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Technology Name: Small molecule CDK8/19 inhibitor

Company Background

The mission of Senex Biotechnology is to develop novel therapeutics for the treatment of cancer and other major diseases by targeting key disease-promoting pathways induced by cellular damage and aging, and by identifying and attacking novel cancer-specific molecular targets. Founded by Dr. Igor Roninson, on the basis of discoveries in his laboratory in 2002, the company is located in Columbia, SC, and currently supports three scientists.  Senex has won a series of grants, including two Phase II SBIR grants, and concluded a strategic licensing agreement with a foreign pharmaceutical company in 2014. Senex has identified several novel targets and generated first-in-class small molecules against three of these targets. The drug for the most advanced program is about a year from clinical trials.

Technology Overview 

Senex’s most advanced program targets CDK8/19, a transcription-regulating oncogenic kinase. CDK8/19 inhibition has multiple anti-cancer effects at the molecular level, including the inhibition of oncogenic transcription factors, as well as stimulating immune surveillance by NK cells. The lead molecule, Senexin B, is fully optimized and exceptionally selective for CDK8/19. It is orally available, non-toxic, and extremely potent in numerous in vivo studies: Senexin B directly suppresses prostate and breast tumor growth, exhibits strong synergistic effects with several widely used drugs, and has anti-metastatic activity in several cancer types.

Market Potential

Senex will initially develop Senexin B for treatment of metastatic castration-resistant prostate cancer (mCRPC), the second leading cause of cancer related death in the United States. Over 29,000 people die from prostate cancer every year; 1 out of every 36 men will die from prostate cancer.  Median survival for mCRPC is less than 2 years.  Although several new drugs have recently been approved, resistance to these drugs develops within several months so there is a large unmet need.  Senexin B acts against those cancers that do not respond to any class of androgen receptor inhibitors, including cancers that are resistant to the newly approved drugs Xtandi and Zytiga.

Competitive Advantage

CDK8/19, Senex’s primary target, belongs to the CDK family, but unlike better-known CDKs, CDK8/19 does not mediate cell cycle progression, and is not required by normal cells under homeostatic conditions. As a consequence Senexin B is extremely well tolerated. Senex is the only company to describe selective CDK8/19 inhibitors in a peer-reviewed article. Based on the known poster presentations and published patent applications, CDK8/19 inhibitors have been recently developed by Selvita (Poland), Bayer Pharma, and CNIO (Spain). Based on the available information, none of the competitors’ compounds appear to be as selective as Senex’s CDK8/19 inhibitors, and no comparable in vivo studies have been reported.

Financial Overview

Senex has received over $2.8 million in NIH funding and over $3.5 million from other sources, including angel investors, licensees, charitable foundations and the DOD. Senex is seeking $10 million to fund additional pre-clinical and clinical studies through proof-of-concept in castration-resistant prostate cancer.  The plans for this study have been developed with a NCI-designated cancer center.

Intellectual Property

The key issued patents for Senex’s CDK8/19-related IP are US patents 8,598,344 protecting the composition-of-matter of its CDK8/19 inhibitors and 8,592,147 protecting the general screening method for identifying inhibitors of transcriptional pathways including those regulated by CDK8/19. Senex also has several pending utility patent applications protecting other novel applications of CDK8/19 inhibitors that Senex and its collaborators have discovered.

Commercialization Strategy

Senexin B has been licensed to a foreign pharmaceutical company for minor markets. Marketing rights for all major markets are retained by Senex. The licensee will provide Senex with GMP manufactured Senexin B, the results of FDA acceptable preclinical safety studies, and clinical trials that will be conducted to international GCP standards. Senex will receive milestone payments and royalties from sales of drugs in the licensee’s minor markets. These results will enable Senex to partner with a major pharmaceutical company to perform additional clinical trials and to market the drug.  Anticipated milestone payments will fund other programs in Senex’s pipeline.

