On December 10, 2021 Candel Therapeutics, Inc. (Nasdaq: CADL), a late clinical stage biopharmaceutical company developing novel oncolytic viral immunotherapies, reported a collaboration with Partnership for Accelerating Cancer Therapies (PACT) and the Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) to profile the biomarker response to a combination of CAN-2409 + valacyclovir in combination with anti-PD-1 and PD-L1 immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC) (Press release, Candel Therapeutics, DEC 10, 2021, View Source [SID1234596770]).

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Analysis of longitudinal biologic samples from a Candel phase 2 clinical trial will be performed by the CIMAC-CIDC research centers and sponsored by PACT. The assays proposed include in depth immunophenotyping of serial lung biopsies and peripheral blood samples obtained during the clinical trial. Candel’s clinical trial in NSCLC is designed to assess the tumor response to CAN-2409 when added to anti-PD-1 or PD-L1 immune checkpoint inhibitor (ICI) treatment after patients have inadequately responded to ICI with or without chemotherapy. The trial comprises three cohorts; 1) patients whose best response to ICI treatment has been stable disease; 2) patients who have initially responded to ICI treatment, but whose disease is now progressing; and 3) patients who have refractory disease, meaning they are progressing rapidly despite ICI treatment. In each of these settings, minimal to no response is expected from further ICI treatment. The collaboration will analyze samples from each of these cohorts with the aim to identify early biological indicators of response and further stratify potential responders to treatment.

"We have shown that local administration of CAN-2409 monotherapy induces significant remodeling of the tumor immune microenvironment coupled with systemic activation of the immune response," said Francesca Barone, MD, PhD, Vice President and Head of Research at Candel. "We are honored by the selection of our clinical trial by the PACT consortium, which provides an important validation of Candel’s approach to embed the highest levels of scientific rigor in our clinical trials. The data generated through this collaboration will broaden our understanding of the biological response to combination therapy of CAN-2409 with ICI, as we endeavor to bring effective new treatment options to patients with cancer."

About PACT

The Partnership for Accelerating Cancer Therapies (PACT) is a five-year public-private research collaboration launched by the National Institutes of Health, the Foundation for the National Institutes of Health (FNIH), and 12 leading pharmaceutical companies as part of the Cancer MoonshotSM Research Initiatives. The PACT initiative is partnered with the Cancer Immune Monitoring Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC) Network to develop and validate a set of standardized and harmonized biomarker assays that profile the response to immuno-oncology interventions, including combination therapies, oncolytic viral immunotherapy, and other novel immunotherapy treatments.

For more information about PACT, visit View Source

About CAN-2409

CAN-2409, Candel’s most advanced oncolytic viral immunotherapy candidate, is a replication-deficient adenovirus that delivers the herpes simplex virus thymidine kinase (HSV-tk) gene to cancer cells. HSV-tk is an enzyme that locally converts orally administered valacyclovir into a toxic metabolite that kills nearby cancer cells. The intra-tumoral administration results in the release of tumor-specific neoantigens in the microenvironment. At the same time, the adenoviral serotype 5 capsid protein elicits a strong pro-inflammatory signal in the tumor microenvironment. This creates the optimal conditions to induce a specific CD8+ T cell mediated response against the injected tumor and uninjected distant metastases for broad anti-tumor activity.

Because of its versatility, CAN-2409 has the potential to treat a broad range of solid tumors. Monotherapy activity as well as combination activity with standard of care radiotherapy, surgery, chemotherapy, and immune checkpoint inhibitors have previously been shown in several preclinical and clinical settings. Furthermore, CAN-2409 presents a favorable tolerability profile; more than 700 patients have been dosed to date, supporting the potential for combination with other therapeutic strategies without inordinate concern of overlapping adverse events. Currently, Candel is evaluating the effects of treatment with CAN-2409 in non-small cell lung cancer, high-grade glioma, pancreatic cancer, and localized, non-metastatic prostate cancer in ongoing clinical trials.

For more information on this clinical study, please visit: View Source

On December 10, 2021 Carrick Therapeutics, an oncology-focused biopharmaceutical company discovering and developing highly differentiated therapies, reported at the 2021 San Antonio Breast Cancer Symposium (SABCS), presented encouraging clinical data on samuraciclib (CT7001), an oral and first-in-class inhibitor of CDK7, that support its continued development in breast cancer (Press release, Carrick Therapeutics, DEC 10, 2021, View Source [SID1234596751]).

