On November 14, 2022 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported financial results for the quarter ended September 30, 2022 and provided a corporate update (Press release, Syros Pharmaceuticals, NOV 14, 2022, View Source [SID1234624044]).

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"The third quarter was transformative for Syros. In September, we announced the closing of our merger with TYME Technologies and concurrent oversubscribed PIPE, with combined gross proceeds of approximately $190 million," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "With this additional capital, we believe we are well-positioned to build Syros into a commercial-stage company. We are now focused on advancing our late-stage hematology programs toward important clinical milestones, beginning with the presentation of initial results, including clinical activity, from the safety lead-in portion of the SELECT-AML-1 Phase 2 trial at the ASH (Free ASH Whitepaper) Annual Meeting in December. In addition, we remain on track to report data from the pivotal SELECT-MDS-1 trial in late 2023 or early 2024 and, based on the preliminary data from our dose confirmation study of SY-2101 that we announced in August, expect to initiate a Phase 3 trial in patients with APL in the second half of next year."

Dr. Simonian continued, "Today, we are excited to announce initial data from the safety lead-in portion of our Phase 1 trial evaluating SY-5609 in combination with chemotherapy in patients with relapsed/refractory metastatic pancreatic cancer as well as an update from the single agent portion in advanced solid tumor patients. Importantly, the data reinforce our belief in the promise of selective CDK7 inhibition to benefit many difficult to treat cancers. To maximize the potential of SY-5609, we made the strategic decision to seek partnership opportunities for this program while we continue dose escalation in the ongoing trial, and to focus our internal resources on advancing our late-stage hematology portfolio for the frontline treatment of MDS, AML and APL."

UPCOMING MILESTONES

Tamibarotene: Oral RARα agonist

Higher-Risk Myelodysplastic Syndrome (HR-MDS)

On track to report pivotal data from the SELECT-MDS-1 trial in newly diagnosed HR-MDS patients with RARA gene overexpression in the fourth quarter of 2023 or the first quarter of 2024, with a potential new drug application (NDA) filing expected in 2024.
Acute Myelodysplastic Syndrome (AML)

Present safety and clinical activity data from the safety lead-in portion of the ongoing SELECT-AML-1 Phase 2 trial in newly diagnosed unfit AML patients with RARA overexpression at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December. The presentation, titled "Initial Results from SELECT-AML-1, a Phase 2 study of Tamibarotene in Combination with Venetoclax and Azacitidine in RARA-positive Newly Diagnosed AML Patients Ineligible for Standard Induction Chemotherapy," is scheduled to be presented in a poster session on December 10, 2022.
Expect to initiate the randomized portion of the SELECT-AML-1 Phase 2 trial in an additional eighty patients evaluating the triplet regimen of tamibarotene, venetoclax and azacitidine compared to venetoclax and azacitidine with data expected in 2023 or 2024.
SY-2101: Oral arsenic trioxide (ATO)

Expect to initiate the Phase 3 trial of SY-2101 in patients with newly diagnosed acute promyelocytic leukemia (APL) in the second half of 2023.
RECENT PIPELINE HIGHLIGHTS

