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Santaris Advances Two Hypercholesterolemia Rx Candidates; One Poised to Enter Clinical Trials in 2010

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By Doug Macron

Santaris Pharma last month said that it has advanced two hypercholesterolemia drug-development programs further within its preclinical pipeline, with one poised to enter human testing next year.

And while the locked nucleic acid technology upon which the drugs are based is novel, the targets are currently being pursued by at least three major RNAi and antisense firms, which could set the stage for a showdown between the three therapeutic modalities.

Santaris’ pipeline disclosure came as part of an announcement of the company’s third-quarter financial results, which included a 31 percent drop in its loss amid lower research and development spending.

Currently, Santaris has two hypercholesterolemia programs: the first targets apolipoprotein B, while the second targets proprotein convertase subtilisn/kexin type 9.

According to the company, it has selected a lead candidate, dubbed SPC4955, against apoB and expects to advance the drug into phase I studies “in early 2010” after having demonstrated in rodents and primates that inhibition of the target lowers low-density lipoprotein and triglyceride levels “effectively.”

At the same time, an earlier-stage effort in hypercholesterolemia has yielded a number of lead candidates against PCSK9, all of which are moving into pharmacological studies, Santaris said.

Santaris is not alone in its efforts to knock down apoB and PCSK9 levels as a means to control cholesterol. Isis Pharmaceuticals currently has an antisense-based apoB inhibiter, mipomersen, in late phase III development, and early last year exclusively licensed the drug’s global rights to Genzyme as part of a broader strategic alliance.

On the RNAi side, Tekmira Pharmaceuticals began in July a phase I study of ApoB SNALP, an apoB-targeting siRNA delivered using its proprietary stable nucleic acid-lipid particle delivery technology (see RNAi News, 7/9/2009).

Meanwhile, Alnylam Pharmaceuticals is developing an siRNA-based therapy for hypercholesterolemia that targets PCSK9, and expects the program to yield an investigational new drug application filing as early as next year (see RNAi News, 8/13/2009).

And while apoB and PCSK9 are each well validated, there has been some disagreement among those in the RNAi space about which is superior, and Santaris appears to be hedging its bets somewhat by pursuing both.

In May, Alnylam CEO John Maraganore told investors that Tekmira’s target, apoB, is “less compelling” than the one being pursued by his company, in part due to the body of data demonstrating the role of PCSK9 in regulating low-density lipoprotein-receptor levels and the ability to accelerate plasma LDL clearance (see RNAi News, 5/14/2009).

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The following month, Alnylam Vice President of Drug Discovery Muthiah Manoharan disclosed to RNAi News that his company also had concerns over the safety of an apoB-targeting drug after observing the onset of fatty liver disease in animals when apoB was down-regulated (see RNAi News, 6/11/2009).

As a result, Alnylam opted against pursuing apoB itself, which cleared the way for Tekmira to go after the target pursuant to the terms of an ongoing technology- and intellectual property-licensing arrangement between the companies.

Tekmira has since defended its decision to develop ApoB SNALP, and in August President and CEO Mark Murray noted during the company’s second-quarter earnings conference call that apoB has been validated not only by animal data, but also the clinical data generated in trials of mipomersen (see RNAi News, 8/13/2009).

In doing so, Murray also added a new dimension to the debate, suggesting that while Isis had shown that knocking down apoB could lower LDL levels, an RNAi approach would have “better potency, better durability, [and the ability to] knock down apoB and LDL more rapidly” than an antisense one.

In moving ahead with an LNA-based drug targeting apoB, Santaris has added a third technology to the mix.

Q3 Loss Narrows

For the three-month period ended Sept. 30, Denmark-based Santaris said its loss narrowed 31 percent to DKK26.9 million ($5.3 million) from DKK39.1 million one year ago.

Revenues slipped to DKK15.6 million from DKK24.7 million, but this decline was more than offset by a nearly 28 percent drop in R&D costs to DKK35.4 million, which reflects the impact of a recent corporate refocusing onto metabolic and infectious diseases, and the divestiture of its cancer activities.

Administrative costs, meanwhile, edged up slightly in the quarter, to DKK6.7 million from DKK5.3 million.

At the end of the third quarter, Santaris had cash and cash equivalents totaling roughly DKK179.9 million, which it said is “expected to be sufficient to finance [its] operations beyond 2010.”

Looking ahead, Santaris said it anticipates an end-of-the-year loss in the range of DKK90 million to DKK100 million.

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