On September 13, 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 publication of a manuscript in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which describes the design and characterization of NVL-655 and details Nuvalent’s approach to rationally targeting ALK (Press release, Nuvalent, SEP 13, 2024, View Source [SID1234646572]). NVL-655 is currently being studied in the ongoing ALKOVE-1 Phase 1/2 clinical trial for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors.

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The manuscript, entitled "NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK mutant oncoproteins, including lorlatinib-resistant compound mutations," is published online and can be accessed here: View Source

"Currently available ALK tyrosine kinase inhibitors (TKIs) are important treatment options for patients with ALK-driven lung cancer. However, limitations including treatment-emergent drug resistance, off-target neurological adverse events, and inadequate control of brain metastases, support the need for continued development in this disease," said senior author Alexander Drilon, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, and investigator in the ALKOVE-1 trial. "As detailed in this publication, preclinical characterization and preliminary clinical data provide a compelling rationale for the ongoing clinical investigation of NVL-655 and evaluation of its potential to address the limitations of available ALK TKIs for patients with ALK-positive NSCLC."

The manuscript details the design principles underlying the activity of NVL-655 against ALK single and compound resistance mutations, including the most commonly occurring resistance mutation, ALK G1202R. Additionally, it outlines a molecular rationale for the selectivity of NVL-655 for ALK over the structurally related tropomyosin receptor kinase (TRK) family, whose inhibition has been associated with neurological adverse events that can be dose limiting. Preclinical characterization of the activity and selectivity of NVL-655 is presented, including in vivo xenograft studies, preclinical assessments of brain penetrance and intracranial activity, and a comparison of eight ALK TKIs across multiple biochemical and cellular assays.

The manuscript further documents three case studies from the ALKOVE-1 trial of patients with ALK fusion-positive lung cancers who had received a range of ALK TKIs, including lorlatinib, and presented with brain metastases or with tumors that harbored ALK G1202R. NVL-655 elicited tumor responses in these patients without accompanying CNS effects attributed to off-target TRK inhibition. These findings support the potential for NVL-655 as a future treatment for these patient populations that may also enhance tolerability through improved selectivity for ALK.

"With this publication in Cancer Discovery, we are pleased to have now also elucidated our focused approach for ALK-positive NSCLC. Along with our parallel lead program for ROS1-positive NSCLC, these selective inhibitors form the foundation for our pipeline of precisely targeted therapies which aim to deliver potential best-in-class activity against recalcitrant targets through solving for multiple, and at times competing, challenges in structure-based drug design," said Joshua Horan, Ph.D., Vice President, Chemistry at Nuvalent. "We are grateful to our collaborators for their contributions to this manuscript and to the continued advancement of NVL-655."

Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, designed with registrational intent. Updated data from the Phase 1 portion of the trial will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain during a Proffered paper session on Saturday September 14, 2024 from 9:30 – 9:40 a.m. CEST.

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 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 breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with two or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC. NVL-655 is currently being evaluated in the Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626).

On September 13, 2024 GlaxoSmithKline reported that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China has granted Breakthrough Therapy Designation (BTD) for Blenrep (belantamab mafodotin) combined with bortezomib plus dexamethasone (BorDex) for the treatment of relapsed or refractory multiple myeloma (Press release, GlaxoSmithKline, SEP 13, 2024, View Source [SID1234646569]). NMPA BTD is intended to expedite the development of therapies for serious and life-threatening diseases for which there are no existing treatments or where initial evidence has shown an improvement in patient outcomes over available treatment options.2

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Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: "Breakthrough Therapy Designation in China underscores the potential for Blenrep to redefine outcomes for patients with multiple myeloma at or after their first relapse. We look forward to continuing to work with the health authority in China and others worldwide to bring Blenrep-based combinations to patients as expeditiously as possible."

BTD was granted based on the interim results of the phase III head-to-head DREAMM-7 trial, which met its primary endpoint, showing statistically significant and clinically meaningful improvements in progression-free survival (PFS) for belantamab mafodotin combined with BorDex compared to daratumumab plus BorDex in relapsed or refractory multiple myeloma.

A positive overall survival (OS) trend was observed but was not statistically significant at the time of interim analysis. Follow-up for OS continues. Results also showed clinically meaningful improvements across all other secondary efficacy endpoints, including deeper and more durable responses compared to the standard of care combination. The safety and tolerability profile of the belantamab mafodotin combination in the DREAMM-7 trial was broadly consistent with the known profiles of the individual agents.

