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Menarini Ricerche Announces SEL24/MEN1703 Pharmacodynamic Data from the Dose Escalation Part of DIAMOND-01 Trial

On December 1, 2020 Menarini Ricerche, the R&D division of the Menarini Group, reported today the positive results of the pharmacodynamic assay demonstrating target engagement in the dose escalation part of the DIAMOND-01 trial (CLI24-001; clinicaltrials.gov identifier NCT03008187), a study investigating SEL24/MEN1703, a first-in-class, orally available, dual PIM/FLT3 inhibitor as single agent in Acute Myeloid Leukemia (AML) (Press release, Menarini, DEC 1, 2020, View Source [SID1234572061]).

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The poster entitled "SEL24/MEN1703 provides PIM/FLT3 Downstream Pathway Inhibition in Acute Myeloid Leukemia (AML) Blast Cells: Results of the Pharmacodynamic (PD) Assay in the Dose Escalation Part of First-in-Human DIAMOND Trial" will be presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, which will take place virtually on December 5-8.

"We are pleased with the preliminary, positive results observed with SEL24/MEN1703, a PIM/FLT3 inhibitor under investigation for the treatment of AML. As outlined in our ASH (Free ASH Whitepaper) poster presentation, the dose escalation phase of the DIAMOND-01 trial showed that SEL24/MEN1703 has a manageable safety profile and results in a meaningful target engagement in peripheral blood and bone marrow blast cells from patients treated with SEL24/MEN1703," said Andrea Pellacani, General Manager of Menarini Ricerche. "We look forward to continuing our investigation of SEL24/MEN1703 as a potential new treatment for this aggressive and hard-to-treat cancer, as part of our commitment to develop effective innovative therapies that can make a difference in the lives of cancer patients."

DIAMOND-01 is the First-in-Human, Phase I/II dose escalation and cohort expansion trial of SEL24/MEN1703, in-licensed by Menarini from Ryvu Therapeutics, in AML. The study has completed the dose escalation part showing a manageable safety profile up to the recommended dose of 125 mg/day, with initial evidence of anti-leukemic activity in a single agent setting.

The objective of the pharmacodynamic assessment was to investigate the degree of target engagement achieved at different doses of SEL24/MEN1703, by measuring the phosphorylation of S6 (pS6), a downstream effector of the PIM/FLT3 signaling pathway. In addition, the correlation between pS6 levels and the anti-leukemic effect of SEL24/MEN1703 was assessed in samples collected from patients enrolled in the dose escalation part of the DIAMOND-01 trial. The quantitative assessment of pS6 at a single-cell level was performed both on peripheral blood (PB) and bone marrow (BM) blast cells samples.

The results of this assay confirmed that meaningful target engagement was achieved, both in PB and BM blast cells, in patients treated with SEL24/MEN1703 at 100 mg/day (one dose level below the recommended dose) and at 125 mg/day. Moreover, preliminary data suggest that the PIM/FLT3 pathway inhibition might be associated with blast count reduction, particularly in those patients showing high phosphorylation of S6 at baseline.

We will continue to measure target engagement with this assay in the cohort expansion part of the DIAMOND-01 trial, which is currently recruiting patients with relapsed or refractory AML in both the EU and the US.

About MEN1703

SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 inhibitor in-licensed by Menarini from Ryvu Therapeutics. It is an investigational compound, not approved for use by regulatory authorities, currently being evaluated in the DIAMOND-01 trial (CLI24-001; clinicaltrials.gov identifier NCT03008187) for the treatment of Acute Myeloid Leukemia.

Dragonfly Therapeutics Announces Merck Opt-In of TriNKET™ Immunotherapy Candidate for Patients with Solid Tumors

On December 1, 2020 Dragonfly Therapeutics, Inc. ("Dragonfly"), reported that Merck, known as MSD outside the United States and Canada, has licensed its first TriNKET immunotherapy candidate from Dragonfly (Press release, Dragonfly Therapeutics, DEC 1, 2020, View Source [SID1234572060]). Merck and Dragonfly’s collaboration, initially focused on a number of solid tumor targets, began in October 2018. Earlier this year, the companies expanded their collaboration with a multi-target agreement to develop and commercialize additional natural killer ("NK") cell engager immunotherapies in oncology, infectious disease and immune disorders.

"Merck is a powerful world leader in drug development across a wide number of therapeutic areas and continues to be a strong scientific collaborator," said Bill Haney, co-founder and CEO of Dragonfly Therapeutics. "We are delighted that Merck has exercised its option for this first immunotherapy candidate from our collaboration, and excited by the progress we are making together on bringing Dragonfly’s TriNKET technology to targets across a broader set of diseases."

