Doxorubicin is effectively used in various cancers despite a significant risk of cardiotoxicity associated with treatment usage. In an attempt to manage cardiotoxicity risk, there is a lifetime dosage limit. With each dose, the risk of cardiac dysfunction increases. Despite the attempt to manage cardiotoxicity risk up to about one third of patients experience cardiac dysfunction and many go on to develop heart failure. Dantrolene is a muscle relaxant that was first approved by the US FDA in1974. Its primary use is treatment of malignant hyperthermia, an anesthesia emergency. Research at UHN has shown that dantrolene is protective of the myocardium when used as a pre-treatment for doxorubicin. Dantrolene administration thus has significant potential to increase or remove the lifetime dosage limit for patients and protect the heart, preventing cardiac dysfunction and eventual chemotherapy induced heart failure.
UNMET NEED
Doxorubicin is commonly used to treat breast cancer, leukemia, lymphoma, and myeloma. It is also a second line drug in many additional cancers. About one third of all doxorubicin is used in breast cancer, making it the greatest use of the drug. Breast cancer is often first diagnosed at a relatively young age. Surviving breast cancer only to go on to develop cardiac dysfunction adds tragedy to a difficult situation. Reducing or eliminating the risk of cardiac dysfunction can add many years and quality of life for cancer survivors.
INNOVATION
Dantrolene is traditionally used for the acute treatment of malignant hyperthermia. It also finds some niche applications managing other symptoms that malignant hyperthermia patients can experience. Research at UHN has demonstrated that dantrolene can prevent the damage to the heart caused by doxorubicin. Literature demonstrates that use of dantrolene does not impact the efficacy of cancer treatments. Further, dantrolene has applications in ventricular arrhythmias.
APPLICATION/UTILITIES
· Prophylaxis of chemotherapy induced cardiotoxicity
· Acute treatment of Ventricular Tachycardia (VT)
INVESTMENT & OBJECTIVES
$5M - $15M required to conduct:
· Phase I pharmacokinetics of reformulated Dantrolene in a UHN Clinic.
· Phase I/II dose escalation study in the target disease (breast cancer) sample
· Phase I/II study of dantrolene on patients suffering from idiopathic PVCs.
COMPETITIVE ADVANTAGE
To date, one drug has been approved for the mitigation of cardiac dysfunction associated with doxorubicin. It is marginally effective and as a result experiences minimal sales. Many other drugs including beta blockers, calcium channel blockers, and statins, have been tested to reduce cardiotoxicity of doxorubicin. None have shown sufficient activity to warrant further development.
MARKET SIZE
In the US, nearly 300,000 patients are diagnosed annually with breast cancer. Two thirds of them are eligible for chemotherapy and but half choose to undergo the treatment. This results in about 90,000 addressable patients annually in the US. Doxorubicin currently sells US$1.3B annually and its use is increasing despite substantial risk of cardiotoxicity. The success of an abatement for cardiotoxicity as well as potentially selling as much as doxorubicin may increase the demand for doxorubicin-based chemotherapy.
IP PORTFOLIO
Two patent families, including issued patents in EU and US, covering multiple applications of the technology.
CURRENT READINESS LEVEL
Pre-clinical technology, requires demonstration in clinical trial.
EIR
Nigel deGruyther
Nigel deGruyther is a pharmacist and entrepreneur with experience in drug repositioning efforts and venture capital and the former Head of Business Development at Cynapsus Therapeutics.
SCIENTIFIC FOUNDER(S)
Dr. Kumaraswamy Nanthakumar is a clinical cardiologist and cardiac electrophysiologist at UHN and a Senior Scientist at the Toronto General Hospital Research Institute, with a focus in cardiac arrhythmia modulation and stabilization of RyR2. He is also Professor of Medicine at the University of Toronto.
