LOR-2040
Targeted therapies have revolutionized the treatment of cancer because they selectively block disease-causing proteins and biochemical pathways that contribute to cancer progression while sparing normal cells and reducing toxicity. An essential part of successful targeted therapy is finding a good target, and then using the right technology to inhibit its activity or expression. Lorus is committed to this approach, and we have several targeted drug candidates in our pipeline.
LOR-2040 (formerly GTI-2040) is our lead targeted therapy currently in clinical development. LOR-2040 is an RNA-targeting agent that dramatically decreases expression of the R2 subunit of ribonucleotide reductase (RNR). RNR is a protein that is essential for DNA synthesis and cell growth in normal cells, where expression of RNR is tightly controlled. Cancer cells, however, highly overexpress RNR, which contributes to tumor growth and malignancy. Overexpression of RNR also promotes resistance to certain chemotherapy drugs, and RNR cooperates with a variety of cancer-causing oncogenes to further promote cancer progression and metastasis. These properties make RNR an excellent target for cancer treatment, so it is not surprisingly that many approved cancer therapies target RNR.
Lorus has demonstrated that targeting the R2 subunit with LOR-2040 can inhibit RNR expression and activity in cancer cells. LOR-2040 specifically binds to the R2 mRNA, which is the template that the cell uses for production of the R2 protein. Binding of LOR-2040 results in the destruction of the mRNA, leading to a significant reduction in R2 protein levels and decreased proliferation of cancer cells. Extensive preclinical studies have shown that LOR-2040 has significant antitumor activity that correlates with decreased expression of R2 mRNA and protein. These studies have shown that LOR-2040 is a selective and specific anticancer agent against a broad range of human cancers, including renal cancer, leukemia, bladder cancer and breast cancer, and have provided support for clinical use of LOR-2040 in solid tumors and hematological cancers.
Lorus has selected Acute Myeloid Leukemia (AML) as a lead cancer indication for clinical development of LOR-2040. LOR-2040 has recently completed an advanced Phase II clinical trial in combination with high dose Ara-C (HiDAC) as salvage therapy in refractory and relapsed AML patients under 60 years of age to the end-of-stage assessment time point. This Phase II trial was initiated based on the results of a Phase I trial with LOR-2040 plus HiDAC in this same patient population, which showed a high clinical response rate compared to clinical responses that are generally seen in these patients. Results of the Phase II trial confirm these Phase I findings in a larger population of AML patients, and increase our understanding of how LOR-2040 works to enhance Ara-C activity in this cancer by assessing target downregulation and intracellular drug levels. In addition, this trial paves the way for moving forward in a pivotal Phase III randomized clinical study for eventual registration and commercialization in an oncology indication. LOR-2040 has potential to be the first RNA-targeted drug to achieve this distinction.
Consistent with our focus on AML, Lorus recently initiated a Phase I clinical trial with LOR-2040 in patients with Acute Leukemias (AL) and high grade Myelodysplastic Syndromes (MDS). High grade MDS patients typically have a survival expectation of one year or less and their disease may frequently progress to AML. This clinical study is designed to evaluate the safety and activity of LOR-2040 as a single agent in these blood-based cancers. LOR-2040 is also being studied in combination with various chemotherapy drugs in a multiple Phase I/II clinical program in several solid tumor types, which is sponsored by the U.S. National Cancer Institute. As with many targeted therapies, LOR-2040 has shown a high safety profile in clinical trials with minimal adverse side effects to patients.
In addition to these clinical programs, we recently completed a toxicology program to examine direct (intravesical) administration of LOR-2040 into the bladder as a treatment for superficial (non-invasive) bladder cancer. Intravesical treatment is a standard route of administration for commonly used immunotherapy treatment of locally confined, superficial bladder tumors, but has only recently been explored for administration of newer targeted therapeutics. Direct administration of targeted therapies to the bladder has the potential to maximize drug exposure to the tumor and increase target downregulation in tumor cells without significant side effects. A pilot study of LOR-2040 as single agent, administered intravesically in patients with superficial bladder cancer has been designed and prepared for IND submission.
The United States FDA has designated LOR-2040 as an Orphan Drug both for treatment of AML and renal cell carcinoma, providing seven years of market exclusivity in the U.S. upon the drug’s approval for treatment of these cancers. LOR-2040 is protected under several patents both for composition and cancer uses in a number of countries worldwide, including Canada, Europe, Australia, China, and the U.S. LOR-2040 has significant partnership potential, and Lorus is actively seeking commercial partners for this drug product.