Kevetrin™ – Our Lead Compound
The Phase 1 trial for solid tumors is at Harvard Cancer Center’s Dana-Farber Cancer Institute and partner Beth Israel Deaconess Medical Center.
The trial, titled, “A Phase I, Open-Label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin (thioureidobutyronitrile) Administered Intravenously in Patients with Advanced Solid Tumors,” will be conducted for the determination of the pharmacokinetics, pharmacodynamics, tolerance, safety, and maximum tolerated dose in patients with the diagnosis of refractory solid tumors. Approximately 40 patients will be enrolled in the dose escalation portion of study. In addition, once the MTD has been established, up to 12 additional patients may be enrolled at the MTD dose level to further evaluate this dosage safety and pharmacodynamics.
The Principal Investigator for the trial is Geoffrey Shapiro, MD, PhD, Director, Early Drug Development Center and Associate Professor of Medicine, Harvard Medical School.
The primary objectives are:
- To determine the maximum tolerated dose (MTD) of Kevetrin.
- To determine the dose limiting toxicities (DLT) of Kevetrin.
- To establish a safe dose level of Kevetrin that can be used for future studies.
The secondary objectives are to determine the following:
- The pharmacokinetics of Kevetrin in humans.
- Observe for evidence of antitumor activity following administration of Kevetrin.
- If there is a pharmacodynamic relationship between the plasma concentrations of Kevetrin and a clinical/cellular effect.
- If Kevetrin induces changes in the biomarker p21 in peripheral blood lymphocytes.
About Kevetrin
» has demonstrated the potential for a major breakthrough in cancer research by inducing activation of p53. p53, often referred to as the “Guardian Angel Gene” or the “Guardian Angel of the Human Genome” due to its crucial role in controlling cell mutations, is a tumor suppressor protein that is encoded by the TP53 gene in humans and has been widely regarded as possibly holding a key to the future of cancer therapies. p53 has been shown to play critical roles in the homeostatic health of the human body by activating proteins required to repair DNA and plays a major role in the life cycle of cells by inducing cell cycle arrest and apoptosis to maintain cellular and genetic stability.
» In more than 50 percent of all human carcinomas, p53 is limited in its anti-tumor activities by mutations in the protein itself. Currently, there are greater than 10 million people with tumors that contain inactivated p53, while a similar number have tumors in which the p53 pathway is partially abrogated by inactivation of other signaling components. This has left cancer researchers with the grand challenge of searching for therapies that could restore the protein’s protective function, which Kevetrin appears to be doing the majority of the time.
» Mechanism of action studies showed that Kevetrin strongly induced apoptosis by activation of Caspase 3 and cleavage of PARP. Kevetrin induced phosphorylation of p53 at Ser15 leading to a reduced interaction between p53 and MDM2, an ubiquitin ligase for p53 that plays a central role in p53 stability. Phosphorylation of p53 induced apoptosis by inducing the expression of PUMA. In addition, Kevetrin increased expression of p53 target genes such as p21 (Waf1), an inhibitor of cell cycle progression.
» Kevetrin also induced transcription-independent p53 mediated apoptosis. Kevetrin enhanced the phosphorylation of MDM2. Phosphorylation of MDM2 alters the E3 ligase processivity. Stable monoubiquitinated form of p53, induced by Kevetrin, accumulates in the cytoplasm and mitochondria and interacts with BAK or BAX proteins in mitochondria to induce apoptosis.
» Since Kevetrin activates both transcription-dependent and transcription-independent pathways to promote apoptosis through p53 activation, Kevetrin can function as a major inducer of apoptosis in many types of tumors independent of p53 mutation status.
» Excellent results in animal model experiments in drug-resistant cancers.
Kevetrin, our lead product candidate, is a small molecule compound proprietary to the Company. Its structure is distinct from other anti-cancer agents currently on the market. Kevetrin was discovered by the Company’s founder, Dr. Krishna Menon, and has been studied extensively (in vitro and in vivo) demonstrating potent anti-cancer activity against various cancer cell lines. Kevetrin’s recent success in a series of animal model experiments with drug-resistant cancer cell lines, has galvanized the Company to focus on Kevetrin’s development potential in this area. Kevetrin’s primary mechanism of action has been shown to be p53 activation which induces the expression of p21 and acts as an inhibitor of cell cycle progression. Activated p53 induces expression of PUMA and initiates apoptosis.
Some highlights of the pre-clinical studies:
» Small molecule drug that is structurally different from anti-cancer agents currently on the market
» Potent anti-tumor efficacy against various carcinoma xenograft models: lung, breast, colon, prostate and squamous cell carcinoma, and in a leukemia tumor model.
» Anti-tumor activity in multi-drug resistant tumor models.
» Efficacy was either equivalent to or greater than standard chemotherapeutic agents, given at approximately equitoxic doses.
» In a human head and neck cancer xenograft model in combination with local radiation, the delay in tumor growth was significantly increased by 36 days when Kevetrin was administered in conjunction with radiation, more than two-fold compared to controls.
» In GLP toxicology and safety pharmacology tests, Kevetrin was well tolerated.
Chemistry
Kevetrin is a small molecule that is different in structure from all currently marketed cancer drugs. It is water-soluble and simple to synthesize from commercially available starting materials. It will initially be administered as an intravenous (IV) product.
Patent Protection
On December 25, 2012 the United States Patent and Trademark Office (USPTO) awarded the Company U.S. Patent No. 8,338,454 B2, titled “Nitrile Derivatives and their Pharmaceutical Use and Compositions.” The patent covers pharmaceutical compositions comprising Kevetrin™, the Company’s novel anti-cancer compound currently being evaluated in clinical trials against advanced solid tumors. The patent also covers related compounds and compositions.
