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Tekmira Adds HBV to Pipeline, Aims to Move Drug into Clinic in '14

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Tekmira Pharmaceuticals this week announced that it has added hepatitis B to its pipeline, and that it anticipates filing an investigational new drug application for the program in 2014.

Speaking during a conference call, Tekmira officials also provided updates on the company's other drug-development efforts, including ones in alcohol use disorder, rare forms of hypertriglyceridemia, and glycogen-storage diseases.

Notably, President and CEO Mark Murray said that, as the firm transitions "from a technology company into a product company," it will handle the development and commercialization of most of its programs in North America on its own.

"We certainly expect a partner, but we will [find one] for large indications or ex-North American territories," he added. In other cases, "we will be able to demonstrate clinical value and proceed efficiently toward product approval with our own resources."

Among these in-house programs is Tekmira's newest in HBV, which involves a cocktail of siRNA compound that targets multiple sites on the virus' genome in order to reduce the expression of surface antigen — a viral protein that causes the liver inflammation that can lead to cirrhosis and cancer, Tekmira CSO Ian MacLachlan said during the call.

In addition to eliminating the pathology associated with surface antigen expression, Tekmira expects its drug to allow patients to seroconvert, developing antibodies against the virus and thereby resulting in a functional cure, he said.

To design the drug's payload, "we screened over 37,000 HBV genome sequences from 4,000 distinct HBV genotypes using a proprietary bioinformatics screening algorithm," he noted.

And while the compound, called TKM-HBV, is primarily designed to target HBV genotypes A, C, B, and D — the ones predominant in North America, Europe, and China — "the siRNAs we've designed exhibit high degrees of cross-reactivity with other HBV genotypes, as well," he added.

Should it meet its goal of filing an IND on TKM-HBV next year, Tekmira anticipates having phase I data from chronically infected HBV patients ready by 2015.

In line with its strategy of keeping certain programs in-house, MacLachlan said that Tekmira will first pursue regulatory approval in the US and Europe, then seek a partner for commercialization in Asia.

During the call, Murray also highlighted Tekmira's work in alcohol dependency, a program that the company has long kept on a steady pace to the clinic.

It's drug candidate, called TKM-ALDH2, is designed to silence aldehyde dehydrogenase 2, or ALDH2, a liver enzyme involved in ethanol metabolism.

According to Murray, after ethanol is consumed, it is converted to acetaldehyde, which ALDH2 in turn converts into acetic acid. "If ALDH2 is blocked, acetaldehyde builds up and produces an acute sensitivity to ethanol, which can produce ethanol avoidance," he explained.

Murray noted that this therapeutic approach has already been validated in humans, citing the small molecule ALDH2 blocker disulfiram, which is approved for use in alcohol dependency treatment.

That drug, however, suffers from patient compliance issues since it must be administered once a day, he said. In contrast, Tekmira's preclinical data indicates that TKM-ALDH2 can silence its target for more than 30 days after a single dose.

Importantly, animal behavioral studies also indicate that alcohol aversion after TKM-ALDH2 treatment increases upon repeated ethanol exposure — an effect seen with disulfiram treatment, which further validates Tekmira's compound, Murray added.

An IND for TKM-ALDH2 is slated for the second half of 2014, with human proof of concept data likely available in 2015.

With Tekmira aiming to nominate another clinical candidate sometime next year, newly appointed CMO Mark Kowalski said during the call that the company is evaluating a variety of new indications, particularly ones where the firm can achieve "early clinical proof of concept and where there may be an accelerated approval path" such as orphan diseases.

Among those that appear most promising are rare forms of hypertriglyceridemia and glycogen-storage disorders, he said.

In regards to the former, Tekmira has been exploring conditions where patients' genetic makeups render them unable to control their triglycerides, even with available drug therapy. These include familial hypertriglyceridemia and familial partial lipodystrophy.

Tekmira has also been investigating the rare childhood glycogen storage disorder Anderson's disease, which is caused by a mutation in glycogen-branching enzyme and results in autoimmune damage and lethal hepatic cirrhosis.

Continued development

As these initiatives move forward, Tekmira has also been making strides with its more advanced compounds, including the cancer drug TKM-PLK1.

This drug, which silences polo-like kinase 1, was recently moved into a phase I/II study in patients with either adrenocortical carcinoma, known as ACC, or advanced gastrointestinal neuroendocrine tumors, also known as GI-NET (GSN 8/15/2013).

Kowalski said during the conference call that results from this trial are expected by mid-2014. "If supported by the data, we will then commence a pivotal trial in GI-NET before the end of 2014," he said.

Tekmira is also preparing to launch another phase I/II trial of TKM-PLK1 in hepatocellular carcinoma in the first half of next year.

"This clinical trial will be a multi-center, open-label, non-randomized, dose-escalation study designed to evaluate the safety, the tolerability, and pharmacokinetics of TKM-PLK1," he said. "It will also determine the maximum tolerated dose [in liver cancer patients] and measure the anti-tumor activity" of the drug.

Meanwhile, Tekmira continues to push forward with its Ebola virus treatment TKM-Ebola. A phase I trial of a reformulated version of this agent is expected to begin phase I testing in the first quarter of 2014, with data available by the second half of that year.

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