Pipeline Products

Senex also has programs targeting CDK3 and COPZ1. Senex has identified CDK3 as a cancer-specific target and is optimizing the first CDK3-selective small molecule inhibitors. COPZ1 is a component of the vesicle-coating complex and Senex has discovered the first COPZ1-targeting small molecules. COPZ1 inhibition should kill most types of tumor cells, including dormant cells and cancer stem cells, which are resistant to conventional therapy.

Management Team

• President and CSO Igor Roninson is the founder of Senex and the inventor on 41 issued US patents.
• CEO Lawrence Friedhoff has a long history of successful and rapid FDA approval of new drugs, including two blockbusters, one of which is Aricept, the main drug used to treat Alzheimer’s disease.
• Karthik Gopalakrishnan brings several years of experience in business development and negotiation skills to Senex.  He has successfully concluded business transactions with several pharmaceutical companies.

Company Background

StemMed is a pre-clinical stage drug discovery, development, and testing company that is developing C188-9, a first-in-class, oral inhibitor of signal transducer and activator of transcription (Stat) 3, for treatment of ER-, PR-, HER2- (triple negative) breast cancer (TNBC). StemMed also provides state-of-the-art pre-clinical drug testing services using a panel of 44 breast cancer patient-derived xenograft (PDX) models developed from a diverse patient population, which includes 23 PDX models derived from patients with TNBC; 4 pancreatic cancer PDX models also are available.

Technology Overview 

Stat3 plays a central role in breast cancer stem cell development and has been validated as a drug target in these cells, as well as in the treatment of TNBC, for which no targeted therapy exists. StemMed used computer-based docking to screen 920,000 compounds and identified three small-molecule probes that targeted the phosphotyrosyl peptide-binding pocket within the Src homology 2 domain of Stat3. The most active probe, C188, reduced TNBC PDX tumor volumes and improved tumor-free survival of engrafted mice 4-fold when used in combination with standard chemotherapy. StemMed performed 2-D similarity screening, 3-D pharmacophore analysis, and 3-rounds of structure-activity relationship (SAR)-directed medicinal chemistry to identify C188-9, its lead, first-in-class drug for targeted treatment of TNBC.

Market Potential

The first patients that will be targeted to receive C188-9 will be those patients with locally invasive, metastatic, or treatment-refractory TNBC. An estimated 230,480 new cases of invasive breast cancer were diagnosed in the United States in 2011. Of these, ~40,000 will suffer breast cancer recurrence including 50% of those with TNBC. Unfortunately, standard therapies cannot eradicate the disease and these patients succumb to metastatic disease with a median survival of 2 years. The size of the U.S. market for C188-9 for metastatic/refractory TNBC on a yearly basis is ~20,000 cases for 7 cycles, or a total of 140,000 cycles. C188-9 will be administered orally once daily in the interval between cycles of first-line chemotherapy. Using a conservative figure of $2,000 per cycle, the income generated from 140,000 cycles of C188-9 would be $280 million.

Competitive Advantage

There are two orally bioavailable, small-molecule competitors of C188-9 in development, BP-1-102 and HJC0123. BP-1-102’s modest potency coupled with its low MTD will make it challenging to establish a safe and effective dose of BP-1-102 in humans. HJC0123’s mechanism of action has not been established and the mouse toxicity data presented in the original report was very limited. Other oral agents under development have mechanisms of action that are not understood, substantial toxicity, and did not demonstrate an efficacy signal in Phase I studies.

Financial Overview

StemMed’s drug testing revenue since 2010 totals $913,000. Revenue from STTR grant awards totals $417,000. StemMed also received $100,000 from PDX licensing and $213,000 from partner contributions.

StemMed needs $1 million in external funds for IND-enabling safety and PK studies and for IND filing.

Intellectual Property

StemMed has an exclusive license to ten patents issued to, or filed by, BCM and ownership of composition for C188-9. StemMed also has an exclusive license to use all 48 PDX models for drug testing services, as well as sublicensing to other companies for their in-house use.

