MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), MEK2 inhibitors(Dual specificity mitogen-activated protein kinase kinase 2 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesRespiratory Diseases+ [9]

Active Indication

Low grade gliomaBRAF mutation positive hairy cell leukemiaBRAF mutation Solid Tumors+ [109]

Inactive Indication

Adenocarcinoma of LungAdult Acute Myeloblastic LeukemiaAdvanced biliary tract cancer+ [39]

Originator Organization

GSK Plc

Active Organization

Novartis Pharmaceuticals Corp.

National Cancer InstituteNovartis Europharm Ltd.

+ [10]

Inactive Organization

GlaxoSmithKline (China) Investment Co., Ltd.GlaxoSmithKline Trading Services Ltd.

Drug Highest PhaseApproved

First Approval Date

US (29 May 2013),

BRAF V600E Mutation-Positive MelanomaBRAF V600K Mutation-Positive Melanoma

RegulationFast Track (US), Accelerated Approval (US), Orphan Drug (EU), Priority Review (CN), Conditional marketing approval (CN), Orphan Drug (JP), Orphan Drug (KR), Priority Review (AU), Breakthrough Therapy (US), Orphan Drug (US)

Structure

Molecular FormulaC28H29FIN5O5S

InChIKeyOQUFJVRYDFIQBW-UHFFFAOYSA-N

CAS Registry1187431-43-1

297

Clinical Trials associated with Trametinib dimethyl sulfoxide

NCT05275374 / Not yet recruitingPhase 1/2

A Dose-escalation and Expansion Phase I/IIa Study of XP-102 and XP-102 in Combination With Trametinib in Advanced Solid Tumor Patients With a BRAF V600 Mutation (ENHANCE)

This is a first-in-human multi-center study which will be conducted in advanced malignant solid tumors patients. The solid tumor type is limited to melanoma, colorectal, non-small-cell lung, and thyroid cancer with positive BRAF V600 mutation. This study is divided into three stages: Phase Ia: a dose-escalation phase of XP-102; Phase Ib: a dose-escalation and sample size expansion phase of XP-102 plus trametinib; Phase IIa: an expansion phase of XP-102 plus trametinib.

Start Date01 Dec 2024

Sponsor / Collaborator

Xynomic Pharmaceuticals, Inc.

NCT06712875 / RecruitingPhase 1/2IIT

A Pilot Study Evaluating the Toxicity and Clinical Benefit of Mitogen-activated Protein Kinase (MAPK) Pathway Inhibition Combined with Programmed Cell Death-1 Checkpoint Blockade (anti-PD1) for the Treatment of BRAF-altered Pediatric Gliomas

Pediatric gliomas harboring BRAF-alterations, commonly BRAFV600 mutation or KIAA1549-BRAF fusion, are currently treated with either chemotherapy or mitogen activated protein kinase (MAPK) inhibitors, such as, dabrafenib and/or trametinib. Unfortunately, some BRAF-altered gliomas can progress or have rebound growth after discontinuation of therapy. Data from BRAFV600E-mutant melanoma has shown potential synergy between MAPK inhibition and anti-programmed cell death 1 (anti-PD1) checkpoint blockade. Anti-PD1 therapy, such as, nivolumab can block the PD1 receptor on T cells, a marker of T cell exhaustion, allowing a continued or more robust anti-tumor immune response. Here, we combine MAPK inhibition with anti-PD1 therapy in recurrent, refractory low grade BRAF-altered glioma and newly diagnosed or recurrent BRAF-altered or NF-altered high grade glioma.

Start Date01 Dec 2024

Sponsor / Collaborator

Ann & Robert H. Lurie Children's Hospital of Chicago

ChiCTR2400091473 / SuspendedNot ApplicableIIT

Redifferentiation of radiodine-refractory metastatic papillary thyroid carcinoma with BRAFV600E mutation by dabrafenib in combination with trametinib

Start Date01 Nov 2024

Sponsor / Collaborator-

100 Clinical Results associated with Trametinib dimethyl sulfoxide

100 Translational Medicine associated with Trametinib dimethyl sulfoxide

100 Patents (Medical) associated with Trametinib dimethyl sulfoxide

2,197

Literatures (Medical) associated with Trametinib dimethyl sulfoxide

01 Jan 2025·BIOORGANIC CHEMISTRY

Trametinib and M17, a novel small molecule inhibitor of AKT, display a synergistic antitumor effect in triple negative breast cancer cells through the AKT/mTOR and MEK/ERK pathways

Article

Author: Han, Hongwei ; Fang, Rongjun ; Sun, Shucun ; Wen, Zhongling ; Wang, Xiaoming ; Qi, Jinliang ; Lin, Hongyan ; Yin, Tongming ; Yang, Yonghua ; Chen, Qingqing ; Zhang, Yahan ; Lai, Xiaohui ; Ma, Yudi ; Mei, Feng ; Yang, Minkai

