On December 8, 2020 Candel Therapeutics ("Candel") reported that Paul-Peter Tak, M.D., Ph.D., was appointed president and chief executive officer of Candel Therapeutics in a planned transition to lead a new phase of growth as the Company advances its broad pipeline of oncolytic viral immunotherapies (Press release, Candel Therapeutics, DEC 8, 2020, View Source [SID1234572454]). Dr. Tak is a world-renowned immunologist, drug developer, entrepreneur and patient advocate who brings more than 25 years of demonstrated success to the role. The company has also appointed Nathan Caffo as chief business officer, John Canepa as chief financial officer and Susan Stewart as chief regulatory officer.

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"Candel has tremendous potential to change the cancer treatment paradigm for the many patients who aren’t well served by currently available treatment options," said Paul-Peter Tak, M.D., Ph.D., CEO of Candel Therapeutics. "Our approach, which is based on two differentiated oncolytic virus-based platforms, enables local destruction of tumor cells while eliciting a robust, systemic, long-lasting immune response. With our lead compound currently in a phase 3 clinical trial, our rQNestin 34.5 oncolytic HSV in phase 1, and our recently initiated discovery program, Candel is leveraging a unique platform to develop innovative immunotherapies for patients with an unmet need."

Candel is focused on developing immunotherapies that induce immunogenic cell death in cancer cells at the site of injection, unmasking tumor neo-antigens while activating immuno-inflammation in the tumor microenvironment. This process leads to a broad, systemic immune response against the cancer cells, with the potential to change disease outcomes across a variety of solid tumor indications. Candel currently has clinical programs in prostate cancer, glioblastoma, non-small cell lung cancer and pancreatic cancer.

Dr. Aguilar-Cordova commented, "Candel has made tremendous progress in advancing its viral immunotherapy platforms. Having now administered our investigational therapies to over 700 patients in multiple phase 1 to phase 3 clinical trials, we are at an important stage of the company’s growth. Building on this foundation, we are proud to have attracted such accomplished industry veterans as Paul-Peter, Nathan, John and Sue to join us and help realize Candel’s potential in this next stage of growth."

With a career spanning nearly three decades in the life science and biopharma industry, Dr. Tak was most recently president and chief executive officer of Kintai Therapeutics as well as venture partner at Flagship Pioneering. Previously, he was senior vice president and global head of R&D for immuno-inflammation, oncology and infectious disease, as well as chief immunology officer and global development leader at GlaxoSmithKline (GSK), while also serving as co-chair of GSK’s scientific review board. Prior to that, Dr. Tak was president and CEO of Tempero Pharmaceuticals, where he facilitated the company’s acquisition by GSK. He co-founded Sitryx Therapeutics and Arthrogen, and serves on the boards of Sitryx Therapeutics, Levicept, and Citryll. He previously served on the board of a variety of companies, including ViiV Healthcare, Galvani Bioelectronics, and Omega Therapeutics. Dr. Tak is board certified in internal medicine, was trained as an immunologist, earned a Ph.D., and later became a professor of medicine at various universities. He has been elected Fellow of the Academy of Medical Sciences (UK).

"With his strong leadership, broad drug development experience and unwavering patient advocacy, Paul-Peter embodies Candel’s mission, values and core strengths," said Paul Manning, chairman of Candel and chairman and CEO of PBM Capital. "We, alongside CandeI’s board, look forward to working with this outstanding team as the company moves through its next evolution, advances multiple late-stage clinical programs across various tumor types, and evaluates its next steps in the capital markets."

Nathan Caffo brings a depth of experience to Candel. His 26-year industry career has been focused on cancer therapeutics, personalized medicine and applications of genomic technology. He was most recently chief business officer at ALX Oncology, an immuno-oncology company where he played an instrumental role in multiple private and debt financings totaling $120 million, as well as the company’s $186M IPO in July 2020. Prior to ALX Oncology, he was president and CEO of Presage Biosciences, an oncology company that developed the first intratumoral microdosing platform for evaluation of multiple oncology agents. While at Presage, he also led the company’s partnering strategy, resulting in numerous biopharma partnerships, including strategic equity investments from Celgene and Takeda. He also held business development and management roles at Perlegen, Applied Biosystems and Celera.

