{"id":4458,"date":"2016-07-07T13:15:00","date_gmt":"2016-07-07T13:15:00","guid":{"rendered":"https:\/\/www.waters.com\/blog\/oligonucleotide-therapeutics-on-the-rise-again\/"},"modified":"2022-07-28T03:06:18","modified_gmt":"2022-07-28T03:06:18","slug":"oligonucleotide-therapeutics-on-the-rise-again","status":"publish","type":"post","link":"https:\/\/www.waters.com\/blog\/oligonucleotide-therapeutics-on-the-rise-again\/","title":{"rendered":"Oligonucleotide Therapeutics on the Rise\u2026 Again"},"content":{"rendered":"

Oligonucleotide drug development has seen its share of ups and downs over the past 20 years \u2013 but why?<\/p>\n

The promise of antisense oligonucleotides (ASOs) and later small interfering oligonucleotides (siRNAs) as therapeutics that can \u201cdial down\u201d or even \u201cturn off\u201d the expression of specific genes\/proteins (\u201cgene silencing\u201d) remains high, yet companies dedicated to their development have come and gone, the level of investment across the industry has waxed and waned considerably, and to date only two oligo-based drugs have been approved by the FDA.<\/p>\n

So what\u2019s going on here?<\/p>\n

It\u2019s a question that Dr. Muthiah Manoharan, Senior Vice President for Drug Discovery at Alnylam Pharmaceuticals, Inc., addressed head-on in his keynote talk at the Oligonucleotide Therapeutics and Delivery<\/a> conference, hosted by the Cambridge Healthtech Institute (CHI) on April 4-5th<\/sup> in Cambridge, Mass. Dr. Manoharan provided context around the current state of oligonucleotide based drug\u00a0 development by referencing the \u201cTechnology Curve\u201d (also known as the \u201cHype Cycle\u201d) \u2013 a generalized development pattern that occurs with many new technologies across a range of industries \u2013 and he went on to show how the course of oligonucleotide therapeutic development fits this pattern to a T.<\/p>\n

The \u201cTechnology Curve\u201d or \u201cHype Cycle\u201d<\/strong><\/p>\n

\"559px-Gartner_Hype_Cycle.svg\"<\/a>
Source: Jeremykemp at English Wikipedia, CC BY-SA 3.0, https:\/\/commons.wikimedia.org\/w\/index.php?curid=10547051<\/figcaption><\/figure>\n

As shown in the accompanying image, the Technology Curve is divided into five segments beginning with the \u201cTechnology Trigger<\/strong>,\u201d which spawns commercial development. For oligonucleotides, this \u201cTechnology Trigger\u201d occurred in the mid 1990s, when the promise of antisense oligonucleotides as agents of \u201cgene silencing\u201d really began to take root.<\/p>\n

\u201cPeak of Inflated Expectations\u201d<\/strong><\/p>\n

Next comes a wave of optimism, excitement and investment that builds up to a peak of inflated expectations. For oligonucleotide therapeutics, this peak occurred in the mid to late 2000s after many large pharma and biotech companies had invested heavily in the development of antisense oligonucleotides, and the subsequently discovered RNA interference (RNAi) technologies (siRNA, shRNA, and micro RNA), all of which effect targeted \u201cgene silencing.\u201d<\/p>\n

Prominent examples of this bullishness include Merck\u2019s acquisition of Sirna Therapeutics in 2006 for $1.1 billion, and Alnylam\u2019s receipt of $431 million up front from Roche and Takeda in 2007 for certain rights to their RNAi technology.<\/p>\n

\u201cTrough of Disillusionment<\/strong>\u201d<\/p>\n

Then a sober reality sets in, and the key development challenges that need to be overcome for the technology to be commercialized, and the ever-increasing time and cost estimates to do so begin to overwhelm many. As Dr. Manoharan described, this clearly happened for oligonucleotide therapeutics in the 2009\u20132011 timeframe as scientists struggled mightily with the inherent instability and short half-life of these molecules, and with the equally problematic drug-delivery challenges they pose.<\/p>\n

Early on, drug companies believed that synthetic oligonucleotides could be developed and advanced through the drug discovery funnel much faster than small molecule drugs or proteins, and could therefore quickly bolster their clinical pipelines. When this turned out not to be the case, many became disillusioned and either discontinued their oligonucleotide drug development efforts entirely, or pulled back significantly on their investments, and as a result market expectations bottomed out.<\/p>\n

\u201cThe Slope of Enlightenment<\/strong>\u201d<\/p>\n

Today, however \u2013 as was clearly in evidence at the CHI Oligonucleotide Therapeutics and Delivery conference \u2013 the tide has turned yet again. Oligonucleotides are once again on the rise.<\/p>\n

Dr. Manoharan conveyed his belief that while oligonucleotide therapeutics have been through a rocky and tumultuous period, they are now poised to enter the next segment of the Technology Curve: \u201cThe Slope of Enlightenment.\u201d Thanks to a lot of great development work done by those who have forged on, many of the key challenges with stability and drug delivery have been or are being overcome.<\/p>\n

Oligonucleotides can now be synthesized using 3rd<\/sup> and 4th<\/sup> generation chemically-modified nucleosides that vastly improve their stability, extending their half-life from two days to two weeks or more. And on the delivery side, GalNAc (N-Acetylgalactosamine) conjugation has proven to be a great way of facilitating uptake by liver cells, and Lipid NanoParticles (LNPs) are proving to be highly effective delivery vehicles for many other cell types.\u00a0 There\u2019s even work being done by Avidity, Inc., and others that show lots of promise with conjugating oligonucleotides to antibodies for target delivery.<\/p>\n

In short, the story of oligonucleotide therapeutic development is not an uncommon one. Marked by industry hype and overly-inflated expectations early on, development challenges that were once glossed over eventually led to a wave of disillusionment and contraction.<\/p>\n

In spite of this, organizations committed to the long-term vision and promise of oligonucleotide therapeutics continued to forge on, and because of their ongoing efforts, many of those challenges have been overcome. As a result, the promise of the technology has in a sense been renewed and oligonucleotide therapeutics are now poised for a period of steady advancement and growth.<\/p>\n

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To learn about Waters\u2019 work in analyzing oligonucelotides using LC and LC-MS, visit www.waters.com\/oligos<\/a>.<\/em><\/p>\n

Quick links to recent application notes:<\/p>\n