Today, Syros announced initial safety and clinical activity data from the safety lead-in portion of the ongoing Phase 1 trial evaluating SY-5609 in combination with chemotherapy in patients with relapsed/refractory metastatic Pancreatic Ductal Adenocarcinoma (PDAC) as well as from the ongoing single agent portion in relapsed/refractory patients with select solid tumors. The data showed:
As of October 12, 2022, SY-5609 was generally safe with enhanced tolerability being maintained in the 7 day on/ 7 day off regimen at the highest doses evaluated to date, up to 10 mg when administered as a single agent, up to 5 mg when administered in combination with gemcitabine, and up to 4 mg when administered with gemcitabine/nab-paclitaxel.
The single agent 10 mg dose level did not result in any dose limiting toxicities (DLTs), further supporting the tolerability of the 7 day on/7 day off dosing regimen in which 30 patients have been dosed across five dose levels (4, 5, 6, 7, and 10 mg), with only one DLT observed at the 4 mg single agent dose level.
A maximum tolerated dose (MTD) has not yet been reached in either the single agent or in the chemotherapy combination cohorts in the 7 day on/ 7 day off dosing regimen. The adverse event profile of SY-5609 in combination with chemotherapy was consistent with the safety profile of single agent SY-5609 or gemcitabine monotherapy or gemcitabine/nab-paclitaxel, and the majority of adverse events were low grade and reversible, with no new safety signals identified.
The most common related adverse events in the cohort with SY-5609 and gemcitabine, where the highest SY-5609 doses were evaluated in combination with chemotherapy, included fatigue, nausea, decreased appetite and decreased platelet count (all low grade), with one patient experiencing a DLT of grade 3 diarrhea at the 5 mg SY-5609 dose level. No DLTs were reported in patients treated with SY-5609 in combination with gemcitabine/nab-paclitaxel.
As of October 20, 2022, in the single agent cohort at 10 mg of SY-5609, two of three enrolled patients with select solid tumors were response evaluable, including one patient with PDAC and one with Colorectal Cancer both achieved stable disease (SD). The one patient with PDAC with SD experienced a 10% tumor reduction.
In the cohort evaluating the doublet combination of SY-5609 and gemcitabine in patients with PDAC, one of four (25%) response evaluable patients treated at the 4 mg SY-5609 dose level experienced a confirmed partial response (PR) with a 98% reduction in the CA 19-9 tumor marker from a baseline of 60,357 U/mL to 968 U/mL, and three of four (75%) response evaluable patients treated at the 5 mg SY-5609 dose level had SD, for an overall disease control rate (DCR) of 50% (4 of 8 patients).
Data from the doublet and the 10 mg single agent dose support an emerging exposure-response relationship; notably, the patient with the PR demonstrated higher-than-average exposure relative to other patients at that dose.
In the cohort evaluating the triplet combination of SY-5609 and gemcitabine/nab-paclitaxel in PDAC patients, one of two response evaluable patients treated at the 4 mg dose level achieved SD.
Syros plans to continue dose escalation of SY-5609 to 15 mg as a single agent and to 10 mg in the gemcitabine combination cohort and in parallel, will be seeking a partnership for further development of SY-5609.

In September, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to SY-5609 for the treatment of pancreatic cancer. The FDA’s Office of Orphan Drug Products grants orphan status to support development of medicines for the treatment of rare diseases that affect fewer than 200,000 people in the United States. Orphan drug designation may provide certain benefits, including a seven-year period of market exclusivity if the drug is approved, tax credits for qualified clinical trials and an exemption from FDA application fees.
CORPORATE

In September, Syros announced the closing of its merger with TYME Technologies, pursuant to which Syros acquired TYME, including its pipeline assets and net cash at closing of approximately $60 million. Concurrent with the closing of the merger, Syros also closed the previously announced oversubscribed $130 million private investment in public equity (PIPE) financing. New and existing investors in the PIPE, which was led by a life-sciences focused investment fund, include Syros co-founder and founding investor Flagship Pioneering, Avidity Partners, Deep Track Capital, Bain Capital Life Sciences, Invus, Samsara BioCapital, Adage Capital Partners LP, Ally Bridge Group and Cowen Healthcare Investments, as well as other investors.
Third Quarter 2022 Financial Results

Revenues were $3.9 million for the third quarter of 2022, consisting of $3.7 million in revenue recognized under Syros’ collaboration with Global Blood Therapeutics, Inc. (GBT), now a subsidiary of Pfizer, and $0.2 million recognized under its collaboration with Incyte. Syros recognized $5.7 million in revenue in the third quarter of 2021, consisting of $5.6 million in revenue recognized under its collaboration with GBT and $0.1 million recognized under its collaboration with Incyte.
Research and development expenses were $25.8 million for the third quarter of 2022, as compared to $27.3 million for the third quarter of 2021. This decrease was primarily due to a decrease in external costs related to our preclinical programs.
General and administrative (G&A) expenses were $8.1 million for the third quarter of 2022, as compared to $5.3 million for the third quarter of 2021. This increase was primarily due to employee-related expenses and recruiting fees.
Transaction related expenses were $9.5 million for the third quarter of 2022 and consisted of the PIPE financing transaction cost allocated to warrant classified liabilities and severance paid to former Tyme employees.
For the third quarter of 2022, Syros reported a net loss of $30.3 million, or $3.21 per share, compared to a net loss of $26 million, or $4.14 per share, for the same period in 2021.
Cash and Financial Guidance

Cash, cash equivalents and marketable securities as of September 30, 2022 were $244.5 million, as compared with $143.4 million on December 31, 2021.

