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At this year’s ASCO meeting, researchers reported findings that mark the most encouraging clinical results in the history of RNAi therapeutic development. If later-stage clinical trials produce positive results as well, the data would vindicate small biotech companies that were abandoned by big pharma when times for RNAi-based drugs got tough.

These molecules initially generated enormous excitement in drug development circles, bolstered by the imprimatur of a Nobel Prize in physiology and medicine awarded to discoverers Andrew Z. Fire and Craig C. Mello. The hope was that synthetic siRNAs could shut off expression of disease-associated genes, providing therapies for previously untreatable human diseases ranging from cancer to genetic disorders.

Initially caught up in the excitement of access to an entirely new class of therapeutics to fill withering pipelines, pharma put serious money into RNAi programs. Leading the acquisition pack, Merck & Co. bought research company Sirna Therapeutics for $1.1 billion in 2006. Investment in RNAi was about $500 million between 2007 and 2010; RNAi pioneer Alnylam Pharmaceuticals alone recorded $57 million in research revenues from Roche.

Over the last couple of years, though, big pharma has bailed out of backing RNAi-based therapeutics. Mounting technical difficulties, especially delivery issues and immunogenicity, with the molecules were cited as the main reason. Clinical results making their way out of development programs may help assuage some of these concerns, as might the settlement of patent litigation involving Alnylam, Max Planck Society, the Whitehead Institute for Biomedical Research, and the University of Massachusetts (UMass).

To attract big pharma back, though, late-stage results will need to validate early clinical success. As the RNAi therapeutic field comes closer to reality, however, it will likely have to survive further lawsuits, as is the situation with the recently filed case against Alnylam by manufacturing partner Tekmira; Alnylam was among presenters at ASCO touting good news for RNAi with its candidate that uses Tekmira technology.

Big Pharma's Entry and Exit

As big pharma reconsidered its love affair with RNAi-based drugs, small companies cut back on programs and personnel. Five years after Merck’s mega purchase of Sirna, the biotech firm’s technology is being primarily used for laboratory studies rather than searching for the next blockbuster therapy.

Pharma’s attack of cold feet also hurt RNAi pioneer Alnylam Pharmaceuticals. The company said it planned to cut about 25 to 30 percent of its workforce as one of its pharma partners, Novartis, terminated a five-year alliance with it.

Last February Pfizer announced that it was dropping its therapeutic RNAi drug development work as part of a global R&D restructuring plan aimed at saving the company $1.5 billion. Also last year, in November, Roche said that it would close down RNAi research at three sites: Kulmbach, Germany; Madison, WI; and Nutley, NJ.

Roche had paid Alnylam $331 million in cash and equity for the Klumbach facility in 2007 as part of an agreement that included RNAi drugs for oncology and respiratory diseases. In 2008, Roche took over Mirus Bio for $125 million. The deal gave it the site in Madison, 20 employees, and an siRNA delivery system based on polyconjugate technology.

Then, in 2009, Roche paid $18.4 million up front to use Tekmira’s lipid nanoparticle (LNP) delivery technology to put its RNAi products into the clinic. The goal was to get its first RNAi-based product into the clinic by the end of 2010.

Instead, Roche is effectively out of the RNAi drug development business. The company said that there were ongoing challenges with cell-specific delivery and that the most promising indications for the technology were not part of its strategy.

Positive Early-Stage Data

Despite pharma’s defection from the space, small companies developing siRNA drug molecules are beginning to see glimmers of success, and business deals continue to go forward. As Pfizer left the space in 2010, Marina Biotech announced a product-specific development deal with Debiopharm.

The agreement covers a preclinical-stage bladder cancer program based on the topical delivery of LNP-siRNs. Marina will perform the early development work, funded by Debiopharm, and has the potential to earn milestone-based fees and royalties.

At the 2011 ASCO meeting, Silence Therapeutics reported positive data from its ongoing Phase I study of Atu027 in patients with advanced solid tumors. It is a liposomal siRNA formulation targeting PKN3, which is reportedly a key regulator of angiogenesis and lymphangiogenesis as well as metastasis and motility during pathological processes.

Data showed that nine of the 24 patients treated with the molecule achieved stable disease after repeated treatment. Six of these cases were confirmed at study end (three months after treatment initiation), and three other patients are continuing to receive treatment.