Triple negative breast cancer (TNBC) is associated with a poor prognosis and limited response to traditional chemotherapy, necessitating the exploration of novel treatment approaches. Recent researches have highlighted the interconnected roles of the PI3K/AKT pathway and MAPK pathway in TNBC cells, contributing to the efficacy of treatments. Therefore, the concurrent inhibition of both pathways presents a potential new therapeutic strategy for TNBC patients. This study aimed to evaluate the antitumor efficacy of M17, an AKT allosteric inhibitor and a new synthesized shikonin derivative, both alone and in combination with the MEK inhibitor trametinib. We applied various cellular assays and a subcutaneous 4T1 tumor bearing BALB/c mice model were utilized to assess the in vitro and in vivo antitumor effects. Computational docking and Bio-Layer Interferometry (BLI) were employed to investigate the binding of M17 with AKT. Additionally, flow cytometry, transwell assays, western blotting, and tumor xenograft assays were conducted to explore the potential synergistic mechanisms of the combined therapy. The results demonstrated that M17 exhibited moderate antitumor activity against TNBC cells, but significantly enhanced the apoptotic effects and inhibited proliferation and migration when combined with trametinib. Furthermore, the combination of M17 and trametinib showed even more pronounced antitumor activity in vivo. Mechanistically, the dual therapy synergistically suppressed TNBC by targeting the AKT/mTOR and MEK/ERK signaling pathways and inhibiting epithelial-mesenchymal transition. In conclusion, the findings suggested that the combination of M17 and trametinib holds promise as a synergistic treatment option for TNBC patients.

01 Jan 2025·NEOPLASIA

A novel regimen for pancreatic ductal adenocarcinoma targeting MEK, BCL-xL, and EGFR

Article

Author: Licht, Jonathan ; Trevino, Jose G ; Hughes, Steven J ; Zheng, Guangrong ; Trevino, Jose G. ; Huo, Zhiguang ; Tushoski-Alemán, Gerik W ; Zhang, Peiyi ; Han, Song ; Zhou, Daohong ; Allegra, Carmen ; Hughes, Steven J. ; George, Thomas J. ; George, Thomas J ; Tushoski-Alemán, Gerik W.

Oncogenic KRAS signaling plays a critical role in pancreatic ductal adenocarcinoma (PDAC) biology. Recent studies indicate that the combination of MEK and BCL-xL inhibition is synthetically lethal and holds promise for some types of solid cancers, however, patient response was poorly observed in PDAC predominantly due to amplified EGFR signaling. Here, we leverage the advantage of the combinational treatment strategy and designed a triplet regimen targeting the comprehensive RAS activation networks through simultaneously blocking MEK/BCL-xL/EGFR. The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Patient-derived xenograft (PDX) model was employed for the evaluation of the therapeutic efficacy and safety of the combinational regimen. Targeted pathway cascades activities were analyzed using multiplex phosphor-immune assays. In vitro comparisons showed the addition of afatinib as a third agent was statistically superior compared to a doublet of trametinib+DT2216 in suppressing cell growth and inducing cell death in all cell lines tested. This triplet similarly demonstrated significant superiority over the doublet of MEK/BCL-xL inhibition in the in vivo murine model. The triplet regimen was well tolerated in vivo. Overall tumor growth rates were significantly reduced in doublet treatment compared to controls, and further reduced in the triplet treatment group. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.

01 Jan 2025·LUNG CANCER

Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort

Article

Author: Tomasini, Pascale ; Pichon, Eric ; Morin, Franck ; Domblides, Charlotte ; Debieuvre, Didier ; Geier, Margaux ; Bayle-Bleuez, Sophie ; Larivé, Sébastien ; Couraud, Sébastien ; Fabre, Elizabeth ; Lerolle, Ulrike ; Swalduz, Aurélie ; Beau-Faller, Michèle ; Planchard, David ; Daniel, Catherine ; Wislez, Marie ; Missy, Pascale ; Cortot, Alexis ; Mazieres, Julien ; Auliac, Jean-Bernard ; Westeel, Virginie ; Fallet, Vincent

BACKGROUND:

BRAF V600E mutations occur in 2-5 % of advanced non-small cell lung cancer (NSCLC) patients. The dabrafenib-trametinib (D-T) combination was associated with improved and durable OS in patients in phase II. This study (IFCT-2004 BLaDE study) reported the efficacy of D-T combination in a large retrospective French real-world multicenter cohort of patients with advanced BRAF V600E-mutated NSCLC.

METHOD:

Patients with advanced BRAF V600E-mutated NSCLC diagnosed between 01.01.2016 and 31.12.2019 and treated with D-T in combination, regardless of the treatment line, were included. The primary endpoint was the 12-month OS rate (%) in patients receiving D-T as a second-line therapy or beyond.

RESULTS:

A total of 163 patients were included: 50.3 % were female, 30.2 % were never smokers, 95.1 % had adenocarcinoma, and 78.2 % had a PDL1 ≥ 1 %. The median age was 68.3 years. At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage IV disease, and 20.9 % had brain metastasis. At the cutoff, the median follow-up was 27.4 months. The 12-month OS rate in patients receiving D + T as a second-line therapy or beyond (n = 119) was 67.4 %, with a median progression-free survival (mPFS) of 10.4 months. Among the 44 patients who received D + T as a first-line therapy, the 12-month OS rate was 67.4 %, with an mPFS of 18.2 months. D-T discontinuation for toxicity was reported in 10.3 % of patients.

CONCLUSIONS:

To our knowledge, this is the largest retrospective cohort of BRAF-mutated patients reported. The findings confirmed the significant efficacy of D-T in combination with BRAF V600E-mutated metastatic NSCLC in pretreated and untreated patients. These results under real-world conditions are consistent with those of other registered studies.

