NEW YORK (GenomeWeb) – Roughly four months after Roche acquired Santaris Pharma, the locked nucleic acid drugmaker — now known as Roche Innovation Center Copenhagen (RICC) — has transitioned into the centerpiece of the Roche's return to RNA therapeutics.
And while RICC is tasked primarily with discovering targets and developing new LNA-based drugs against them, it has already yielded its first clinical candidate in one of Santaris' existing drugs, according to a company official.
As RICC, Santaris now acts as Roche's discovery unit for RNA therapeutics, working with the various arms of Roche's Pharma Research and Early Development (pRED) group to identify targets and discover LNA-based drugs that fit into the company's various diseases of interest, Henrik Orum, RICC head and former Santaris CSO, told GenomeWeb.
"The idea is to implement RNA … as a therapeutic modality as broadly in the Roche therapeutic areas as possible," he said, noting that Roche already has capabilities in antibodies and small molecules.
Although Roche made huge investments in the RNAi space several years ago, the company sold off these assets after finding the delivery hurdles facing siRNAs and other double-stranded RNA molecules too high.
But given the maturity of antisense technologies and the relative ease with which antisense oligos can be delivered, Roche views LNAs as having near-term potential — so much so that it has already opted to bring one of Santaris' LNA cancer drug candidates into its own pipeline, Orum noted.
Specifically, Roche has decided to continue working on Santaris' LNA-based antagonist of hypoxia-inducible factor-1 alpha (HIF-1 alpha), a transcription factor that is overexpressed in many cancers and plays a role in tumor metastasis and angiogenesis.
Formerly known as SPC2968, the drug — now called RG6061 — was previously under development with Enzon Pharmaceuticals, but Santaris regained full ownership of the compound last year when that partnership ended.
"HIF-1 alpha, as a target, has caught the imagination of the medical community for many years," Orum said. "But being a transcription factor, it's been difficult to get at with small molecules … [or] antibodies. Our particular modality is clearly a means of reaching that target, and we will see when the clinical trials read out whether we can actually achieve that and have the expected clinical benefit."
RG6061 had previously completed two Phase I trials in solid tumor patients under the Santaris/Enzon alliance. Although Orum declined to provide details on the drug's status at Roche, the company lists it as under Phase I development on its website.
Meanwhile, Roche continues to evaluate Santaris' other drug candidates, including the Phase II microRNA-122 inhibitor miravirsen, which was being developed to treat hepatitis C, according to Orum. However, a number of factors suggest that miravirsen, while ground-breaking as the first ever miRNA antagonist to move into humans, might not make the cut.
Firstly, the competitive landscape for HCV has changed significantly in recent years as a number of highly effective treatments have come to the market.
Secondly, miRNA drug shop Regulus Therapeutics recently released robust Phase I data on its own miR-122 inhibitor for HCV, showing that a single dose of the drug led to an average 4.1-log reduction in patients' viral loads, putting it on par with existing therapies. In comparison, available clinical data on miravirsen showed that that drug could achieve a maximum of a 2.73-log reduction in viral load after four weekly doses.
Lastly, miRNAs as drug targets are, for the most part, "currently insufficiently validated for industry to take an interest … [and] also are competing with a lot of highly validated messenger RNAs for attention," Orum said.
Though not commenting on miravirsen or miR-122 specifically, he added that "it's somewhat of a challenge to find a microRNA where the dataset is sufficient to warrant a full-scale drug discovery and development effort." However, should one of Roche's discovery and translational areas find that a miRNA makes sense as a drug target, RICC has the expertise to develop an LNA-based compound against it efficiently, he said.
Despite the high-profile departure of several key pharmaceutical players, including Roche, from the RNAi space in 2010/2011, Roche's January acquisition of Santaris for $250 million upfront and up to $200 million in milestone payments reflects a broader renewal of interest in RNA therapeutics by the industry.
For instance, Pfizer in late 2011 announced its acquisition of privately held antisense firm Excaliard, and early this year Genzyme forged a sweeping genetic diseases alliance with Alnylam Pharmaceuticals that included a $700 million equity purchase.
Moderna Therapeutics, which is developing mRNA-targeting drugs, signed a $240 million partnership with AstraZeneca in 2013, and just last month BioMarin Pharmaceuticals agreed to pay $680 million to buy Prosensa Holding, which is developing exon-skipping and antisense therapeutics.