Syros expects that its existing cash, cash equivalents and marketable securities will be sufficient to fund its planned operating expenses and capital expenditure requirements into 2025.

Conference Call and Webcast

Syros will host a conference call today at 8:30 a.m. ET to discuss these third quarter 2022 financial results and provide a corporate update. Participants may register for the conference call here. While not required, it is recommended that participants join the call ten minutes prior to the scheduled start.

A live webcast of the call will also be available on the Investors & Media section of the Syros website at View Source An archived replay of the webcast will be available for approximately 30 days following the call.

On November 14, 2022 Apollo Therapeutics (‘Apollo’), a portfolio biopharmaceutical company focusing on translational biology and drug development, and The Institute of Cancer Research, London, a world-leading cancer research organisation, reported they have entered into a strategic collaboration to discover and develop new cancer medicines (Press release, Apollo Therapeutics, NOV 14, 2022, View Source [SID1234624043]). The collaboration combines the strengths and resources of both organisations to bring forward the development of novel therapies for cancer patients worldwide.

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As one of the world’s leading cancer research institutions, with more than 800 scientists working across the full spectrum of cancer research, The Institute of Cancer Research (ICR) delivers substantial expertise in cancer biology and drug discovery. Together with its hospital partner The Royal Marsden NHS Foundation Trust, the ICR also brings leading cancer clinical trial experience, including through their joint Drug Development Unit which is the leading oncology-focused Phase I trial unit in the UK.

Apollo’s translational scientists and drug development specialists, who are already developing a diverse portfolio of over 20 therapeutic programs, will work with the ICR on research programs to rapidly and efficiently progress those with the greatest promise through preclinical and clinical development and ultimately to patients globally.

Cancer remains a highly important health challenge, being responsible for around 10m deaths worldwide in 2020 according to the WHO, demonstrating the significant remaining unmet need for effective oncology treatments.*

Dr Richard Mason, Chief Executive Officer of Apollo commented:

"I am delighted to be entering into this collaboration with the ICR, an elite global cancer research organisation. The ICR has a hugely impressive track-record of scientific break-throughs and the discovery of important new medicines which have been approved and are in use globally. I am pleased that Apollo’s strength and experience in drug discovery and development together with our unique collaboration model has attracted an institution with ICR’s credibility and capabilities, allowing us to further deliver on our strategy of capital efficient portfolio drug development, at scale. We look forward to working with the ICR and jointly developing new medicines for cancer patients."

Dr Kristian Helin, Chief Executive Officer of the ICR said:

"It’s a great opportunity for the ICR to be entering this strategic partnership with Apollo. By working together, I hope we can accelerate our ability to translate our scientific discoveries for the benefit for cancer patients. We are looking forward to working with Apollo".

The ICR joins Apollo’s other top global research partners; the University of Cambridge, Imperial College London, UCL and King’s College London.

On November 14, 2022 Gamida Cell Ltd. (Nasdaq: GMDA), the leader in the development of NAM-enabled cell therapies for patients with hematologic and solid cancers and other serious diseases, reported financial results for the quarter ended September 30, 2022 (Press release, Gamida Cell, NOV 14, 2022, View Source [SID1234624042]). Net loss for the third quarter of 2022 was $17.8 million, compared to a net loss of $23.2 million in the third quarter of 2021. As of September 30, 2022, Gamida Cell had total cash, cash equivalents and investments of $61.3 million.

