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.

On December 1, 2020 Tallac Therapeutics, Inc., a privately held biopharmaceutical company harnessing the power of innate and adaptive immunity to fight cancer, reported the completion of its Series A financing totaling $62 million (Press release, Tallac Therapeutics, DEC 1, 2020, View Source [SID1234572043]). Tallac is backed by a syndicate of leading global life science venture firms including venBio Partners, Morningside Venture, Lightstone Ventures, Matrix Partners China, and MRL Ventures Fund. The Company plans to use the Series A funding to advance the discovery and development of immunotherapy candidates for multiple solid tumor maligniancies. Its pipeline of next generation immunotherapies are derived from its novel Toll-like Receptor Agonist Antibody Conjugate (TRAAC) platform.

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Immunotherapies such as checkpoint inhibitors and adoptive CAR-T therapies have become foundational treatment options in oncology, yet the majority of patients only receive a temporary benefit or no benefit as they either develop resistance to treatment or are non-responsive to treatment. Novel immunotherapies known as Toll-like receptor (TLR) agonists are a class of immunotherapy that generates both an innate and adaptive immune response which may produce more robust and durable anti-cancer immunity to help overcome resistance.

"We believe targeting innate immunity represents a transformative approach to creating the next-generation of breakthrough therapeutics in cancer immunotherapy," said Dr. Hong I. Wan, president, CEO and co-founder of Tallac Therapeutics. "Our team has generated robust preclinical data on the Toll-like Receptor Agonist Antibody Conjugate (TRAAC) platform that we recently presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting. With the support of our existing and new investors, I am excited to lead the Tallac team on its mission to advance first-in-class therapies for the benefit of patients in desperate need of new treatment options."

"Tallac has developed a scientifically innovative technology platform to create potent, systemically delivered therapeutics with the potential to provide powerful innate and adaptive anti-tumor immunity across multiple tumor types," said Corey Goodman, board chair, co-founder of Tallac Therapeutics and Managing Partner at venBio. "We are pleased to see the progress made by the team during the seed stage and look forward to supporting Tallac as they advance their pipeline towards the clinic."

Tallac Therapeutics was founded in 2018 by Drs. Goodman and Wan (previously CSO of ALX Oncology) with two other co-founders, Dr. Jaume Pons (currently CEO of ALX Oncology) and Dr. Curt Bradshaw (most recently CSO at Arrowhead Pharmaceuticals), to develop technology for targeted immune activation using an antibody-immune activator conjugate. The research team at Tallac has significant biologics discovery and development expertise. Most recently, under Dr. Wan’s leadership at ALX Oncology, the team designed and advanced ALX148, a best-in-class myeloid checkpoint inhibitor, for multiple tumor indications.

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.

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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.