At the same meeting Alnylam reported results from a Phase I trial with its ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. Data showed that ALN-VSP was generally well tolerated, demonstrated evidence for anti-tumor activity, and was found to mediate RNAi activity in both hepatic and extra-hepatic tumors. The study demonstrated evidence of antitumor activity in heavily pretreated patients at doses of 0.7 mg/kg. Disease stabilization occurred in 64% (7 of 11) of patients who received the recommended Phase II dose of 1 mg/kg.

ALN-VSP comprises two siRNAs designed to target two genes required for the growth and development of cancer cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP), also known as eglin 5 (Eg5). The siRNA drug is formulated using a first-generation lipid nanoparticle developed by Tekmira Pharmaceuticals, Alnylam’s manufacturing partner for LNPs for RNAi drug delivery.

“At a high level, this was a first-in-human study in refractory cancer patients with metastatic disease, including liver involvement,” Akshay Vaishnaw, M.D., Ph.D., Alnylam’s svp of clinical research, pointed out to GEN. “The drug’s safety profile was very encouraging, but beyond safety, we got a lot of interesting mechanistic information.

“We did a series of DCE-MRI tests on the patients before and after treatment. This type of study allows visualization of blood flow through tumors. Since one of the drug components was an anti-VEGF siRNA, we wanted to monitor its effects. We found that 13 of the 28 study patients had a greater than 40 percent reduction in tumor blood flow, which is very comparable to other anti-angiogenic agents.”

Dr. Vaishnaw explained that the investigators also looked for evidence of specific mRNA cleavage in liver biopsies from patients taken before and after treatment. “We could show target mRNA cleavage in tumor biopsies that was present after but not before treatment,” he noted. “That is a very important molecular proof-of-concept for the field of RNAi therapeutics.”

Dr. Vaishnaw also commented on the lipid nanoparticles used in the drug formulation. “We have shown that LNPs provide a tractable way to achieve siRNA delivery. We think that bodes well for other areas of the platform, where we will use these particles for other siRNA applications.”

Alnylam’s drug candidate for transthyretin mediated amyloidosis, ALN-TTR01, uses the same LNP but has an siRNA directed against transthyretin. The company expects data from its Phase I study with ALN-TTR01 in the third quarter of this year. Finally, Alnylam has a Phase II-stage RNAi therapeutic called ALN-RSV01, which is being tested in lung transplant patients infected with respiratory syncytial virus.

Will Lawsuits Hamper R&D?

Alnylam, however, has more than just clinical development challenges on its plate. It will have to get through a lawsuit filed by Tekmira after having just settled another case regarding the Tuschl patents. The firm signed a global settlement agreement with Max Planck Society, Whitehead Institute, and UMass. MIT, formerly a party to the litigation, also agreed to the terms of the settlement.

As part of the settlement agreement, Max Planck, Whitehead, UMass, and MIT have agreed that future prosecution of the Tuschl I and Tuschl II patent families in the U.S. should be coordinated and led by a single party. Max Planck will assume that role, in addition to its ongoing leadership in the continued prosecution of the Tuschl II patent family outside the U.S. Importantly, UMass received the right to license Tuschl II to Merck/Sirna with certain limitations and to prosecute Tuschl I outside the U.S.

Now, however, Alnylam will have to contend with litigation around the LNP technology it uses to deliver its siRNA drugs. Tekmira said the suit was filed in response to “misappropriation and misuse of trade secrets, know-how and other confidential information, unfair and deceptive trade practices, unjust enrichment, unfair competition, and false advertising.”

Tekmira is seeking what could amount to more than $1 billion from Alnylam. Alnylam filed a legal response and counterclaim against Tekmira, saying that it plans to “fully defend itself.”

So while 2011 has looked like a validating year for RNAi technology, with the advent of clinical results and one major patent dispute getting settled, there is still concern over lawsuits that could crop up around enabling technologies. Additionally, small companies developing siRNA drug molecules or focused on delivery systems are trying to soldier on despite big pharma’s dysfunctional planning processes.

It is hoped that no one involved will get so distracted with all this tap dancing that much needed novel drug development fails to proceed, which would leave shareholders and patients alike holding a bag of hot air. Maybe pharma companies who bailed out saw it coming.