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Results From Combination of APR-246 with Immuno-Oncology Agents Presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting in Atlanta

On April 3, 2019 Aprea Therapeutics reported the results of studies with APR-246 in combination with immune checkpoint blockade presented by researchers from Memorial Sloan Kettering Cancer Center at the 2019 AACR (Free AACR Whitepaper) Annual Meeting in Atlanta (Press release, Aprea, APR 3, 2019, View Source [SID1234534946]). The studies collectively support a role for p53 activity in the tumor microenvironment and suggest that stabilization of the tumor suppressor protein, p53, by APR-246 can enhance anti-tumor immune response, particularly when combined with immuno-oncology agents.

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The studies characterized changes in the tumor immune microenvironment in melanoma and colorectal cancer in vivo models when treated with APR-246 and immuno-oncology agents, either alone or in combination. APR-246 monotherapy treatment of melanoma tumors induced a pro-inflammatory tumor microenvironment. The analysis of tumor infiltrating immune cells demonstrated a pattern of gene expression suggesting that stabilization of p53 by APR-246 alters the immune tumor microenvironment and enables the immune system to target tumor cells more effectively. Anti-tumor activity was observed with APR-246 monotherapy; the combination treatment with APR-246 and anti-PD-1 enhanced the effects of PD-1 blockade in a T cell-dependent manner, as assessed by reduced tumor growth and improved survival. Also, the administration of APR-246 together with anti-PD-1 and anti-CTLA-4 dual immune checkpoint blockade significantly augmented anti-tumor control.

Abstract: 4843

Poster Title: TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models.

Session Title: Targeted Therapies and Immunological/Tumor Microenvironment Effects

Poster Presentation Date and Time: Wednesday April 3, 2019, 8:00 am – 12:00 pm EDT

About p53 and APR-246

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

APR-246 has been shown to reactivate mutant and inactivated p53 protein – by restoring wild-type p53 conformation and function – and thereby induce programmed cell death in human cancer cells. APR-246 has demonstrated pre-clinical anti-tumor activity in a wide variety of solid and hematological (blood) tumors, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.

Clarity Senior Executive Changes – Dr Colin Biggin to Acting Chief Executive Officer, Dr Matt Harris to Chief Scientific Officer

On April 3, 2019 Clarity Pharmaceuticals, a radiopharmaceutical company focused on the treatment of serious disease, is reported changes to its senior executive team to help its focus on commercial development and execution of its pipeline of radiopharmaceutical products for the treatment of children and adults with cancer (Press release, Clarity Pharmaceuticals, APR 3, 2019, View Source [SID1234534941]).

Dr Matt Harris, the current Managing Director of Clarity, will move to Chief Scientific Officer and remain on the Board of Directors, and Clarity’s current Chief Operating Officer, Dr Colin Biggin, will move to Acting Chief Executive Officer, whilst an international search, expected to take 6-9 months, for a CEO will begin.

Dr Biggin’s background in radiopharmaceutical development is extensive with over 15 years in the industry, including his experience at Algeta ASA (Algeta) where he worked in multiple roles from 2006 up to Algeta’s acquisition by Bayer for US$2.9 billion in 2014. Dr Biggin was among the first ten employees at Algeta and was responsible for providing scientific and project support across all departments, gaining broad expertise in Regulatory & Quality Assurance, Quality Control, Research and Clinical Development, Manufacturing and Commercial. He was significantly involved in the development and launch of Xofigo, Algeta’s lead radiopharmaceutical product targeting metastatic prostate cancer.

Dr Biggin gained his PhD in Environmental Radiochemistry and a BSc in Environmental Biogeochemistry from the University of Glasgow.

Dr Matt Harris has been integral to the successful development of the company from inception through to its early stage development and will continue his role on the Board of Directors and within the senior executive team as Chief Scientific Officer. These changes at the senior executive level will accommodate Clarity’s focus on moving from an early to a later stage clinical development company. This also coincides with the recent addition of Dr Robert Miller as Contract Chief Medical Officer and Dr Thomas Ramdahl to the Board of Directors, having all gained significant clinical and commercialisation experience through their involvement at Algeta.

