On January 19, 2023 Cyteir Therapeutics, Inc. ("Cyteir") (Nasdaq: CYT) reported the strategic prioritization of clinical development of CYT-0851, an investigational monocarboxylate transporter inhibitor, as a potential combination therapy for the treatment of ovarian cancer (Press release, Cyteir Therapeutics, JAN 19, 2023, View Source [SID1234626408]). The prioritization follows encouraging preliminary clinical activity in a small number of patients observed in the Phase 1 dose escalation cohort with CYT-0851 in combination with capecitabine in advanced ovarian cancer. Cyteir plans to expand its evaluation of CYT-0851 in combination with capecitabine to treat advanced ovarian cancer and enroll additional patients in the first half of 2023 to further support these early signals. If successful, the combination of CYT-0851 with capecitabine has the potential to be an all-oral treatment for ovarian cancer. In conjunction with focusing clinical activities on ovarian cancer, Cyteir is reducing headcount by approximately 70% and deferring research and development in other areas, which is expected to extend Cyteir’s cash runway into 2026.

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CYT-0851 Development to Prioritize Combination Therapy

Phase 1 dose escalation cohorts with CYT-0851 in combination with capecitabine for the treatment of advanced ovarian cancer have shown encouraging preliminary clinical activity. To date, thirteen patients have been treated with CYT-0851 (from 100-400mg daily) and capecitabine, including five patients with advanced ovarian cancer. Responses and disease stabilization observed in these ovarian cancer patients in the 300mg and 400mg CYT-0851 dose levels are encouraging, and have led to Cyteir’s decision to focus on further development of this capecitabine combination in advanced ovarian cancer. Overall, CYT-0851 continues to be generally well tolerated with no new safety concerns.
In the first quarter of 2023, Cyteir expects to determine a maximum tolerated dose ("MTD") for CYT-0851 in combination with capecitabine and focus its efforts on enrolling and treating additional patients with advanced ovarian cancer at the MTD. If the data from these additional patients further support Cyteir’s focus on ovarian cancer, Cyteir intends to pursue development and potential registration of CYT-0851 in combination with capecitabine as an all-oral treatment for platinum resistant ovarian cancer.

In addition, Cyteir is evaluating CYT-0851 in Phase 1 dose escalation cohorts in combination with gemcitabine. To date, ten patients have been treated with CYT-0851 (from 100-200mg daily) and gemcitabine. Cyteir will continue the ongoing dose escalation cohorts with CYT-0851 and gemcitabine in solid tumor patients to identify an MTD, which could provide an additional opportunity to develop CYT-0851 as a combination therapy to treat patients with platinum resistant ovarian cancer.

Enrollment in the Phase 2 monotherapy cohorts with CYT-0851 will be suspended due to insufficient monotherapy activity observed to date. Cyteir plans to disclose the Phase 1 combination data for CYT-0851 in mid-2023.
"We are encouraged by these early signals and believe that an initial focus on the combination of CYT-0851 and capecitabine represents the greatest likelihood of success and an opportunity to serve patients with advanced ovarian cancer that have a high unmet medical need. This combination, if successful, has the potential to be an all-oral treatment regimen for patients with platinum resistant ovarian cancer," said Markus Renschler, MD, Cyteir’s President and CEO. "This strategic prioritization and the difficult decision to reduce our workforce is expected to extend our cash runway into 2026 and, if supported by the data and regulatory feedback, allows us to advance CYT-0851 into a potentially registrational trial as early as the second half of 2024. I personally would like to thank all of our dedicated employees and express my gratitude for their hard work in advancing our pipeline, and I wish them the best in the future."

In the United States, it is estimated that a total of approximately 13,000 patients are available for drug treatment per year who are platinum resistant and have progressed after two lines of prior therapy, or have progressed after at least three prior lines of therapy.