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Recently, Gamida Cell:

Advanced commercial readiness activities to support the potential launch of omidubicel in preparation for the target action date of January 30, 2023 under Prescription Drug User Fee Act (PDUFA).
Presented new data supporting the potential of omidubicel for the treatment of patients with blood cancers in need of allogeneic hematopoietic stem cell transplant at the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO) and the 2022 Cord Blood Connect Meeting (CBC). Data presented included new three-year follow-up data from the Phase 3 study that demonstrated that patients treated with omidubicel had an overall and disease-free survival rate of 63% and 56% at three years, respectively. Additional data presentations demonstrated that treatment with omidubicel led to higher health-related quality of life scores, and that, if approved, omidubicel is projected to meaningfully improve patient outcomes among racial and ethnic minorities by extending access and reducing time to transplant for patients who may not be able to currently find a donor source.
Appointed Abigail "Abbey" Jenkins as President and CEO as part of a planned succession.
Executed an underwritten public offering in September 2022 that raised $20 million before deducting underwriting discounts, commissions and offering expenses. The company also announced a commitment letter for a $25 million senior secured convertible loan in September 2022 with Highbridge Capital Management, LLC.
Continued pre-clinical development of the company’s proprietary NAM-enabled NK cell pipeline, including genetically modified product candidates GDA-301, GDA-401, GDA-501 and GDA-601, which aim to treat solid-tumor and hematological cancers. These cell therapy candidates utilize CAR, membrane bound- and CRISPR-mediated technologies to increase the NK cell targeting, potency and persistence against hematologic malignancies and solid tumors. At the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 37th Annual Meeting (SITC) (Free SITC Whitepaper), Gamida Cell announced encouraging preclinical data on GDA-501, supporting its continued pre-clinical development. "Gamida Cell is entering a pivotal time of growth as we prepare to transition from being a clinical stage to commercial stage company upon the potential approval of omidubicel. The January 30, 2023 PDUFA date for omidubicel is rapidly approaching and, if approved, omidubicel will offer a transformative new option to patients in need of an allogeneic stem cell transplant," said Abbey Jenkins, president and CEO of Gamida Cell. "The Gamida Cell team has utilized robust market insights to understand the important role that omidubicel can play for transplanters, if approved, in terms of both improving patients outcomes and increasing access for patients who cannot currently find a donor source. We have now accelerated launch preparations across our commercial, operations and medical affairs teams to ensure we can begin making omidubicel available upon potential approval in January. Beyond omidubicel, we are enrolling patients in our company-sponsored Phase 1/2 study of GDA-201 and are continuing to develop our genetically modified NK cell immunotherapy programs that leverage CAR- and CRISPR-mediated technologies. We are excited about the progress across our pipeline as we advance on our mission to deliver potentially curative therapies to patients with cancer and other serious diseases."
Third Quarter and Recent Developments

Omidubicel: Advanced Cell Therapy Candidate

Data presentations at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting: In November, Gamida Cell announced it will present new real-world analysis data comparing the safety and efficacy of omidubicel to alloHCT donor sources used in clinical practice from the Center for International Blood and Marrow Transplant Research (CIBMTR) database at the December ASH (Free ASH Whitepaper) annual meeting. The analysis demonstrated that omidubicel was associated with more rapid neutrophil recovery (median: 10 days) than all other donor sources (median 15-20 days; p-value <0.001) and evaluated other outcomes comparing omidubicel Phase 3 results and those from the CIBMTR database. Overall survival (OS) was comparable across donor sources.
Presented new long-term data from Phase 3 trial at SOHO: In September, at SOHO, Gamida Cell presented new long term follow-up data and health-related quality of life scores of patients treated with omidubicel. In an analysis of 105 patients transplanted with omidubicel between 2006 and 2020 (median follow-up of 22 months), the data demonstrated an overall and disease-free survival rate of 63% (95% CI, 53%-73%) and 56% (95% CI, 47%-67%) at three years, respectively. A second presentation featured an analysis of 108 patients that completed validated health-related quality of life (HRQL) surveys on screening and days 42, 100, 180, and 365 post-transplant. Measures of physical and functional well-being and other HRQL scores were more favorable with omidubicel and suggest clinically meaningful and sustained improvements in physical, functional and overall well-being compared to umbilical cord blood (UCB) transplantation.
Presented data demonstrating the impact of transplantation with omidubicel for patients with hematologic malignancies at CBC: In September, at CBC, Gamida Cell presented data supporting the potential of omidubicel for the treatment of patients with blood cancers in need of an allogeneic hematopoietic stem cell transplant. The data suggest during the first-year post-transplant, patients receiving omidubicel had meaningfully greater preservation or improvement of important HRQL domains compared to UCB recipients. A second poster featured an analysis of the projected impact of allogeneic hematopoietic cell transplant on clinical outcomes and potential access for patients who currently cannot find a donor source, with the greatest improvements among the racial and ethnic groups underserved by the current standard of care. In a third poster, results of a translational sub-study from the Phase 3 trial showed that patients transplanted with omidubicel had more rapid and robust immune reconstitution than controls, including higher numbers of Recent Thymic Emigrants in peripheral blood at one year post transplant compared to transplantation with UCB, which suggest faster thymopoiesis and provide a mechanistic rational for the lower infection rates in these patients.
Continued launch preparations in preparation for January 30, 2023 PDUFA date: The company’s Biologics License Application (BLA) for omidubicel is under review with the U.S. Food and Drug Administration (FDA) with a target action PDUFA date of January 30, 2023. Gamida Cell continues to advance readiness activities throughout the organization to support the potential launch of omidubicel.
GDA-201: NAM-Enabled NK Cell Therapy