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Carrick presented updated data from a Phase 1b/2 clinical trial for samuraciclib in combination with fulvestrant in women with hormone receptor positive (HR+), HER2- advanced breast cancer (BC) previously treated with a CDK4/6 inhibitor (abstract: GS3-10) that reinforces encouraging clinical activity and tolerability and supports further development of the combination.

"The data we announced at SABCS both demonstrated clinical activity and tolerability, which has reinforced our conviction that samuraciclib has potential to be a first and best-in-class treatment," said Tim Pearson, Chief Executive Officer of Carrick Therapeutics. "Our pre-clinical studies have established that CDK7 inhibition activates the p53 pathway in TP53 wild-type, HR+ breast cancer cells. More importantly, p53 pathway activation by samuraciclib in combination with CDK7 inhibition has been effective in controlling cancer growth in our HR+ clinical study. Samuraciclib, provides meaningful benefit most notably in those women that are TP53 wildtype, which accounts for nearly 70% of patients in this setting. Samuraciclib in combination with fulvestrant in the post CDK4/6 setting has demonstrated a median mPFS of 32 weeks. This is a meaningful prolongation of PFS considering the limited benefit these patients have with endocrine monotherapy therapy, which is limited to only ~8 weeks mPFS with fulvestrant alone in previously reported studies. Having now validated the biology for SERD combination, we continue to explore additional options, including our collaboration with Roche’s giredestrant, a next-generation oral SERD. We believe there is potential for synergy in combining samuraciclib with oral SERDs to significantly enhance the benefits already demonstrated with fulvestrant. We are excited with the progress we’ve made, and we look forward to additional data readouts from our ongoing programs."

The study recruited patients with advanced HR+, HER2- BC, 31 patients were enrolled with difficult-to-treat disease. All patients enrolled had progressed following treatment with a CDK4/6 inhibitor and 23% had received chemotherapy for advanced disease. All patients had advanced disease with 81% having visceral involvement, including 45% with liver metastasis and only 6% with bone only disease.

Of the 31 patients enrolled in this ongoing study, 25 patients were evaluable for response at the time of data cut-off:

Overall the clinical benefit rate (CBR) of patients who received treatment for at least 24 weeks was 36% (9 patients).
However clinical benefit was particularly evident in patients with no deleterious mutation in the TP53 gene and patients without liver metastases.
Median progression-free survival (mPFS) TP53 wild-type (n=19) was 32 weeks vs 7.9 weeks for TP53 mutant (n=6).
mPFS with no liver metastases (n=17) was not reached (?48 weeks) vs 11.9 weeks for patients with liver metastases (n=14).
18 (72%) had tumour shrinkage including 3 partial responses (1 confirmed, 2 unconfirmed)
The combination treatment was generally well tolerated. Adverse events were predominantly low-grade gastrointestinal (GI) events such as nausea, vomiting and diarrhea with the majority of patients staying on treatment until disease progression.
This additional data supports the further development of samuraciclib in HR+ advanced breast cancer.
Carrick also presented data for the use of samuraciclib in patients with advanced triple negative breast cancer (TNBC) (abstract: P1-18-10) which demonstrated evidence of antitumor activity that support its further development as a platform for combination approaches in TNBC. In this study, 23 patients with advanced TNBC were recruited and dosed with samuraciclib 360mg OD.

Samuraciclib demonstrated evidence of long-term benefit in patients who had received one to three lines of prior chemotherapy:
One patient had a partial response as defined by RECIST, and stable disease was achieved in 11 patients.
Five patients have been on treatment for at least 24 weeks of whom 3 have exceeded 1 year.
Treatment was generally well tolerated with all patients staying on treatment until disease progression. Adverse events were predominantly GI events of low-grade.
Samuraciclib has shown evidence of target engagement on several biomarkers that supports its mechanism of action. In addition, plasma thymidine kinase activity, a measure of cell cycle progression, was inhibited with samuraciclib administration.
About Samuraciclib (CT7001)
Samuraciclib is the most advanced oral CDK7 inhibitor in clinical development. Inhibiting CDK7 is a promising therapeutic strategy in cancer as CDK7 regulates the transcription of cancer-causing genes, promotes uncontrolled cell cycle progression and resistance to anti-hormone therapy. Samuraciclib has demonstrated a favorable safety profile and encouraging efficacy in early clinical studies. In addition to the above studies, it is currently being evaluated in prostate cancer with further potential in pancreatic, ovarian and colorectal cancers. Samuraciclib has been granted Fast Track designations from the U.S. Food and Drug Administration (FDA) for use in combination with fulvestrant for the treatment of CDK4/6i resistant HR+, HER2- advanced breast cancer and in combination with chemotherapy for the treatment of locally advanced or metastatic TNBC.

