This story has been updated to include a comment from Tekmira's president and CEO.
Despite the high quality of Tekmira Pharmaceuticals' investigational new drug application for its phase I hypercholesterolemia therapy ApoB SNALP, the siRNA-based drug's target is less "compelling" than the one chosen by partner Alnylam Pharmaceuticals for its competing high-cholesterol program, Alnylam's top official said last week.
The statements by Alnylam CEO John Maraganore came during a conference call held to discuss the firm's first-quarter financial results, which included a sharp rise in losses amid increased operating costs.
Tekmira this week announced that the US Food and Drug Administration gave the company clearance to begin human trials of ApoB SNALP, which combines the company's stable nucleic acid-lipid particle, or SNALP, delivery technology with an siRNA designed to silence apolipoprotein B, a protein involved in cholesterol metabolism (see RNAi News, 5/7/2009).
During the conference call, Maraganore called the news "fantastic," noting that both companies expect to benefit from data generated through the ApoB SNALP in light of their long-standing alliance (see RNAi News, 11/13/2008).
Nonetheless, in response to an analyst's question, he stressed that Alnylam's hypercholesterolemia target — proprotein convertase subtilisn/kexin type 9, or PCSK9 — is superior to apoB.
According to Maraganore, the body of data demonstrating the role of PCSK9 in regulating low-density lipoprotein-receptor levels and the ability to accelerate plasma LDL clearance by PCSK9 silencing make the target "the most compelling" one for treating high cholesterol with an RNAi drug.
At the same time, he indicated that Alnylam's choice to go after PCSK9 was based solely on the company's confidence in it as a target, he said, adding that "we could certainly have pursued apoB if we wanted to."
This decision "is simply based on the very clear-cut human genetic data corroborated by lots of other data that argue PCSK9 is, in fact, the preferred target," he said.
Indeed, apoB had been on Alnylam's radar for some time. In late 2004, the company published data showing that cholesterol-conjugated siRNAs targeting apoB delivered intravenously into mice could cut apoB mRNA levels in the liver and jejunum, decrease plasma levels of apoB protein, and reduce total cholesterol (see RNAi News, 11/11/2004).
About two years later, the RNAi shop reported additional data showing that lipid-encapsulated siRNAs targeting apoB could be used with clinical efficacy after systemic administration in non-human primates (see RNAi News, 3/30/2006).
However, additional in-house research, along with genetic data in the literature linking PCSK9 and cholesterol levels, ultimately led Alnylam to drop apoB as a hypercholesterolemia target and instead focus on PCSK9 (see RNAi News, 12/7/2006).
In doing so, Tekmira was free to begin developing ApoB SNALP pursuant to its arrangement with Alnylam, under which Tekmira may develop seven RNAi drug candidates based on Alnylam intellectual property.
Maraganore stressed, however, that Alnylam's optimism over PCSK9 doesn't necessarily mean that apoB won't prove to be the better target.
"One could have a group of very smart people around a table and, as often happens in science and medicine, have a range of different views," he said. "Our view is that PCSK9 is clearly an extremely well-validated genetic target in the context of the treatment of hypercholesterolemia.
"Other people … have different views and it's just a difference of views and … opinions," he added. "We'll ultimately see which approach is best."
In an e-mail to RNAi News, Tekmira President and CEO Mark Murray said that his company selected apoB since it is "well-validated" and because "our extensive body of preclinical data supports targeting apoB is very effective at lowering LDL cholesterol."
For the three-month period ended March 31, Alnylam's net loss surged to $7.9 million, or $0.19 per share, from a year-ago loss of $1.2 million, or $0.03 per share.
Contributing to the higher losses was a nearly 25 percent rise in research and development spending to $25.3 million, which the company attributed in part to IP license fees paid to Isis Pharmaceuticals and expenses associated with its clinical programs and industry alliances.
First-quarter general and administrative costs, meanwhile, jumped to $7.7 million from $5.9 million the year, helping to push Alnylam's total operating expenses up roughly 26 percent to $33 million.
Revenues in the quarter rose to $25.1 million from $22.2 million in the first quarter last year, largely reflecting $5.4 million Alnylam received from its partnership with Takeda Pharmaceutical (see RNAi News, 5/29/2008).
At the end of the first quarter, Alnylam had cash, cash equivalents, and marketable securities totaling $504.7 million. Looking ahead, the company said it continues to expect it will end 2009 with a cash position of greater than $435 million and a net operating loss of between $35 million and $45 million.