100

News (Medical) associated with Trametinib dimethyl sulfoxide

27 Nov 2024

·endpts.com

Novartis to cut 139 jobs in NJ as part of commercial refocus

Novartis is laying off 139 employees in East Hanover, NJ, as the company shifts its commercial resources away from two “well-established” medicines. The layoffs will mainly affect members of the commercial field sales team who work on Novartis’ allergy and asthma medicine Xolair and its cancer treatment combining Tafinlar and Mekinist, a Novartis spokesperson said. Those drugs remain on the market, but the company says it’s pivoting its focus to a “new wave of innovation.” Novartis has announced ambitions to launch 15 new medicines or expanded labels over the next three years. It recently raised sales guidance through 2028, attributing the update in part to its transformation into a “pure-play” company. The new, leaner structure has allowed Novartis to focus on “the biggest opportunities that we have in the pipeline,” CEO Vas Narasimhan said last week at an investor event. Novartis said it completed a multi-year restructuring in 2023, though “additional streamlining” has led to cuts on the development side this year. On Novartis’ third-quarter earnings call with the media last month, Narasimhan said the company will always “be fine-tuning at a low level.” The cuts in East Hanover will occur between February and August of next year. Affected employees are encouraged to “apply for open positions in other areas of our business,” the Novartis spokesperson said. “As external factors continue to shift, our business priorities, capabilities and resource allocation must also evolve to ensure that we are best positioned to bring the next wave of innovation to patients in need,” the spokesperson said.

