On February 12, 2024 Purple Biotech Ltd. ("Purple Biotech" or "the Company") (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class therapies that harness the power of the tumor microenvironment to overcome tumor immune evasion and drug resistance, reported that it convened a Scientific Advisory Board (SAB) focusing the discussions on NT219’s indication in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) (Press release, Purple Biotech, FEB 12, 2024, View Source [SID1234640039]).

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"This scientific advisory board of head and neck cancer key opinion leaders, who are oncologists, researchers, and investigators, provided us their insights on the therapeutic landscape of R/M SCCHN treatment and invaluable guidance on clinical studies for NT219 in combination with cetuximab as a second/third line treatment and potentially in combination with a PD1 inhibitor as a first line treatment," stated Purple Biotech CEO, Gil Efron. "Their recognition of the critical unmet need in recurrent and metastatic head and neck cancer provides further support and momentum to our development program. Now that we have determined the recommended Phase 2 dose, we are prepared to move to our next phase of development. We look forward to the head and neck cancer SAB’s continued guidance and support."

Head & Neck Cancer SAB Members Include:

Douglas Adkins, MD – Dr. Adkins is a Professor of Medicine and Director, Head and Neck and Thyroid Medical Oncology, at the Siteman Cancer Center, Washington University School of Medicine. He is a nationally recognized expert in head and neck cancer known for his commitment to advancing patient care through clinical research. With approximately 350 publications to his name, Dr. Adkins serves on committees including the National Cancer Institute: Head and Neck Steering Committee and Focus Group Member, Metastatic and Recurrent Head and Neck Cancer Task Force from 2015 to 2021.

Ezra Cohen, MD – Dr. Cohen is a Chief Medical Officer of oncology of Tempus AI. He was most recently the Chief of the Division of the Hematology-Oncology and Associate Director of Translational Science at Moores Cancer Center in San Diego, California, and Lead Principal Investigator of Purple Biotech’s Phase 1 /2 dose escalation study of NT219 in the treatment of R/M SCCHN. Dr. Cohen is a medical oncologist and an internationally recognized cancer researcher. He cares for patients with all types of head and neck cancers, including esophageal, thyroid and salivary gland cancers. As a physician-scientist, Dr. Cohen also leads a laboratory that studies novel cancer treatments, including immunotherapy, and has made major contributions in understanding how targeted cancer therapies work. A frequent speaker at national and international meetings, he has authored more than 170 peer-reviewed papers and has been the principal investigator of multiple clinical trials of new drugs for head and neck cancer and other solid tumors in all phases of development.

Antonio Jimeno, MD, PhD – Dr. Jimeno is a Professor at the University of Colorado School of Medicine, the Director of the Head and Neck Cancer (HNC) Program and the Communicating PI of the Colorado HNC SPORE. Clinically, he has an active portfolio of trials investigating relevant targets to modulate immunity and the microenvironment in HNC. Preclinically, his focus is studying how HNC regulates key immune ligands deploying humanized models of HNC to investigate susceptibility to immune modulation and immune evasion mechanisms. Overall, his work furthers understanding of cancer and microenvironment interactions and the development of increasingly powerful and complex models.

Lisa Licitra Francesca Linda, MD – Professor Licitra is a Scientific Director of CNAO, the Hadrontherapy facility in Pavia, Italy. Prof. Licitra served as Associate Professor, Department of Oncology and Hemato-Oncology and Chief of Head and Neck Cancer Medical Oncology Department at Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. She is Co-founder and member of the European Head and Neck Cancer Society. Prof. Licitra has authored nearly 400 papers in peer-reviewed journals, written 20 book chapters, and approximately 150 scientific articles.

Ari Rosenberg, MD – Dr. Rosenberg is Assistant Professor of Medicine at the University of Chicago and an oncologist who specializes in using basic, translational, and clinical research to improve the lives of his patients. As a clinical investigator, Dr. Rosenberg develops and conducts clinical trials that incorporate novel tissue and blood-based biomarkers, and he has a particular focus on novel therapies and immunotherapeutic strategies, as well as developing multimodality treatment paradigms to reduce treatment-related toxicity.

About NT219

NT219 is a first-in-class, small molecule that promotes Insulin Receptor Substrates 1/2 (IRS) degradation and inhibits Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation, two major complementary signaling pathways that play a key role in the tumor and its microenvironment. IRS1/2 acts as scaffolds, organizing signaling complexes that mediate mitogenic, metastatic, angiogenic, and anti-apoptotic signals from IGF1R and other oncogenes, consisting of an important driver in multiple cancers and is highly involved in triggering drug resistance. STAT3 is a transcription factor that is broadly hyperactivated in many cancers, promoting proliferation, survival, angiogenesis, metastasis, and tumor immune evasion. Feedback activation of STAT3 plays a prominent role in mediating drug resistance to various anti-cancer therapies. As an inhibitor of both IRS1/2 and STAT3, NT219 has the potential to prevent the development of resistance to multiple approved therapies.

