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RNA interference has tremendous potential to revolutionize therapeutics as we know it. Even though there has been exponential rise in the development and understanding RNAi at the level of Research and Development inside the laboratory, there is no denying that the field is still naive and in its raw stages in the industry. The First Phase - The Discovery Phase (2002-05) The first phase of RNAi in the industry, the discovery phase was defined by the early adopters of RNAi as a therapeutic modality following the discovery of RNAi in human cells. These were small, risk-taking biotechnology companies such as Ribozyme Pharmaceuticals (aka Sirna Therapeutics), Atugen (aka Silence Therapeutics) and Protiva (aka Tekmira). As much as they may have believed in the potential of RNAi therapeutics, their strategic reorientation was also a gamble on a technology with considerable technical uncertainties in order to turn around declining business fortunes by leveraging their nucleic acid therapeutics know-how to become leaders in a potentially disruptive technology. This phase also saw the founding of Alnylam Pharmaceutical based on the idea of cornering the IP on the molecules that mediate RNAi (RNAi triggers) so that it may finance its own drug development by collecting a toll from all those engaged in RNAi therapeutics. The Second Phase - The Boom Phase (2005-08) Till the end of the first phase of RNAi therapeutics, larger pharmaceutical companies like Big Pharma, saw the value of RNAi largely as a research tool only. This perspective, however, changed quickly when a few of them, including Medtronic, Novartis, and Merck, were seen by their peers to take an interest in RNAi as a therapeutic modality. The defining feature of the second, boom phase of RNAi therapeutics, was the impending patent cliff and the hope that the technology would mature in time to soften its financial impact. A bidding war, largely for access to potentially gate-keeping RNAi trigger IP erupted. Most notably, Merck and Roche paid US$1.1B for acquiring Sirna Therapeutics and US$300M+ for a limited platform license from Alnylam, respectively. These deals were only rivaled in attention by the award of a Nobel Prize to Andrew Fire and Craig Mello for their seminal discovery of double-stranded RNA (dsRNA) as the trigger of RNAi. The industry naturally did not mind the attention and in some cases fanned the fire by raising unrealistic expectations. This atmosphere also gave rise to controversial publications in high-profile journals which lent credence to the mistaken notion that the technical barriers to exploiting the RNAi trigger IP would be low. The Third Phase - General Backlash (2008-11) It is not surprising that the period of high expectations and blockbuster deals was followed by general backlash, the financial consequences of which were exacerbated by global economic turmoil and healthcare rationing in the West. Roche, a year after their IP license from Alnylam, felt compelled to pay US$125M for Dynamic PolyConjugates from Mirus Bio, one of the more promising and differentiated delivery technologies, for which, however, significant risks related to translation into organisms beyond rodents and manufacturing/scale-up remained. As much as delivery, it was the potential of certain RNAi formulations to stimulate innate immunity that caused much of the scientific angst that contributed to the deteriorating business sentiment in 2008. It almost came to be assumed that an in vivo RNAi efficacy claim was in fact an innate immunostimulatory artefact. Making matters worse still, innate immune stimulation is a safety issue. Although today innate immunostimulatory potential is widely considered to be manageable through chemical modification and choice of RNAi trigger structure, the reputational damage persists. Suffering from RNAi-specific scientific and credibility issues and with first drug approvals still years away, RNAi therapeutics was among the first to feel the cost-cutting axe at companies like Pfizer, Merck, Abbott Labs, and Roche which all started to suffer from patent expirations, drug approval and productivity issues, worsening drug reimbursement climates, and the general loss of confidence in their innovative abilities. Particularly the exit of Roche from in-house RNAi therapeutics development sent shockwaves through the industry. Having invested heavily in the technology only 2–3 years ago and being considered an innovation bellwether within Big Pharma, Roche’s decision in late 2010 found a number of imitators among Big Pharma and has been functioning as a major barrier to new investments in RNAi therapeutics. The Fourth Phase: The Recovery Phase (2011-present) The backlash also had cleansing effects which form the basis for the fourth - recovery phase of RNAi therapeutics. As a result of the financial restrictions and increased scientific scrutiny, there has been an overall increase in the quality of the science. RNAi therapeutics has also become less of a target for the quick-rich biotech schemes that constantly chase the next hot area in drug development. This quality shift is most evident in the evolution of the RNAi therapeutics clinical pipeline which has become more and more populated with candidates based on sound scientific rationales, especially in terms of delivery approaches and anti-immunostimulatory strategies. For the recovery, however, to firmly take root and for the long-term health of the industry, it is important for the current clinical dataflow to bring back investors [59]. Downloads | Glossary | References | Contact © 2012, Saie Mogre. All Rights Reserved. |