John Canepa has over 40 years of experience in the life science industry as an audit partner with a large international public accounting firm, and as a financial executive with public and private life science companies. Prior to joining Candel, he served as CFO of Frequency Therapeutics. During his tenure, Frequency completed several public and private financings, including its initial public offering in October 2019. Prior to joining Frequency, he served as CFO of Agilis Pharmaceuticals, Inc. and was instrumental in its sale to PTC Therapeutics in August 2018. Prior to Agilis, he was COO and CFO of Asterand Bioscience and led its sale to a private equity group in 2017. Mr. Canepa began his career at Arthur Andersen & Co. and was with the firm for 23 years.

Susan Stewart, J.D. has worked for more than 28 years in biopharmaceutical regulatory affairs, with significant experience devising innovative strategies for novel therapeutics, overseeing regulatory submissions at various stages of product development and leading interactions with global health authorities. She served as the program lead on several products that received FDA approval including Renagel (sevelamercarbonate) and Thyrogen (thyrotropinalpha). As an independent consultant, she also serves as chief regulatory officer at Kaleido Biosciences, and had served as senior vice president of regulatory affairs and quality. She held previous regulatory and leadership positions at Abbott, Genzyme, Tokai, and Transmolecular.

On December 8, 2020 Paige, a global leader in AI-based digital diagnostics, reported it received a CE mark for Paige Breast, its breast cancer detection software that indicates suspicious areas for further review to pathologists evaluating breast biopsies (Press release, Paige AI, DEC 8, 2020, View Source [SID1234572453]). The company also received a CE mark for Paige Prostate Grading & Quantification, a digital diagnostic that offers slide level information for primary and secondary Gleason patterns and tumor size to inform treatment planning. With these CE marks, both products are now available for use in laboratories and hospitals in the European Economic Area, Switzerland and the UK.

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"The CE mark in breast cancer represents an important regulatory validation for our computational pathology products as we broaden our applications in oncology, while the CE mark in prostate cancer adds valuable grading and quantification features for our existing CE marked Paige Prostate offering," said Leo Grady, Ph.D., Chief Executive Officer of Paige. "We continue to rapidly advance new products that improve pathology workflow and improve diagnostic confidence for some of the most prevalent cancers including breast cancer. I am incredibly grateful to all the Paige team members and our physician colleagues worldwide who have helped advance this technology in order to ultimately optimize patient outcomes."

Paige Breast Enables Slide and Case Level Predictions on Breast Cancer Presence

For pathologists diagnosing breast cancer – the most commonly diagnosed cancer among women in European countries1 – the potentially large volume of breast tissue slides to be reviewed can pose challenges for workload management and pathologist productivity. Paige Breast is designed to draw pathologists’ attention to concerning features on a breast tissue slide and provides slide and case level predictions about the presence of cancer. This functionality enables pathologists to more easily, efficiently and confidently identify small foci of cancer that can be easily missed.

"By reducing inter-observer variability, uncertainty, and time, this technology will enable pathologists to drive informed treatment more efficiently, helping to ensure patients receive the best care," said Matthew Hanna, M.D., Director of Digital Pathology Informatics at Memorial Sloan Kettering Cancer Center. "These technologies have the potential to increase physician productivity while minimizing burnout, particularly for diseases with high incidence, such as breast cancer, where hospitals may be faced with a large volume of patient cases."

Paige continues to enhance functionality for Paige Breast, including quantification and subtyping functionality, for future deployment.

Streamlining Prostate Cancer Diagnosis Through AI-based Grading and Quantification

Grading and quantification of prostate tissue are time consuming tasks that are often subjective with high inter-observer variability as part of the diagnosis process. With the addition of the new grading and quantification functionality, Paige Prostate can enhance diagnostic confidence for the pathologist while increasing consistency and standardization.

Paige Prostate Grading & Quantification provides slide level information for primary and secondary Gleason patterns, tumor length and tumor percentage. The product provides visual overlays that indicate the specific regions of the slide corresponding to each Gleason pattern, which can reduce the time it takes a pathologist to determine and measure a grade. Furthermore, Paige Prostate Grading & Quantification exhibits high concordance with sub-specialized pathologists which means the technology has the potential to decrease a pathologist’s need to defer cases for additional review without compromising diagnostic accuracy. This technology thereby streamlines workflows to decrease turnaround time for the patient and clinician.

On December 8, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported its lead drug candidate, repotrectinib, has been granted breakthrough therapy designation by the Food and Drug Administration (FDA) for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have not been treated with a ROS1 tyrosine kinase inhibitor (TKI-naïve) (Press release, Turning Point Therapeutics, DEC 8, 2020, View Source [SID1234572452]).

