Tekmira’s leading RNAi platform ready for prime time

As a global leader in the emerging field of RNA interference (RNAi), which holds the potential of revolutionizing medicine with new therapeutics, upstart Tekmira Pharmaceuticals (TSX:TKM) is at the precipice of confirming that the highly touted science works in humans.

“We really are at the crux,” CEO Dr. Mark Murray says in an exclusive interview with biotuesdays.com.  “The next one-to-two years will be very important not only for our company but also for the field of RNAi because … we’re going to demonstrate that RNAi will work in humans in a number of different applications.”

As the name implies, RNAi is a mechanism for controlling the flow of genetic information in cells.  By interfering with specific messenger-carrying RNA in cells, researchers hope to silence disease-causing genes, using a new class of drugs often referred to as small interfering RNA (siRNA).

In 2006, American scientists Andrew Fire and Craig Mello received the Nobel Prize for Physiology or Medicine for their discovery of RNAi in 1998.

Though still in its infancy, Big Pharma has made some big bets for preclinical RNAi assets.  In 2006, for example, Merck paid an eye-popping $1.1 billion (U.S.) to acquire upstart Sirna Therapeutics.  The following year, Roche anted up $300 million to Alnylam Pharmaceuticals for a non-exclusive license and access to its intellectual property.  And in mid-2008, Roche further strengthened its RNAi position by paying $125 million to swallow Mirus Technologies.

Tekmira, which is developing its own RNAi drugs, also has companies flocking to use its unique delivery technology called SNALP or stable nucleic acid-lipid particles, which encapsulates the drug.  The company, which has been working in the field of nucleic acid delivery for over a decade, has alliances with Alnylam and Roche to deliver their RNAi drug candidates inside a SNALP molecule.

“We have the only delivery technology that’s ready for prime time,” Mr. Murray states.  “So we’re really in a great spot at the moment and our value is driven by our partnerships and the product candidates we’re pushing forward for them.”

Bristol-Myers Squibb is also collaborating with Tekmira, using RNAi technology to validate targets in its drug pipeline rather than for developing its own RNAi drugs.  And Takeda Pharmaceuticals is in the early stages of deciding what its RNAi drug targets are going to be, using Tekmira’s SNALP delivery punch.

Last month, a highly anticipated Phase 1 trial of Tekmira’s own ApoB SNALP drug, which is designed to reduce elevated “bad” LDL cholesterol levels, achieved its primary endpoints of safety and tolerability, even though the trial ended ahead of schedule.  One of two people receiving the highest delivered dose experienced flu-like symptoms consistent with stimulation of the immune system caused by the drug payload.  The other patient had no side effects.

But the glass was also half full.  As a secondary endpoint, Tekmira observed positive drug activity in the two subjects, with average reductions in the ApoB protein and LDL cholesterol of 21.1% and 16.3%, respectively.

“From our perspective, it was bittersweet,” Mr. Murray contends.  “The good news is we were in the clinic and we showed that the technology and the agent were well tolerated in human subjects.  And we had a trickle of efficacy. One of the consequences of leading the charge is you encounter things that other people have not encountered.”

But Cormark Securities analyst David Dean cuts to the chase.  “This is the first human evidence of drug effect from any systemically delivered siRNA drug,” he said in a recent report.  And he remains confident that Tekmira’s ApoB program will become “one of, if not, the most interesting siRNA programs in the world.”

Mr. Murray says the company has reformulated the chemical features of the ApoB drug candidate and the SNALP delivery platform to prevent an immune reaction from happening again.  Indeed, new research published in the journal Nature Biotechnology disclosed Tekmira’s development of a new lipid component that provides a ten-fold improvement in the potency of its SNALP.

“We’re beyond the discovery phase,” he says of the second generation technology.  “We’ve identified both the new payload and the new lipid formulation, and now we’re putting them together and testing them with the objective of being back in the clinic later in the year.”

Tekmira lost some of its lustre after the Phase 1 clinical trial as investors reacted to the delay in clinical development of the ApoB cholesterol drug.  But Versant Partners analyst Doug Loe, who initiated coverage of Tekmira earlier this month, contends that the company is “clearly undervalued compared to its publicly-traded peers,” including MDRNA Inc., RXi Pharma and Silence Therapeutics, which recently merged with Intradigm.

Being back in the clinic in the second half this year with a reformulated ApoB package for a second Phase 1 study is one of Tekmira’s milestones.

“We view 2010 as an important year to firmly establish RNAi therapeutics as a new class of broadly applicable drugs,” Mr. Murray comments, adding that there should be five SNALP-based RNAi therapeutics in clinical development this year.  Two of those belong to Tekmira and three to its partners “as they advance products using our SNALP technology, clearly demonstrating our leadership in this emerging field.”

Tekmira’s second drug, PLK1 SNALP, is scheduled to start a Phase 1 human trial in the second half of 2010 as a treatment for cancer. In earlier preclinical trials, PLK1 SNALP selectively killed cancer cells by targeting a specific PLK1 protein.  Silencing PLK1 has been shown to prevent tumour cell division, resulting in cell death.

Mr. Murray says the company is evaluating preclinical candidates with efficacy in metabolic and infectious diseases as well as cancer in order to select its third RNAi product candidate for development this year.

On the partnering front, Alnylam (NASDAQ: ALNY) expects to present preliminary data in mid-2010 from a Phase 1 clinical trial evaluating its ALN-VSP drug as a treatment for liver cancer and cancers with liver involvement.  ALN-VSP utilizes Tekmira’s SNALP technology and Tekmira manufactures the drug for Alnylam under a 2009 agreement.

Alnylam also plans to start a clinical trial of ALN-TTR01 in transthyretin-mediated amyloidosis (ATTR) patients in the first half of 2010.   Alnylam will be advancing two formulations, ALN-TTR01 and ALN-TTR02, and both will be manufactured by Tekmira using SNALP technology.  ATTR is caused by a mutation in the transthyretin (TTR) gene, which causes abnormal proteins to damage body organs and tissue.  The only option treatment for patients now is a liver transplant.

Tekmira is also working with Roche to develop its first RNAi therapeutic product using SNALP technology, which is expected to begin human trials by the end of the year.

“Scientific advancement in the RNAi field is still important,” Mr. Murray says, adding that Tekmira plans to publish additional research this year in peer-reviewed journals, representing a “metric of our continuing drive to remain in a leadership position in the field.”

On the drawing board is an article on SNALP efficacy in Ebola virus-infected non-human primates that will show “how potent the technology can be in an infectious disease setting,” he says.  Other peer-reviewed articles include research about a new mechanism for delivering SNALP into target cells and development of second generation RNAi drugs designed to eliminate activation of the immune system.

Tekmira’s milestones for 2010 are a wake-up call that the company “continues to possess one of the highest levels of expertise in delivery technologies and siRNA payload chemistries in the field,” writes Loewen Ondaatje McCutcheon analyst Connie Chen.