12 Nov 2024

·www.globenewswire.com

Erasca Reports Third Quarter 2024 Business Updates and Financial Results

Positive preliminary Phase 1b data in SEACRAFT-1 NRASm melanoma cohort bolsters conviction in ongoing SEACRAFT-2 registrational trial; Stage 1 randomized data expected in 2025 Strong execution across potentially best-in-class RAS targeting franchise; planned IND submissions on track Robust balance sheet with cash, cash equivalents, and marketable securities of $463 million as of September 30, 2024, is expected to fund operations into H1 2027 SAN DIEGO, Nov. 12, 2024 (GLOBE NEWSWIRE) -- Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, today provided business updates and reported financial results for the fiscal quarter ended September 30, 2024. “We made significant progress across our pipeline programs and are pleased with the pace of our execution. Positive preliminary data from SEACRAFT-1, which we reported at the 36th EORTC-NCI-AACR (ENA) Symposium last month, has refined our clinical development focus of naporafenib plus trametinib on patients with NRAS-mutant (NRASm) melanoma, and importantly, heightens our conviction in the ongoing SEACRAFT-2 registrational trial targeting a similar patient population,” said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. “SEACRAFT-2 has the potential for approval based on the high unmet need of these patients as well as the alignment with US and European regulators on the NRASm melanoma indication. We expect randomized dose optimization data from Stage 1 of this Phase 3 trial in 2025.” Dr. Lim added, “Our RAS targeting franchise, which includes a potential best-in-class pan-RAS molecular glue ERAS-0015 and a potential first-in-class pan-KRAS inhibitor ERAS-4001, holds significant promise to help a broad range of patients with RAS-mutant (RASm) solid tumors. Following the in-licensing of these molecules in May, we have rapidly and effectively confirmed in-house the potential best-in-class profiles of both agents and executed across multiple activities to support their planned investigational new drug (IND) application submissions, which remain on track for the first quarter of 2025 for ERAS-4001 and the first half of 2025 for ERAS-0015. We continue to be well capitalized with an anticipated cash runway into the first half of 2027 and are poised for strong execution across our pipeline.” Research and Development (R&D) Highlights Presented Promising SEACRAFT-1 Phase 1 Data: In October 2024, Erasca presented Phase 1b SEACRAFT-1 data for naporafenib plus trametinib (MEKINIST®) in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations at the 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics and as part of a company R&D update. Data support rationale for pursuing an NRASm melanoma indication and reinforces the potential of the ongoing Phase 3 SEACRAFT-2 registrational trial.Announced Progress Across RAS Targeting Franchise: In October 2024, Erasca presented a program update for pan-RAS molecular glue ERAS-0015 and pan-KRAS inhibitor ERAS-4001 as part of a company R&D update, highlighting the rapid progress across both programs including in-house confirmation of potential best-in-class profiles for both agents and advancement of activities to support planned IND application submissions. Key Upcoming Milestones SEACRAFT-2: Randomized pivotal Phase 3 trial for naporafenib plus trametinib in patients with NRASm melanoma Phase 3 Stage 1 randomized dose optimization data expected to be reported in 2025 AURORAS-1: Phase 1 trial for ERAS-0015 (pan-RAS molecular glue) in patients with RASm solid tumors IND filing expected in H1 2025Initial Phase 1 monotherapy data in relevant tumor types expected to be reported in 2026 BOREALIS-1: Phase 1 trial for ERAS-4001 (pan-KRAS inhibitor) in patients with KRASm solid tumors IND filing expected in Q1 2025Initial Phase 1 monotherapy data in relevant tumor types expected to be reported in 2026 Third Quarter 2024 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $463.3 million as of September 30, 2024, compared to $322.0 million as of December 31, 2023. Erasca expects its current cash, cash equivalents, and marketable securities balance of $463.3 million to fund operations into the first half of 2027. Research and Development (R&D) Expenses: R&D expenses were $27.6 million for the quarter ended September 30, 2024, compared to $25.2 million for the quarter ended September 30, 2023. The increase was primarily driven by increases in expenses incurred in connection with clinical trials, preclinical studies, and discovery activities, partially offset by decreases in personnel costs, including stock-based compensation expense, and outsourced services and consulting fees. General and Administrative (G&A) Expenses: G&A expenses were $9.6 million for the quarter ended September 30, 2024, compared to $9.4 million for the quarter ended September 30, 2023. Net Loss: Net loss was $31.2 million, or $(0.11) per basic and diluted share, for the quarter ended September 30, 2024, compared to $30.4 million, or $(0.20) per basic and diluted share, for the quarter ended September 30, 2023. About ErascaAt Erasca, our name is our mission: To erase cancer. We are a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers. Our company was co-founded by leading pioneers in precision oncology and RAS targeting to create novel therapies and combination regimens designed to comprehensively shut down the RAS/MAPK pathway for the treatment of patients with cancer. We have assembled one of the deepest RAS/MAPK pathway-focused pipelines in the industry. We believe our team’s capabilities and experience, further guided by our scientific advisory board which includes the world’s leading experts in the RAS/MAPK pathway, uniquely position us to achieve our bold mission of erasing cancer. Cautionary Note Regarding Forward-Looking Statements Erasca cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: our expectations regarding the potential therapeutic benefits of our product candidates, including naporafenib, ERAS-0015, and ERAS-4001; the planned advancement of our development pipeline, including the anticipated timing of data readouts for the SEACRAFT-2, AURORAS-1, and BOREALIS-1 trials; our alignment with regulatory authorities on the regulatory pathway for naporafenib; the anticipated timing of the IND filings for the AURORAS-1 and BOREALIS-1 trials; our ability to successfully prioritize our pipeline portfolio to focus on existing programs that we believe have the highest probability of success; and the sufficiency of our cash, cash equivalents, and marketable securities to fund operations into the first half of 2027. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; results from preclinical studies or early clinical trials not necessarily being predictive of future results; preliminary results of clinical trials are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; our planned SEACRAFT trials may not support the registration of naporafenib; our assumptions about ERAS-0015’s or ERAS-4001’s development potential are based in large part on the preclinical data generated by the licensors and we may observe materially and adversely different results as we conduct our planned studies and trials; we only have one product candidate in clinical development and all of our other development efforts are in the preclinical or development stage; our assumptions around which programs may have a higher probability of success may not be accurate, and we may expend our limited resources to pursue a particular product candidate and/or indication and fail to capitalize on product candidates or indications with greater development or commercial potential; potential delays in the commencement, enrollment, data readout, and completion of clinical trials and preclinical studies; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; the inability to realize any benefits from our current licenses, acquisitions, and collaborations, and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; later developments with the FDA or EU health authorities may be inconsistent with the feedback received to date regarding our development plans and trial designs; our ability to obtain and maintain intellectual property protection for our product candidates and maintain our rights under intellectual property licenses; we may use our capital resources sooner than we expect; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2023, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Erasca, Inc.Selected Condensed Consolidated Balance Sheet Data(In thousands)(Unaudited) September 30, December 31, 2024 2023 Balance Sheet Data: Cash, cash equivalents, and marketable securities $463,303 $321,992 Working capital 300,149 294,520 Total assets 528,896 395,297 Accumulated deficit (735,431) (606,013)Total stockholders’ equity 450,042 316,686 Erasca, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(In thousands, except share and per share amounts)(Unaudited) Three months ended September 30, Nine months ended September 30, 2024 2023 2024 2023 Operating expenses: Research and development $27,631 $25,213 $89,237 $79,016 In-process research and development — — 22,500 — General and administrative 9,611 9,445 32,138 28,637 Total operating expenses 37,242 34,658 143,875 107,653 Loss from operations (37,242) (34,658) (143,875) (107,653)Other income (expense) Interest income 5,869 4,346 14,810 12,474 Other income (expense), net 173 (49) (353) (162)Total other income (expense), net 6,042 4,297 14,457 12,312 Net loss $(31,200) $(30,361) $(129,418) $(95,341)Net loss per share, basic and diluted $(0.11) $(0.20) $(0.60) $(0.64)Weighted-average shares of common stock used in computing net loss per share, basic and diluted 282,384,964 150,450,201 217,355,959 150,000,613 Other comprehensive income (loss): Unrealized gain on marketable securities, net 2,021 218 1,748 466 Comprehensive loss $(29,179) $(30,143) $(127,670) $(94,875) MEKINIST® is a registered trademark owned by or licensed to Novartis AG, its subsidiaries, or affiliates. Contact:Joyce AllaireLifeSci Advisors, LLCjallaire@lifesciadvisors.com Source: Erasca, Inc.