Multiple myeloma is a growing health concern in China with approximately 30,000 new cases each year.3 The incidence in China has doubled and mortality has increased 1.5-fold in the past three decades.4 This underscores the need for novel, efficacious treatment options for patients in China, particularly those with progressing disease that has become resistant to the current standard of care.

About multiple myeloma
Multiple myeloma is the third most common blood cancer globally and is generally considered treatable but not curable.5,6 There are approximately more than 180,000 new cases of multiple myeloma diagnosed globally each year.7 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.8

About DREAMM-7
The DREAMM-7 phase III clinical trial is a multicentre, open-label, randomised trial evaluating the efficacy and safety of belantamab mafodotin in combination with BorDex compared to a combination of daratumumab and BorDex in patients with relapsed/refractory multiple myeloma who previously were treated with at least one prior line of multiple myeloma therapy, with documented disease progression during or after their most recent therapy.

A total of 494 participants were randomised at a 1:1 ratio to receive either belantamab mafodotin in combination with BorDex or a combination of daratumumab and BorDex. Belantamab mafodotin was scheduled to be dosed at 2.5mg/kg intravenously every three weeks.

The primary endpoint is PFS as per an independent review committee. The key secondary endpoints include OS, duration of response (DOR), and minimal residual disease (MRD) negativity rate as assessed by next-generation sequencing. Other secondary endpoints include overall response rate (ORR), safety, and patient reported and quality of life outcomes.

Results from DREAMM-7 were first presented9 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series in February 2024, shared in an encore presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, and published in the New England Journal of Medicine.

About Blenrep
Blenrep is an antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.

Blenrep is approved as monotherapy in Hong Kong, Israel and Singapore. Refer to the local Summary of Product Characteristics for a full list of adverse events and complete important safety information.

On September 13, 2024 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported initial clinical data from the ongoing clinical trial of CFT1946, an orally bioavailable small molecule degrader of BRAF V600 mutations in solid tumors (Press release, C4 Therapeutics, SEP 13, 2024, View Source [SID1234646568]). These data, the first clinical results for a BRAF V600X degrader, were shared as a proffered paper in an oral presentation by Maria Vieito, M.D., MSc, medical oncologist at Vall d’Hebron University Hospital, Barcelona, Spain, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024, being held September 13 – 17 in Barcelona, Spain.

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"We are thrilled to share initial CFT1946 monotherapy data and highlight how this molecule, the first and only clinical-stage degrader of BRAF V600 mutants, may disrupt the current treatment landscape as it quickly progresses through clinical development," said Andrew Hirsch, president and chief executive officer of C4 Therapeutics. "In addition to addressing the needs of patients with BRAF V600 mutant solid tumors, we believe these clinical data further reinforce the potential of our TORPEDO platform to design innovative small molecule degraders that excite the medical community and have the potential to improve patients’ lives."

"The data presented at the ESMO (Free ESMO Whitepaper) Congress 2024 are impressive given the early stage of development of CFT1946 and the novel modality," said Dr. Vieito. "I am especially encouraged by the safety and tolerability of CFT1946, which may allow for additional monotherapy exploration as well as combination approaches to better understand how this oral degrader medicine may support the needs of patients refractory to BRAF inhibitor therapies."

"We are pleased with the safety profile CFT1946 has demonstrated over a range of doses, as well as its pharmacokinetics, pharmacodynamics and initial anti-tumor activity. Taken together, these data support our hypothesis that degradation may offer a new therapeutic option over inhibition for BRAF V600 mutant solid tumors," said Len Reyno, M.D., chief medical officer of C4 Therapeutics. "We are deeply appreciative of the contributions from patients, caregivers and the oncology community that have enabled us to deliver this preliminary monotherapy data and we look forward to continuing these important relationships as we progress CFT1946 toward additional milestones in 2025 and beyond."

