,000 patients per year having KRAS G12D or G12V mutated cancers in the United States

On April 10, 2021 Nuvalent, Inc., a biotechnology company creating precisely targeted therapies for clinically proven kinase targets in cancer, reported preclinical data supporting advancement of its parallel lead programs in non-small cell lung cancer (NSCLC), including NUV-520 – a potential best-in-class ROS1-selective inhibitor – and NUV-655 – an ALK-selective inhibitor (Press release, Nuvalent, APR 10, 2021, View Source [SID1234577876]). Data are being presented at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting from April 10-15 in two separate poster presentations. Posters will be archived on the Nuvalent website at www.nuvalent.com.

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In addition, Nuvalent announces the appointment of leading medical oncologist Alexander Drilon, M.D., to its Scientific Advisory Board (SAB). Dr. Drilon currently serves as Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK) and brings deep expertise in early-phase clinical trials for cancer. At MSK, his research focuses on the development of novel therapeutics for cancer patients who have developed drug-resistance mutations.

"Our parallel lead compounds NUV-520 and NUV-655 were designed to meet a precise set of patient needs identified through close partnership with leading physician-scientists and advisors. We are pleased to share the data leading to the selection of these drug candidates for advancement towards clinical studies based on their demonstrated preclinical ability to meet the identified needs of selectivity, brain penetrance, and activity against drug-resistance mutations in ROS1-and ALK-driven tumors," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "We are also excited to welcome Dr. Alexander Drilon to our Scientific Advisory Board as part of this ongoing partnership with leading physician-scientists to understand the limitations of existing cancer therapies, with the goal of developing precisely targeted therapies to treat cancer."

NUV-520 and NUV-655 are designed to specifically solve for the dual challenges of kinase resistance and selectivity commonly seen with other kinase inhibitors approved for the treatment of advanced NSCLC. NUV-520 selectively inhibits ROS1 compared to the structurally related tropomyosin receptor kinase (TRK) with the potential to minimize TRK-related central nervous system (CNS) adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients with ROS1-mutant variants. NUV-655 is designed to inhibit ALK fusions and remain active in tumors that have developed resistance to first-, second­–, and third-generation ALK inhibitors.

In addition to selective ROS1 and ALK inhibition, Nuvalent is exploring a robust pipeline of programs with a focus on addressing the limitations of existing therapies for other clinically proven kinase targets in oncology.

"I am both encouraged by the treatment opportunities that targeted kinase inhibitors have enabled for patients and inspired to continue pursuing the development of additional therapy options that can overcome remaining clinical challenges," said Dr. Drilon. "Drug-resistant mutations and off-target adverse events can limit the therapeutic impact of kinase inhibitors across various targets in NSCLC as well as other tumor types. I look forward to working with Nuvalent to inform clinical development and advance its novel discovery pipeline of precisely targeted therapies designed specifically to meet these challenges."

AACR 2021 Presentation Overview:

Title: NUV-520 is a brain-penetrant and highly selective ROS1 inhibitor with antitumor activity against the G2032R solvent front mutation
Authors: Henry E. Pelish*, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan
Poster Number: 1465
Session Title: PO.ET06.07 Tyrosine Kinase and Phosphatase Inhibitors
Date: April 10, 2021, 8:30 a.m. – 11:59 p.m.

Summary:

NUV-520 is a potent, highly selective, and brain-penetrant ROS1 inhibitor as demonstrated by in vitro and in vivo studies.
NUV-520 has broad activity against ROS1 resistance mutations, including G2032R, and multiple ROS1 fusions.
NUV-520 is highly selective for ROS1 and ROS1 G2032R over TRKB, indicating the potential to minimize TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients with ROS1 mutations.
Title: NUV-655 is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation
Authors: Henry E. Pelish*, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan
Poster Number: 1468
Session Title: PO.ET06.07 Tyrosine Kinase and Phosphatase Inhibitors
Date: April 10, 2021, 8:30 a.m. – 11:59 p.m.

Summary:

NUV-655 is a potent, selective, and brain-penetrant ALK inhibitor as demonstrated by in vitro and in vivo studies.
NUV-655 is active against G1202R+ mutations including compound mutations G1202R/L1196M, G1202R/G1269A, and G1202R/L1198F, which confer resistance to all approved ALK therapies.
NUV-655 is selective for ALK and ALK G1202R+ mutations over TRKB, indicating the potential to minimize TRK-related CNS adverse events and drive more durable responses for patients.

On April 10, 2021 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported new in vivo data showing intratumoral (IT) treatment with the murine PD-1 targeting INTASYL (mPH-762) inhibits tumor growth in a dose dependent fashion in PD-1 responsive and refractory models (Press release, Phio Pharmaceuticals, APR 10, 2021, View Source [SID1234577828]). Furthermore, on target efficacy was supported by modulation of immune cell populations toward antitumor phenotypes. The Company believes these data further support the potential for INTASYL mPH-762 to provide strong local immune checkpoint blockade (ICB), without the dose immune-related adverse effects (irAEs) seen with systemic ICB antibody therapy. Phio is planning to advance this program with a first-in-human clinical study of PH-762 as a directly administered drug in patients with advanced melanoma at the Gustave Roussy Institute, which is scheduled to be initiated in the fourth quarter of 2021.

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"We are pleased to announce new in vivo data today that show INTASYL mPH-762 offered strong tumor control in Hepa 1-6 and CT26 models, which are PD-1 responsive and PD-1 refractory models, respectively. The modulation of key immune cell populations in the tumor microenvironment (TME) by local application of INTASYL mPH-762 provides further evidence that the desired efficacy to treat these cancers can be attained by direct intratumoral administration. Such local administration can have several advantages such as avoiding dose limiting systemic side effects which are often dose-limiting," stated Dr. Simon Fricker, Phio’s VP of Research. "These data further support our excitement around this asset and to bring PH-762 to patients, starting with our first clinical study later this year."

All INTASYL treatments were well tolerated. Treatment with mPH-762 inhibited tumor growth in both CT26 and Hepa 1-6 models in a dose dependent manner compared to control treated tumors, with mPH-762 providing tumor growth inhibition analogous to systemic anti-PD-1 monoclonal antibody (mAb) use. Hepa 1-6 is a PD-1 inhibition-responsive hepatoma model and CT26 is a PD-1 inhibition-refractory colon cancer model. Dose-correlating on-target silencing of PD-1 protein expression across key TME cell populations was observed under treatment with mPH-762, but not with anti-PD-1 mAb. The modulation of tumor immune cell populations toward antitumor phenotypes, supporting on target efficacy, included significantly increasing overall %CD45+ and %NK1.1+ / CD45+ populations and increasing median M1 (immunostimulatory) / M2 (immunosuppressive) polarized tumor associated macrophage ratios.

These data were presented today during the AACR (Free AACR Whitepaper) Annual Meeting 2021 in a poster titled "Intratumoral INTASYL self-delivering RNAi targeting PD-1 provides in vivo tumor control and mechanistic modulation of tumor microenvironment analogous to that of systemic anti-PD-1 antibody". An archived version of the poster presentation will be made available on the "Investors – Events and Presentations" section of the Company’s website (click here).

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.