Dr Biggin commented on his appointment: "I am looking forward to steering Clarity and the team as Acting CEO through this important stage of development when we are both expanding our clinical program, and preparing for extensive commercial growth of our theranostic platform. I have enjoyed working at Clarity and seeing the Company expand significantly in the last few years and am excited to apply the experience I gained at Algeta to lead Clarity to further success."

Clarity’s Executive Chairman, Dr Alan Taylor commented "The changes at the executive and Board level will prepare us for transitioning the Company to a new commercial stage of development. We want to bring the right expertise to successfully drive our clinical program and with Dr Thomas Ramdahl joining our Board recently, we are now building a Board and management team with people who have relevant clinical and commercial experience and a track record of successfully growing radiopharmaceutical companies."

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Actinium Highlights Actimab-A and Venetoclax Synergies Observed in New Studies Presented at AACR

On April 3, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) reported its data from its poster presentation at the AACR (Free AACR Whitepaper) or American Association of Cancer Research annual Meeting 2019 demonstrating that the targeted radiation delivered by Actimab-A to CD33 expressing cells can deplete MCL-1 levels in tumor cells, thereby removing a mechanism of resistance and rendering them more susceptible to venetoclax (Press release, Actinium Pharmaceuticals, APR 3, 2019, View Source [SID1234534939]). 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. Actimab-A is an ARC or Antibody Radiation Conjugate comprised of the anti-CD33 monoclonal antibody lintuzumab and the potent alpha-particle emitting radioisotope Ac-225 or Actinium-225. Venetoclax is a BCL-2 or B-Cell Lymphoma 2 inhibitor that is jointly developed and marketed by AbbVie and Genentech and is approved for patients with AML or Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, and Small Lymphocytic Leukemia. The poster can be viewed on Actinium’s website here.

Highlight’s of Actinium’s poster presentation are as follows:

Actimab-A treatment of venetoclax resistant AML cells led to a decrease in MCL-1 levels. MCL-1 is a protein in the BCL-2 family of anti-apoptotic proteins, which is overexpressed in relapsed or refractory AML cells and has been shown to mediate resistance to venetoclax.
The same Actimab-A treatment reduced BCL-XL. BCL-XL is another protein in the BCL-2 family and also been proposed to mediate resistance to venetoclax.
Additional studies demonstrated that Actimab-A produced double-stranded DNA breaks in two cell lines resistance to venetoclax.
At all dose levels and time points, Actimab-A significantly increased double-stranded DNA breaks compared to cells treated with lintuzumab alone.
In a venetoclax resistant AML in vivo tumor model, statistically significant reduction in tumor size was observed in animals receiving the combination of Actimab-A and venetoclax compared to venetoclax alone.
At evaluation on day 38, complete responses were reported in 3 of 5 animals receiving the combination of Actimab-A and venetoclax while no animals receiving venetoclax alone achieved a complete response at any time point.
100% survival at day 40 was observed in cohorts receiving Actimab-A and venetoclax while no animals treated with venetoclax alone survived beyond day 30.
Dr. Dale Ludwig, Actinium’s Chief Scientific Officer, said, "The results of these studies further our enthusiasm for the combination of Actimab-A and venetoclax. Expanding on our previous in vitro work, it is validating to observe multiple synergies derived from Actimab-A’s unique targeted radiation mechanism of action including MCL-1 reduction. Given the role this protein plays in AML cell resistance to venetoclax, it is exciting to see its depletion with Actimab-A, resulting in increased cell death and tumor control in these studies. We are also excited to demonstrate that Actimab-A causes double-stranded DNA breaks for which there is no known resistance or repair mechanism. It is important to note that these findings were observed in cell lines and xenograft animal models based on venetoclax resistant cell lines. These data further support the advancement of the combination of Actimab-A and Venetoclax into clinical trials as we are doing with two distinct clinical trials."

Actinium has filed a patent on the combination of a targeted alpha-emitting therapeutic such as Actimab-A together with a BCL-2 inhibitor, which includes venetoclax, as a method to treat cancer. Actinium has initiated a Phase 1/2 trial that is studying Actimab-A in combination with venetoclax for patients with relapsed or refractory AML and is planning a Phase 1/2 trial that will study Actimab-A and venetoclax with a hypomethylating agent also for patients with relapsed or refractory AML, which is expected to be initiated in the first half of 2019.

