Robust Phase I findings for ALN-TTRsc, a subcutaneously administered RNAi therapy targeting transthyretin (TTR) in TTR-mediated amyloidosis, propelled Alnylam Pharmaceuticals Inc. to a 52-week high Thursday morning.

The stock (NASDAQ:ALNY) opened 14.2 percent higher – topping $40 for the first time since the RNAi therapeutics developer closed its initial public offering in 2004 – and gained momentum throughout the morning as executives and scientists took a deep dive into the company's pipeline during its R&D day presentation.

Shares hit a high mark of $44.65 before closing at $43.53 for a gain of $5.93, or 15.8 percent, on the day. Volume was more than five times heavier than average, with 2.6 million shares changing hands.

With the ALN-TTRsc findings, Cambridge, Mass.-based Alnylam continued to make a compelling case for its GalNAc-siRNA conjugate delivery platform. ALN-TTRsc achieved knockdown of serum TTR protein levels of greater than 80 percent in healthy volunteers, in line with results for ALN-TTRsc reported in nonhuman primates. The therapy was found to be generally safe and well tolerated.

The study results were the first reported for Alnylam's GalNAc-siRNA conjugate delivery platform, which enables subcutaneous dosing of RNAi therapeutics with a wide therapeutic index. GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor.

To date, the company has dosed more than 625 individuals in its clinical studies – some for as long as two years – providing "encouraging" findings on tolerability and overall safety, said Akshay Vaishnaw, the company's executive vice president and chief medical officer.

Dose escalation in the randomized, double-blind, placebo-controlled ALN-TTRsc trial continues, and the company plans to present additional findings at the annual scientific meeting of the Heart Failure Society of America in September. The next step will be a Phase II study in familial amyloidotic cardiomyopathy (FAC) patients by year-end, with the goal of initiating a pivotal Phase III trial for ALN-TTRsc in FAC in 2014.

ALN-TTRsc – along with ALN-TTR02, which targets familial amyloidotic polyneuropathy (FAP) amyloidosis – represents just the beginning for Alnylam, as company executives made clear at their R&D day. At the leading edge of its pipeline, the company has ALN-AT3 in hemophilia and rare bleeding disorders. Alnylam also has earlier-stage programs in hypercholesterolemia – where candidate ALN-PCS showed up to 84 percent knockdown of proprotein convertase subtilisin/kexin type 9 (PCSK9) and up to a 50 percent decrease in LDL cholesterol – as well as complement-mediated diseases, beta-thalassemia and iron-overload disorders and other indications.

Earlier this year, Alnylam struck a potential $205 million deal, including $25 million up front, with the Medicines Co., of Parsippany, N.J., for the PCSK9 program. (See BioWorld Today, Feb. 5, 2013.)

ALN-TTRsc 'an Efficacy Home Run'

All told, the company's internal pipeline includes five RNAi therapeutic candidates Alnylam plans to move into the clinic by 2015, representing an R&D strategy known as "5x15."

In each case, the company is pairing a genetically defined target with a specific disease and applying its intravenous lipid nanoparticle-based or subcutaneous conjugate-based technology.

"Because of the availability of relevant circulating biomarkers, we'll establish proof of concept in our first-in-human studies in Phase I," Vaishnaw explained. "And because of prudent choices in terms of the targets and diseases that we're going after, we'll have clear development paths that allow us to rapidly proceed to significant commercial opportunities."

The common thread, according to CEO John Maraganore, is that "we're focusing in every single case on liver-expressed target genes," where the company's programs produce good knockdowns. Alnylam also targets genes that were validated in human genetics, dramatically reducing biological and clinical risk. The company is committed to move programs forward only if they have a biomarker in Phase I studies, "increasing the likelihood that we'll get to the right dose quickly," Maraganore said.

Although Alnylam has a raft of partnering deals, the company is increasingly selective. In 2012, Alnylam inked an exclusive alliance with Genzyme, a unit of Sanofi SA, of Paris, to develop and commercialize its RNAi therapeutics, including ALN-TTR02 and ALN-TTRsc, for ATTR in Japan and the broader Asia-Pacific region. Genzyme made an up-front cash payment of $22.5 million and agreed to development milestone payments and tiered royalties expected to yield an effective rate in the mid-teens to mid-twenties on sales of ALN-TTR products in its territory.

But Alnylam held on to development and commercialization rights for the ALN-TTR program in North and South America, Europe and rest of the world – a strategy Maraganore emphasized during the R&D presentation.

"The clear and undeniable path to building great companies is to ultimately control your drug development effort and to retain significant market rights," he said, noting that Alnylam intends to retain similar rights "for the vast majority of programs that we have in our pipeline."

In an alert released prior to the R&D presentation, Deutsche Bank analyst Alethia Young wrote that the ALN-TTRsc data represented "the key to our long-term thesis of Alnylam. The subcutaneous dose achieved [statistically significant] knockdown of TTR of >80% in healthy volunteers," which she called an "efficacy home run" and a validation of Alnylam's platform technology.

Young correctly predicted the company's shares would top $40 and could hit $49 per share following the positive Phase I data. In July 2012, Alnylam's shares soared 50 percent on Phase I data in FAP patients, climbing overnight from $12.52 to $19.16.

Remarkably, just 18 months ago with its stock hovering around $10, Alnylam implemented a strategic restructuring that slashed its work force by one-third, saving the company $20 million in 2012 while it focused on its "5x15" strategy. The company now has 140 employees and expects to finish 2013 with $320 million in the bank, according to Maraganore.