Phase 1Financial StatementAACRPhase 3

31 Oct 2024

·www.globenewswire.com

C4 Therapeutics Reports Third Quarter 2024 Financial Results and Recent Business Highlights

Cemsidomide Phase 1/2 Trial in Multiple Myeloma and non-Hodgkin’s Lymphoma Continues to Progress: Data from Both Indications to be Presented at the 66th American Society of Hematology (ASH) Annual Meeting in San Diego, CA Initial Monotherapy CFT1946 Phase 1 Data Demonstrated Well-Tolerated Safety Profile and Early Evidence of Anti-tumor Activity; Phase 1/2 Trial Continues to Progress with Multiple Data Readouts Expected in 2025 Appointed Paige Mahaney, Ph.D. as Chief Scientific Officer Bringing More than 25 Years of Pharmaceutical and Biotech Experience Cash, Cash Equivalents and Marketable Securities of $284.4 million as of September 30, 2024; Expected to Provide Runway into 2027 WATERTOWN, Mass., Oct. 31, 2024 (GLOBE NEWSWIRE) -- C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported financial results today for the third quarter ended September 30, 2024, as well as recent business highlights. “2024 has been a successful year for C4T marked by strong execution across our entire portfolio, which has continued to position us as a leader in targeted protein degradation science. We recently shared initial clinical data on CFT1946 demonstrating a well-tolerated safety profile and evidence of monotherapy anti-tumor activity in BRAF inhibitor exposed patients, and we delivered our second development candidate to Biogen,” said Andrew Hirsch, president and chief executive officer of C4 Therapeutics. “We look forward to continuing this momentum with cemsidomide Phase 1 data in multiple myeloma and in non-Hodgkin’s lymphoma being presented at ASH, and multiple CFT1946 data readouts expected in 2025. Our continued focus on discovery research, clinical development and collaborations sets us up for an exciting future and for the potential to improve patients’ lives.” THIRD QUARTER 2024 AND RECENT ACHIEVEMENTS Cemsidomide: Cemsidomide is an oral degrader of IKZF1/3 for the potential treatment of relapsed/refractory (R/R) multiple myeloma (MM) and R/R non-Hodgkin’s lymphoma (NHL). Advanced the Phase 1/2 Clinical Trial. The cemsidomide Phase 1/2 trial in combination with dexamethasone for R/R MM and as a monotherapy for R/R NHL continues to enroll patients. Dose escalation continues as the maximum tolerated dose has not yet been reached. For the combination with dexamethasone MM arm, patients are now enrolling at dose level 6 (100 µg once daily (QD)) and enrollment in the dose level 5 (75 µg QD) expansion cohort is complete. The monotherapy NHL arm continues to progress and dose level 5 (100 µg QD) is the highest dose level evaluated to date. CFT1946: CFT1946 is an oral degrader targeting BRAF V600 mutations for the potential treatment of solid tumors including colorectal cancer (CRC), melanoma and non-small cell lung cancer (NSCLC). Presented New Preclinical Data at the 7th Annual Targeted Protein Degradation (TPD) Summit: In October 2024, C4T shared new in vivo data for CFT1946 describing Kpu,u (range: 0.34 - 0.88), experimentally determined using independent methods in two different species. These results demonstrate CFT1946’s ability to cross the blood brain barrier and highlight the potential for activity in primary and metastatic central nervous system (CNS) disease.Presented Monotherapy Clinical Data Demonstrating Proof of Mechanism and Early Evidence of Proof of Concept from the Ongoing CFT1946 Phase 1 Trial at the European Society for Medical Oncology (ESMO) Congress 2024: CFT1946 demonstrated a well-tolerated safety profile and evidence of monotherapy anti-tumor activity, which supports further clinical development as monotherapy and in combination with MEK and EGFR targeted therapies.Advanced the Phase 1/2 Clinical Trial. The CFT1946 Phase 1/2 trial for BRAF V600 mutant solid tumors continues to enroll patients across multiple arms of the trial: CFT1946 Monotherapy Dose Escalation in BRAF V600 Mutant Solid Tumors: Patients continue to enroll in the 640 mg twice daily (BID) pharmacodynamic (PD) backfill cohort.CFT1946 Monotherapy Melanoma Expansion Cohorts: Enrollment at the 320 mg BID dose level is complete and patients are enrolling at the 640 mg BID dose level.CFT1946 with Cetuximab Phase 1b Dose Escalation for CRC: The 160 mg BID dose level has been declared safe and patients are enrolling at the 320 mg BID dose level. RESEARCH UPDATES: Presented at the 7th Annual TPD Summit Highlighting C4T’s TORPEDO® Platform: In October 2024, at the 7th Annual TPD Summit, C4T presented kinetics-based pharmacokinetic (PK) and PD models, demonstrating the company’s ability to predict clinical PD responses across target classes. COLLABORATIONS: Delivered Second Development Candidate to Biogen. In September 2024, C4T earned an additional $8 million milestone payment after Biogen accepted delivery of a second development candidate in an undisclosed indication. Biogen is responsible for all future clinical development and commercialization for this program. This marks the final development candidate under this strategic collaboration. CORPORATE UPDATES: In October 2024, C4T appointed Paige Mahaney, Ph.D., as the company’s chief scientific officer, succeeding Stew Fisher, Ph.D., who is retiring to pursue personal interests. Dr. Mahaney brings over 25 years of pharmaceutical executive leadership with multidisciplinary expertise in discovery research and development along with successfully building clinical portfolios across a wide range of disease indications and treatment modalities.In September 2024, C4T appointed Stephen Fawell, Ph.D., to the Board of Directors. Dr. Fawell brings decades of experience leading discovery and development strategies for global pharmaceutical companies. KEY UPCOMING MILESTONES Cemsidomide: Present updated dose escalation and expansion cohort data from the 50 µg M/W/F, 37.5 µg QD, 62.5 µg QD, and 75 µg QD dose levels in approximately 40 patients from the ongoing Phase 1/2 clinical trial with dexamethasone in R/R MM at the ASH Annual Meeting in December 2024.Present dose escalation data from the 25 µg M/W/F, 50 µg M/W/F, 37.5 µg QD, 62.5 µg QD, and 100 µg QD dose levels in approximately 25 patients from the ongoing monotherapy Phase 1/2 clinical trial in R/R NHL at the ASH Annual Meeting in December 2024.Complete Phase 1 dose exploration in R/R MM and R/R NHL by year-end. CFT1946: Initiate the Phase 1b dose escalation cohort evaluating CFT1946 in combination with trametinib in melanoma by year-end.Present data from multiple anticipated readouts in 2025, including: Full monotherapy CFT1946 dose escalation cohorts in BRAF V600 mutant solid tumors.Expansion cohorts evaluating CFT1946 as a monotherapy in melanoma.Phase 1b dose escalation cohort evaluating CFT1946 in combination with cetuximab in CRC. UPCOMING INVESTOR EVENTS: November 20, 2024, at 8 am GT: Management will participate in a fireside chat at the Jefferies London Healthcare conference taking place in London, UK.December 8, 2024: Management will host an investor call to discuss MM and NHL data from the ongoing Phase 1/2 trial of cemsidomide. THIRD QUARTER 2024 