Continued advancement of Phase 1/2 study of cryopreserved formulation of GDA-201: Gamida Cell continues to advance its company-sponsored Phase 1/2 study evaluating a cryopreserved formulation of GDA-201 for the treatment of follicular and diffuse B-cell lymphomas.
NAM-Enabled NK Cell Pipeline Development

Presented preclinical data on GDA-501: At the SITC (Free SITC Whitepaper) Annual Meeting, Gamida Cell announced new preclinical data on GDA-501, a genetically modified HER2-CAR NAM-NK cell therapy candidate, that provide support for its continued preclinical development. GDA-501 displayed significantly enhanced in vitro cytotoxicity when cultured with HER2+ targeted cancer cells, as well as increased potency based on elevated levels of proinflammatory cytokines and biomarkers compared with control cells. Importantly, increased cytotoxicity and potency were persistent. These preclinical data demonstrate potent antitumor activity.
Continued the development of NAM-enabled genetically modified NK pipeline: Gamida Cell continues to progress its NAM-enabled genetically modified NK pipeline, which utilizes CAR, membrane bound- and CRISPR-mediated technologies to increase targeting, potency and persistence against hematologic malignancies and solid tumors. In order to both prioritize resources to the commercialization of omidubicel and advancement of GDA-201, as well as enable development activities to progress further, the company will hold on selecting an IND candidate and will continue to conduct in vitro and in vivo preclinical proof-of-concept studies for these genetically modified NK therapeutic targets.
Corporate Updates

Appointed Abigail Jenkins as President and CEO: As part of a CEO succession plan, Julian Adams retired as CEO and Abigail "Abbey" Jenkins was appointed as President and CEO. Ms. Jenkins has also been appointed to Gamida Cell’s Board of Directors. Ms. Jenkins brings over 25 years of leadership experience in the biopharmaceutical industry developing life-enhancing therapies from research to commercialization. Julian Adams will remain on the company’s Board of Directors.
Strengthened financial position: In September 2022, Gamida Cell executed an underwritten public offering raising approximately $20 million, before deducting underwriting discounts, commissions and offering expenses. Also, in September 2022, the company announced it entered into a commitment letter with Highbridge Capital Management, LLC for a $25 million senior secured, convertible term loan. These capital commitments will be used to fund the commercial readiness activities to support the potential launch of omidubicel, if approved, and to further the clinical development of its NK product candidates, including GDA-201.
Third Quarter 2022 Financial Results