On December 10, 2021 Merus N.V. (Nasdaq: MRUS) ("Merus", "the Company", "we", or "our"), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported clinical data on zenocutuzumab (Zeno) in combination with trastuzumab and vinorelbine in patients (pts) with HER2 positive/amplified (HER2+) metastatic breast cancer (MBC) who had progressed on anti-HER2 antibody drug conjugates (ADC), at the San Antonio Breast Cancer Symposium in San Antonio, Texas (Press release, Merus, DEC 10, 2021, View Source [SID1234596771]).

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Andrew Joe, Chief Medical Officer at Merus, said, "We are pleased to present the final analysis of the triplet Zeno combination which has demonstrated clinically meaningful activity in heavily pretreated patients with HER2+/amplified MBC. We are encouraged by Zeno’s potential to be active in indications outside NRG1 fusion cancers, opening opportunities for potential collaborations in these areas."

The reported data are from the completed phase 2 study, designed to explore the efficacy of a triplet combination of Zeno plus trastuzumab and vinorelbine in MBC patients (NCT03321981). Preliminary results for patients treated with the triplet regimen were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Annual Meeting. The combination was observed to be well-tolerated in the run-in cohort and the cohort was expanded. The primary endpoint of the study was clinical benefit rate (CBR) at 24 weeks of 45%. Updated results from the cohort expansion are presented here:

At the efficacy data cut-off, March 31, 2021, 39 patients, with a median age of 57 and with a median number of five prior therapies, had received the Zeno-based triplet combination, 4 of whom were ongoing. All patients had completed at least 6 months of treatment or discontinued
37 patients with locally confirmed HER2 overexpression (IHC 3+ or IHC 2+/FISH-positive) were evaluable for antitumor activity
The clinical benefit rate (CBR: complete response + partial response + stable disease ≥24 weeks) per investigator assessment was 49% (18/37 patients; 90% CI 34 – 63)
Confirmed responses (per investigator) were reported in 10 patients, including 2 patients with complete response (CR)
Median duration of response was 4.2 months (90% CI 2.8 – 12.4), including 2 patients with CR lasting 4.2 and 7.2+ months, and 8 patients with partial responses (PR) lasting from 2.6 to 12.4 months
Median progression-free survival was 5.5 months (90% CI 4.1 – 5.6); 7 patients (19%) were censored. Estimated overall survival rates at 12 and 24 months were 73% and 61%, respectively
The combination was observed to be well tolerated, with AEs primarily related to chemotherapy
As previously reported, with completion of this phase 2 trial, Merus does not have plans to advance into a phase 3 clinical trial in metastatic breast cancer in the absence of a partner. The company continues to focus on the eNRGy trial to potentially support a BLA submission seeking a tumor agnostic indication for Zeno in patients with previously treated NRG1+ cancers.

The full poster is available on our website.

About Zeno
Zeno is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced Biclonics that utilizes the Merus Dock & Block mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 gene fusions (NRG1+). Through its unique mechanism of binding to HER2 and potently blocking the interaction of HER3 with its ligand NRG1 or NRG1-fusion proteins, Zeno has the potential to be particularly effective against NRG1+ cancers. In preclinical studies, Zeno also potently inhibits HER2/HER3 heterodimer formation and tumor growth in models harboring NRG1 fusions.

On December 10, 2021 APIM Therapeutics (APIM), a clinical stage biotech company focusing on the development of novel peptide therapeutics targeting PCNA (Proliferating Cell Nuclear Antigen), reported that a Phase II Investigator Initiated Study (IIS) of ATX-101 will begin enrolling patients with sarcoma at Columbia University Irving Medical Center (Press release, APIM Therapeutics, DEC 10, 2021, View Source,c3468947 [SID1234605479]).

