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Alnylam 'Highly Likely' To Name TTR Amyloidosis Rx as Its Next IND Candidate

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SAN FRANCISCO — If Alnylam Pharmaceuticals meets its goal of filing at least one investigational new drug application this year, it is "highly likely" that the company will move forward with its TTR amyloidosis program rather than those in hypercholesterolemia and Huntington's disease, a company official told RNAi News this week.

Speaking on the sidelines of Cambridge Healthtech Institute's RNA Interference Summit held here this week, Alnylam Vice President of Drug Discovery Muthiah Manoharan also provided additional details on the company's choice of proprotein convertase subtilisn/kexin type 9 over apolipoprotein B as the target for its cholesterol program, indicating that safety concerns played a role in the decision.

In early 2008, Alnylam unveiled a series of goals to reach by the end of 2010, including having at least four RNAi therapeutic programs into clinical trials (see RNAi News, 1/10/2008).

Thus far, the company has a treatment for respiratory syncytial virus in phase II development (see RNAi News, 6/11/2009) and recently began a phase I study of its liver cancer therapy ALN-VSP (see RNAi News, 4/9/2009).

In January, Alnylam said that it is on track to file at least one IND this year, with the likely candidates being its PCSK9-targeting hypercholesterolemia drug ALN-PCS, ALN-HTT for Huntington's disease, or ALN-TTR for TTR amyloidosis (see RNAi News, 1/15/2009).

But this week, Manoharan said that Alnylam would likely file the IND for ALN-TTR since the firm views the delivery hurdle for this drug to be lower than for ALN-PCS or ALN-HTT.

On Huntington's disease, for example, Alnylam is collaborating with medical device giant Medtronic to develop an implantable infusion pump capable of delivering therapeutic siRNAs directly to the site of disease (see RNAi News, 8/2/2007) — an approach novel to the RNAi field.

But for ALN-TTR, Alnylam will use partner Tekmira Pharmaceuticals' stable nucleic acid lipid particle delivery technology, which is already being used in its liver cancer program, Manoharan said.

And although SNALPs could potentially be used in the PCSK9 program, Manoharan noted that Alnylam prefers to wait for further refinements to its own stable of delivery technologies, which also includes the so-called lipidoid technology being developed with researchers from the Massachusetts Institute of Technology (see RNAi News, 3/12/2009) and an as-of-yet undisclosed in-house technology.

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As with many other metabolic diseases, hypercholesterolemia requires chronic, long-term treatment, he noted. And because it is not a life-threatening condition for which greater risk can be taken in order to achieve a therapeutic benefit, "we have to set for ourselves higher standards," he added.

Fatty Liver

In taking aim at hypercholesterolemia, Alnylam had been initially pursuing apoB, a protein involved in cholesterol metabolism, 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).

But Alnylam ultimately passed on apoB to pursue PSCK9, a protease that degrades the cell-surface receptor for low-density lipoprotein, citing the extensive body of literature supporting its potential as a drug target (see RNAi News, 12/7/2006).

The move, meanwhile, freed Alnylam partner Tekmira to go after apoB in its own hypercholesterolemia program, which was just cleared to enter the clinic (see RNAi News, 5/7/2009).

Last month, Alnylam CEO John Maraganore called PCSK9 a more "compelling" target than apoB in light 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 (see RNAi News, 5/14/2009).

But according to Manoharan, safety issues also guided Alnylam's decision, namely the onset of fatty liver disease company researchers observed when apoB is down-regulated.

"With PCSK9, [however,] we don't see the fatty liver phenomenon," he said.

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