Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

As a pioneer in RNAi therapeutics, Alnylam has really had some ups and downs over the years (some of them chronicled on this blog). Today would be one of the “up” moments, for sure. The company (in collaboration with Sanofi) has just announced positive Phase 3 data on their therapy for hereditary ATTR amyloidosis – the RNAi, patisiran, met the primary and secondary endpoints with what look like solid numbers. This is the first time that an RNA interference therapy has made it all the way through clinical trials, so that’s a landmark. The company plans to file for FDA approval early next year.

It’s worth thinking back a bit to the earlier days of both Alnylam and RNAi. At one point about fifteen years ago, this was the hottest area in biotech, with everyone piling into it. Then came the backlash – several backlashes, actually, with some of the larger companies pulling out of the field completely and writing off their investments in it. Alnylam has stuck with it the whole way, and in light of this recent discussion of drug development costs, Andy Biotech on Twitter estimates that they’ve spend at least $1.9 billion along the way (and I think that’s not including opportunity costs/cost of capital, either).

Alnylam’s most recent Phase III trial also ended suddenly just last month, when an RNAi for hemophilia had to be dropped (update: put on hold) after a patient death. The company’s previous attempt at ATTR amyloidosis was also disastrous – rivusiran had gone into Phase III, but was abruptly pulled due to what was memorably described as a “mortality imbalance”. (As I understand it, Patisiran is from a later chemical series (update: actually earlier!), and the data-monitoring committee for its trial recommended that it continue after the rivusiran failure). So this is not exactly a well-worked-out path through the clinic, and a lot of onlookers were holding their breath waiting for these latest results.

hATTR amyloidosis is a nasty disease, and there is (until now) absolutely nothing that can be done about it. Note that American College of Cardiology’s recommendation of “supportive therapy and clinical trials”, which can be exactly translated as “Try to make the patients comfortable while they get worse, and hope that somebody discovers something that can help”. It’s caused by mutations in the transthyretin protein, which is produced in the liver and normally carries Vitamin A, among other things. The mutant form, though, forms amyloid fibrils, as many proteins will do under the right (wrong?) conditions. This manifests as toxic deposits of bunched protein in both the heart and nervous system, leading to heart problems and neuropathy of various kinds, which get worse and worse every year until you die.

This is a natural fit for an RNAi approach, on a couple of levels. Decreasing the amount of mutant TTR protein should slow the progression of the disease, and decreasing specific protein levels is what RNAi does for you, as it goes after the relevant messenger RNA. And the liver is one of the few places that we know for sure that you can get even the most advanced RNAi molecules to show up. The problems of drug delivery and stability are some of the big reasons it’s taken so long to get to this point (the same goes for all oligonucleotide ideas), and even now they represent serious limitations. But the liver, everything goes to the liver just for circulatory and digestive plumbing reasons. Things don’t necessarily make it back out of the liver, but they do go in.

So congratulations to Alnylam! This really is a major achievement, and the amount of time, effort, money and heartbreak it’s taken to get this far should serve as a monument to how hard it is to advance something really new in drug therapy. The work continues.

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer