LAS VEGAS — Despite some recent setbacks, including ones in the RNAi field, oligonucleotide therapeutics are still likely to become the third major drug-development platform alongside small molecules and biologics in a matter of a few years, according to Art Krieg, the former CSO of Pfizer's oligonucleotide therapeutics unit and current president and CEO of RaNA Therapeutics.
Krieg's statements, made during a keynote presentation at this year's Tides: Oligonucleotide and Peptide Research, Technology, and Product Development conference in Las Vegas, echo similar sentiments expressed by Isis co-founder Frank Bennett last month (GSN 4/19/2012).
Krieg, however, took a somewhat more ambitious stance, predicting that “by 2015, people will be talking generally about how oligonucleotides are a third platform for drug development.”
Thus far, oligonucleotide medicines have traveled an uneven path, he noted, with just two drugs approved — Isis Pharmaceuticals' antisense-based cytomegalovirus retinitis treatment Vitravene and OSI Pharmaceuticals' aptamer-based wet age-related macular degeneration agent Macugen — despite an estimated $10 billion invested in research and development since the mid-1980s.
On top of this, neither drug has proven to be a “significant commercial success,” Krieg noted. At the same time, a number of big pharmas have exited the oligo drugs space, particularly as it relates to RNAi. These include Roche and Pfizer, which both ended their in-house efforts with the gene-silencing technology over the course of a few months in late 2010/early 2011.
“So, there is a very well-justified perspective on the part of many in the field that oligonucleotides are not a validated platform for drug development,” he said.
Yet key pharmaceutical players have quietly maintained their RNAi programs. Some examples are Merck, which expects to move an siRNA drug into human testing by 2013 (GSN 12/8/2011), and Novartis, which continues to work on RNAi targets covered under its now-ended alliance with Alnylam Pharmaceuticals.
And even those companies that no longer play in oligo drugs directly have kept an eye on the field, notably Pfizer, which late last year acquired Isis spinout Excaliard for its phase II antisense skin scarring treatment EXC 101.
“As products are being developed, pharmas are going to look at the data and commercial opportunity, and if it is an oligonucleotide or not an oligonucleotide, they can be interested,” Krieg said.
Overall, the oligonucleotide therapeutics field is experiencing a pattern of growth common to any new field of drug development wherein “pharma partners get incredibly excited, see the vast potential, [and] don't yet see any of the pitfalls” ahead, he explained. “Once they do see … the challenges of the new field … they overreact in the opposite direction. Finally, as the pitfalls are better understood and pathways forward emerge, we see resurging enthusiasm.”
With oligos, “we're really getting into that third phase” now, Krieg said.
The difficulties thus far encountered by the field are par for the course, he added. Drawing parallels with the early days of therapeutic antibody development, he noted that ”you can have an outstanding platform technology, [but] it still takes waves of new discoveries to actually have it reach its full maturity as a [validated] platform that is going to contribute to drug discovery.”
Ultimately, true validation is only achieved through commercial success, but there are already signs that such milestones are on the horizon for the oligo field.
For instance, Isis' cholesterol-lowering anisense drug mipomersen has now been filed with US and EU regulators after being partnered with Genzyme, and Dynavax Technologies recently began ramping up a sales infrastructure in anticipation of US approval of its hepatitis B treatment Heplisav, an immunostimulatory DNA sequence and hepatitis B surface antigen combo.
Alnylam has generated phase I human proof-of-efficacy data with its liver-directed siRNA-based hypercholesterolemia agent ALN-PCS (GSN 4/26/2012), while advances have been made in delivery to tissues outside of the liver such as muscle, with Prosensa and partner GlaxoSmithKline reporting positive phase II data with the splice-altering oligo PRO51 for Duchenne muscular dystrophy.
And on the microRNA front, Santaris Pharma has reported efficacy data with its phase II hepatitis C drug miravirsen (GSN 4/26/2012).
All the while, next-generation chemistries are proving capable of boosting efficacy while eliminating adverse effects, and Krieg anticipates a number of other “game-changing innovations” coming in the next few years that could further advance the oligo medicines field.
These include the ability to either avoid or escape endosomal entrapment of oligos, which could boost drug potency 100-fold, or ways to avoid plasma protein-binding to improve pharmacokinetics.
But even without these kinds of breakthroughs, Krieg said, “where we are today, we can see the validation of oligonucleotides as becoming the third platform for drug development after small molecules and biotherapeutics within the next few years.”