RNA polymerase II

On September 30, Genentech, a division of Roche, entered into a major agreement with Rueger, with Genentech successfully acquiring Rueger's portfolio of next-generation CDK inhibitors for $850 million in upfront cash and other potential milestone payments. This transaction not only refreshes the down payment record for the foreign authorization of domestic molecules, but also marks a new milestone in the cooperation between the two sides. The previous record was held by Benefi Tianheng's agreement with BMS for the BL-B01D1 molecule, which was valued at $800 million. It is worth noting that the transaction between Benefi Tianhengand BMS only involves a single molecule BL-B01D1, which is already in the late clinical stage, and both parties share the subsequent overseas clinical costs. The collaboration with Genentech builds on a broader portfolio of next-generation CDK inhibitors, which is expected to include the Phase I CDK2/4/6 inhibitor RGT-419B and the preclinical CDK2 inhibitor QR-6401. Under the terms of the agreement, Genentech will be responsible for the global clinical development, manufacturing and commercialization of these products after the end of the existing Phase 1 clinical phase. Recently, the field of CDK inhibitors has become a hot spot pursued by many companies. In addition to Genentech, Beigene also announced the introduction of ETX-197, a CDK2 inhibitor from Onsun Pharma, at the end of November last year. Although the amount of the upfront payment was not disclosed, taking into account potential future milestone payments and sales sharing, the total value of the deal is up to $1.33 billion. With some generic CDK4/6 inhibitors entering the market in bulk, some investors are questioning whether the competitive landscape on the CDK inhibitor circuit has reached saturation. However, leading companies such as Roche and Beigene are still actively developing next-generation CDK inhibitors, which has a profound scientific and commercial logic behind it. CDKs (cyclin-dependent kinases), as an important member of the serine/threonine protein kinase family, play a crucial role in cell cycle regulation. CDK family targets are mainly divided into two categories: one is involved in cell cycle regulation and related mitosis, such as CDK1, 2, 4, 6; The other group is mainly involved in transcriptional regulation and phosphorylation of RNA polymerase II, such as CDK7, 8, 9, 11. Among them, CDK4/6 and CDK2 have attracted much attention due to their important roles in the development of tumors. CDK4/6 is a key condition protein in the human cell division and proliferation cycle, which can trigger the cell cycle transition from the growth phase (G1 phase) to the DNA replication phase (S phase). In many cancer cells, CDK4/6 is overexpressed, which promotes the disorderly proliferation of cancer cells through over-phosphorylation and inhibition of Rb protein. Therefore, CDK4/6 inhibitors can inhibit the proliferation of tumor cells by blocking the cell growth cycle in the G1 phase. CDK2 plays a key role in the early phase of DNA synthesis (G1 phase) and the phase of DNA synthesis (S phase) of the cell cycle, and its overexpression is closely related to the abnormal regulation of the cell cycle and the excessive proliferation of cancer cells. From a market perspective, breast cancer, as the world's largest malignant tumor (accounting for about 24.5% of all malignant tumors), provides a broad application space for CDK inhibitors. In particular, the large population of HR+/HER2- advanced breast cancer patients (about 60%-70%) makes endocrine therapy combined with CDK4/6 inhibitors a first-line treatment in this area. This also explains why CDK4/6 inhibitors can occupy an important position in the treatment of breast cancer and create a large drug market size. Despite the proliferation of blockbuster drugs in recent years, existing and older CDK4/6 inhibitors inevitably have several shortcomings, the most significant of which are drug toxicity and resistance. First, in terms of toxicity, hematotoxicity is the most common side effect of CDK4/6 inhibitors. These inhibitors inhibit cell proliferation by blocking the cell cycle, thus killing rapidly dividing cells, but this mechanism also leads to myelosuppression, which reduces blood cell production. Specifically, neutropenia, leukopenia, anemia, and thrombocytopenia are the most common hematological toxic side effects of commercialized CDK4/6 inhibitors. In addition, CDK4/6 inhibitors may also cause gastrointestinal adverse reactions, which should not be ignored. Second, in terms of drug resistance, although CDK4/6 inhibitors have achieved remarkable results in improving disease control in HR+/ HER2-breast cancer patients, 15-20% of patients still develop primary resistance to the drug at the beginning of treatment, while 30-40% of patients develop resistance gradually over the course of treatment. The mechanisms of drug resistance are complex and diverse, including but not limited to ESR1 gene