FINANCIAL RESULTS Revenue: Total revenue for the third quarter of 2024 was $15.4 million, compared to $11.1 million for the third quarter of 2023. The increase in revenue was primarily due to recognition of an $8.0 million milestone from Biogen as well as $2.9 million of revenue recognized under our license and supply agreement with Betta, partially offset by reduced revenue from our agreement with Roche due to the completion of research activities in the third quarter of 2023 for a nominated target. Total revenue for the third quarter of 2024 reflects revenue recognized under our collaborations with Biogen, Betta, Merck, Merck KGaA, Darmstadt, Germany (MKDG) and Roche, and total revenue recognized in the third quarter of 2023 reflects revenue recognized under collaboration agreements with Biogen and Roche. Research and Development (R&D) Expense: R&D expense for the third quarter of 2024 was $31.8 million, compared to $28.3 million for the third quarter of 2023. The increase in R&D expense was primarily due to increased clinical trial expense as cemsidomide and CFT1946 continue to advance, partially offset by lower personnel costs. General and Administrative (G&A) Expense: G&A expense was $11.8 million for the third quarter of 2024, compared to $10.5 million for the third quarter of 2023. The increase in G&A expense was primarily attributable to higher personnel expense related to stock-based compensation. Net Loss and Net Loss per Share: Net loss for the third quarter of 2024 was $24.7 million, compared to $27.0 million for the third quarter of 2023. Net loss per share for the third quarter of 2024 was $0.35 compared to $0.55 for the third quarter of 2023. Cash Position and Financial Guidance: Cash, cash equivalents and marketable securities as of September 30, 2024 were $284.4 million, compared to $295.7 million as of June 30, 2024, and $281.7 million as of December 31, 2023. The reduction in cash, cash equivalents and marketable securities during the third quarter was primarily the result of cash used in operating activities, partially offset by $10.3 million in net proceeds raised through our at-the-market (ATM) facility. C4T expects that its cash, cash equivalents and marketable securities as of September 30, 2024 will be sufficient to fund planned operating expenses and capital expenditures into 2027. About C4 Therapeutics C4 Therapeutics (C4T) (Nasdaq: CCCC) is a clinical-stage biopharmaceutical company dedicated to delivering on the promise of targeted protein degradation science to create a new generation of medicines that transforms patients’ lives. C4T is progressing targeted oncology programs through clinical studies and leveraging its TORPEDO® platform to efficiently design and optimize small-molecule medicines to address difficult-to-treat diseases. C4T’s degrader medicines are designed to harness the body’s natural protein recycling system to rapidly degrade disease-causing proteins, offering the potential to overcome drug resistance, drug undruggable targets and improve patient outcomes. For more information, please visit www.c4therapeutics.com. About CemsidomideCemsidomide is an orally bioavailable MonoDAC® degrader designed to be highly potent and selective against its intended targets of Ikaros (IKZF1) and Aiolos (IKZF3) and overcome shortcomings of currently approved therapies to treat multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). Cemsidomide is currently in a Phase 1 dose escalation study in MM and NHL. Initial clinical data show cemsidomide is well tolerated, demonstrates anti-myeloma activity and displays evidence of immunomodulatory effects. More information about this trial may be accessed at www.clinicaltrials.gov (identifier: NCT04756726). About CFT1946CFT1946 is an orally bioavailable BiDAC™ degrader designed to be potent and selective against BRAF V600X mutant targets. In preclinical studies, CFT1946 is active in vivo and in vitro in models with BRAF V600E driven disease and in models resistant to BRAF inhibitors. CFT1946 is currently in a Phase 1 dose escalation study in BRAF V600X mutant solid tumors including colorectal cancer, melanoma and non-small cell lung cancer. More information about this trial may be accessed at www.clinicaltrials.gov (identifier: NCT05668585). Forward-Looking Statements This press release contains “forward-looking statements” of C4 Therapeutics, Inc. within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements may include, but may not be limited to, express or implied statements regarding our ability to develop potential therapies for patients; the design and potential efficacy of our therapeutic approaches; the anticipated timing and content of presentations of data from our clinical trials; and our ability to fund our future operations. Any forward-looking statements in this press release are based on management’s current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties related to the initiation, timing, advancement and conduct of preclinical and clinical studies and other development requirements for our product candidates; the risk that any one or more of our product candidates will cost more to develop or may not be successfully developed and commercialized; and the risk that sufficient capital to fund our future operations will be available to us on acceptable terms or at the times required. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in C4 Therapeutics’ most recent Annual Report on Form 10-K and/or Quarterly Report on Form 10-Q, as filed with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and C4 Therapeutics undertakes no duty to update this information unless required by law. Contacts: Investors:Courtney SolbergSenior Manager, Investor RelationsCSolberg@c4therapeutics.com Media:Loraine SpreenSenior Director, Corporate Communications & Patient AdvocacyLSpreen@c4therapeutics.com Condensed Consolidated Balance Sheet Data(in thousands) (unaudited) (audited) September 30, 2024 December 31, 2023Cash, cash equivalents and marketable securities$284,400 $281,689Total assets 376,060 376,451Deferred revenue 49,417 37,285Total stockholders' equity 242,656 246,114 Condensed Consolidated Statements of Operations(in thousands, except share and per share amounts)(Unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenue from collaboration agreements$15,362 $11,072 $30,407 $17,495 Operating expenses: Research and development 31,838 28,347 78,124 87,315 General and administrative 11,768 10,533 31,751 31,784 Restructuring — — 2,437 — Total operating expenses 43,606 38,880 112,312 119,099 Loss from operations (28,244) (27,808) (81,905) (101,604)Other income (expense), net: Interest expense and amortization of long-term debt − related party — (167) — (1,373)Loss on early extinguishment of debt — (621) — (621)Interest and other income, net 3,578 2,562 11,162 6,862 Total other income, net 3,578 1,774 11,162 4,868 Loss before income taxes (24,666) (26,034) (70,743) (96,736)Income tax expense — (1,003) — (1,003)Net loss$(24,666) $(27,037) $(70,743) $(97,739)Net loss per share − basic and diluted$(0.35) $(0.55) $(1.03) $(1.99)Weighted-average shares outstanding − basic and diluted 69,627,190 49,212,126 68,958,938 49,103,351