Sandesh Seth, Actinium’s Chairman and CEO, said, "As we advance towards the clinic with our second Actimab-A venetoclax combination trial, it is encouraging to see multiple synergies in robust pre-clinical models. With many patients not responding to or having limited duration of their responses with venetoclax treatment, these important findings together with our extensive clinical data with Actimab-A will be beneficial to the advancement of our two combination trials. This work also showcases Actinium’s integration of our research and development and clinical development efforts that can result in rapid translation to the clinic. With a robust intellectual property portfolio around our AWE technology platform, we see a multitude of opportunities to leverage targeted radiation via our ARC’s in combination with other therapeutic modalities to generate potential therapies for patients with high unmet medical needs that are underserved by current therapeutic approaches."

Oncolytics Biotech(R) to Present at the 18th Annual Needham Healthcare Conference

On April 3, 2019 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), currently developing pelareorep, an intravenously delivered immuno-oncolytic virus, reported that it will present at the 18th Annual Needham Healthcare Conference (Press release, Oncolytics Biotech, APR 3, 2019, View Source [SID1234534938]). The presentation, by Dr. Matt Coffey, President & CEO of Oncolytics, will take place at 1:30 pm ET, on Wednesday, April 10, 2019 at the Westin Grand Central Hotel in New York City.

A live audio link to the webcast session will be available on the Company’s website at View Source It is recommended that listeners log on 10 minutes in advance of the live session to register and download any necessary software. An audio replay will be accessible approximately two hours following the presentation on the Oncolytics website.

Sumitomo Dainippon Pharma Submits an Application of RETHIO for an Additional Indication of Conditioning Treatment Prior to Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoma

On April 2, 2019 Sumitomo Dainippon Pharma Co., Ltd. (Head Office: Osaka, Japan; Representative Director, President and CEO: Hiroshi Nomura hereinafter called "Sumitomo Dainippon Pharma") has reported that on March 29 the company applied for a partial change in the marketing approval previously acquired in Japan for RETHIO 100 mg for I.V. infusion (generic name, thiotepa; hereinafter called "RETHIO") (Press release, Sumitomo Dainippon Pharma, FEB 2, 2019, View Source [SID1234605564]). The change applied for this time involves an additional indication of RETHIO for conditioning treatment prior to autologous hematopoietic stem cell transplantation (auto-HSCT) for malignant lymphoma.

RETHIO is a drug indicated for conditioning treatment prior to auto-HSCT for pediatric malignant solid tumors. Sumitomo Dainippon Pharma obtained the marketing approval for this drug on March 26, 2019 and plans to launch it after NHI drug price listing.

Malignant lymphoma, a hemocytes-derived cancer, is a disease that lymphocytes, a subpopulation of leukocytes (white blood cells), become cancerous. This disease occurs typically in lymphoid tissues, such as lymph nodes, spleens, and tonsils, but it also often develops in other sites. It has been reported that the incidence of malignant lymphoma is around ten in 100,000 persons in Japan annually, the most common hematapostema in Japanese adults. As with conditioning treatment prior to autologous HSCT for pediatric malignant solid tumors, the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs of the Ministry of Health, Labour and Welfare (MHLW) determined similarly high medical need in conditioning treatment prior to auto-HSCT for malignant lymphoma. Thus, Sumitomo Dainippon Pharma conducted Phase 1 trials in Japan and subsequently applied for the additional indication.

Sumitomo Dainippon Pharma believes that, upon approval of its additional indication, this drug will contribute to improved healthcare as a new treatment option for patients indicated for conditioning treatment prior to auto-HSCT for malignant lymphoma, a therapeutic area with high unmet medical need.

About autologous hematopoietic stem cell transplantation (auto-HSCT)
Autologous hematopoietic stem cell transplantation is a therapy that aims to reconstruct hematopoietic capacity via intravenous transfusion of normal hematopoietic stem cells of the patient himself/herself after eradicating intractable cancers by conditioning myeloablative treatment prior to transplantation using maximum levels of anti-cancer drugs or radiation.

About the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs
The Evaluation Committee on Unapproved or Off-label Drugs with High Medical Needs is a committee established to promote the development of unapproved or off-label drugs by pharmaceutical companies that are approved for use in Europe and the United States, etc., but not approved in Japan. It is organized under the Ministry of Health, Labour and Welfare of Japan and consists of academic experts in medical and pharmaceutical fields.