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The clinical study (ClinicalTrials.gov Identifier: NCT05116683) will investigate ATX-101, the lead compound of APIM’s development program, as single agent therapy for patients with leiomyosarcoma and liposarcoma who have received at least one prior treatment. An IND has been granted by the FDA and the local IRB approved the study.

Sarcoma is a rare malignant tumor that originates from connective tissue. Lipo- and leiomyosarcoma are the most frequently observed soft tissue sarcomas. About 12,750 new cases of soft tissue sarcoma are diagnosed in the US every year. Late-stage disease has a poor prognosis with a 5-year survival rate below 20%.

"Sarcoma is a disease with a very high medical need, and new treatments are needed to fight this cancer," said Matthew Ingham, MD, assistant professor of medicine in Hematology & Oncology at Columbia and Principal Investigator of the study. "We are interested in exploring the potential of inhibiting PCNA activity in cancer cells as a potential new therapy for sarcoma patients."

Columbia’s Division of Hematology & Oncology, led by Gary Schwartz, MD, professor of oncology at Columbia, is a leader in translational and clinical research on sarcoma. "ATX-101 has shown encouraging pre-clinical data published in peer reviewed journals," said Dr. Schwartz. "We have been able to confirm these data in our lab. Our study will help us determine if this therapeutic approach has clinical benefit for sarcoma patients."

APIM supports the study financially and provides the investigational drug ATX-101. "APIM is happy to support this IIS. Data from our Phase I study indicate a favorable safety profile of ATX-101, including anticancer activity. This sarcoma study is a valuable complement to our own clinical development program investigating ATX-101 in combination with chemotherapy for patients with ovarian cancer," explained Dr. Jens-Peter Marschner, CMO of APIM.

"Our work with distinguished sarcoma specialists at Columbia University Irving Medical Center is an important step for APIM Therapeutics and indicates that our first in class approach is of academic interest," said Dr. Kostas Alevizopoulos, CEO of APIM. "With this IIS and its translational investigations, additional data will be collected that advance our understanding of complex PCNA-dependent activities in cancer and their inhibition by ATX-101."

About ATX-101

ATX-101 is a first-in-class, cell penetrating peptide featuring a novel PCNA-interacting motif (AlkB homolog 2 PCNA Interacting Motif or APIM). In preclinical experiments, it was shown that APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 competitively inhibits interaction of PCNA with APIM-containing protein complexes resulting in cancer cell death and altered cellular signaling. These properties translate in anticancer effects of ATX-101 as demonstrated in several preclinical models in vitro and in vivo.

On December 10, 2021 aTyr Pharma, Inc. (Nasdaq: LIFE), a biotherapeutics company engaged in the discovery and development of innovative medicines based on novel biological pathways, reported a presentation at the Antibody Engineering & Therapeutics Conference which is being held December 12 – 16, 2021 in San Diego, CA, and virtually (Press release, aTyr Pharma, DEC 10, 2021, View Source [SID1234596772]).

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The presentation will discuss the practical utility of repertoire data for antibody affinity maturation, including clonal grouping of sequencing data with lead candidates to understand likely maturation pathways and partially mature antibodies with minimal effort, complementing existing methods. aTyr’s tRNA synthetase biology platform is focused on elucidating novel pathways mediated through extracellular response and creating new biologics to modulate these pathways, by either developing protein therapies based on extracellular tRNA synthetase fragments or generating monoclonal antibodies to target the pathway. Engineering techniques that enhance the affinity and selectivity of antibodies can accelerate the development of antibody therapeutics against novel targets.

Details of the presentation are as follows:

Title: Practical Utility of Repertoire Data for Antibody Affinity Maturation
Presenter: Luke Burman, Senior Scientist. aTyr Pharma, San Diego, CA.
Session: Workshop B: When High Affinity is Necessary in Antibody Therapeutics
Date: Sunday, December 12, 2021
Time: 2:15pm PST / 5:15pm EST

"We are excited to present on this novel approach that highlights aTyr’s cutting-edge, in-house antibody engineering techniques," said Leslie Nangle, Ph.D., Vice President, Research at aTyr. "These methods have broad applicability for aTyr’s tRNA synthetase platform and present an opportunity to support the expansion of our pipeline with enabling technology that accelerates the development of antibody candidates with high affinity and selectivity for their receptor targets."