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"Breakthrough therapy designation is another milestone in our development of repotrectinib and one more step towards our goal to get this potentially important drug candidate to patients as quickly as possible," said Athena Countouriotis, M.D., president and chief executive officer. "I am incredibly proud of our Turning Point team with the achievement of our fourth regulatory designation from the FDA for repotrectinib, and pleased with how our enrollment specifically in the ROS1 TKI-naive population of the TRIDENT-1 study has progressed since we reported initial early Phase 2 data. We look forward to sharing more information on our overall study timelines early next year, and providing updated data from the TRIDENT-1 study next month."

Turning Point plans to present updated TRIDENT-1 Phase 2 study data from patients with TKI-naive ROS1-positive NSCLC during a mini-oral presentation at the World Conference on Lung Cancer on Jan. 31, 2021.

The breakthrough therapy designation for repotrectinib was supported by the initial data from TKI-naïve ROS1-positive NSCLC patients enrolled in the Phase 1 and Phase 2 portions of the TRIDENT-1 study, which is currently evaluating patients in multiple potentially registrational cohorts.

Breakthrough therapy designation is granted by the FDA to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. Repotrectinib was previously granted three Fast Track designations by the FDA, in ROS1-positive NSCLC patients who are TKI naïve, ROS1-positive NSCLC patients who have been previously treated with one prior platinum chemotherapy and one prior ROS1 TKI, and NTRK-positive patients with advanced solid tumors who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs.

On December 8, 2020 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing a novel class of T cell engagers, reported a pipeline update and reported a confirmed partial response based on RECIST v1.1 criteria for its most advanced program, HPN424 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) (Press release, Harpoon Therapeutics, DEC 8, 2020, View Source [SID1234572451]). As of December 1, 2020, in the 160ng/kg cohort, which is the highest fixed dose tested to date, 7 patients have been enrolled and one patient has achieved a confirmed partial response. In addition, 3 patients enrolled in this cohort had serum PSA reductions, including one with a reduction of 50% (PSA50). Dose escalation continues in this trial, in the Phase 1/2a clinical trials for HPN536 as a treatment for ovarian cancer and other mesothelin-expressing solid tumors and in the HPN217 Phase 1/2 clinical trial for multiple myeloma. Step dosing is being utilized in all programs to accelerate testing of higher doses. Dosing of the first patient in the Phase 1/2 trial for Harpoon’s fourth TriTAC development program, HPN328, in small cell lung cancer and other DLL3-associated tumors is expected to occur by the end of the year.

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"We are pleased to provide a trial update to our shareholders today, as well as outline our expectations for 2021. We have made significant progress in all of our clinical development programs in 2020," stated Gerald McMahon, Ph.D., President and CEO of Harpoon Therapeutics. "We are excited to report our first confirmed partial response in the continuing dose escalation trial for HPN424, especially in a heavily pretreated patient population with advanced metastatic disease. We are also excited by the potential for multiple data releases in 2021 on all four of our programs, which we believe represent meaningful milestones for our company."

"We are pleased to report the activity we are seeing with HPN424 in late-stage prostate cancer patients in our highest fixed dose cohort tested to date," said Natalie Sacks, M.D., Chief Medical Officer of Harpoon. "We are implementing step dosing in all of our programs, which allows rapid escalation to higher doses. We look forward to sharing data from these higher-dose cohorts in 2021."

Clinical Program Updates
(All data as of December 1, 2020)

Dose escalation continues in Phase 1/2a trial for HPN424 in the treatment of mCRPC. As of the December 1, 2020 data cutoff date, 69 patients have been dosed across 14 cohorts at fixed doses of 1.3 to 160ng/kg and in step dosing cohorts up to 300ng/kg administered as a weekly intravenous infusion. Enrolled patients had a median of 6 prior systemic therapies, and 76% of patients had prior chemotherapy in the metastatic castration-resistant setting. Ten of 44 patients (23%) with treatment start dates at least 6 months ago remained on study treatment for more than 24 weeks.

At the highest fixed dose tested to date, 160ng/kg, one patient out of 7 has experienced a confirmed partial response with tumor lesion reduction of 43%, and 3 of 7 patients have had serum PSA declines from baseline, including one patient with a PSA reduction greater than 50%.

