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 Agendia, Inc., a world leader in precision oncology for breast cancer, reported that it will present a spotlight poster at the 2021 San Antonio Breast Cancer Symposium (SABCS 2021) which confirms the utility of BluePrint in guiding neoadjuvant treatment decisions (Press release, Agendia, DEC 10, 2021, View Source [SID1234597140]).

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The spotlight presentation, resulting from a research collaboration between Agendia and the Netherlands Cancer Institute and titled Effect of pertuzumab plus neoadjuvant trastuzumab-based chemotherapy in early-stage HER2-positive breast cancer according to BluePrint molecularly defined breast cancer subtypes [PD15-07], evaluates the BluePrint 80-gene molecular subtyping test for predicting response to neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab in a large nationwide cohort of patients from the TRAIN2 study (NCT01996267) and the Netherlands Cancer Registry.

Results showed that BluePrint reclassified 15% of the IHC/FISH HER-2+ patients in this study to a different molecular subtype. These reclassified patients typically do not respond as expected to HER2-targeted therapies, indicating a potential role for genomics in treatment planning for HER2+ patients. The data also support the pronounced benefit of adding pertuzumab to neoadjuvant trastuzumab-based chemotherapy in patients with the BluePrint-defined HER2-subtype, with other subtypes having a less pronounced benefit from pertuzumab. These new findings reinforce the heterogeneity of pathologically HER2+ breast cancer and provide support for the results of a prior translational analysis of the APHINITY trial, which also showed that BluePrint may identify subgroups of HER2+ patients with differing degrees of benefit from the addition of pertuzumab based on gene expression.

"In addition to these results reclassifying 15% of patients in this cohort, the data confirm the genomic heterogeneity of clinically HER2+ patients, and suggest that genomic information could help make more precise decisions following diagnosis," said William Audeh, MD, Chief Medical Officer at Agendia. "HER2 is an extremely complex histological subtype of breast cancer. The results presented in this spotlight poster show again the incredible diversity of this subtype, and the importance of looking at these tumors at a genomic level in order to adjust treatment appropriately even before surgery."

In addition, Agendia shared updates and study results from the 30,000-patient breast cancer genome project, the FLEX study:

[OT2-07-01] The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer shares data from some of the 38 investigator-initiated sub-studies approved within the FLEX Registry, the real-world, large-scale, prospective, observational breast cancer study (NCT03053193) intended to enable the discovery of novel genomic profiles to improve precision in the management of breast cancer. With purposefully-wide inclusion criteria, and more than 9,000 patients enrolled towards the 30,000-patient goal, the registry aims to enable researchers to investigate the differences and trends between breast cancer subgroups and allow focus on smaller, more diverse patient populations, which have traditionally been challenging to recruit in sufficient numbers for clinical trials.
[P5-07-05] Deciphering the inferior prognosis of young women with estrogen receptor-positive early-stage breast cancer through full transcriptome analysis: a FLEX database sub-study aims to better understand the biological basis for the disparity in outcomes between older and younger women with early-stage breast cancer by identifying genes that distinguish tumors in these two groups. Data demonstrated that there were relatively few gene expression changes identified by age, and that few transcriptional differences were observed between tumors from women aged 40-54 and women older than 55. These results suggest that observed chemotherapy benefit represents differences in host biology rather than intrinsic tumor biology. Additionally, these findings indicate that age is potentially a more relevant cutoff than menopausal status when observing genes to aid in treatment decisions, reinforcing the need for genomic testing to be available to all women with early stage breast cancer regardless of menopausal status.
[P2-08-06] Defining transcriptomic profiles of breast cancer with early lymph node metastases: a FLEX database sub-study provides a foundation for understanding the mechanisms that promote lymph node (LN) metastasis, with data indicating more biological differences between MammaPrint risk and BluePrint subtype than by pathological stage. Early LN metastasis often precedes systemic metastasis and corresponds with a 20% decrease in 10-year survival compared to patients without LN metastasis,1 underscoring the importance of understanding biologic pathways involved in early LN metastasis to identify promising drug targets for early-stage breast cancer treatment.
"The robust variety and value of the data being collected by the FLEX project cannot be overstated," said Cynthia X Ma, MD, PhD, oncologist and FLEX national principal investigator at Washington University School of Medicine in St. Louis. "In the data presented at SABCS 2021 alone, we see insights that can be turned into clinical actions immediately. Especially interesting is the representation of extreme MammaPrint risk groups, with over 1,100 Ultra Low Risk and over 1,200 High Risk 2 patients enrolled in the study. The insights from these analyses will guide physicians supporting the entire breast cancer community in hard-to-treat cases they may see in their practice today. This project could be one of the most impactful, inclusive studies in breast cancer research to date, and the constant learnings from it allow us to better understand biologic drivers of breast cancer and ultimately result in more personalized, precise treatment plans."