On February 12, 2024 RadioMedix, Inc. and Orano Med, two clinical stage radiopharmaceutical companies, reported that the United States Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to AlphaMedixTM (212Pb-DOTAMTATE) for the treatment of adult patients with unresectable or metastatic, progressive somatostatin receptor expressing gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who are naïve to peptide receptor radionuclide therapy (PRRT) (Press release, RadioMedix, FEB 12, 2024, View Source [SID1234639991]). AlphaMedixTM is a Targeted Alpha Therapy currently in Phase 2 clinical development, which consists of an SSTR-targeting peptide complex radiolabeled with lead-212 (212Pb) that serves as an in vivo generator of alpha particles. Due to their high energy and short path length, alpha emitters enable specific targeting and killing of individual cancer cells, while minimizing toxicity to surrounding healthy tissue. AlphaMedixTM is the first Targeted Alpha Therapy to receive Breakthrough Therapy Designation.

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"The FDA’s Breakthrough Therapy Designation underscores AlphaMedixTM potential as an innovative treatment that could redefine how patients with neurendocrine tumors are treated. We believe that AlphaMedix has potential to demonstrate substantial benefit over currently FDA approved PRRT with beta-particle emitters for patients with metastatic or inoperable SSTR-expressing GEP-NETs. The FDA’s decision is a great news for patients suffering from this illness, and an important milestone to expedite the development of this new therapy," said Ebrahim Delpassand, MD, Chairman and Chief Executive Officer of RadioMedix.

The Breakthrough Therapy Designation is based on the results from phase 1 and the ongoing phase 2 clinical trials that assessed the safety and efficacy of AlphaMedixTM. In the phase 1 study, treatment was well-tolerated, with a response rate (ORR according to RECIST 1.1) of 62.5% for the GEP-NET patients who had never received PRRT with LutatheraTM, which is based on the beta-particle emitter Lutetium-177. In the phase 2 trial, the target response rate has already been achieved ahead of top-line data, expected in mid-2024.

"Receiving FDA Breakthrough Therapy Designation for AlphaMedixTM is a great achievement for everyone involved and confirms the strong interest of the medical community for Targeted Alpha Therapies with lead-212. Based on positive results from our clinical studies to date, we are convinced that Targeted Alpha Therapies, such as AlphaMedixTM, will lead the next generation of radioligand therapies, providing increased cytotoxicity against cancer cells but limited toxicity to adjacent healthy cells. This recognition from the FDA reinforces Orano Med’s commitment to make innovative lead-212-based therapies available to the medical community and patients worldwide," said Julien Dodet, President and Chief Executive Officer of Orano Med.

About Breakthrough Therapy Designation

Breakthrough Therapy Designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

About neuroendocrine tumors

Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms that originate from neuroendocrine cells. These neoplasms occur mostly in the gastrointestinal tract and pancreas (GEP-NETs) but can also occur in other tissues including the thymus, lung, and other uncommon sites such as ovaries, heart, and prostate. Most NETs strongly express somatostatin receptors (SSTRs). In the United States, around 12,000 patients annually are expected to be diagnosed with neuroendocrine tumors, with an average 5-year survival rate of 60% at a metastatic stage.

About Targeted Alpha Therapy

Targeted alpha therapy (TAT) relies on a simple concept: combining the ability of biological molecules to target cancer cells with the short-range and highly energetic cell-killing capabilities of alpha-emitting radioisotopes. Alpha decay consists of the emission of a helium nucleus (alpha particle) together with very high linear energy transfer and a range emission of only few cell layers, resulting in irreparable double strand DNA breaks in cells adjacent only to area of alpha emission. This approach results in an increased cytotoxic potential toward cancer cells while limiting toxicity to nearby healthy cells. As a result, alpha emitters are considered as the most powerful payloads to be found for targeted therapies.

On February 12, 2024 Calidi Biotherapeutics, Inc. (NYSEAM: CLDI) ("Calidi"), a clinical-stage biotechnology company developing a new generation of targeted immunotherapies, reported an upcoming presentation to provide details on the development of the Company’s systemic enveloped oncolytic virotherapy platform which has the potential to provide a universal treatment for a broad range of advanced tumor types (Press release, Calidi Biotherapeutics, FEB 12, 2024, View Source [SID1234639990]). Stephen Thesing, Chief Business Officer of Calidi, will be presenting at the Biocom Global Life Science Partnering & Investor Conference on February 28, 2024 at 3:00 p.m. PT, to discuss the Company’s newly announced systemic enveloped oncolytic virotherapy program targeting all tumor types, including advanced metastatic disease, and provide an update on the clinical development progress of Calidi’s CLD-101 (NeuroNova) and CLD-201 (SuperNova) programs.