mutation, upregulation of PI3K/AKT/mTOR signaling pathway, and BRCA2 gene mutation. In view of the influx of generic drugs of the older generation of CDK4/6 inhibitors and the urgent need to solve the existing toxicity and drug resistance problems, the new generation of CDK inhibitors ushered in more development opportunities. The RRT-419B that Roche is concerned about is a new generation of CDK2/4/6 small molecule inhibitor developed by Rueger Pharmaceutical. The drug is not commercially available worldwide, and its kinase activity profile has been optimized to target "better" safety and resistance CDK inhibitors from the outset. Regal's RRT-419B shows unique ingenuity in both design ideas and drug mechanisms, and has achieved preliminary validation of ideas in existing breast cancer clinical data. Unlike existing commercialized CDK inhibitors, which mainly inhibit subtypes 4 and 6, RGT-419B aims to reduce the occurrence of resistance to existing CDK4/6 inhibitors by increasing the inhibition of CDK2 subtypes, thereby achieving long-term efficacy. When CDK4/6 activity is inhibited, expansion of Cyclin E and activation of the oncogene MYC lead to up-regulation of MYC and activation of CDK2. CDK2-CyclinE, as a compensatory pathway, phosphorylates Rb, thereby releasing E2F transcription factors and promoting tumor cell proliferation. This process is the key to the development of acquired resistance to CDK4/6 inhibitors. Preliminary data from overseas studies such as Pfizer's CDK2 inhibitor PF-07104091 also revealed an association between CDK2 activation and acquired resistance to CDK4/6 inhibitors. In December 2023, Rueger presented the latest clinical data for RGT-419B at the SABCS Conference. The drug performed well in a Phase 1a clinical trial of monotherapy in 12 patients with HR+/ HER2-metastatic breast cancer receiving CDK4/6is and ET progression: three patients achieved partial response (PR) and continued treatment; Six patients received RGT-419B for more than 24 weeks; The drug was safe and well tolerated, no dose-limiting toxicity occurred, and no patient stopped treatment due to adverse events. Given the huge potential of next-generation CDK inhibitors in second-line breast cancer monotherapy, and the successful performance of commonly used second-line endocrine drugs such as fluvestrant in the market (such as the peak sales of $1.028 billion for fluvestrant in 2018), the global market for next-generation CDK inhibitors is expected to reach at least $2-3 billion. That is one of the reasons Roche is willing to bet so heavily. Faced with such a broad market prospect, many domestic pharmaceutical companies have also devoted themselves to the research and development of a new generation of CDK2/4/6 inhibitors or CDK2 inhibitors. One kind of large pharmaceutical companies further expand the development of CDK2 inhibitors on the basis of CDK4/6 inhibitor layout, such as Hengrui Pharmaceutical and First Sound Pharmaceutical; The other category is the first to enter the CDK inhibitor track of Biotech or big pharmaceutical companies such as Ruge Pharmaceutical, Stone pharmaceutical Group and Homology Kang Pharmaceutical. These companies are advancing the CDK inhibitor field and competing for future market share through continuous research and development and innovation. Although most of the CDK2/4/6 inhibitors that have entered the clinical stage in China are still in the early clinical stage, and most of them have not yet been validated by clinical data, it can be observed from the transaction cases of Regal Medicine and Beigene that these two authorized molecules have been deeply optimized by AI technology. From the information that has been made public, the AI pharmaceutical platform has played a key driving role in Genentech/Regal Pharma's RGT-419B and Beigene/Angsen Pharma's ETX-197 project. It is worth noting that the high degree of similarity among CDK family members makes the development of highly selective CDK2 inhibitors a great challenge. If the molecular selectivity is insufficient, it may lead to off-target phenomenon, which will affect the efficacy and safety of the drug. With the assistance of the AI model Kinetic EnsemNET, Onson has successfully identified a key hidden dynamic binding pocket of CDK2, thereby developing a potential BIC CDK2 candidate with high activity, high selectivity and a wide therapeutic window, which lays the foundation for its subsequent collaboration with Beigene. On the other hand, Ruge Pharmaceutical relied on its self-developed AI-assisted new drug research and development platform CARD to achieve the best selective screening of multiple CDK targets, and successfully promoted the clinical trial process of RGT-419B in the United States. From the licensing trend of CDK inhibitors, we can take a lesson: in the future, investors may need to pay more attention to the investment opportunities of Biotech companies that use AI technology to solve the difficult drug target or hot target iterative drug development challenges.

