Products
In addition to delivery platform research and development, Tekmira is advancing three internal RNA interference (RNAi) product candidates.
TKM-ApoB is being developed for the treatment of hypercholesterolemia, or elevated cholesterol, a condition associated with increased risk of atherosclerosis, a build-up of cholesterol and fat in artery walls that underlies many cardiovascular diseases, such as angina, myocardial infarction, congestive heart failure, stroke, transient ischemic attacks or peripheral artery disease.
TKM-PLK1 is being developed as a novel, safe and effective anti-tumour drug in the treatment of cancer. LNPs are particularly well suited for the delivery of siRNA to treat cancer because the lipid nanoparticles preferentially accumulate within tissues and organs having leaky blood vessels, such as cancerous tumours. Once at the target site, LNPs are taken up by tumour cells and the siRNA payload is delivered inside the cell where it reduces expression of the target protein. Through careful selection of the appropriate molecular targets, LNPs are designed to have potent anti-tumour activity yet be well tolerated by healthy tissue adjacent to the tumour.
TKM-Ebola is being developed as a novel anti-viral drug in the treatment of Ebola infection. Tekmira conducted a series of studies demonstrating the ability of an RNAi therapeutic utilizing Tekmira’s lipid nanoparticle (LNP) technology to protect nonhuman primates from Ebola virus, a highly contagious and lethal human infectious disease. The studies were done in collaboration with leading infectious disease researchers from Boston University and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). The results, which have been published in the prominent medical journal The Lancet (Geisbert et al., “Post exposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof of concept study”, The Lancet, Vol 375, May 29, 2010) describe antiviral activity of small interfering RNAs (siRNA) encapsulated in a LNP formulation targeting the Ebola virus (TKM-Ebola). When used to treat infected nonhuman primates, TKM-Ebola resulted in complete protection from an otherwise lethal dose of Zaire Ebola virus. For many years, the Zaire species of Ebola virus (ZEBOV) has been associated with periodic outbreaks of hemorrhagic fever in human populations with mortality rates reaching 90%. There are currently no treatments for Ebola or other hemorrhagic fever viruses.
Tekmira has the opportunity to advance additional RNAi product candidates based on access to Alnylam’s intellectual property. Tekmira's research efforts are focused on identifying the Company's next product candidate for development.
TKM-ApoB
It is estimated that more than 100 million North Americans have elevated cholesterol levels, with nearly half of these characterized as “extremely high”. The vast majority of these patients take some form of drug therapy, HMG-CoA reductase inhibitors such as statins being the most commonly prescribed drugs. Although effective at decreasing LDL cholesterol levels by up to 50%, their relative risk reduction is only about 30% illustrating the significant need for additional new therapeutic approaches to treating high cholesterol.
Tekmira’s approach is to address the underlying cause by targeting ApoB, a protein synthesized in the liver that is essential to the assembly and secretion of very low density lipoprotein (VLDL), a precursor to LDL, both of which are required for the transport and metabolism of cholesterol. The ApoB protein facilitates the uptake of these lipoproteins into various tissue types and, as such, is an important and validated target for reduction of hypercholesterolemia. ApoB is considered untreatable by conventional small molecule drugs and thus requires a molecular approach.
TKM-ApoB consists of an siRNA designed to silence ApoB delivered using Tekmira's lipid nanoparticle (LNP) delivery technology. Compared to other molecular approaches in development, such as antisense, TKM-ApoB appears to have significant advantages including markedly improved drug potency in preclinical models. TKM-ApoB is delivered with high efficiency into the liver hepatocytes, the cells which produce ApoB, where the siRNA acts to knock down the precursor mRNA coding for ApoB protein. The resulting decrease in circulating VLDL and LDL results in significant reductions in LDL or “bad” cholesterol and triglycerides.
In pre-clinical studies, rodents with diet-induced hypercholesterolemia that received a single administration of TKM-ApoB saw elevated blood cholesterol levels fall to normal. The suppressive effect of a single dose lasted for nearly five weeks and is expected to last considerably longer in larger animal models. Importantly, levels of high density lipoproteins (HDL), also known as “good” cholesterol, in TKM-ApoB treated animals remained unaffected.
Tekmira initiated a Phase 1 human clinical trial for TKM-ApoB in July, 2009, to evaluate the safety, tolerability and pharmacokinetics of escalating single doses of TKM-ApoB in patients with elevated LDL cholesterol. The trial was also designed to provide preliminary data on the ability of TKM-ApoB to lower serum LDL cholesterol levels.
In January, 2010, Tekmira announced that it concluded its TKM-ApoB Phase 1 human trial. Tekmira enrolled a total of 23 subjects in the trial; 17 subjects received a single dose of TKM-ApoB at one of seven different dosing levels and six subjects received a placebo. TKM-ApoB was well tolerated overall in this study with no evidence of liver toxicity, which was the anticipated dose-limiting toxicity observed in preclinical studies. Of the two subjects treated at the highest dose level, one subject experienced flu-like symptoms consistent with stimulation of the immune system caused by the ApoB siRNA payload. The other subject treated at the highest dose level experienced no side effects. Of the two subjects treated at the highest dose, the average transient reduction of ApoB protein and LDL cholesterol was 21.1% and 16.3%, respectively.
Tekmira has selected a new siRNA payload and LNP formulation for TKM-ApoB. Tekmira has made significant improvements in its LNP formulation technology over the past two years and the new TKM-ApoB formulation will be several fold more potent than the current formulation. Tekmira is targeting the second half of 2010 to re-initiate a Phase 1-2 clinical trial with its next generation TKM-ApoB.
TKM-PLK1
Tekmira has taken advantage of this passive targeting effect to develop a LNP formulation directed against PLK1 (polo-like kinase 1), a protein involved in tumour cell proliferation. Inhibition of PLK1 prevents the tumour cell from completing cell division, resulting in cell cycle arrest and cell death.
Because the standard of care for cancer treatment often involves the use of drug combination therapies, Tekmira has selected gene targets for its oncology applications that synergize with conventional drugs that are currently in use. TKM-PLK1 has the potential to provide both direct tumour cell killing and sensitization of tumour cells to the effects of chemotherapy drugs such as Taxol.
In preclinical studies, TKM-PLK1 displayed potent and specific anti-tumour effects in a variety of tumour models in animals, translating into significant survival benefits even when measured in aggressive liver cancer models.
Formal safety studies for TKM-PLK1 were completed in 2010. The Company filed an IND with the FDA in August 2010 and intends to initiate a Phase 1 human clinical trial in the second half of 2010. This Phase 1 study will establish safety and identify the maximum tolerated dose in relapsed or refractory cancer patients. Subsequent studies will be designed to confirm the safety and efficacy of TKM-PLK1 as a single agent or in combination with other anticancer drugs. Ongoing development is expected to identify additional cancer targets and LNP formulations with further improved potency.
TKM-Ebola
In July 2010, Tekmira was awarded up to a $140 million contract from the United States Government's Transformational Medical Technologies (TMT) Program to advance TKM-Ebola. In the initial phase of the contract Tekmira is eligible to receive up to U.S. $34.7 million over the next three years. This initial funding is for the development of TKM-Ebola through pre-clinical development, filing of an Investigational New Drug (IND) application with the United States Food and Drug Administration (FDA), and completion of a Phase 1 human safety clinical trial.
Additional Product Candidates