At the ESMO (Free ESMO Whitepaper) Congress 2024, C4T reported initial monotherapy data from the ongoing dose escalation Phase 1 clinical trial evaluating twice daily oral dosing of CFT1946, a degrader of BRAF V600 mutants, in patients with BRAF V600X solid tumors who have received at least one prior standard of care therapy for unresectable locally advanced or metastatic disease. Prior therapy must include a BRAF inhibitor, unless access is limited by regional regulatory approvals or reimbursement. As of the data cutoff date of July 19, 2024, a total of 36 patients received CFT1946 monotherapy across five dose escalation cohorts (20 mg BID, 80 mg BID, 160 mg BID, 320 mg BID and 640 mg BID). Patients received a median of three prior therapies; 35 patients (97 percent) had received prior BRAF inhibitor therapy. Thirty-three patients (92 percent) had a BRAF V600E mutation, two patients (six percent) had a BRAF V600K mutation and one patient (two percent) had a BRAF V600R mutation. Fourteen patients (39 percent) had melanoma, 14 patients (39 percent) had colorectal cancer, two patients (six percent) had non-small cell lung cancer and six patients (17 percent) had other cancers. All patients had unresectable, locally advanced or metastatic disease, and 32 patients (89 percent) entered the study with Stage IV cancer.

Safety and Tolerability: CFT1946 has a well-tolerated safety profile that supports further clinical development as monotherapy and in combination with MEK and EGFR inhibitors.

There were no dose-limiting toxicities and no treatment-related serious adverse events.
Adverse events occurring in more than 10 percent of patients were all Grade 1 or Grade 2.
No patients discontinued therapy or experienced treatment interruptions due to treatment-related adverse events.
No patients receiving CFT1946 monotherapy experienced a Grade 3 or higher treatment-related cutaneous adverse event. These cutaneous adverse events, which are related to BRAF wild-type inhibition, are commonly seen with BRAF inhibitors.
Pharmacokinetics (PK) and Pharmacodynamics (PD): Initial data demonstrating dose-dependent bioavailability and degradation of BRAF V600E protein support CFT1946 proof of mechanism.

CFT1946 exhibits dose-dependent bioavailability in the five dose levels explored to date.
In all available post-treatment biopsies collected to date, degradation of BRAF V600E protein is observed.
Anti-Tumor Activity: CFT1946 demonstrates evidence of monotherapy anti-tumor activity, supportive of early proof of degrader concept.

At data cutoff, 27 patients were evaluable for anti-tumor activity, which is measured by RECIST 1.1 criteria.
16 patients demonstrated reduction of target metastatic lesions.
Two patients achieved a confirmed Partial Response.
Reduction of target lesion tumors was observed across histologies. Of the 27 patients evaluable for anti-tumor activity:
Eleven patients had melanoma, eight of whom had evidence of tumor reduction. One patient with Stage IV BRAF V600K melanoma enrolled in the 320 mg BID cohort achieved a 67 percent decrease in target lesions as measured by RECIST 1.1 criteria. This patient remains on CFT1946 treatment and in response.
Nine patients had colorectal cancer, three of whom had evidence of tumor reduction.
Seven patients have other tumor histologies, three of whom had evidence of tumor reduction. One patient with Stage IV BRAF V600E pancreatic cancer, who has liver metastases, enrolled in the 640 mg BID cohort achieved a 55 percent decrease in target lesion as measured by RECIST 1.1 criteria. This patient remains on CFT1946 treatment and in response.
As of data cutoff, 11 of the patients who were evaluable for anti-tumor activity remain on therapy.
Next Steps and Future Milestones for CFT1946
The CFT1946 Phase 1 trial is ongoing and multiple indication-specific cohorts are advancing. Next steps and related milestones for CFT1946 include:

Complete Phase 1 monotherapy dose escalation – This portion of the trial is enrolling patients with BRAF V600X mutations across solid tumor indications. Patients are currently enrolling in the 640 mg BID PD backfill cohort as this dose level was recently declared safe. The full monotherapy dose escalation data are expected in 2025.
Complete expansion cohort exploring CFT1946 monotherapy in melanoma – This Phase 1 exploratory expansion cohort is evaluating the potential of CFT1946 monotherapy for melanoma patients refractory to BRAF inhibitor therapies. Enrollment for the 320 mg BID dose level is complete, and enrollment is ongoing for the 640 mg BID dose level. Data from these dose levels are expected in 2025.
Complete dose escalation cohort exploring CFT1946 in combination with cetuximab in colorectal cancer – This Phase 1b dose escalation cohort is enrolling patients at the 160 mg BID dose level to explore safety and tolerability, PK, PD and anti-tumor activity of CFT1946 in combination with cetuximab. These data are expected in 2025.
Initiate dose escalation cohort exploring CFT1946 in combination with trametinib in melanoma – This Phase 1b dose escalation cohort will explore safety and tolerability, PK, PD and anti-tumor activity of CFT1946 in combination with trametinib. C4T expects to initiate this cohort by year-end 2024.
C4T Webcast for Analysts and Investors
C4T will host an investor webcast today, September 13, 2024, at 12:00 pm ET. To join the webcast, please visit this link or the "Events & Presentations" page of the Investors section on the company’s website at www.c4therapeutics.com. A replay of the webcast will be archived and available following the event.