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Calidi’s systemic enveloped virotherapy program, ImmunoNova, leverages extensive experience in utilizing cells to protect, potentiate and deliver virotherapies. Utilizing an engineered and enveloped vaccinia virus, ImmunoNova shows promising potential in targeting advanced metastatic disease across the body, while maintaining survival in the bloodstream. Preclinical models have demonstrated ImmunoNova’s efficacy in transforming tumor immune microenvironments and eradicating distant and diverse tumors. In addition, the program exhibits synergistic potential with other immunotherapies, including cell therapies, enhancing its ability to attack and eliminate disseminated solid tumors.

"Calidi’s groundbreaking systemic enveloped virotherapy holds immense promise in revolutionizing the treatment landscape for cancer patients with advanced solid tumors. By priming the tumor microenvironment, our therapy empowers immune cells, activates the immune system, and ultimately eliminates tumors," said Allan Camaisa, CEO and Chairman of the Board of Calidi Biotherapeutics. "We are encouraged by the promising preclinical data from our new program and while continuing to advance our existing clinical pipeline to fight cancer on all fronts."

On February 12, 2024 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported that it will regain global development and commercialization rights to camonsertib (RP-3500), a potential best-in-class oral small molecule inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein kinase), following termination of its collaboration agreement with Roche (Press release, Repare Therapeutics, FEB 12, 2024, View Source [SID1234639989]).

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Roche notified Repare that, effective May 7, 2024, it is terminating its worldwide license and collaboration agreement for the development and commercialization of camonsertib following a review of Roche’s pipeline and evolving external factors. Repare regains full control of all rights for camonsertib, a potential best-in-class inhibitor of ATR.

"Camonsertib is a valuable, high-potential precision oncology medicine that has achieved clinical proof-of-concept in multiple tumor types and genotypes both as monotherapy and in combination, as previously reported. We have been continuously running clinical trials for camonsertib since July 2020 and are excited to steward the progress of this promising therapy," said Lloyd M. Segal, President and Chief Executive Officer of Repare. "While we are disappointed to end this collaboration, we appreciate the contributions Roche has made to the program. With the return of camonsertib, Repare’s deep clinical pipeline consists of four wholly-owned synthetic lethal therapies."

Camonsertib is also part of Repare’s ongoing Phase 1 MYTHIC trial evaluating the combination of camonsertib and lunresertib, a first-in-class, oral small molecule inhibitor of PKMYT1, in patients with molecularly selected, advanced solid tumors. In October 2023, Repare presented data on the camonsertib and lunresertib combination, demonstrating clear evidence of clinical benefit across multiple tumor types and all selected genotypes, with an overall response of 33.3% across all tumor types and 50% RECIST objective response in patients with heavily pre-treated gynecologic tumors at the preliminary recommended Phase 2 dose of the combination. Repare expects to report additional camonsertib and lunresertib combination therapy data from the expansion cohorts of this trial in the second half of 2024. ​

Repare has met all obligations under the Roche agreement to date, and recently earned a $40 million milestone payment from Roche. Repare continues to expect that its existing cash, cash equivalents, and marketable securities will provide sufficient capital to fund planned operations into mid-2026.

On February 12, 2024 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the initiation of the Phase 2 portion of ALKOVE-1, its Phase 1/2 clinical trial of NVL-655 for patients with ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors, following alignment with the US Food and Drug Administration (FDA) on a recommended Phase 2 dose (RP2D) of 150 mg once daily (QD) (Press release, Nuvalent, FEB 12, 2024, View Source [SID1234639987]).

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NVL-655 is a novel brain-penetrant ALK-selective tyrosine kinase inhibitor (TKI) created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, brain metastases, and off-target central nervous system (CNS) adverse events associated with inhibition of the structurally-related tropomyosin receptor kinase (TRK) family that may limit the use of currently available ALK TKIs.

In the Phase 1 portion of ALKOVE-1, six dose levels (15 mg to 200 mg QD) of NVL-655 were evaluated in heavily pre-treated patients with ALK-positive solid tumors, and a maximum tolerated dose was not reached. The RP2D of 150 mg QD maintained steady state plasma levels above target efficacy thresholds (ALK wild type fusions and ALK single and compound mutations in both the periphery and in the CNS).

"The transition of our NVL-655 program into Phase 2 advances a second, parallel opportunity towards our goal of bringing potential best-in-class therapies to patients as efficiently as possible," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent. "This sense of urgency is reflected in the thoughtful design of the Phase 2 portion of the ALKOVE-1 trial which aims to accelerate the clinical investigation that may support a potential marketing application towards an initial approval for previously treated patients with ALK-positive NSCLC. The Phase 2 portion also includes a TKI-naïve cohort which may provide an opportunity to generate early data, and could be conducted in parallel with a front-line registration-directed trial."