Kevetrin Pharmacokinetics
Kevetrin showed a biphasic time vs. drug concentration curve with an elimination half-life of about 0.7 to 2.2 hours in mice and rats, respectively, and 1 hour in dogs and a dose dependent pattern in terms of the plasma concentration, C max, and exposure.
Biomarker
We identified the increased expression of p21 in peripheral blood lymphocytes as a potential biomarker in our upcoming clinical trial for Kevetrin.
Genotoxicity
Kevetrin was shown to be non-genotoxic. Most currently available chemotherapeutic are genotoxic in nature and damage DNA. Our results showed that Kevetrin, in a non-genotoxic way, induces p53 leading to apoptosis. DNA damaging drugs result in rapid phosphorylation of H2A.X at Ser 139 by PI3K-like kinases. Kevetrin did not induce phosphorylation of H2A.X protein.
Toxicology
» A GLP repeated dose toxicity study in rats with 5 weekly doses of Kevetrin, in the range of 60 to 120 mg/kg given intravenously showed a NOAEL of Kevetrin of 90 mg/kg.
» A GLP repeated dose toxicity study in dogs with 5 weekly doses of Kevetrin, in the range of 5 to 60 mg/kg given intravenously showed a NOAEL of 5 mg/kg.
Kevetrin Efficacy Studies
Drug-Resistant Cancer Cell Lines
» One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Kevetrin has been studied against several drug-resistant cancer cell lines.
» Lung Cancer
» Kevetrin has been studied in animal models using a number of drug-resistant cell lines. Kevetrin was studied in two cell lines of multi-drug resistant lung cancer. In two studies with the A549 cell line, Kevetrin showed average tumor growth delay of 72% and average tumor volume reduction of 81% compared to controls. Both tumor growth delay and tumor volume reduction were also significantly greater with Kevetrin than with paclitaxel. (p<0.001).
Please click here to see a more detailed summary of these studies.
» In two studies with the NCI-H1975 cell line of multi-drug resistant lung cancer, Kevetrin showed average tumor growth delay of 149% and tumor volume reduction of 94% compared to controls. Both tumor growth delay and tumor volume reduction were greater with Kevetrin than with paclitaxel (p<0.001).
Please click here to see a more detailed summary of these studies.
» Breast Cancer
» In tests on two multi-drug resistant non-small-cell lung carcinoma human cell lines, A549 and NCI-H1975 -in each cell line- tumor volume was reduced by more than 90% and tumor growth was delayed by more than 100%. In addition, both the tumor volume reduction and the tumor growth delay were greater in each cell line with Kevetrin than with paclitaxel (p<0.01).
» In animal model testing on a taxane-resistant, estrogen receptor-negative breast cancer human cell line, MDA-MB-435s, tumor volume was reduced by 72% and tumor growth was delayed by more than 52% with Kevetrin when compared with paclitaxel. Please click here to see a more detailed summary of these studies.
» Colon Cancer
» Kevetrin showed tumor growth delay of 43% compared to controls and paclitaxel when tested on animals with HCT-15 P-glycoprotein drug resistant colon cancer.
Please click here to see a more detailed summary of these studies.
Other Cancer Cell Lines
» Head and Neck Cancer
» Kevetrin was studied in multiple experiments alone and in conjunction with radiation against the SCC-15 cell line of head and neck cancer. Kevetrin alone showed an average tumor growth delay of 45% compared to controls, similar to radiation alone. When administered in conjunction with radiation, Kevetrin showed an average tumor growth delay of 116%.
Please click here to see a more detailed summary of these studies.
» Colon Cancer
» Kevetrin was studied in two experiments alone and in combination with 5-FU against the HT-29 cell line of colon cancer. Kevetrin alone demonstrated average tumor growth delay of 43% compared to controls. 5-FU alone showed an average tumor growth delay of 20%. The combination of Kevetrin and 5-FU resulted in an average tumor growth delay of 97%.
» Breast Cancer
» In a study with the MDA-MB-231 breast cancer cell line, Kevetrin demonstrated tumor growth delay of 90% compared to controls.
» Prostate Cancer
» Kevetrin was studied against the PC-3 cell line of prostate cancer. In two studies, Kevetrin demonstrated an average tumor growth delay of 54% compared to controls, while cisplatin showed an average tumor growth delay of 49%.
» Retinoblastoma
» The Company conducted pre-clinical studies using human retinoblastoma cells (WERI-Rb-1) in nude mice that were implanted either subcutaneously or directly into the eye, intravitreally. Treatment with Kevetrin significantly reduced the tumor volume by more than half in the subcutaneous tumor model and showed a significant improvement in the clarity of the eye in mice treated with Kevetrin.
Summary
Kevetrin is a small molecule easily synthesized from commercially available starting materials. On December 25, 2012 the United States Patent and Trademark Office (USPTO) awarded the Company U.S. Patent No. 8,338,454 B2, titled “Nitrile Derivatives and their Pharmaceutical Use and Compositions.” Kevetrin has been extensively studied in animal models of cancer, including several drug-resistant cell lines. It has consistently shown activity as good as or better than standard therapies. In drug-resistant cell lines, Kevetrin has shown excellent activity, indicating potential for development as a treatment for drug-resistant cancers. Kevetrin has generally been well tolerated by the test animals, as evidenced by GLP toxicology and safety pharmacology studies.