Research and development expenses were $9.9 million in the third quarter of 2022, compared to $11.7 million in the same quarter in 2021. The decrease was attributable mainly to a $1.6 million decrease in clinical activities relating to the conclusion of the Phase 3 clinical trial and a decrease of $0.2 million in GDA-201 clinical program.
Commercial expenses were $2.8 million in the third quarter of 2022, compared to $5.8 million in the third quarter of 2021. The decrease was attributable mainly to an $2.5 million decrease in launch readiness activities, and $0.6 million decrease in headcount related expenses.
General and administrative expenses were $4.4 million in the third quarter of 2022, compared to $5.0 million in the same period in 2021. The decrease was mainly due to a $0.3 million decrease in professional services expenses and $0.3 million decrease in headcount related expenses.
Finance expenses, net, were $0.7 million in the third quarters of 2022 and 2021, with no material changes.
Net loss was $17.8 million in the third quarter of 2022, compared to a net loss of $23.2 million in the third quarter of 2021.
2022 Financial Guidance

Gamida Cell expects that its current total cash position, together with recent financing, will support the company’s ongoing operating activities into mid-2023, excluding the cost of commercializing omidubicel beyond the initial launch. This cash runaway guidance is based on the company’s current operational plans and excludes any additional funding and any business development activities that may be undertaken. Gamida Cell continues to assess all financing options that support its corporate strategy.

Expected Milestones in 2023

Omidubicel

PDUFA target action date of January 30, 2023.
Conference Call Information

Gamida Cell will host a conference call today, November 14, 2022, at 8:00 a.m. ET to discuss these financial results and company updates. To access the conference call, please register here and be advised to do so at least 10 minutes prior to joining the call. A live webcast of the conference call can be accessed in the "Investors & Media" section of Gamida Cell’s website at www.gamida-cell.com. A replay of the webcast will be available approximately two hours after the event, for approximately 30 days.

About NAM Technology
Our NAM-enabling technology is designed to enhance the number and functionality of targeted cells, enabling us to pursue a curative approach that moves beyond what is possible with existing therapies. Leveraging the unique properties of NAM (nicotinamide), we can expand and metabolically modulate multiple cell types — including stem cells and natural killer cells — with appropriate growth factors to maintain the cells’ active phenotype and enhance potency. Additionally, our NAM technology improves the metabolic fitness of cells, allowing for continued activity throughout the expansion process.

About Omidubicel
Omidubicel is an advanced cell therapy candidate developed as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant for patients with blood cancers. Omidubicel demonstrated a statistically significant reduction in time to neutrophil engraftment in comparison to standard umbilical cord blood in an international, multi-center, randomized Phase 3 study (NCT0273029) in patients with hematologic malignancies undergoing allogeneic bone marrow transplant. The Phase 3 study also showed reduced time to platelet engraftment, reduced infections and fewer days of hospitalization. One-year post-transplant data showed sustained clinical benefits with omidubicel as demonstrated by significant reduction in infectious complications as well as reduced non-relapse mortality and no significant increase in relapse rates nor increases in graft-versus-host-disease (GvHD) rates. Omidubicel is the first stem cell transplant donor source to receive Breakthrough Therapy Designation from the FDA and has also received Orphan Drug Designation in the US and EU.

The BLA for omidubicel has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of January 30, 2023. If approved, omidubicel will be the first allogeneic advanced stem cell therapy donor source for patients with blood cancers in need of a stem cell transplant.

Omidubicel is an investigational stem cell therapy candidate, and its safety and efficacy have not been established by the FDA or any other health authority. For more information about omidubicel, please visit View Source

About GDA-201
Gamida Cell applied the capabilities of its nicotinamide (NAM)-enabled cell expansion technology to develop GDA-201, an innate NK cell immunotherapy candidate for the potential treatment of hematologic and solid tumors in combination with standard of care antibody therapies. GDA-201, the lead candidate in the NAM-enabled NK cell pipeline, has demonstrated promising initial clinical study data. Preclinical studies have shown that GDA-201 may address key limitations of NK cells by increasing the cytotoxicity and in vivo retention and proliferation in the bone marrow and lymphoid organs. Furthermore, these data suggest GDA-201 may improve antibody-dependent cellular cytotoxicity (ADCC) and tumor targeting of NK cells. There are approximately 40,000 patients with relapsed/refractory lymphoma in the US and EU, which is the patient population that will be studied in the currently ongoing GDA-201 Phase 1/2 clinical trial.

On November 14, 2022 Rakovina Therapeutics Inc. (TSX-V: RKV) ("the Company"), reported publication of a scientific article on the anti-cancer activity of the Company’s novel dual PARP-HDAC inhibitor in models of Ewing sarcoma (Press release, Rakovina Therapeutics, NOV 14, 2022, View Source [SID1234624041]).