Under the agreement Merck has exercised its option to license exclusive worldwide intellectual property rights on its first immunotherapy candidate developed using the TriNKET technology platform and Dragonfly has received an undisclosed payment associated with this milestone.

Karyopharm Announces Investor and Analyst Event at the American Society of Hematology 2020 Annual Meeting

On December 1, 2020 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported that it will host a virtual investor and analyst event to discuss the Company’s pipeline of clinical programs and highlights from the data presentations being given at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting (Press release, Karyopharm, DEC 1, 2020, View Source [SID1234572058]). This Karyopharm-sponsored event is scheduled for Tuesday, December 8, 2020 from 1:00 – 2:30 p.m. ET.

The Karyopharm management team will be joined by a group of recognized multiple myeloma, diffuse large B-cell Lymphoma and leukemia experts to provide additional external context and participate in the Q&A portion of the call.

To access the event, please dial (877) 870-4263 (local) or (412) 317-0790 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call will be available under "Events & Presentations" in the Investor section of the Company’s website, View Source An archived webcast will be available on the Company’s website approximately two hours after the event.

Ascentage Pharma Announces Clearances in China and the US for the Phase IIa Study of APG-115 Single Agent or in Combination with APG-2575 for the Treatment of Relapsed or Refractory T-cell Prolymphocytic Leukemia

On December 1, 2020 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) has approved a Phase IIa clinical study of the company’s novel MDM2-p53 inhibitor APG-115, as a single agent or in combination with the company’s novel Bcl-2 inhibitor APG-2575, for the treatment of patients with relapsed/refractory T-cell prolymphocytic leukemia (r/r T-PLL) (Press release, Ascentage Pharma, DEC 1, 2020, View Source [SID1234572057]). Prior to this approval in China, the study had already received clearance from the US Food and Drug Administration (FDA).

This global multicenter, open-label Phase IIa clinical study was designed to evaluate the safety, pharmacokinetics, and preliminary efficacy of APG-115 as a single agent or in combination with APG-2575 for the treatment of patients with r/r T-PLL.

T-PLL is an aggressive T-cell leukemia1 and an ultra-rare disease with an incidence rate of just 0.6 cases per million, and a median age of onset of 61 years2,3. The treatment options for T-PLL remain very limited. T-PLL is not very responsive to conventional chemotherapies, and there have been very few clinical studies targeting this disease4. To date, no therapy has been approved by the US FDA, European Medicines Agency (EMA), or China National Medical Products Administration (NMPA) for the treatment of T-PLL. Relapsed T-PLL often has a very poor prognosis, with an overall survival rate of just six to nine months5-8. There is an urgent need for identifying effective novel therapies for T-PLL.

Ataxic telangiectasia mutation (ATM) caused by the deletion or missense mutation of 11q23 occurs in up to 80-90% of patients with T-PLL9. In patient-derived xenograft (PDX) models harboring the ATM mutation， APG-115 demonstrated impressive antitumor activity. In a panel of cancer cell line or patient-derived xenograft models (CDX or PDX) representing human hematologic or solid malignancies, APG-115 plus APG-2575 has demonstrated potent synergistic effect and significantly enhanced antitumor activities. It is worth noting that the combination produced a response rate of 100% in xenograft models of MV-4-11 acute myeloid leukemia (AML) and Z138 mantle cell lymphoma (MCL) cell lines.

APG-115 is an orally administered, selective, small-molecule inhibitor of the MDM2 protein. APG-115 has strong binding affinity to MDM2 and is designed to activate tumor suppression activity of p53 by blocking the MDM2-p53 protein-protein interaction. APG-115 is the first MDM2-p53 inhibitor entering clinical development in China, with multiple ongoing clinical studies in solid tumors and hematologic malignancies in China and the US.

APG-2575 is a novel, orally administered small-molecule Bcl-2‒selective inhibitor being developed by Ascentage Pharma. APG-2575 is designed to treat hematologic and solidmalignancies by selectively blocking antiapoptotic protein Bcl-2 to restore the normal apoptosis process in cancer cells. As a bona fide Bcl-2 inhibitor, APG-2575 demonstrated desired target engagement. APG-2575 selectively binds to Bcl-2, disrupts Bcl-2:BIM complexes, and releases proapoptotic protein BIM. Freed BIM subsequently activates BAX/BAK for pore formation on the mitochondria membrane, leading to mitochondrial outer-membrane permeabilization (MOMP), cytochrome c release, caspase activation, and apoptosis of cancer cells. APG-2575 is the first China-developed Bcl-2 inhibitor having entered clinical development in China. As a single agent, APG-2575 has potent antitumor activity in Bcl-2-dependent tumor cells, and has shown a broad range of antitumor activities when combined with other oncologic drugs. Previously, APG-2575 had received clearances and approvals for multiple Phase Ib/II clinical studies in China, Australia, and the US, and is currently being developed in a range of hematologic malignancies globally.