Commercialization Strategy

StemMed’s objectives for the next two years are to continue developing its lead product candidate C188-9 by taking it through various studies. StemMed is also in discussions with Atara Biotherapeutics regarding licensing C188-9 for use in cachexia in chronic kidney disease.

Pipeline Products

StemMed has compelling pre-clinical results in cancer cell line xenograft models that also support the use of C188-9 either alone or with radiation therapy in patients with non-small cell lung cancer and head and neck squamous cell cancer. In addition, results from mouse pre-clinical models support its use in patients with cachexia secondary to chronic kidney disease or cancer, and in patients with idiopathic pulmonary fibrosis, scleroderma, inflammatory bowel disease, asthma, and immediate-type hypersensitivity reactions.

Management Team

• President, CEO, and director of drug discovery and development, David Tweardy, MD, discovered key molecular and cellular features of Stat3 during his 28-year research career supported by NIH and other extramural funding totaling over $16 million as PI.
• Vice president and director of drug testing, Michael Lewis, PhD, is an expert in breast cancer biology and developer of 48 breast and pancreatic cancer PDX models whose 15 year research career has been supported by NIH and other extramural funding totaling over $11 million as PI.
• Consultant and vice president of Texas BioAlliance, Jeffrey Larson, PhD, is a drug developer with extensive experience in pharmaceutical, biotechnology, and contract research industries, as well as a record of successful early- and late-stage regulatory meetings with the FDA.
• Consultant and Principal of Soller Regulatory & Research Services, R. William Soller, PhD, has extensive regulatory experience including serving as team leader and lead presenter for over 60 FDA or advisory committee meetings on drug development or postmarketing issues.

Surgisense Corporation is a privately held C-corporation founded in 2006 with the mission of improving surgical care through intra-operative assessment of a patient’s risk for surgical complications. The company is developing a new category of surgical instruments that integrate a novel oxygen sensing technology which directly measures tissue oxygenation. This enables surgeons to identify patients at risk of surgical complication due to alterations in blood flow and oxygenation through real-time assessment of tissue viability, and propensity to heal.

Surgisense’s efforts initially target colorectal cancer for which surgical resection remains the mainstay of treatment. After removal of the tumor, the free ends of bowel are surgically joined to form an anastomosis. Surgisense's Stapled Anastomosis Viability Evaluation (SAVE) System strives to reduce the most dreaded complication: the anastomotic leak; a condition in which fecal material leaks into the abdominal cavity from the surgical junction. The technology integrates into the surgical workflow by replacing the anvil of commercially available, circular staplers with a sensing anvil that wirelessly transmits actionable data to the operative team. The System aims to reduce patient suffering while saving $2 billion annually in excess healthcare costs.

Surgisense’s core technology is protected in the largest medical device markets, and is extensible into many clinical applications. The company has been funded through a combination of federal grants and commercial revenue totaling $2.3 million and is looking to raise $6 million in Series A financing to support first-in-human clinical trials, U.S. and E.U. regulatory approval, and product launch.

Synergys Biotherapeutics is a privately held antibody therapeutics company developing multifunctional anti-vasculogenic antibody therapeutics for cancer and other angiogenesis-related diseases of significant unmet medical needs. The Company focuses on in-licensing early stage candidates from external sources for additional development in-house as well as through building collaboration and partnering with larger pharma and biotech organizations. The Company’s current preclinical programs include Anti-EGFR-ATAP, an antibody fusion molecule being developed for Triple Negative Breast Cancer and other EGFR+ malignancies, as well as a bi-targeted, bifunctional “first-in-class” fully human Anti-Ang-1/2 antibody for various cancers.   Synergys’ management and the members of its scientific and business advisory boards are veterans of biotech business having more than 20 years of average expertise and experience in cancer drug development.