Deferral of R&D Activities Beyond Clinical Development of CYT-0851 to Extend Cash Runway

In conjunction with focusing development activities on CYT-0851, Cyteir announced that it will be suspending all preclinical research. Specific actions include:

Ceasing drug discovery projects focused on identifying inhibitors of DNA damage repair; and
Reducing company headcount to approximately 15 full-time employees.
Based on current estimates, including assumptions for continuation of clinical development of CYT-0851 towards registration as a combination therapy, Cyteir expects that these actions will extend its cash runway into 2026. As of December 31, 2022, on an unaudited basis, Cyteir had approximately $147 million in cash and cash equivalents. Cyteir estimates that it will incur aggregate charges of approximately $2.5 million to $3 million, all of which are anticipated to result in future cash expenditures, primarily for one-time employee severance and benefit costs, the majority of which are expected to be incurred in the first quarter of 2023.

On January 19, 2023 EpicentRx, a leading edge, clinical stage biopharmaceutical company, reported the publication of Phase 2 results of the PREVLAR trial which demonstrated that RRx-001 protects against severe oral mucositis in patients receiving radiation and chemotherapy for head and neck cancer (Press release, EpicentRx, JAN 19, 2023, View Source [SID1234626407]). The study was published in the International Journal of Radiation Oncology, Biology and Physics, also known as The Red Journal.

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PREVLAR, a multi-institutional, randomized trial compared the safety and efficacy of three dosing schedules of RRx-001 to mitigate oral mucositis in patients receiving concomitant chemoradiation for the treatment of oral and oropharyngeal cancers. Among the findings reported by Dr. David Sher from University of Texas Southwestern in Dallas and his colleagues in their paper "PREVLAR: Phase 2 randomized trial to assess the safety and efficacy of RRx-001 in the attenuation of oral mucositis in patients receiving head and neck chemoradiotherapy" was the observation that pre-radiation RRx-001 alone favorably impacted the incidence and duration of severe oral mucositis (SOM) safely. Importantly, RRx-001 patients responded no differently to their cancer than did patients in a control arm when evaluated two years after the completion of their chemoradiation treatment.

SOM is among the most common and symptomatically severe complications of concomitant chemoradiation used routinely to treat cancers of the head and neck. SOM occurs in approximately 70% of head and neck cancer patients. The sores or ulcerations associated with mucositis are often present throughout the mouth and throat and are associated with unmanageable pain, impaired nutrition, and dehydration, which result in more emergency room visits and hospitalizations. Most impactful on survival are the negative effects of SOM on patients’ ability to tolerate optimal treatment of their cancers.

The potential of RRx-001 as a protective agent for non-cancer, normal cells is related to its joint activities as an NLRP3 inflammasome inhibitor and activator of the Nrf2 antioxidant transcription factor. A larger Phase 2 randomized study named KEVLAR is planned with RRx-001 for further clinical evaluation of oral mucositis prevention.

Dr. Stephen Sonis, Harvard Professor of Oral Medicine and member of the Distinguished Faculty of the Dana-Farber Cancer Institute, and manuscript co-author, commented that "the results noted in PREVLAR suggest that RRx-001 may provide protection from severe radiation-associated mucositis with a dosing schedule that is highly desirable for both patients and radiation oncologists. I look forward to further study of this treatment in the subsequent KEVLAR study."

About RRx-001
The lead EpicentRx small molecule, RRx-001 is a highly selective NLRP3 inhibitor with vascular normalization and tumor associated macrophage polarization properties that resensitizes tumors to previously administered therapies. RRx-001 is under investigation in a Phase 3 trial for the treatment of small cell lung cancer (SCLC), and in a Phase 2 trial for protection against oral mucositis in first line head and neck cancer. It is also under development as a medical countermeasure for nuclear and radiological emergencies and as a treatment for neurodegenerative diseases like Parkinson’s and ALS/MND.

On January 19, 2023 NeoPhore Limited, a small molecule neoantigen immuno-oncology company, reported the completion of its £21.5m (US $28.5m) Series B financing, with a £6m (US $7.5m) financing extension (Press release, NeoPhore, JAN 19, 2023, View Source [SID1234626406]). The syndicate comprised its Series B subscribing investors including CRT Pioneer Fund, Claris Ventures, 2Invest, 3B Future Health Fund and Astellas Venture Management.