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The manuscript entitled "A bi-functional PARP-HDAC inhibitor with activity in Ewing sarcoma", indicate a benefit of dual PARP and HDAC inhibition and provide proof-of-concept for a bi-functional single-molecule therapeutic strategy in the treatment of Ewing sarcoma.

Ewing sarcoma is a highly aggressive bone and soft tissue tumor affecting mainly children and young adults, with a dismal 5-year survival rate of 15-30% for metastatic disease. Previous studies have demonstrated that Ewing sarcoma cells are sensitive to FDA-approved PARP inhibitors, but clinical trials have failed to produce a durable treatment response.

PARP inhibitors have been demonstrated to impact tumors that harbor BRCA mutations or other defects in homologous repair (HR). This concept is commonly referred to as "BRCAness".

Ewing sarcoma is characterized by the presence of a genetic fusion involving the EWSR1 gene. This fusion has been shown to impair HR activity indicating a level of "BRCAness" in Ewing sarcoma. The lack of clinical response in Ewing sarcoma to treatment with single-agent PARP inhibitors supports employing combination therapy strategies that further inhibit HR and increase BRCAness in Ewing sarcoma.

Recent studies in leukemia, breast cancer, liver cancer, glioblastoma, prostate cancer and anaplastic thyroid models demonstrated suppression of HR following treatment with HDAC inhibitors, supporting the synergistic potential of dual HDAC and PARP inhibition.

Rakovina Therapeutics researchers characterized and tested kt-3283, a novel dual-function single molecule of PARP and HDAC in Ewing sarcoma model systems. In these studies, kt-3283 demonstrated higher efficacy than treatment with single-agent PARP or HDAC inhibitors. These data indicate the dual activity of kt-3283 is 30- to 80-times more potent in Ewing sarcoma models than an FDA-approved PARP inhibitor, and 30- to 60-times more potent than an FDA-approved HDAC inhibitor. In an Ewing sarcoma metastasis model, kt-3283 prevented metastatic cancer growth in the lungs of mice inoculated with an aggressive Ewing sarcoma cell line.

"These results provide proof-of-concept for a novel single-molecule PARP-HDAC inhibitor in the treatment of Ewing sarcoma," stated Prof. Mads Daugaard Rakovina Therapeutics’ president and chief scientific officer. "This concept will likely be relevant in other cancer indications beyond Ewing sarcoma and potentially offer an opportunity to suppress therapeutic resistance to PARP-inhibitor treatment."

Development of Rakovina Therapeutics’ novel kt-3000 DNA-damage response inhibitors is supported, in part, by the St. Baldrick’s Foundation Martha’s BEST Grant for All, which is aimed at developing new treatments for Ewing sarcoma, an aggressive bone and soft tissue cancer in children and young adults.

On November 14, 2022 Agenus (Nasdaq: AGEN), an immuno-oncology company with a broad pipeline targeting cancer and infectious disease, reported expanded data from the Company’s Phase 1 study of botensilimab (Fc-enhanced anti-CTLA-4) and balstilimab (anti-PD-1) in patients with treatment-resistant tumors, including MSS-CRC, ovarian, sarcoma and NSCLC (Press release, Agenus, NOV 14, 2022, View Source [SID1234624040]). The data presented represents four of the most mature data sets from the nine cancer types where responses have been observed to date. The data was presented at a plenary session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting and a company-hosted R&D event.

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"This expanded dataset demonstrates the tremendous potential of botensilimab and balstilimab to treat a wide range of immunotherapy-resistant tumors," said Steven O’Day, M.D., Chief Medical Officer of Agenus. "Importantly, the superior efficacy we observed in our MSS-CRC presentation at GI ESMO (Free ESMO Whitepaper) earlier this year has remained consistent across a larger dataset. Further, we are seeing a strong signal with higher response rates than has been reported with other immunotherapies in multiple tumor types, including anti-PD-(L)1 relapsed/refractory NSCLC. These data provide compelling support for our ongoing Phase 2 botensilimab development program and highlight the broad therapeutic potential of botensilimab across solid tumors."

