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Otsuka Integrates RNAi Drug Research into Development Operations, Quietly

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While Merck made headlines for striking big pharma’s first collaboration with an RNAi therapeutics firm, it turns out that another traditional drug developer had already embraced the field on its own. Privately held Japanese pharmaceutical firm Otsuka Pharmaceutical Co. Ltd. recently began pursuing the development of RNA interference-based drugs — in part due to the efforts of one of its scientists — and is now hoping to identify a disease against which to apply the technology in the next six months, RNAi News has learned.

Prior to the start of this effort, Otsuka had focused on small-molecule drugs, but these kinds of medicines often carry significant side effects, Zafar Randawa, senior director of new technology evaluation and R&D alliances for Otsuka, told RNAi News. “We believe that the best way to avoid side effects or non-specific effects is to carefully develop drugs which will do the jobs you want and not interfere in many of the metabolic pathways.”

In recent years, gene therapy and antisense offered the promise of this kind of highly specific treatment, he said, but efforts to develop these approaches have been mostly unsuccessful.

Gene therapy’s setbacks are well-known, Randawa said, citing the development of leukemia in two children taking part in a recent clinical trial in France that evaluated gene therapy for X-linked severe combined immunodeficiency.

As for antisense, Randawa said that while it started out as “a beautiful idea,” it became clear to Otsuka that the technology was not quite ready for prime time.

“We were looking at antisense as a refined version of gene therapy,” he said. “We knew it was a good experiment to do in the laboratory, but at the human level, we felt you’d have to overcome many hurdles … before [antisense] would see any success.”

Otsuka didn’t pursue programs with either of these earlier technologies, according to Randawa. But now, despite its seemingly conservative approach, the company has made a leap that virtually all other drug makers have not: advancing its RNAi activities beyond target validation into actual therapeutics development.

“For the last five years, we have been using RNAi to validate drug targets,” Randawa said. “It is a remarkable tool in the laboratory and some of the people [at Otsuka] who use this still believe that this is the only good [use] of RNAi. But these people are too much influenced by the failure of gene therapy and antisense.” People with this view, he added, are not unique to Otsuka and can be found at almost all other pharmaceutical companies.

Indeed, this may very well be the case. Gary Van Savage, director of technology licensing at Johnson & Johnson, recently told RNAi News that his company is circumspect about the use of RNAi beyond target identification and validation purposes and is concerned that the use of viral vectors commonly seen in RNAi experiments has the potential to cause a host of problems if carried over into humans (See RNAi News 9/19/2003). Even Merck has made sure it won’t end up getting its hands dirty: The deal with Alnylam is structured so that the actual effort of developing preclinical RNAi compounds is shouldered by Alnylam, with Merck having the option of either getting involved with later-stage work on the drugs or passing on them altogether.

But Otsuka researcher Kazuo Sekiguchi championed the RNAi-as-therapeutics cause, petitioned the company’s management for the resources to look into the viability of RNAi as a therapeutic technology, and was ultimately given the green light to do so, Randawa said.

About six months ago, the company began conducting very early-stage RNAi-as-therapeutics work, he said, and is now trying to perfect methods of transfecting siRNAs into proprietary cell lines and shutting down the production of specific proteins. Once it has done this, Otsuka will begin evaluating RNAi drug-delivery vehicles. “We have a preference for non-viral vectors,” Randawa added. “But you always owe yourself, in a good scientific experiment, to try all approaches.”

After this preliminary work is complete, he said, Otsuka plans to identify a disease target for RNAi-based drug development. This is expected to happen in the next six months. Although the company has not settled upon an indication for its first program, Randawa said that he expects viral diseases, namely hepatitis C and HIV, will be “the first to enjoy some application [of RNAi-based drugs], although one cannot rule out the solid tumor.”

Randawa further noted that, in his view, RNAi therapies will not obviate the need for traditional small-molecule drugs.

“RNAi is not going to replace conventional therapy,” he said. “What it will do [is] decrease the synthesis of culprit proteins, which are implicated in a given pathology. Once those protein levels are brought down, the treatment that is being given will be very effective.”

Randawa used the targeting of multiple regions of the hepatitis C virus with RNAi as an example.

“Imagine if you stop viral replication in your body ... what you can achieve — [existing but only partially effective therapies such as] interferon or ribavirin could now be very effective.”

—DM

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