On December 1, 2020 Turnstone Biologics Corp., a clinical-stage biotechnology company pioneering the development of engineered viral immunotherapies, reported enrollment of the first patients in a Phase 1/2a clinical trial (RAPTOR) of its RIVAL-01/TAK-605 candidate in patients with solid tumors, conducted in collaboration with Takeda Pharmaceutical Company Limited ("Takeda") (Press release, Turnstone Biologics, DEC 1, 2020, View Source [SID1234572041]). RIVAL-01 consists of Turnstone’s proprietary oncolytic vaccinia virus backbone encoding transgenes for Flt3 ligand, anti-CTLA-4 antibody and IL-12 cytokine, purposefully designed to work together to drive immune activity and re-program the microenvironment to be best suited for tumor eradication.

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"The enrollment of the first patients into our Phase 1/2a trial is a key milestone for Turnstone and meaningfully advances our aim of transforming the treatment paradigm for people with cancer," said Mike Burgess, Ph.D., President of R&D, Turnstone. "The meticulous design of our differentiated vaccinia virus platform enabled us to engineer RIVAL-01 to deliver three powerful immune modulating agents locally to primary and metastatic tumor sites, by either intratumoral or systemic administration. We look forward to sharing future updates as the study progresses."

Turnstone’s RIVAL therapeutic pipeline is based on its proprietary vaccinia virus platform, which has been engineered for enhanced immune-stimulation and tumor cell selectivity, potent oncolysis and large transgene carrying capacity. The transgenes are designed to be expressed when the vaccinia virus, delivered either intratumorally or intravenously, enters and replicates in cancer cells. The resulting local production of these therapeutics at the site of tumors adds to the inherent oncolytic and microenvironment-modifying properties of the virus to form a powerful multi-modal attack on the disease. RIVAL-01 is being co-developed and co-commercialized under a global collaboration with Takeda.

"Takeda’s partnership with Turnstone continues to gain momentum. Our teams successfully collaborated to establish the RIVAL-01/TAK-605 clinical development plan while simultaneously working together to advance additional novel next-generation multi-payload oncolytic virus concepts to the clinic", said Chris Arendt, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. "The trial enrollment represents an important step forward in our collaboration and ongoing efforts to leverage innate and adaptive immunity to overcome the limitations of current immuno-oncology therapies."

The RAPTOR trial will evaluate the safety and efficacy of RIVAL-01 (formerly known as TBio-6517) administered intratumorally as a single agent and in combination with Keytruda (pembrolizumab) in patients with solid tumors, including triple negative breast cancer, microsatellite stable colorectal cancer, melanoma and cholangiocarcinoma. Patients are currently enrolling in Phase 1 dose escalation, which will be followed by an expansion phase in specified tumor types in the Phase 2a portion of the trial.

Additional information about the trial, including eligibility criteria and a list of clinical trial sites, can be found at View Source (ClinicalTrials.gov Identifier: NCT04301011).

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.

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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].

On December 1, 2020 The U.S. Food and Drug Administration approved Gallium 68 PSMA-11 (Ga 68 PSMA-11) – the first drug for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer (Press release, US FDA, DEC 1, 2020, View Source [SID1234572026]).

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Ga 68 PSMA-11 is indicated for patients with suspected prostate cancer metastasis (when cancer cells spread from the place where they first formed to another part of the body) who are potentially curable by surgery or radiation therapy. Ga 68 PSMA-11 is also indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen (PSA) levels. Ga 68 PSMA-11 is a radioactive diagnostic agent that is administered in the form of an intravenous injection.

"Ga 68 PSMA-11 is an important tool that can aid health care providers in assessing prostate cancer," said Alex Gorovets, M.D., acting deputy director of the Office of Specialty Medicine in FDA’s Center for Drug Evaluation and Research. "With this first approval of a PSMA-targeted PET imaging drug for men with prostate cancer, providers now have a new imaging approach to detect whether or not the cancer has spread to other parts of the body."

Prostate cancer is the third most common form of cancer in the United States. It is estimated that there will be more than 190,000 new cases of prostate cancer and an estimated 33,000 deaths from this disease in 2020, according to the National Cancer Institute. While computed tomography (CT) scans, magnetic resonance imaging (MRI) scans and bone scans are conventional methods commonly used to image patients with prostate cancer, these approaches are limited in detection of prostate cancer lesions. F 18 fluciclovine and C 11 choline are two other PET drugs that are approved for prostate cancer imaging. However, they are only approved for use in patients with suspected cancer recurrence.