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NeoPhore is focused on the discovery and development of novel first-in-class small molecule drugs targeting the DNA mismatch repair (MMR) pathway to treat cancer. The additional funding will be used to progress NeoPhore’s expanding pipeline of drugs, encompassing multiple biological targets and modalities of treatment, to the start of IND-enabling studies in 2024.

Dr Robert James, Chairman of NeoPhore, said: "This additional support from NeoPhore’s existing investors is a strong testament to the Company’s novel and differentiated immunotherapy approach. We believe that by altering the tumour genotype to elicit immunological responses, we can offer huge clinical benefit in the level and durability of anti-tumour responses in a wide range of indications for the benefit of cancer patients. 2022 was a year of remarkable progress for NeoPhore in which it demonstrated, for the first time that we are aware of, a number of exciting therapeutic consequences of inhibiting mismatch repair with a small molecule."

In January 2022, NeoPhore achieved all of its investment related scientific milestones significantly ahead of schedule. In February 2022, NeoPhore expanded its research partnership with St George’s, University of London after a successful collaboration investigating novel cancer immunotherapies, and in July 2022, the Company entered a three-year research collaboration agreement with Memorial Sloan Kettering Cancer Center (MSK) to further validate the potential of NeoPhore’s proprietary DNA mismatch repair inhibitor (MMRi) compounds to enhance tumour immunogenicity and induce tumour immunity.

Dr Matthew Baker, Chief Executive Officer of NeoPhore, added: "2022 was a year of progress for NeoPhore. Collaborating with such prominent leaders in the field allowed us to advance our goal of developing next-generation immuno-oncology therapeutics. It is known that drugs designed to spark cancer neoantigen creation and subsequently stimulate the immune system, can improve outcomes for patients who do not benefit from the current generation of cancer immunotherapies. We welcome the continued support from our investors that enables us to further develop our drug discovery pipeline."

On January 19, 2023 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) and Zymeworks Inc. (Nasdaq: ZYME) reported tolerability and efficacy results, including the first overall survival (OS) data, from a Phase 2 trial examining zanidatamab, an investigational HER2-targeted bispecific antibody, in combination with chemotherapy, in first-line patients with HER2-expressing metastatic gastroesophageal adenocarcinoma (mGEA) (Press release, Jazz Pharmaceuticals, JAN 19, 2023, View Source [SID1234626405]).

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The preliminary results showed that, at the time of analysis, the median OS had not yet been reached with a median duration of study follow-up of 26.5 months. The 18-month overall survival rate was 84% [95% confidence interval (CI): 68%, 93%].

"Gastroesophageal adenocarcinoma represents one of the most frequent tumor types worldwide and, tragically, a leading cause of cancer-related deaths. Compared to what has historically been reported for OS with the current approved standard of care1, the OS findings from the combination of zanidatamab and chemotherapy in this trial are very compelling," said Dr. Elena Elimova, lead trial investigator and a medical oncologist at Princess Margaret Cancer Centre. "HER2 has been recognized as a predictive biomarker for these cancers, and it is promising to see a treatment targeting this expression exhibit strong and durable anti-tumor activity when administered with chemotherapy."

"We are very encouraged by the data from this Phase 2 trial, which demonstrate zanidatamab administered with chemotherapy is a highly active treatment regimen and resulted in significant and durable tumor response in the first-line setting for patients with advanced HER2-expressing mGEA," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "These results showcase zanidatamab’s potential as a foundational treatment for patients with HER2-positive mGEA, and we look forward to additional data in 2024 from the ongoing pivotal Phase 3 trial that may support U.S. and global regulatory filings."

Trial Results

The data include efficacy and tolerability findings from an ongoing, open-label Phase 2 study (NCT03929666) evaluating zanidatamab in combination with chemotherapy as first-line treatment for patients with advanced HER2-expressing mGEA, which is comprised of gastric, esophageal and gastroesophageal junction (GEJ) patients. Patients had not received prior HER2-targeted agents nor systemic treatment for mGEA. A total of 46 patients with mGEA were enrolled from 15 sites across the United States, Canada and South Korea, and patients were administered zanidatamab with physician’s choice of chemotherapy treatment (standard first-line combination therapy).

