Innovation of the Year: RNA-targeting therapies
A landmark approval:
In August, Alnylam won the first U.S. OK for an RNAi therapeutic, two decades after Andrew Fire and Craig Mello first sketched out the technology's potential.
Buoyed by the success of Spinraza, Biogen paid Ionis $1 billion to hunt for new antisense blockbusters. J&J and Eli Lilly, meanwhile, have put up hundreds of millions to buy into RNAi.
Approval of Alnylam's Onpattro and Ionis' Tegsedi will raise expectations for further successes. Challenges still remain though and, in some cases, gene therapy could prove more attractive.
In theory, the way Alnylam's newly approved rare disease drug Onpattro works is simple.
Rather than target the protein build-up behind the disease Onpattro treats — hereditary transthyretin amyloidosis — Alnylam's therapy disrupts the genetic instructions that the body uses to make the problematic protein itself. By degrading messenger RNA, Onpattro essentially silences the mutated gene that causes TTR amyloidosis.
The biotech likes to say its approach is "upstream" of how many of the world's top drugs today are designed. But getting gene silencing via RNA interference to work hasn't come easily: Alnylam's spent 16 years and more than $2 billion in R&D to get its RNAi therapeutic across the finish line. Onpattro is the first to ever win approval in the U.S.
While long in the making, Onpattro is the latest evidence of progress in the field of RNA-targeting therapies.
Ionis Pharmaceuticals, a rival of Alnylam, has also been in a decades-long pursuit of medicines that act on RNA rather than on proteins.
Its technology, known as antisense oligonucleotides, works somewhat differently than RNAi and Ionis has successfully secured OKs from the Food and Drug Administration several times. In 2018, the company added another approval to its tally with Tegsedi, which also treats TTR amyloidosis.
"The challenge hasn't been the basic notion," said Stan Crooke, the longtime CEO of Ionis, discussing antisense drugs in an interview with BioPharma Dive. "But actually reducing that to practice has taken 30 years."
Big pharmas have been inconstant companions along that research journey. One of Ionis' first licensing deals, in 1990, was with the Swiss drugmaker Ciba-Geigy, six years before it became Novartis. Others, such as Merck & Co., Roche and Sanofi, would later invest in RNAi.
Setbacks and delays, though, cooled pharma's enthusiasm, spurring pullbacks from RNA-targeting therapeutic research. Now, however, it looks like the titans of the industry are buying back in. Sanofi and Biogen have recommitted to deals with Alnylam and Ionis, respectively, while J&J and Eli Lilly have bet on newer RNA-focused biotechs.
"Does that mean big pharma has outright adopted it like they have antibody technology? No," said Ted Tenthoff, an analyst at Piper Jaffary, in an interview with BioPharma Dive. "But we're certainly seeing more deals."
Pharma interest is suggestive of the wider promise RNA-targeting therapies could hold. To date such treatments have been approved for rare disease, like TTR amyloidosis, Duchenne muscular dystrophy or spinal muscular atrophy.
Recent deals, though, have had broader indications in mind, such as hepatitis B. And Alnylam and Ionis are also separately advancing research in areas like hemophilia, non-alcoholic steatohepatis (NASH) and cardiovascular disease.
Select 2018 deals involving RNA-targeting technology
|Deal between||Terms (paid by first company listed)||Technology||Target(s)|
|Biogen, Ionis||$1B in upfront and equity investment||Antisense oligonucleotide||Neurological diseases|
|J&J, Arrowhead||$250M in upfront and equity investment, as much as $3.5B in milestone payments||RNAi||Hepatitis B|
|Alexion, Dicerna||$37M in upfront and equity investment, as much as $600M in milestone payments||RNAi||Complement-mediated diseases|
|Eli Lilly, Dicerna||$200M in upfront and equity investment, as much as $3.5B in milestone payments||RNAi||Cardio-metabolic, neurodegenation and pain|
As with all biotechnology, success in the lab just opens the door to questions on marketability. There, the early returns for RNA-targeting therapies are very much mixed.
Two early Ionis drugs — a treatment for cytomegalovirus retinitis approved in 1998 and a cholesterol medicine OK'd in 2003 called Kynamro — were both later pulled from market in the U.S.
By contrast, Biogen's Spinraza, which was developed by Ionis and approved in late 2016, has become a clear commercial success. Through the first nine months of 2018, sales of the spinal muscular atrophy drug surpassed $1.2 billion.
Another drug, Exondys 51 for Duchenne's, has had more modest sales, while Onpattro's first three months on the market earned Alnylam only $500,000.
Those data points are few, but it's clear that the broader system is becoming more accustomed to the idea of RNA-targeting therapies.
"It's not only the FDA that's more comfortable [with RNA-targeting therapies], but the specialists who administer these drugs, the payers," said Pipper Jaffray's Tenthoff. "Everybody's becoming more comfortable, more educated with the technology."
Questions on safety could slow adoption, however. Ionis' Tegsedi comes with a black box warning on the risk of low platelet counts while another of its antisense drugs, Waylivra, was rejected in August.
And not everyone is comfortable with the price of the most prominent therapies approved to date. Spinraza costs $750,000 for the first year of use, and $375,000 thereafter. Tegsedi and Onpattro, meanwhile, list at annual prices of $450,000 per patient.
All three are approved for diseases that affect very small groups of patients, even within the broader umbrella of rare disease. Still, the prices are part of a broader wave of costlier, more advanced therapies arriving on market.
Close on the horizon, for example, are a handful of treatments that work by replacing defective, disease-causing genes with functional copies, acting on DNA rather than RNA.
In some cases, gene therapy progress could potentially outflank RNA-based treatments, such as with Spinraza and Exondys 51, or in hemophilia.
An experimental gene treatment bought by Novartis earlier this year, for example, could arrive on market next year for patients with the most severe form of spinal muscular atrophy. If successful, it could pressure Spinraza. And down the road, gene-editing technology like CRISPR could bring further upheaval.
Still, the threat to RNA-targeting therapies broadly may be less zero sum than some on Wall Street fear.
Mark Kay, a professor of genetics at Stanford University, believes that even in areas where RNA-targeting therapies and gene therapies might eventually co-exist there will be room for multiple technologies.
"There will be patients who are not amenable to getting the current AAV vector because of pre-existing immunity," explained Kay in an interview with BioPharma Dive. "There may be patients who don't get a therapeutic dose, and you can't re-dose the vector because people develop antibodies."
With the success of Ionis, Alnylam and others, RNA-targeting therapies are becoming very much a part of the therapeutic landscape. A core promise of RNA interference or antisense oligonucleotide technology, however, is more efficient drug discovery. In that respect, the field still has much to deliver.
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