Agendia will present six posters that were accepted to SABCS 2021, highlighting Agendia’s mission to help guide the diagnosis and personalized treatment of breast cancer for all patients throughout their treatment journey.

On December 10, 2021 Caring Cross, a 501(c)(3) non-profit dedicated to accelerating the development of advanced medicines and enabling access to cures for all patients, everywhere, reported that Nature Communications has published a scientific manuscript highlighting research demonstrating the effectiveness of place-of-care manufacturing of anti-CD19 CAR T cells for treatment of B-cell malignancies (Press release, Caring Cross, DEC 10, 2021, View Source [SID1234597013]). Place-of-care manufacturing is defined as near the point of patient treatment allowing cell products to be produced and infused without need for cryopreservation.

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The manuscript, entitled, "Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients," reported that novel CD19-targeting CAR-T cells (CAR19-T cells) similarly manufactured using automation at separate sites in Cleveland, USA and Moscow, Russia achieved complete response rates of 73% in adult B-cell Lymphoma (NHL) and 89% in pediatric B-cell Acute Lymphocytic Leukemia (ALL), respectively. For NHL complete responders, the one-year survival rate was 92.9%, with a median duration of response yet to be reached. For ALL complete responders with a median follow-up of 17 months, the one-year survival rate was found to be 79.2% with a median duration of response of 10.2 months. Based on these findings, it was concluded that use of place-of-care manufactured CAR-T cell products results in clinical outcomes that are effective in the treatment of patients with B-cell malignancies.

Dr. Marcos de Lima, Director of Stem Cell Transplantation and Cellular Therapy at The Ohio State University Medical Center, and one of the lead investigators on the clinical trial, commented: "Our studies show that place-of-care manufacture of CAR-T cells results in a consistent cell product and produces effective clinical outcomes, despite being manufactured in two disparate clinical centers located in the US and Russia. We were able to make fresh CAR-T cells in as little as 8 days, which is very important for patients with rapidly progressing disease. We therefore conclude that place-of-care manufacture of CAR-T cells is a valid and valuable model for the manufacture and distribution of CAR-T cells among multiple clinical centers, and particularly important for patients with rapidly progressive, symptomatic lymphoma and ALL."

In addition to demonstrating that place-of-care manufacture of CAR-T cells results in a consistent cell product and effective clinical outcomes, the research team determined that fresh CAR19-T cells, which can only be manufactured at the place-of-care, reduce tumor burden faster in vivo in NSG mice than cryopreserved CAR19-T cells, immediately reducing the tumor burden, while frozen CAR19-T cells first permitted tumor growth before controlling growth. Moreover, the researchers found that place-of-care manufacture of CAR19-T cells resulted in a highly comparable CAR-T cell product composition between the multiple clinical centers and a low production failure rate, demonstrating the robustness of the manufacturing process.

Dr. Michael Maschan, Director of the Department of Hematopoietic Stem Cell Transplantation at the Dmitriy Rogachev National Center for Pediatric Hematology and Oncology in Moscow, Russia, commented: "Place-of-care manufacturing of CAR-T cells offers several advantages over centralized manufacturing, including reduced vein-to-vein time due to lack of transport to a centralized facility and the ability to infuse fresh and not necessarily cryopreserved products. Simplified logistics increases the flexibility to make decisions based upon patient disease status, for example split-dosing in the instance of high tumor burden. The high response rates we have seen in our clinical trials are outstanding considering that we were able to essentially treat all-comers due to the short manufacturing times of patient-derived CAR-T cell products, which are only possible when they are manufactured at the place-of-care. This has tremendous benefits for patients, particularly those with advance disease that need to be treated as soon as possible. We are delighted with the clinical results to date and look forward to future innovations to further improve patient outcomes."

Dr. Boro Dropulić, Executive Director of Caring Cross, commented: "This is the first study that definitively demonstrates the feasibility of place-of-care manufacturing of gene-modified cell products between muliple centers. We show that when the same device, materials, reagents and protocols are used to manufacture CAR-T cells, even between two disparate clinical centers, the gene-modified cell products are highly consistent with a low product failure rate. The clinical outcomes for patients were especially remarkable considering that almost all the patients enrolled were treated, even patients that otherwise would not be eligible due to their advanced disease, demonstrating the enormous value of this approach. Place-of-care manufacturing also offers the potential to dramatically reduce the cost of these transformational therapies to a fraction of their current cost due to obviating the need for transportation and the cost of multiple layers of quality and custodial assurance that are required for centralized manufactured CAR-T cell products. The next step will be to expand CAR-T cell clinical trials to include more clinical centers and support the development of regulatory pathways for the approval of CAR-T and other gene-modified cellular products that are manufactured at the place-of-care."