BOSTON, Sept. 23, 2024 (GLOBE NEWSWIRE) -- Carrick Therapeutics Inc., an oncology-focused biopharmaceutical company discovering and developing highly differentiated therapies, today announced that the first patient has been dosed in the Phase 1 clinical trial evaluating CT7439, a novel cyclin dependent kinase 12/13 (CDK12/13) inhibitor / Cyclin-K glue-degrader. CDK12/13 is implicated in multiple cancer types, as they regulate transcription elongation, RNA splicing, as well as cleavage and polyadenylation. DNA damage response genes are particularly suppressed by loss of CDK12/13 activity. The clinical trial is enrolling patients with advanced solid tumors, including ovarian, breast and Ewing's Sarcoma. "Initiation of our CT7439 Phase 1 clinical trial marks the advancement of our second therapeutic into the clinic for aggressive and resistant forms of cancer,” said Tim Pearson, Chief Executive Officer of Carrick Therapeutics. “CT7439 is the first CDK12/13 inhibitor to enter clinical development, and we are encouraged by its potential as monotherapy or combination therapy across multiple tumor types.” The Phase 1 clinical trial is a modular design, beginning with a dose escalation for the initial administration of CT7439 to patients. The initial clinical evaluation will be focused on safety and pharmacokinetics, with an opportunity for early Proof of Principle using a blood based pharmacodynamic assay of the homologous recombination repair (HRR) pathway. Clinical trial details can also be found on www.clinicaltrials.gov under study ID: NCT06600789. For additional information on the clinical trial, please contact hello@carricktherapeutics.com. About CT7439CT7439 is an inhibitor of CDK12/13 as well as a 'glue degrader' of Cyclin-K, which is the obligate co-factor for CDK12/13, giving both first-in-class and best-in-class potential. This dual modality significantly increases the potency of the compound and leads to the inhibition of DNA repair at the transcriptional level. CDK12/13 regulates gene transcription through the activation of RNA Polymerase II. It has the potential to synergise with other agents targeting DDR such as the PARP inhibitors in multiple cancer types, including breast, ovarian and Ewing’s Sarcoma. About Carrick TherapeuticsCarrick Therapeutics is an oncology-focused biopharmaceutical company developing highly differentiated novel therapies that address significant unmet needs. The Company’s lead program, samuraciclib, is a novel oral first-in-class inhibitor of CDK7 currently in multiple Phase 2 clinical trials for metastatic HR+ breast cancer. The Company is collaborating with Roche, Menarini Group and Arvinas/Pfizer to evaluate novel combinations of samuraciclib with oral SERD endocrine therapies. Additionally, Carrick is developing CT7439, a novel CDK12/13 inhibitor / Cyclin-K glue-degrader, which is currently in a Phase 1 clinical trial. For more information about Carrick Therapeutics, please visit www.carricktherapeutics.com Carrick Contact Carrick TherapeuticsJenny Horsfield, Chief Business Officerjenny.horsfield@carricktherapeutics.com Investors and MediaLuke Heagle, Real Chemistrylheagle@realchemistry.com

Vincerx continues to enroll its Phase 1 studies of antibody-drug conjugate (ADC) VIP943, with data expected by the end of Q4 2024, and small molecule drug-conjugate (SMDC) VIP236, with data expected at the end of Q3 2024 Expected cash runway through 2024 PALO ALTO, Calif., Aug. 08, 2024 (GLOBE NEWSWIRE) -- Vincerx Pharma, Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, today reported financial results for the second quarter of 2024 and provided an overview of its clinical programs and anticipated milestones. “During the second quarter, our team focused on execution and the continued enrollment of patients in our ongoing Phase 1 studies for our potentially best-in-class ADC, VIP943, and first-in-class SMDC, VIP236,” said Ahmed Hamdy, M.D., Chief Executive Officer. “We look forward to evaluating the results from additional cohorts and sharing data by end of Q3 for VIP236 and by end of year for VIP943.” SECOND QUARTER 2024 CLINICAL PROGRAM HIGHLIGHTS AND ANTICIPATED MILESTONES VIP943 VIP943, a novel CD123-targeted ADC created from Vincerx’s VersAptx™ platform, consists of an anti-CD123 antibody, a unique linker cleaved intracellularly by legumain, and a novel kinesin spindle protein inhibitor (KSPi) payload enhanced with Vincerx’s CellTrapper® technology. Its next-generation effector chemistry was designed to address challenges associated with many ADCs by improving