Study Design and Highlights

Out of over 250 enrolled patients, data on 125 patients has matured to efficacy and safety evaluation. These include four primary expansion cohorts in MSS CRC, recurrent platinum refractory/resistant ovarian, sarcoma and PD-(L)1 relapsed/refractory NSCLC. Patients in these cohorts received either 1 or 2 mg/kg botensilimab every 6 weeks and 3 mg/kg balstilimab every 2 weeks, with imaging assessments every six weeks. Fixed dosing was also permitted whereby patients received botensilimab 150 mg every 6 weeks, and balstilimab 450 mg every 3 weeks. Trial enrollees were heavily pre-treated with the majority receiving at least 3 prior lines of therapy.

MSS-CRC:

59 evaluable patients
76% failed on ≥3 prior lines of therapy
34% did not respond to prior experimental I-O
22% overall response rate: 1 complete response (CR), 12 partial responses (PR)
Other PD-(L)1 + CTLA-4 combination regimens in comparable patient populations achieved only 1-5% response rates1,2
73% disease control rate
Median duration of response not reached
69% of responses are ongoing
31% of responses have already exceeded 1 year
Median Progression Free Survival (mPFS) of 4.1 months; 12 month Overall Survival (OS) of 60.4%; median Overall Survival (mOS) has not been reached
Other PD-(L)1 + CTLA-4 combination regimens in comparable patient populations achieved a 1.8 mPFS and 6.6 mOS
Ovarian:

19 evaluable patients
71% received ≥3 prior lines of therapy
26% overall response rate: 1 CR, 4 PRs
Other PD-(L)1 + CTLA-4 combination regimens in comparable patient populations achieved only 3-10% response rates3,4
63% disease control rate
Median duration of response not reached
Sarcoma:

12 evaluable patients
73% received ≥3 prior lines of therapy
42% overall response rate: 1 CR, 4 PRs
Other PD-(L)1 + CTLA-4 combination regimens in comparable patient populations achieved only 12-16% response rates5,6
50% response rate in angiosarcoma, including 3 of 4 patients with visceral angiosarcoma
Other PD-(L)1 + CTLA-4 combinations achieved only 20-25% response rates with no reported responses in 7 treated patients with visceral angiosarcoma6,7
67% disease control rate
Median duration of response not reached
60% of responses have already exceeded 1 year and are ongoing
Anti-PD-(L)1 Relapsed/Refractory NSCLC:

5 evaluable patients (including 1 evaluable patient dosed after the data cut-off)
60% overall response rate
Other PD-(L)1 + CTLA-4 combination regimens in comparable patient populations achieved only 6-13% response rates8,9
80% disease control rate
Median duration of response not reached
67% of responses are ongoing
Tolerability:

Botensilimab was well tolerated, with no new immune-mediated safety signals outside of those observed in the class. Rates of gastrointestinal and skin toxicities were comparable to those reported with first-generation CTLA-4 inhibitors, while other immune mediated toxicities were less frequent than expected, consistent with botensilimab’s design to reduce complement binding.

"There is an urgent need to develop new therapies for patients suffering with cold and refractory tumors as current standards of care typically offer only single-digit response rates, "said Breelyn Wilky, M.D., Principal Investigator and Director of Sarcoma Medical Oncology at the University of Colorado School of Medicine. "The robust and durable clinical responses demonstrated by botensilimab and balstilimab in this study across a wide spectrum of refractory tumor types, coupled with its well-tolerated safety profile, provide strong support for the further development of this combination in a broad range of patients."

Presentation Details:

Abstract Number: 778

Abstract Title: Botensilimab, a novel innate/adaptive immune activator, plus or minus balstilimab (anti-PD-1) in ‘cold’ and I-O refractory metastatic solid tumors

Presenting Author: Breelyn A. Wilky, M.D., Director of Sarcoma Medical Oncology, Deputy Associate Director for Clinical Research University of Colorado School of Medicine

The data were presented on Saturday, November 12 at both the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) and "The Road Taken" R&D event hosted offsite by Agenus. An archived version of each presentation will be available on the Agenus website.