The full paper may be accessed via the Nature Communications website at View Source

On December 10, 2021 Exicure, Inc. (NASDAQ: XCUR) reported the results of its previously disclosed independent internal investigation and a number of strategic actions aimed to reduce cash spend and prioritize the Company’s therapeutic pipeline (Press release, Exicure, DEC 10, 2021, View Source [SID1234596793]).

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The Audit Committee of the Board of Directors of the Company (the "Audit Committee") reported the findings of the internal investigation initiated and overseen by the Audit Committee and conducted by outside counsel in connection with alleged improprieties that Grant Corbett, Ph.D., the Company’s former Group Lead of Neuroscience, claimed to have committed with respect to the Company’s XCUR-FXN preclinical program.

The results of the investigation are summarized below.

Beginning in the autumn of 2020, Dr. Corbett misreported raw data from certain research and development experiments related to XCUR-FXN;
Dr. Corbett misreported the results of at least three different experiments that were conducted through at least February 2021;
The misreported data related solely to efficacy rather than safety of XCUR-FXN;
The misreported data was included in various public presentations and SEC filings from as early as January 7, 2021 through as late as August 12, 2021;
Dr. Corbett acted alone in misreporting the data, without the assistance or knowledge of anyone else at the Company, including Company management and other research and development employees and did not inform anyone at the Company of his actions until his resignation in November 2021;
Company management reasonably relied on Dr. Corbett’s analysis when making public statements that included Dr. Corbett’s misreported data; and
No other Company program was impacted by Dr. Corbett’s misreporting of the XCUR-FXN data.
After a review of the Audit Committee’s findings from the investigation and in combination with a previously initiated strategic review of the Company’s business plans and objectives and its existing cash resources, the Company’s Board of Directors has implemented the following approved plan:

A staggered workforce reduction of approximately 50%, expected to be completed by January 2022;
Discontinuation of further enrollment and the ethical wind down of the Company’s ongoing Phase 1b/2 cavrotolimod (AST-008) clinical trial in patients with solid tumors
Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia
Restructuring and realignment of the Company’s executive team as follows, effective today:
Brian C. Bock, the Company’s former Chief Financial Officer, has been appointed as the Company’s President and Chief Executive Officer, replacing David Giljohann, and was appointed as a member of the Board.
Dr. David Giljohann, the Company’s former Chief Executive Officer, has resigned from the Board and will serve as Chief Technology Officer through January 31, 2022.
Matthias Schroff, the Company’s former Chief Operating Officer, has assumed the new role of Chief Scientific Officer;
Sarah Longoria, the Company’s former Vice President of Human Resources has been appointed as the Company’s Chief Human Resources Officer and Chief Compliance Officer; and
Douglas Feltner, M.D., the Company’s Chief Medical Officer, has agreed to assist in the wind down of the cavrotolimod and XCUR-FXN programs and will depart the Company on January 31, 2022.
Exicure expects to realize approximately $6.0 million in employee related cost savings in 2022, plus additional costs relating to the elimination of the cavrotolimod and XCUR-FXN programs. The Company estimates that it will incur total expenses relating to the restructuring of approximately $1.2 million, consisting of severance and termination-related costs and expects to record a significant portion of these charges in the fourth quarter of 2021.

The Company intends to align its research and development resources to support (i) the development of its preclinical program targeting SCN9A for neuropathic pain, (ii) the continued advancement of its partnered programs with Ipsen Biopharm Limited to develop SNA-based treatments in neuroscience targeting Huntington’s disease and Angelman syndrome, (iii) its continued advancement of its partnered program with AbbVie to develop SNA-based treatments for hair loss disorders, as well as (iv) the continued research and development of other undisclosed therapeutic product candidates.

The Company also announced a prepayment of $10.0 million of its outstanding loans under its senior secured term loan debt facility with MidCap Financial Trust, as agent, and Silicon Valley Bank (SVB), leaving a remaining outstanding balance of $7.5 million, which will remain subject to the existing terms under the loan facility.

"This has been a difficult time for all of our stakeholders and Exicure employees. I want to first thank the employees impacted by our workforce reduction for their significant contributions in pursuing treatments for patients with unmet medical needs and wish them success in their future endeavors. Although this unfortunate event will have residual effects, I strongly believe there is great value to be unlocked at Exicure with our proprietary Spherical Nucleic Acid (SNA) technology, and I look forward to advancing our promising programs in pain and other neuroscience diseases and continuing to closely work with our partners to develop innovative therapies for the treatment of genetic disorders," stated Brian Bock, President and Chief Executive Officer, Exicure.

