Alnylam’s subcutaneous success drives shares to record high

The lack of effective delivery mechanisms for gene silencing RNAi-based drugs has long hampered the huge potential of this therapeutic approach. Progress has been made in the last few years, and data from Alnylam yesterday suggests the company has made another big step forward, with success with its first subcutaneously delivered product.

The Massachusetts company revealed very impressive efficacy in a phase I study of a subcutaneous version of its amyloidosis treatment ALN-TTR, a project that already looked hopeful in intravenous form. The results mean the subcutaneous technology the company has developed can be applied to its other projects, and shares in the company surged 16% to a record high of $43.53 yesterday as investors digested the implications.

Clinically validated

Encouraging pre-clinical data on the company’s GalNAc-siRNA conjugates – the technology that Alnylam has developed to allow its siRNA-based products to be delivered subcutaneously – meant hopes were high for this phase I data in TTR-driven amyloidosis.

No safety or tolerability issues had emerged pre-clinically, and the phase I study also revealed a clean profile – no injection site reactions were seen, for example. The drug also appeared to have an extremely wide therapeutic window.

Akshay Vaishnaw, Alnylam’s executive vice president, said on a conference call yesterday that the data establish that Alnylam now has a “clinically validated platform”.

“We don’t see anything to preclude further development of the GalNAc platform,” he said.

In terms of efficacy the phase I results themselves were very encouraging, showing an 80% “knockdown” of serum TTR protein levels in healthy volunteers. Misfolded versions of the TTR protein, produced by a mutated TTR gene, accumulate in particular parts of the body to cause various forms of amyloidosis. Familial amyloidotic polyneuropathy (FAP), where deposits gather in the muscles, affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC), where damage is done to the heart, affects at least 40,000 people worldwide (Therapeutic focus – Amyloidosis options emerging from Pfizer, Alnylam, May 31, 2012).

ALN-TTRsc is being developed to treat FAC while the intravenous version is in development for FAP. Both products are now heading to phase III. The more advanced FAP product should begin a pivotal study later this year, while Alnylam hopes to get the FAC therapy into phase III next year.

Quite a claim

The TTR protein is produced primarily in the liver; Alnylam believes that these results demonstrate that its GalNAc-siRNA conjugate approach can effectively subcutaneously deliver siRNA therapies to the liver. With this technology and its intravenously delivered therapies, the company is claiming it can effectively silence any gene expressed in hepatocytes.

This is quite a claim, and should it be borne out through more rigorous studies of the amyloidosis products, it will bode well for the remainder of the company’s pipeline. As part of what Alnylam is describing as its “5x15” strategy, it wants to have five RNAi therapeutic products for genetically defined diseases in clinical development, including programmes in advanced stages, on its own or with a partner, by the end of 2015. As well as amyloidosis, the pipeline contains products addressing haemophilia and rare bleeding disorders, acute intermittent porphyria, hypercholesterolemia and iron-overload disorders.

The subcutaneous platform will now be pushed forward across the pipeline, where possible.

After years at the fringes of drug research, Alnylam is making RNAi look do-able. Investors will not be the only ones looking interested right now – partners, which are explicitly being sought, will also be sitting up and paying attention.

The path forward for Alnylam is unlikely to be completely straightforward, but it seems that real progress is being made.

To contact the writer of this story email Amy Brown in London at [email protected] or follow @AmyEPVantage on Twitter.

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