> Lack of efficacy
In the ongoing battle against cancer, there is a continuing need for more effective and safer treatments for patients. To address this need, researchers have been focusing on developing drugs that target specific molecular differences between tumors and normal tissues, attempting to target tumors and leave normal tissues relatively undamaged. These drugs are collectively called molecularly-targeted therapies.
Adherex is developing compounds that target cadherins, which are cell adhesion and cell signaling molecules that are crucial to the development of tissues, organs and organisms.
Agents that target and inhibit cadherin function have the potential to attack the progression of cancer at two distinct points:
· direct targeting of cadherins expressed on cancer cells may disturb cadherin-mediated signaling, leading to apoptosis, or death of the cancer cells
· cadherin inhibitors may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis, or disruption of blood vessels, and tumor damage.
ADH-1: Mechanism of Action
Adherex's lead biotechnology compound, ADH-1, targets N-cadherin, a protein present on certain tumor cells and established tumor blood vessels. ADH-1 is currently being developed in combination with a range of chemotherapeutic agents to investigate in humans the synergistic effects noted in our preclinical studies. Single-agent Phase Ib/II and Phase II trials of ADH-1 have already been completed.
Significance of "cadherin switch" in cancer progression
While ADH-1 has a single molecular target, N-cadherin, we believe its anti-cancer effect results from two distinct mechanisms of action – apoptosis and tumor vessel angiolysis.
· N-cadherin appears to act as a tumor cell survival factor. In cell culture studies, inhibition of N-cadherin binding between tumor cells has been shown to cause apoptosis, or death of the tumor cells, we believe as a result of disrupting the cadherin-regulated cell survival signals.
· ADH-1 also appears to disrupt the blood vessels needed for cancerous tumors to grow and flourish, with hemorrhaging having been noted in both our clinical and preclinical studies. We believe the mechanism for this disruption is either a competitive inhibition of the binding of cadherins between the endothelial cells of the tumor blood wall, or apoptosis in the tumor cells that form part of the cancerous blood vessel wall, each leading to leakage and rupture of these vessels. The latter involves the phenomenon of tumor "mosaicism," in which tumor cells form a portion of the vascular wall in cancers (along with the endothelial cells). Induction of cell death of these tumor cells would result in tumor vascular disruption.
ADH-1: Preclinical Studies
ADH-1: Early Phase Clinical Studies
ADH-1: Current Clinical Development
At the end of 2006, Adherex completed patient enrollment in our single-agent Phase Ib/II and Phase II clinical trials. In addition, the Company initiated a clinical program of ADH-1 in combination with other chemotherapeutic agents, based in part on the encouraging preclinical combination study results described above. The first Phase I combination study, which was initiated in October 2006 and completed patient enrollment in May 2008, was intended to define the dose limiting toxicities and maximum tolerated dose of ADH-1 in three separate combinations: ADH-1 + docetaxel (Taxotere®), ADH-1 + carboplatin, and ADH-1 + capecitabine (Xeloda®). Adherex also began a Phase I combination study of ADH-1 in combination with melphalan for the treatment of melanoma in March 2007, which completed patient enrollment and was expanded to a Phase IIB trial in January 2008. The Phase IIB portion of the trial completed enrollment in November 2008.
For additional information about Adherex's ongoing trials of ADH-1, please visit http://www.clinicaltrials.gov.
ADH-1: Market Opportunity
The market for molecularly-targeted oncology therapies is significant. Currently marketed products such as Avastin®, Herceptin®, Tarceva® and Gleevec® have proven both therapeutically and commercially successful. Based on our analysis of the molecular expression of N-cadherin in human cancers, the annual target population for ADH-1 is estimated at approximately 200,000 patients, representing a potential market opportunity of more than US$1 billion annually. ADH-1 may be used alone or in combination with other therapies, such as anti-angiogenics, biologics, radiation and chemotherapy.
Adherex has received Orphan Drug Designation in the U.S. for the use of ADH-1 in conjunction with melphalan for the treatment of Stage IIB/C, III, and IV malignant melanoma.