"On behalf of the Board of Directors, I want to thank David Giljohann for his discoveries and contributions to the development of our proprietary SNA architecture, commitment in building Exicure from the ground up and leadership during his time at the Company," said Tim Walbert, Chairman of the Board, Exicure. "We look forward to working closely with Brian Bock as he assumes leadership of the Company. The Board believes Brian’s disciplined approach as well as his financial and investment banking background make him well suited to develop the new strategic path for Exicure and navigate the Company through the next phase in the Company’s evolution."

On December 10, 2021 Hologic, Inc. (Nasdaq: HOLX) and its subsidiary, Biotheranostics, Inc., reported new data demonstrating that Breast Cancer Index (BCI) not only predicts preferential recurrence-prevention benefit from extended endocrine therapy (EET), but also predicts the overall benefit/risk and likelihood of improved health outcomes from EET in certain hormone receptor positive (HR+) patients (Press release, Hologic, DEC 10, 2021, View Source [SID1234596792]). New data also confirm two biomarkers used in BCI are interconnected molecular drivers of assessing recurrences in HR+ breast cancer. These findings were presented in Spotlight Sessions at the 2021 San Antonio Breast Cancer Symposium (SABCS), which is being held from December 7-10.

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"Extended endocrine therapy often comes with tolerability challenges and even significant adverse events," said study author Marc Buyse, ScD, Associate Professor of Biostatistics at Hasselt University in Belgium. "We found the data to have considerable implications for patient compliance and joint decision-making with their healthcare providers, as patients have a more comprehensive picture of the net benefit of staying on EET so they can better assess the challenges that can come with treatment."

BCI Significantly Predicts Net Treatment Benefit (NTB) of EET in HR+ Breast Cancer

Research has shown that EET may reduce the long-term risk of recurrence in HR+ breast cancer, but treatment is often accompanied by serious adverse events (AEs), such as bone toxicity, endometrial cancer, embolisms, heart disease and more.1-3 The NTB study, which examined novel patient subset data (N=908 HR+ patients) from the Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) study, sought to determine the ability of BCI to predict the net benefit from 2.5 years vs. 5 years of EET. These data suggest patients should consider EET if they have a High HOXB13/IL17BR (H/I) result, and it confirms there is a significant NTB from EET for patients even when balanced against more serious AEs (i.e., Grade 3 or higher).

BCI Biomarkers Independently Contribute to its Ability to Predict EET Benefit

While clinical and pathologic factors are prognostic, they do not reliably predict benefit from EET like BCI [H/I] does.1-4 The Molecular Grade Index (MGI) study assessed the relationship of proliferation (MGI) and endocrine response (H/I) to further support how the BCI assay works. These data confirmed that the two biomarkers contributing to BCI’s risk assessment (H/I and MGI) drove tumor biology, thus validating BCI’s role in offering personalized extended endocrine decisions based on the individual patient’s tumor.

"These data analyzing H/I and MGI genes solidify our understanding of the relationship between these two critical components of BCI," said study author Reshma Mahtani, DO, Professor of Medicine at the University of Miami, Sylvester Comprehensive Cancer Center. "The insights confirm H/I and MGI are interdependent contributors of risk and benefit thus both necessary elements working in combination to determine risk of recurrences in HR+ breast cancer, further ensuring providers are equipped to make informed prognoses in routine care with BCI."

About Breast Cancer Index

Breast Cancer Index is a gene expression-based test uniquely positioned to provide information to help physicians individualize treatment decisions for patients with early-stage, HR+ breast cancer. This breakthrough test helps oncologists and patients navigate the difficult trade-offs between taking steps to prevent recurrence of their disease and facing significant side effects and safety challenges related to unnecessary treatment. Breast Cancer Index has guideline designation from the American Joint Committee on Cancer for cancer staging based on molecular profile. ASCO (Free ASCO Whitepaper), NCCN, the European Group on Tumor Markers (EGTM) and St. Gallen acknowledge Breast Cancer Index as a biomarker to inform the chemotherapy decision; and NCCN and EGTM acknowledge Breast Cancer Index as a biomarker to inform the extended endocrine treatment decision. It is the only validated, commercially available test that predicts benefit from extended endocrine therapy. Breast Cancer Index is intended for routine clinical use, and treatment decisions based on results are the responsibility of the physician. It is a laboratory developed test (LDT) performed in a CLIA-certified and CAP-accredited diagnostic laboratory and is not required to be cleared or approved by the US Food and Drug Administration. For more information, visit www.breastcancerindex.com.