efficacy and reducing severe toxicities.Vincerx expects to share additional Phase 1 study data for VIP943 for patients with relapsed/refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and B-cell acute lymphoblastic leukemia (B-ALL) (NCT06034275) by the end of Q4 2024. VIP236 VIP236 is an αVβ3 SMDC conjugated to an optimized camptothecin (CPT) payload created from Vincerx’s VersAptx platform. VIP236 is a first-in-class drug designed to deliver its optimized CPT payload directly to tumor tissues to overcome chemotherapy-related side effects. Preclinical studies have shown 11 times more optimized CPT is delivered to the cancerous tissues than found circulating in the blood. In addition, the optimized CPT is designed to limit drug transporter liabilities, a common mechanism for cancer resistance to chemotherapy.Vincerx looks forward to sharing additional data from this Phase 1 study (NTC05371054) by the end of Q3 2024. Enitociclib Enitociclib is a highly selective CDK9 inhibitor designed to block the activation of RNA polymerase II, leading to the reduction of oncogenes, including MYC and MCL1.Enitociclib is currently in a Phase 1 dose-escalation study (NTC05371054) evaluating the combination of enitociclib, venetoclax and prednisone in diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL). This study is being conducted in collaboration with the National Institutes of Health (NIH). At the AACR Advances in Malignant Lymphoma meeting in June 2024, the NIH presented the interim study results previously shared by Vincerx in January 2024 and May 2024. VIP924 VIP924 is a first-in-class CXCR5-targeted ADC created from Vincerx’s VersAptx platform.VIP924 can be evaluated in B-cell malignancies, including mantle cell lymphoma, follicular lymphoma, DLBCL, and chronic lymphocytic leukemia , as a monotherapy and in combination.IND application is anticipated in early 2026, pending funding. VersAptx™ Platform VersAptx is Vincerx’s versatile and adaptable, next-generation bioconjugation platform. The modular nature of this platform enables the combination of different targeting, linker, and payload technologies to develop bespoke bioconjugates to address different cancer biologies. SECOND QUARTER 2024 FINANCIAL RESULTS Vincerx had approximately $16.3 million in cash, cash equivalents and marketable securities as of June 30, 2024, as compared to approximately $5.1 million as of March 31, 2024. Based on its current business plans and assumptions, Vincerx believes its available capital, including the proceeds of its April financing of approximately $16.9 million, will be sufficient to meet its operating requirements through the end of 2024.Research and development expenses for the second quarter ended June 30, 2024 were approximately $3.8 million, as compared to approximately $8.2 million for the same period in 2023. This decrease is primarily the result of decreases in research services of approximately $1.8 million, manufacturing services associated with our ADC program of approximately $1.6 million, and personnel related expenses of approximately $0.8 million.General and administrative expenses for the second quarter ended June 30, 2024 were approximately $3.6 million, as compared to approximately $3.8 million for the same period in 2023. This decrease is primarily driven by decreases in personnel-related expenses of approximately $0.3 million.For the second quarter ended June 30, 2024, Vincerx reported a net loss of approximately $1.8 million, or $0.05 per share. For the second quarter ended June 30, 2023, Vincerx reported a net loss of approximately $11.6 million, or $0.54 per share. About Vincerx Pharma, Inc.Vincerx Pharma, Inc. is a clinical-stage biopharmaceutical company committed to developing differentiated and novel therapies to address the unmet medical needs of patients with cancer. Vincerx has assembled a seasoned management team with a proven track record of successful oncology drug development, approvals, and value creation. Vincerx’s diverse pipeline consists of the next-generation antibody-drug conjugate, VIP943, in Phase 1; small molecule-drug conjugate, VIP236, in Phase 1; preclinical antibody-drug conjugate, VIP924; CDK9 inhibitor, enitociclib, in an NIH-sponsored Phase 1; and VersAptx, its versatile and adaptable, next-generation bioconjugation platform. Vincerx is based in Palo Alto, California, and has a research facility in Monheim, Germany. For more information, please visit www.vincerx.com and follow Vincerx on LinkedIn. Forward-Looking StatementThis