A whole new class of human therapeutics

RNA interference, believe John Hastewell and John Maraganore, is at the heart of that innovation.

By Julia Puppe

The discovery of ribonucleic acid interference (RNAi) goes back to observations made in the plant world in 1990. While trying to deepen the purple color of petunias, Richard Jorgensen, PhD, then at DNA Plant Technology in Oakland, and colleagues introduced a pigment-producing gene under the control of a powerful promoter. The result was the exact opposite from what they were anticipating. Instead of a deeper purple, the petunias bloomed white due to post-transcriptional gene silencing. Jorgensen named the observed phenomenon “cosuppression”.

In 1998, the scientists Andrew Fire and Craig Mello extended this observation in a worm genetic study and discovered that the process of RNAi, which they coined as a term, was a process that was mediated by a long double-stranded RNA molecule. A landmark paper lead to them being awarded the Nobel Prize in 2006.

In 2001, Thomas Tuschl showed that the RNAi Fire and Mello observed in worms could be replicated in mammalian cells. In addition, this phenomenon could be employed using synthetic short double-stranded RNA molecules called small interfering RNA (siRNA) to selectively and very potently silence a gene in a mammalian system. This opened up the potential that this gene silencing technology could be used to develop a whole new class of human therapeutics to treat diseases in a fundamentally new way.

With this vision, a group of venture capitalists led by Polaris Ventures and Cardinal Partners brought together a number of the key pioneers in the field of RNAi (including Tuschl) and formed Alnylam in June 2002. And you better be nice to them: in the early days of the company, it effectively and proactively consolidated key patents and patent applications. These, believes John Maraganore, Alnylam’s President and CEO, are ultimately going to be required by every company developing and commercializing RNAi therapeutics. Their only publicly traded competitor in the US, Sirna Therapeutics, was recently acquired by Merck for $1.1 billion.

Compared to other biopharmaceutical companies, Alnylam is very young. However, in its short existence, the company has been busy focusing on the translation of Tuschl’s important discovery and in the application of that discovery for the development of human therapeutics.

“It’s very clear that this technology, while young in some ways, has the potential of transforming medicine. If we can target any gene either from a human origin or from a viral origin with our technology, we can effectively turn off a disease causing protein from being made,” says Maraganore. “Therefore we can effectively target any human disease or any viral infection that causes human disease.”

This, understandably, has widened the eyes of R&D teams in almost every major pharmaceutical company, who are now mutually seeking partnerships with Alnylam.

The future of RNAi depends on its advances

One such partner is Novartis, which was amongst the first pharmaceutical companies to take an early interest in RNAi therapeutics. John Hastewell, Global Head, Biologics Center, Novartis Institutes for BioMedical Research (NIBR), is hopeful that when siRNAs become a standard approach, Novartis will be at the forefront and able to move fast and effectively to capitalize on their investments.

Hastewell has no doubts about the new technology’s potential: “It offers a new therapeutic approach to modulating proteins, using a natural mechanism to knock down the endogenous messenger RNA (mRNA) in a highly specific way. Thus we should be able to target any protein, irrespective of its previous tractability, with a drug that has exquisite selectivity.” Together, Alnylam and Novartis are currently focusing on a number of therapeutic opportunities, including pandemic influenza.

Undoubtedly, RNAi has been transformative and created a high impact. Still, like any other innovative technology, developing RNAi therapeutics involves challenges and does not happen overnight. “The major challenges,” says Hastewell, “are pharmaceutical in nature. Identifying and selecting the sequence capable of the specific effect is relatively straightforward. Guaranteeing safe and effective delivery to the desired site of action are the real challenges.”

Maraganore agrees: “Clearly all technologies require the ability of addressing technical hurdles that are inherent in these technologies. In the case of RNAi, the challenge has been to achieve in vivo delivery of this approach so that we can get to the right cells in the right tissues, where our drugs can do what they need to do.”

Addressing these challenges, Alnylam has already made some major accomplishments. In March 2006, the company’s scientists were able to silence a disease-causing gene involved in hypercholesterolemia in primates and achieved an over 85 percent reduction of LDL cholesterol, the so-called bad cholesterol. About one month ago, the study was updated and showed that a single injection of the drug could reduce the LDL cholesterol level for about a month.

However, there are no marketed siRNA drugs as yet and only four have entered clinical trials so far. These include Alnylam’s RSV program and three other drugs that are focused on ocular disease applications. How long will it take for siRNA drugs to enter the market? “Some time,” says Maraganore, “because the drug development process is a lengthy process. I would expect that by the end of this year, there will be as many as 10 RNAi therapeutics in clinical development.” The timeframe for a drug to enter the market from the point at which it has entered clinical development ranges, depending on the disease indication, from five to seven years, which means that the first drugs based on RNAi could enter the market as early as 2011.

Maraganore hopes that over the next 12 to 18 months, clear human efficacy results will begin to demonstrate the potential of this technology in the clinical setting. In 2004, Alnylam scientists published key data showing that RNAi works in mice. In 2006, they proved that this technology works in primates. “We have obviously entered our drugs into clinical testing but to date we have been evaluating the safety of these drugs. We expect that in 2007 or 2008 this technology will demonstrate efficacy – clear activity in a human disease setting. So we are hopeful and believe quite importantly that this is the next major milestone for this technology as it advances,” says Maraganore.

At Novartis, the future of RNAi is linked to these advances. “The degree of focus we put on RNAi drugs will depend on the success in the clinic and the extent to which the natural tropisms limit or offer opportunities. As a large pharmaceutical company, we will continue to build a diversified portfolio including siRNA and also antibody, protein and low-molecular-weight (LMW) therapeutics as required by the unmet medical need,” foresees Hastewell.

At Alnylam scientists will be working on optimizing their technology to improve delivery of these therapeutics. “One of the most critical features of our business has been the consolidation of intellectual property. We have achieved a very rich and unparalleled intellectual property estate. Any company developing RNAi therapeutics is either today an Alnylam partner or will be an Alnylam partner in the future,” predicts Maraganore with confidence.

John Maraganore
John Maraganore became President and CEO of Alnylam in 2002. In only five years, his company has built between $700 and $800 million of market value.

John Hastewell
John Hastewell is Head of the NIBR Biologics Center. He has experience of thrombosis, respiratory and immunological drug discovery.

John Maraganore: “Any company developing RNAi therapeutics is either today an Alnylam partner or will be an Alnylam partner in the future”

John Hastewell: “When siRNAs become a standard approach we will be at the forefront and able to move fast and effectively to capitalize on our investments”