Phase 1Financial StatementExecutive ChangeLicense out/inASH

100 Deals associated with Trametinib dimethyl sulfoxide

External Link

KEGG	Wiki	ATC	Drug Bank
D10176	Trametinib dimethyl sulfoxide	L01XE25	DB08911

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Low grade glioma	EU	Novartis Europharm Ltd.	05 Jan 2024
Low grade glioma	IS	Novartis Europharm Ltd.	05 Jan 2024
Low grade glioma	LI	Novartis Europharm Ltd.	05 Jan 2024
Low grade glioma	NO	Novartis Europharm Ltd.	05 Jan 2024
BRAF mutation positive hairy cell leukemia	JP	Novartis Pharma AG	24 Nov 2023
BRAF mutation Solid Tumors	JP	Novartis Pharma AG	24 Nov 2023
BRAF V600E mutation-positive low grade glioma	US	Novartis Pharmaceuticals Corp.	16 Mar 2023
BRAF Mutation Non-small Cell Lung Cancer	JP	Novartis Pharma AG	28 Mar 2016
BRAF mutation positive Melanoma	JP	Novartis Pharma AG	28 Mar 2016
BRAF V600E Mutation-Positive Solid Tumors	KR	Novartis Korea Ltd.	01 Oct 2015
BRAF V600 Mutation-Positive Non-small Cell Lung Cancer	EU	Novartis Europharm Ltd.	30 Jun 2014
BRAF V600 Mutation-Positive Non-small Cell Lung Cancer	IS	Novartis Europharm Ltd.	30 Jun 2014
BRAF V600 Mutation-Positive Non-small Cell Lung Cancer	LI	Novartis Europharm Ltd.	30 Jun 2014
BRAF V600 Mutation-Positive Non-small Cell Lung Cancer	NO	Novartis Europharm Ltd.	30 Jun 2014
BRAF V600 mutation low-grade glioma	AU	Novartis Pharmaceuticals Australia Pty Ltd.	14 Feb 2014
BRAF V600 mutation-positive Melanoma	AU	Novartis Pharmaceuticals Australia Pty Ltd.	14 Feb 2014
BRAF V600E mutant Non-small Cell Lung Cancer	AU	Novartis Pharmaceuticals Australia Pty Ltd.	14 Feb 2014
BRAF V600E Mutation-Positive Anaplastic Thyroid Cancer	AU	Novartis Pharmaceuticals Australia Pty Ltd.	14 Feb 2014
High grade glioma	AU	Novartis Pharmaceuticals Australia Pty Ltd.	14 Feb 2014
BRAF V600E Mutation-Positive Melanoma	US	Novartis Pharmaceuticals Corp.	29 May 2013