press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended, that are intended to be covered by the “safe harbor” created by those sections. Forward-looking statements, which are based on certain assumptions and describe future plans, strategies, expectations and events, can generally be identified by the use of forward-looking terms such as “believe,” “expect,” “may,” “will,” “should,” “would,” “could,” “suggest,” “seek,” “intend,” “plan,” “goal,” “potential,” “on-target,” “on track,” “project,” “estimate,” “anticipate,” or other comparable terms. All statements other than statements of historical facts included in this press release are forward-looking statements. Forward-looking statements include, but are not limited to, Vincerx’s business model, cash runway, pipeline, strategy, timeline, product candidates and attributes, and preclinical and clinical development, timing, and results. Forward-looking statements are neither historical facts nor assurances of future performance or events. Instead, they are based only on current beliefs, expectations, and assumptions regarding future business developments, future plans and strategies, projections, anticipated events and trends, the economy, and other future conditions. Forward-looking statements are subject to inherent uncertainties, risks, and changes in circumstances that are difficult to predict, many of which are outside Vincerx’s control. Actual results, conditions, and events may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause actual results, conditions, and events to differ materially from those indicated in the forward-looking statements include, but are not limited to, general economic, financial, legal, political, and business conditions; risks associated with preclinical or clinical development and studies, including those conducted prior to Vincerx’s in-licensing; failure to realize the benefits of Vincerx’s license agreement with Bayer; risks related to the timing of expected business and product development milestones; changes in the assumptions underlying Vincerx’s expectations regarding its future business or business model; Vincerx’s ability to successfully develop and commercialize product candidates; Vincerx’s capital requirements, availability and uses of capital, and cash runway; and the risks and uncertainties set forth in the Form 10-Q for the quarter ended March 31, 2024 and subsequent reports filed with the Securities and Exchange Commission by Vincerx. Forward-looking statements speak only as of the date hereof, and Vincerx disclaims any obligation to update any forward-looking statements. Vincerx, the Vincerx logo, CellTrapper, and VersAptx are our trademarks. ContactsGabriela JairalaVincerx Pharma, Inc.gabriela.jairala@vincerx.com Cassidy McClainInizio Evoke CommsCassidy.McClain@inizioevoke.com Vincerx Pharma, Inc.Condensed Consolidated Balance Sheets(in thousands) June 30, 2024 December 31, 2023 (unaudited) ASSETS Current assets: Cash and cash equivalents$7,923 $12,782 Short-term marketable securities 8,396 - Prepaid expenses 530 51 Grant receivable 1,018 1,044 Other current assets 416 856 Total current assets 18,283 14,733 Right-of-use assets 1,693 2,201 Property, plant and equipment, net 98 125 Other assets 1,453 1,158 Total assets$ 21,527 $ 18,217 LIABILITIES AND STOCKHOLDERS' EQUITY Current liabilities Accounts payable$1,536 $2,497 Accrued expenses 2,428 1,755 Lease liability 1,236 1,162 Common stock warrant liabilities 132 191 Total current liabilities 5,332 5,605 Lease liability, net of current portion 697 1,340 Other noncurrent liabilities 50 50 Total liabilities 6,079 6,995 Total stockholders' equity 15,448 11,222 Total liabilities and stockholders' equity$ 21,527 $ 18,217 Vincerx Pharma, Inc.Condensed Consolidated Statements of Operations(unaudited)(in thousands, except per share amounts) For the three months ended For the six months ended June 30, June 30, 2024 2023 2024 2023 Operating expenses: General and administrative$3,612 $3,811 $6,534 $8,308 Research and development 3,754 8,248 8,310 19,159 Total operating expenses 7,366 12,059 14,844 27,467 Loss from operations (7,366) (12,059) (14,844) (27,467)Other income (expense) Change in fair value of warrant liabilities 5,263 (118) 59 (100)Interest income 157 327 256 793 Other income (expense) 138 300 292 574 Total other income (expense) 5,558 509 607 1,267 Net loss $ (1,808) $ (11,550) $ (14,237) $ (26,200) Net loss per common share, basic and diluted$(0.05) $(0.54) $(0.48) $(1.23)Weighted average common shares outstanding, basic and diluted 38,339 21,274 29,869 21,231