HPN424 was generally well tolerated and cytokine-related adverse events have been manageable. Reported Grade 3 or higher adverse events have included cytokine release syndrome (CRS) (10%), ALT increase (11%) and AST increase (11%). CRS events and transaminitis have been transient and have not resulted in treatment discontinuation. Dose-limiting toxicities (DLTs) have been observed and have not limited escalation. A maximum tolerated dose (MTD) has not been identified. Presentation of Phase 1 data and initiation of an expansion cohort is planned for the first half of 2021. Interim data from this expansion cohort is anticipated by the end of 2021.

HPN536 (mesothelin TriTAC) Phase 1/2a clinical trial continues escalation. Dosing has occurred across 9 fixed-dose cohorts of 6 to 280ng/kg and 1 step dose cohort up to 600ng/kg. Tumor types treated include late-stage ovarian and pancreatic cancers and peritoneal mesothelioma. Enrolled patients had a median of four prior systemic therapies, and 66% of patients had progressive disease as best response to their most recent prior therapy. Pharmacokinetic analysis shows median half-life of more than 70 hours. Among the relapsed/refractory ovarian cancer patients with at least one post-baseline scan, 8 of 12 (67%) patients showed stability of target lesions.

HPN536 appears to be well tolerated. One CRS grade 3 occurred in the absence of dexamethasone premedication treatment. The CRS resolved, and the patient continued on study with dexamethasone premedication. As of December 1, 2020, no DLTs have been observed. Initiation of an expansion cohort is anticipated by the second half of 2021, with a presentation of Phase 1 data by year-end 2021.

Dose escalation for HPN217 (BCMA TriTAC) Phase 1/2 clinical trial progressing rapidly. Relapsed/refractory multiple myeloma patients have been treated across 6 single-patient fixed dose cohorts of 5 to 810µg, reflecting a more than 100-fold increase in dose in 8 months. HPN217 has been well-tolerated, and no DLTs have been observed as of the December 1, 2020 cutoff date. A presentation of interim data is anticipated in 2021, with initiation of a dose expansion cohort in the second half of 2021.

First patient dosing anticipated for HPN328 (DLL3 TriTAC) by the end of 2020. The first site is open and recruiting for the dose escalation portion of this Phase 1/2 clinical trial. In the first cohort, the patients will receive a flat dose of 15µg of HPN328 administered once weekly by intravenous infusion. Eligible patients include small cell lung cancer patients who have relapsed after platinum chemotherapy and patients with other tumors associated with DLL3 expression. Presentation of initial data is planned for the second half of 2021.

Webcast and Conference Call

Harpoon’s management will host a webcast and conference call at 8 a.m. ET / 5 a.m. PT on December 8, 2020. The live call may be accessed by dialing (866) 951-6894 for domestic callers and (409) 216-0624 for international callers with conference ID code number 1388395. A webcast of the live call will be available online in the investor relations section of the Harpoon website at www.harpoontx.com. A replay of the webcast will be available shortly after the event and can be accessed at the same weblink.

On December 8, 2020 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company") reported that first-in-human data from the first dose cohort of the Phase 1 portion of the Actimab-A venetoclax Phase 1/2 combination trial in patients with relapsed or refractory Acute Myeloid Leukemia (AML) were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting (Press release, Actinium Pharmaceuticals, DEC 8, 2020, View Source [SID1234572450]). The poster presentation highlighted results from the first three patients treated with the initial subtherapeutic dose level of 0.5 μCi/kg of Actimab-A and venetoclax.

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The enrolled patients had a median of 2 prior therapies (range 2-3) and a median bone marrow blast percentage of 30% (range 20 – >60). All 3 patients had poor risk disease with adverse cytogenetics, and each patient had an additional high-risk marker (FLT3-ITD+, antecedent JAK2+ myelofibrosis, or TP53 mutation). One patient who had multiple genetic mutations including IDH2, RUNX1, TP53 and others, achieved a complete remission with incomplete blood count recovery (CRi) after the first cycle of Actimab-A and venetoclax. Next generation sequencing at the end of the first cycle showed that patient was negative for the known IDH2 and RUNX1 mutations. This patient has continued treatment receiving the second cycle and their bone marrow remains normocellular with no excess blasts. In addition, another patient achieved a partial response after one cycle of Actimab-A and venetoclax. There were no Actimab-A related dose limiting toxicities or nonhematologic Grade 3 or greater related AEs reported in the first cohort. The trial has advanced to the second dose cohort of 1.0 μCi/kg of Actimab-A and venetoclax with patient enrollment ongoing.