About BRAF V600 Mutant Solid Tumors
BRAF mutations are found in approximately five percent of all cancers, including melanoma, colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and other malignancies. Of these BRAF mutation cancer diagnoses, up to 90 percent contain an activating BRAF V600 mutation. BRAF V600 mutations are observed in up to 50 percent of patients with melanoma, nearly 10 percent of patients with CRC and approximately five percent of patients with NSCLC. Resistance to FDA-approved BRAF inhibitors results in median progression-free survival rates of less than 15 months across all indications.

About CFT1946
CFT1946 is an investigational, orally bioavailable small molecule degrader of BRAF V600 mutations in solid tumors currently being evaluated in a Phase 1/2 global clinical trial in patients refractory to BRAF inhibitors. CFT1946 is designed to be potent and selective against the BRAF V600 mutant form. Initial clinical data from the Phase 1 trial demonstrate that CFT1946 has a well-tolerated safety profile, demonstrates dose-dependent bioavailability and degradation of BRAF V600E protein, and demonstrates evidence of monotherapy anti-tumor activity. CFT1946 is the only degrader of BRAF V600 mutant solid tumors in clinical trials. More information about this trial may be accessed at www.clinicaltrials.gov (identifier: NCT05668585).

On September 13, 2024  CorMedix Inc., a biopharmaceutical company focused on developing and commercializing therapeutic products for the prevention and treatment of life-threatening conditions and diseases, reported that management will be participating in a fireside chat and investor meetings at the 2024 Cantor Healthcare Conference, being held in New York, NY on September 17 – 19, 2024 (Press release, CorMedix, SEP 13, 2024, View Source [SID1234646565]).

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Cantor Global Healthcare Conference
Date: Thursday, September 19, 2024
Time: 10:55AM EDT
Format: Fireside Chat and 1×1 Meetings
Webcast: Click Link

A replay of the fireside chat will also be available in the "Events and Presentations" page on the investor relations portion of the Company’s website at: www.cormedix.com

On September 10, 2024 Centessa Pharmaceuticals plc, a clinical-stage pharmaceutical company that aims to discover and develop medicines that are transformational for patients, reported that it has commenced an underwritten public offering of $150 million of American Depositary Shares ("ADSs"), each representing one ordinary share (Press release, Centessa Pharmaceuticals, SEP 13, 2024, View Source [SID1234646564]). All of the ADSs are being offered by Centessa. In addition, Centessa intends to grant the underwriters a 30-day option to purchase up to an additional $22.5 million of ADSs offered in the public offering. The proposed offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

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Goldman Sachs & Co. LLC, Leerink Partners, Evercore ISI, Guggenheim Securities and BMO Capital Markets are acting as joint book-running managers for the offering.

The ADSs are being offered pursuant to a registration statement on Form S-3 that was filed with the Securities and Exchange Commission ("SEC") on September 11, 2024 and became automatically effective upon filing. A preliminary prospectus supplement and accompanying prospectus relating to the offering will be filed with the SEC and will be available on the SEC’s website located at View Source Copies of the preliminary prospectus supplement and the accompanying prospectus relating to the offering, when available, may be obtained from: Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, telephone: (866) 471-2526, email: [email protected]; Leerink Partners LLC, Syndicate Department, 53 State Street, 40th Floor, Boston, MA 02109, telephone: (800) 808-7525 ext. 6105, email: [email protected]; Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, NY 10055, telephone: (888) 474-0200, email: [email protected]; Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, NY 10017, telephone: (212) 518-9544, email: [email protected]; or BMO Capital Markets Corp., Attention: Equity Syndicate Department, 151 W 42nd Street, 32nd Floor, New York, NY 10036, email: [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.