The data demonstrated zanidatamab combined with standard chemotherapy is a highly active treatment regimen for first-line therapy of HER2-positive mGEA. In 42 patients evaluable for OS receiving zanidatamab in combination with chemotherapy, the 18-month OS rate was 84% (95% CI: 68%, 93%), the 12-month OS rate was 88% (95% CI: 73%, 95%), and the median overall survival had not yet been reached (with 26.5 months median duration of study follow-up). Treatment with zanidatamab resulted in a confirmed objective response rate (cORR) of 79% (95% CI: 63-90%), a disease control rate (DCR) of 92% (95% CI: 79-98%), with three patients achieving complete response among 38 response-evaluable patients.

The median duration of response was 20.4 months (95% CI: 8.3-NE) with a median progression-free survival (mPFS) of 12.5 months (95% CI: 7.1-NE) with 17 patients having an ongoing response at the time of data cutoff. The regimen was manageable, tolerable and consistent with the observed safety profiles reported for other standard combination regimens for patients with HER2-positive GEA.

Data were presented in a poster session entitled Zanidatamab + Chemotherapy as First-Line Treatment for HER2-expressing Metastatic Gastroesophageal Adenocarcinoma (mGEA) during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Gastrointestinal Cancers Symposium (ASCO GI) taking place in San Francisco. The presentation is available to conference registrants on the ASCO (Free ASCO Whitepaper) GI conference website (Abstract Number 347), and will be available to the general public on Zymeworks’ website.

Zymeworks continues to enroll patients in the Phase 3 randomized clinical trial, HERIZON-GEA-01 (NCT05152147), evaluating zanidatamab in combination with chemotherapy plus or minus tislelizumab as a first-line treatment for HER2-expressing mGEA.

About Zanidatamab
Zanidatamab is an investigational bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks, along with collaborators Jazz and BeiGene, Ltd. (BeiGene), are developing zanidatamab in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for first-line GEA. Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.

About Gastroesophageal Adenocarcinoma

Gastroesophageal adenocarcinoma (GEA) is the fifth most common cancer worldwide, and approximately 20% of patients are HER2–positive.2,3,4 HER2–positive GEA has high morbidity and mortality, and patients are urgently in need of new treatment options.

On January 19, 2023 Linnaeus Therapeutics, Inc. (Linnaeus), a privately held clinical-stage biopharmaceutical company focused on the development and commercialization of novel small-molecule oncology therapeutics, reported that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for LNS8801 for the treatment of patients with metastatic cutaneous melanoma (Press release, Linnaeus Therapeutics, JAN 19, 2023, View Source [SID1234626404]).

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The FDA’s Office of Orphan Drug Products grants orphan drug status to support drug candidates in development for underserved patient populations or rare disorders that affect fewer than 200,000 people in the United States. Orphan drug designation provides certain benefits, including market exclusivity upon FDA approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

"We are extremely pleased to have received orphan drug designation for cutaneous melanoma from the FDA. This is an important milestone that has emerged from the very promising data we have seen in biomarker-defined patients with metastatic cutaneous melanoma in our dose-expansion cohorts," commented Patrick Mooney, MD, CEO of Linnaeus. "We look forward to further opening a randomized controlled study in patients with treatment-refractory cutaneous melanoma to explore the promising results we have already seen with LNS8801 alone and also in combination with pembrolizumab."

Having completed dose escalation, Linnaeus is currently testing LNS8801 in its phase 1/2 adaptive-design clinical trial as a monotherapy and in combination with KEYTRUDA (pembrolizumab) in various cancers and patient populations.

About LNS8801

LNS8801 is an orally bioavailable and highly specific and potent agonist of GPER whose activity is dependent on the expression of GPER. GPER activation by LNS8801 rapidly and durably depletes c-Myc protein levels. In preclinical cancer models, LNS8801 displays potent antitumor activities across a wide range of tumor types, rapidly shrinking tumors and inducing immune memory.

In the ongoing clinical study in humans, LNS8801 monotherapy has been safe and well tolerated. Additionally, LNS8801 has demonstrated target engagement, c-Myc protein depletion, and clinical benefit in patients with advanced cancers, and a predictive biomarker has been identified.