Sandesh Seth, Actinium’s Chairman and Chief Executive Officer, commented, "This ASH (Free ASH Whitepaper) meeting, we are excited to highlight the promising data emerging from both our combination trials with Actimab-A in the R/R AML setting, namely the Actimab-A venetoclax and Actimab-A CLAG-M trials. Particularly compelling is the complete response reported in a patient with complex mutations like TP53 with Actimab-A and venetoclax and the high MRD negativity rate with Actimab-A and CLAG-M. The results clearly demonstrate that a superior clinical effect without adding meaningful toxicity is achievable using Ac-225 ARC’s to precisely deliver powerful internal radiation and elicit a potentiating and synergistic treatment effect with chemotherapy and targeted agents. With this clinical validation in hand, we look forward to expanding our ARC combinations with other therapeutic modalities in AML and into additional indications to further establish our leadership position in the field by leveraging our enhanced R&D capabilities including new research facilities and key hires."

Dr. Mark Berger, Actinium’s Chief Medical Officer, said, "We were thrilled to report a complete response in the Actimab-A venetoclax combination trial, in addition to the partial response previously highlighted in the abstract. Both responses occurred after just one cycle of a subtherapeutic dose of Actimab-A. These initial results, the one complete response and safety profile to date, support the potential mechanistic synergy of Actimab-A with venetoclax. As a single agent, venetoclax has produced low response rates of 19% in patients with R/R AML1 so we are pleased with the results seen in our first dose cohort. In addition, the clinical data from Actimab-A and Iomab-B presented at this year’s ASH (Free ASH Whitepaper) demonstrates our strong commitment to addressing the unmet needs of patients with R/R AML with our ARCs as best in class therapeutics, bridge to transplant and targeted conditioning for potentially curable bone marrow transplant. With this in mind, we look forward to guidance on Iomab-B expected from the ad-hoc DMC meeting before year-end."

This Phase 1/2 trial is a multicenter, open label trial of Actimab-A (lintuzumab-Ac225) added to venetoclax for patients with CD33 positive R/R AML. A Phase 2 trial studying Actimab-A as a single agent produced a 69% overall response rate in older unfit patients with newly diagnosed AML. In a poster presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019, Actimab-A was shown to be synergistic with venetoclax in venetoclax resistant cell lines, by depleting MCL-1, a protein shown to mediate resistance to venetoclax. Further, the induction of direct AML cell death via double-stranded DNA breaks by Actimab-A provides a second mechanism for enhancing synergistic potency with venetoclax. Venetoclax is a B-Cell Lymphoma 2 (BCL-2) inhibitor that is jointly developed and marketed by AbbVie and Genentech and is approved for patients with AML, Chronic Lymphocytic Leukemia (CLL), and Small Lymphocytic Leukemia (SLL). Despite its approval in AML, venetoclax has produced low response rates of 19% as a single agent in R/R AML.1 This is due in part to the type of AML, risk factors, and cytogenetics of this patient population. The Phase 2 trial results, together with a synergistic mechanism of action with venetoclax demonstrated in pre-clinical studies, are driving this combination trial with an initial focus on the high unmet needs of R/R patients including those who have relapsed or do not respond to treatment with venetoclax based regimens.

1 Aldosset al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica2018.1888094.

About Actinium’s CD33 Program

Actinium’s CD33 program is evaluating the clinical utility of Actimab-A, an ARC comprised of the anti-CD33 mAb lintuzumab linked to the potent alpha-emitting radioisotope Actinium-225 or Ac-225. CD33 is expressed in the majority of patients with AML and myelodysplastic syndrome, or MDS, as well as patients with multiple myeloma. The CD33 development program is driven by data from over one hundred treated patients, including a Phase 1/2 trial where Actimab-A produced a remission rate as high as 69% as a single agent. This clinical data is shaping a two-pronged approach for the CD33 program, where at low doses the Company is exploring its use for therapeutic purposes in combination with other modalities and at high doses for use for targeted conditioning prior to bone marrow transplant. Actinium currently has multiple clinical trials ongoing including the Phase 1 Actimab-A CLAG-M and Phase 1/2 Actimab-A venetoclax combination trials and is exploring additional CD33 ARC combinations with other therapeutic modalities such as chemotherapy, targeted agents or immunotherapy.