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioma	Phase 3	US	Novartis AG	10 Jun 2022
Differentiated Thyroid Gland Carcinoma	Phase 3	US	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	CN	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	AR	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	BR	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	CA	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	IN	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	MY	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	KR	Novartis Pharmaceuticals Corp.	15 Nov 2021
Differentiated Thyroid Gland Carcinoma	Phase 3	TW	Novartis Pharmaceuticals Corp.	15 Nov 2021

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03148275 (SARC033, CTgov)	Phase 2	Epithelioid Hemangioendothelioma	44	Questionnaire Administration+Trametinib	orujziiltz(ahacnazven) = xnfewjjhxv tlxyhdofjd (snshbekpsc, mvdvlpgggq - mycgfgolib) View more	-	26 Nov 2024
NCT02974725 (Pubmed \| Lung Cancer) Manual	Phase 1	NRAS Mutant Melanoma \| KRAS mutant Non-small Cell Lung Cancer \| BRAF Mutation Non-small Cell Lung Cancer KRAS Mutation \| BRAF Mutation \| NRAS Mutation	216	Naporafenib + Rineterkib	chjefzkous(nzxtcnvvwq) = hyqczojcou wmgtwspneb (htdoikczec ) View more	Negative	01 Nov 2024
				Naporafenib + Trametinib	chjefzkous(nzxtcnvvwq) = mojgxkybjv wmgtwspneb (htdoikczec ) View more
NCT02097225 (Cancer Therapy Evaluation Program study 9557, CTgov)	Phase 1	BRAF V600E Mutation-Positive Melanoma \| Melanoma, Cutaneous Malignant \| Metastatic Solid Tumor ... View more	22	Dabrafenib+Trametinib+Onalespib (Treatment (Dabrafenib, Trametinib, Onalespib))	wvsraqewua(pximxfnwyi) = uhccrbymsa logmjwohfa (psenyuuosq, pwlbpucowj - fboeschuez) View more	-	16 Oct 2024
				Dabrafenib+Trametinib+Onalespib (Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2)	ysejlynfhn(pzipoqgrah) = tqnrrfvlqx pzzxjsqagr (fppnqiiupz, iuxgevzxai - vnabgvmmtn) View more
ESMO2024 Manual	Not Applicable	Recurrent Glioblastoma BRAF V600E	17	Dabrafenib-trametinib	rseaozdigf(blhrbfnkkt) = None rpmmqcsyvv (bzglrqipkk )	Positive	16 Sep 2024
				Larotrectinib
ESMO2024 Manual	Not Applicable	Differentiated Thyroid Gland Carcinoma Second line \| First line BRAFV600E mutation	37	Dabrafenib trametinibinib (D+T)	hgkhntfnwo(mjxmotszrt) = zbinzvwfxp wqubedpxsj (lttqbixvjr, 49.2 - 95.3) View more	Positive	16 Sep 2024
				Dabrafenib+trametinib (≥ 2nd line)	hgkhntfnwo(mjxmotszrt) = uabvuhpmxd wqubedpxsj (lttqbixvjr, 16.3 - 61.6) View more
NCT04527549 (CTgov)	Phase 2	Melanoma, Cutaneous Malignant \| Unresectable Melanoma \| Locally Advanced Melanoma	5	Dabrafenib mesylate+Hydroxychloroquine+Trametinib dimethyl sulfoxide (Arm A (Dabrafenib, Trametinib, Hydroxychloroquine))	zskrdnvhwn(xhsepakbhm) = omnzoxjkqk wjqaerzyre (mlpucdlvli, dnpxnjlgig - rselndjtcg) View more	-	22 Aug 2024
				Placebo Administration+Dabrafenib mesylate+Trametinib dimethyl sulfoxide (Arm B (Dabrafenib, Trametinib, Placebo))	zskrdnvhwn(xhsepakbhm) = mpkoefjbqo wjqaerzyre (mlpucdlvli, scdwldrjgo - wzcqjoeeil) View more
NCT03190915 (phase II, CTgov)	Phase 2	Juvenile Myelomonocytic Leukemia \| Neurofibromatosis 1	10	Biopsy+Trametinib	uhncdozrwx(pnlulbljwa) = xigdyflseh bbqkcfdqve (woqntkytuf, dkfrksbcme - rhwqngfmqn) View more	-	16 Jul 2024
NCT01682083 \| EUCTR2012-001266-15-NO (COMBI-AD, Literature) Manual	Phase 3	Melanoma	870	Dabrafenib plus Trametinib	mzbipnrnqz(qwytygfjgr): HR = 0.80 (95% CI, 0.62 - 1.01), P-Value = 0.06 View more	Positive	19 Jun 2024
				Placebo
NCT03190915 (phase II, Pubmed)	Phase 2	Juvenile Myelomonocytic Leukemia mutations that increase Ras signaling output	10	Trametinib	ihxlgagkqa(bmuppxlkld) = iqgxhuaund wwlyimdkum (bcildcpfxg )	Positive	11 Jun 2024
NCT01682083 (COMBI-AD, ASCO2024) Manual	Phase 3	BRAF mutation positive Melanoma Adjuvant BRAF V600E	-	Dabrafenib plus trametinib	jtaciskwyf(cececmcmec) = udmzjrvxnl etgourrcja (jrioebfdbu ) View more	Positive	24 May 2024
				Placebo	jtaciskwyf(cececmcmec) = cqikqbkhww etgourrcja (jrioebfdbu ) View more

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