Based on T-PLL’s pathogenesis and the molecular therapy’s potential in bringing about a clinical breakthrough to the treatment of T-PLL, supported by the positive preclinical results and early clinical data of APG-115 and APG-2575, the Investigational New Drug Application (IND) for this Phase IIa study of APG-115 as a single agent or in combination with APG-2575 for the treatment of r/r T-PLL has already received clearance from the US FDA.

"Both APG-2575 and APG-115 are key drug candidates in our apoptosis-targeted pipeline. We look forward to commencing this study evaluating the combination of our two novel compounds in T-PPL in China and the US, which hopefully will lead to a safe and effective novel therapy for T-PPL that currently has no approved treatment," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Combination therapy is playing an increasingly important role in cancer treatment. Concurrent inhibition of both MDM2-TP53 and BCL-2 apoptosis pathways by the combination of APG-115 and APG-2575 has great therapeutic potential in triggering ‘synthetic lethality’ and effectively induce cell death by simultaneously blocking two important nodes of both apoptosis pathways10. Second，both APG-115 and APG-2575 are orally bioavailable, targeted agents. The combination may provide a chemo-free treatment option for patients with T-PLL. Further, the combination treatment in T-PLL is an innovative experimental therapy worldwide. We will strive to deliver a clinical breakthrough for patients with T-PPL."

References

1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.

2. Matutes E, Brito-Babapulle V, Swansbury J, et al. Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood. 1991;78(12):3269-3274.

3. Herling M, Khoury JD, Washington LT, Duvic M, Keating MJ, Jones D. A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories. Blood. 2004;104(2):328-335.

4. Mercieca J, Matutes E, Dearden C, MacLennan K, Catovsky D. The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype. J Clin Oncol. 1994;12(12): 2588-2593.

5. Herbaux C, Genet P, Bouabdallah K, et al. Bendamustine is effective in T-cell prolymphocytic leukaemia. Br J Haematol. 2015; 168(6):916-919.

6. Jain P, Aoki E, Keating M, et al. Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL). Ann Oncol. 2017;28(7):1554-1559.

7. Dearden CE, Khot A, Else M, et al. Alemtuzumab therapy in T-cell prolymphocytic leukemia: comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route. Blood. 2011;118(22):5799-5802.

8. Keating MJ, Cazin B, Coutré S, et al. Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol. 2002;20(1): 205-213.

9. Schrader A, Crispatzu G, Oberbeck S, et al. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun. 2018;9(1):697.

10. Pan R, Ruvolo V, Mu H, et al. Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy. Cancer Cell. 2017 Dec 11; 32(6): 748–760.e6.

Cogent Biosciences Announces Pricing of Upsized Public Offering of Shares of Common Stock

On December 1, 2020 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported the pricing of an underwritten public offering of 10,256,411 shares of its common stock, offered at a public offering price of $9.75 per share (Press release, Cogent Biosciences, DEC 1, 2020, View Source [SID1234572056]). In addition, Cogent Biosciences has granted the underwriters a 30-day option to purchase up to an additional 1,538,461 shares of its common stock at the public offering price less underwriting discounts. The size of the offering was upsized from $60 million to approximately $100 million. All of the shares of common stock sold in the offering are being sold by Cogent Biosciences. The offering is expected to close on or about December 4, 2020, subject to customary closing conditions.

The gross proceeds from the offering are expected to be approximately $100 million before deducting customary underwriting discounts, offering expenses and excluding any exercise of the underwriters’ option. Cogent Biosciences intends to use the net proceeds from the offering for development, regulatory and commercial preparation activities relating to PLX9486 and other product candidates, as well as for working capital and general corporate purposes.

Jefferies and Piper Sandler & Co. are acting as joint book-running managers for the offering. Wedbush PacGrow, LifeSci Capital and Ladenburg Thalmann are also acting as co-managers for the offering.

The securities described above are being offered pursuant to a shelf registration statement (File No. 333-230678) filed with the Securities and Exchange Commission (SEC), which became effective on May 1, 2019.

A final prospectus supplement and accompanying base prospectus relating to and describing the terms of the offering will be filed with the SEC. The securities described above have not been qualified under any state blue sky laws. 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 other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction. The offering can be made only by means of a prospectus supplement and accompanying base prospectus, copies of which may be obtained at the SEC’s website at www.sec.gov, or by request to Jefferies LLC (Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, New York 10022; telephone: 877-821-7388; email: [email protected]); or Piper Sandler & Co., Attention: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, Minnesota 55402, or by telephone at (800) 747-3924, or by email at [email protected].