Ms. Noci continued, "Support for the design of the Phase 2 cohorts includes the broad clinical activity and favorable tolerability observed to date in heavily pre-treated patients in the Phase 1 portion of ALKOVE-1. Combined with the demonstrated nonclinical activity of NVL-655 in the periphery and in the CNS, and its selective inhibition of ALK and ALK single and compound drug-resistance mutations over the structurally-related TRK kinases, we believe there is the potential for NVL-655 to provide durable responses while minimizing adverse events and dose limiting toxicities for patients with ALK-positive cancers throughout the treatment paradigm."

"With today’s announcement, we’ve delivered on the first of the key 2024 milestones laid out in our OnTarget 2026 operating plan, an achievement made possible by the tireless dedication of our team to our mission of delivering precisely targeted therapies to patients with cancer," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "With all of our programs, our goal is to not only address the existing medical needs for later-line patients but to ultimately deliver therapies that can move up the treatment paradigm, and our multi-pronged development strategy for NVL-655 exemplifies this approach. We look forward to sharing an update from the ALKOVE-1 trial as well as more detail on our broader front-line development strategy for ALK later this year."

ALKOVE-1 Phase 2 Design

The Phase 2 portion of the ALKOVE-1 trial will be conducted globally across North America, Europe, Asia, and Australia. The single arm, open label Phase 2 portion is designed with registrational intent for TKI pre-treated patients with ALK-positive NSCLC and to enable preliminary investigation for patients with ALK-positive NSCLC who are TKI naïve. The Phase 2 cohorts are designed to evaluate NVL-655 in:

TKI Pre-Treated ALK-Positive NSCLC
2 – 3 Prior TKIs: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs. Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
1 Prior 2G TKI: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior second-generation (2G) ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
1 Prior 3G TKI: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib (third-generation, 3G) as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
TKI-Naïve ALK-Positive NSCLC
Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
Other
Other ALK-Positive NSCLC: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
Other ALK-Positive Solid Tumors: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.
Additional details can be found on www.clinicaltrials.gov (NCT05384626).

Selection of NVL-655 RP2D

The selection of 150 mg QD as the RP2D for NVL-655 was supported by the FDA based on clinical data from the Phase 1 dose escalation portion of the ALKOVE-1 trial. The company believes that the preliminary Phase 1 data support the opportunity for NVL-655 as a potential best-in-class therapy that may be able to move up the treatment paradigm for patients with ALK-positive NSCLC.

The selection was based on the following considerations:

The dose level of 150 mg QD maintained steady state plasma levels above target efficacy thresholds (ALK wild type fusions and ALK single and compound mutations in both the periphery and in the CNS).
Favorable tolerability of NVL-655 was observed at the 150 mg QD dose level, continuing to suggest the potential for a highly ALK-selective, TRK sparing safety profile.
Early anti-tumor activity was observed in ALK-positive NSCLC patients across a broad range of doses, including 150 mg QD. Objective responses (RECIST 1.1) were observed in heavily pre-treated patients including patients who had received one or more second-generation TKIs (alectinib, brigatinib, or ceritinib) plus lorlatinib, patients who were lorlatinib-naïve, patients with ALK single and compound resistance mutations, and patients with CNS metastases.
Preliminary Phase 1 data were presented in October 2023, and the company expects to share an update from the ALKOVE-1 trial at a medical meeting in 2024.

About NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with both single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. NVL-655 has received orphan drug designation for ALK-positive non-small cell lung cancer (NSCLC) and is currently being investigated in the ALKOVE-1 clinical trial (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.

About OnTarget 2026

OnTarget 2026 delineates Nuvalent’s 3-year operating plan towards bringing new, potential best-in-class medicines to patients with cancer. As part of this plan announced in January 2024, Nuvalent outlined the following anticipated milestones throughout 2024, leading to the company’s first potential pivotal data in 2025 and first potential approved product in 2026:

2024: Execute on Global Registrational Strategies
Progress the Phase 2 portion of the ARROS-1 trial of NVL-520 in patients with advanced ROS1-positive NSCLC with registrational intent;
Initiate the Phase 2 portion of the ALKOVE-1 trial of NVL-655 in patients with advanced ALK-positive NSCLC, including cohorts in pretreated patients with registrational intent;
Launch the front-line development strategy for its ALK program;
Present interim data from the ongoing ARROS-1 and ALKOVE-1 clinical trials at medical meetings; and,
Initiate the Phase 1 trial for its HER2 program.
2025: First Pivotal Data
2026: First Approved Product