Once administered via injection, Ga 68 PSMA-11 binds to PSMA, which is an important pharmacologic target for prostate cancer imaging because prostate cancer cells usually contain elevated levels of the antigen. As a radioactive drug that emits positrons, Ga 68 PSMA-11 can be imaged by PET to indicate the presence of PSMA-positive prostate cancer lesions in the tissues of the body.

The safety and efficacy of Ga 68 PSMA-11 were evaluated in two prospective clinical trials with a total of 960 men with prostate cancer who each received one injection of Ga 68 PSMA-11. In the first trial, 325 patients with biopsy-proven prostate cancer underwent PET/CT or PET/MRI scans performed with Ga 68 PSMA-11. These patients were candidates for surgical removal of the prostate gland and pelvic lymph nodes and were considered at higher risk for metastasis. Among the patients who proceeded to surgery, those with positive readings in the pelvic lymph nodes on Ga 68 PSMA-11 PET had a clinically important rate of metastatic cancer confirmed by surgical pathology. The availability of this information prior to treatment is expected to have important implications for patient care. For example, it may spare certain patients from undergoing unnecessary surgery.

The second trial enrolled 635 patients who had rising serum PSA levels after initial prostate surgery or radiotherapy, and thus had biochemical evidence of recurrent prostate cancer. All of these patients received a single Ga 68 PSMA-11 PET/CT scan or PET/MR scan. Based on the scans, 74% of these patients had at least one positive lesion detected by Ga 68 PSMA-11 PET in at least one body region (bone, prostate bed, pelvic lymph node, or extra-pelvic soft tissue). In patients with positive Ga 68 PSMA-11 PET readings who had correlative tissue pathology from biopsies, results from baseline or follow-up imaging by conventional methods, and serial PSA levels available for comparison, local recurrence or metastasis of prostate cancer was confirmed in an estimated 91% of cases. Thus, the second trial demonstrated that Ga 68 PSMA-11 PET can detect sites of disease in patients with biochemical evidence of recurrent prostate cancer, thereby providing important information that may impact the approach to therapy.

No serious adverse reactions were attributed to Ga 68 PSMA-11. The most common adverse reactions to Ga 68 PSMA-11 were nausea, diarrhea and dizziness. There is a risk for misdiagnosis because Ga 68 PSMA-11 binding may occur in other types of cancer as well as certain non-malignant processes which may lead to image interpretation errors. There are radiation risks because Ga 68 PSMA-11 contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk for cancer.

The FDA granted approval to the University of California, Los Angeles and the University of California, San Francisco.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

On December 1, 2020 LianBio, a biotechnology company focused on bringing paradigm-shifting medicines to patients in China and other major Asian markets, reported that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has cleared the Company’s Clinical Trial Application (CTA) to conduct the Phase 2a trial of infigratinib in patients with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with FGFR2 gene amplification (Press release, LianBio, DEC 1, 2020, View Source [SID1234572042]).

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LianBio has in-licensed the oncology rights for infigratinib from QED Therapeutics, an affiliate of BridgeBio Pharma, Inc., and is responsible for the clinical development, registration application and future commercial operations of the product candidate in Mainland China, Hong Kong and Macau.

Infigratinib is an investigational oral, selective inhibitor of fibroblast growth factor receptor (FGFR) 1-3 that has shown activity in clinical measures, such as overall response rate, in patients with chemotherapy-refractory cholangiocarcinoma with FGFR2 fusions and advanced urothelial carcinoma with FGFR3 genomic alterations [1][2]. The Phase 2a trial is a multicenter, single-arm study designed to explore and evaluate the pharmacokinetic profile, efficacy and safety of infigratinib in patients with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with FGFR2 gene amplification. Infigratinib is also currently under Phase 3 global development by LianBio and BridgeBio for patients with FGFR2 fusion positive cholangiocarcinoma.

"With strong support from our partner, BridgeBio, the exploratory study highlights LianBio’s continued commitment to expand its global footprint and develop potential breakthrough therapeutics in China," said Dr. Bing Li, Chief Executive Officer of LianBio. "Gastric cancer is the third most common cancer in China, causing approximately 300,000 deaths every year. This clearance by the China NMPA to conduct the Phase 2a trial of infigratinib in gastric cancer will enable LianBio to work towards addressing the significant unmet medical need for this growing patient population."

References

Javle M. et al. A phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor (TKI), in patients with previously-treated advanced cholangiocarcinoma containing FGFR2 fusions; ESMO (Free ESMO Whitepaper) 2018 Annual Meeting. Poster #LBA28.
Pal K. et al. Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations; Cancer Discovery 2018.

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).

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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.