Tuesday, January 31, 2012

RNAi Therapeutics and Whole-Genome Sequencing

It is my expectation that in 15-20 years, every newborn and newly diagnosed cancer patient with good healthcare coverage will have their genomes sequenced. Personally, I cannot wait for consumer genomics companies like 23andMe to provide services that would allow me, a non-bioinformaticist, to readily analyze the sequences of friends and family. All this is made possible by the technical advances in bringing down the cost of sequencing so that for the price of a semi-luxurious holiday (~$4000) you can get your genome sequenced these days. Roche’s bid for the 800 pound gorilla of DNA sequencing, Illumina, illustrates that with its other molecular Dx costing not that much less, next-gen sequencing, especially that of whole genomes, has reached a stage where it has become relevant for diagnostic applications.

15-20 years is also about the time-frame when we should see a healthy flow of RNAi Therapeutics getting approved, many of those as personalized medicines, e.g. for the treatment of dominant-negative diseases such as TTR amyloidosis, Huntington’s Disease, or, of course, cancer. With many people knowing their genome sequence from birth, it will be possible to monitor and then start treating many of these gene carriers before they manifest symptoms and progress to more debilitating states. Others will benefit from an improved ability to correctly diagnose a disease in genetic terms, thus allowing the physician to prescribe the appropriate medicine. As a genetic medicine (aka gene therapy), RNAi Therapeutics is ideally suited to address many of these diseases. Sequencing technologies will also help unearth which gene targets such RNAi Therapeutics ought to go after and thus reduce target risk.

There is considerable discussion in biotech what would be the best business model for sequencing companies. The buzz around PacBio has fizzled a bit as there is a sense that their machines are too expensive and not best suited for the mainstream sequencing applications. Illumina meanwhile has a dual model: It caters to those that don’t want to mess with the sequencing themselves but would rather hand over the job to somebody with experience; it also does well in selling sequencing machines to those that prefer doing it themselves. This model, however, is agnostic to the type of sequence (human or not; whole genome or exome).

Complete Genomics, on the other hand, has specialized on just human whole genome sequencing. I like this model a lot from a commercial perspective as this is the area where the future diagnostic sequencing volume will be, and specialization not only allows the company to optimize its technology for this single application but also to put relatively more resources into developing the requisite, value-adding bioinformatic analysis tools. The company is struggling with convincing the market that the currently more widely used/pushed exome sequencing is not more than a blip in the history of sequencing, a history which will inevitably culminate in routine whole genome sequencing. Claiming that exomes, which cost almost as much as whole genomes to sequence, have staying power feels kind of like arguing that Alnylam has 'proprietary' SNALP technology, just because Alnylam has a larger advertising budget. Maybe not the best analogy, I admit, but if you are still reading this, then chances are that you don't mind and even agree with me.

Ultimately, what I find exciting and scary at the same time about this business model is that at one point a company like Complete Genomics will have assembled a treasure trove of sequence information. It will e.g. have a very good idea where to find the families with severe hypercholesterolemia, information that I imagine a Genzyme or healthcare insurance providers would love to know about.

Vertex Pharmaceuticals today received approval for a genetically personalized Cystic Fibrosis drug, Kalydeco (probably named by the same consultants that gave Kynamro its name), for which it has plans to charge around…three hundred thousand US dollars per annum (note: an earlier version mistakenly referred to Genzyme as the CF drug maker). It’s difficult for me to understand what a 10% improvement in lung function means to a CF patient (probably a lot), but even if it’s a great relieve who does not wonder whether such costs are sustainable: have 10-15 adults work for nothing else but to pay for the treatment of an unfortunate CF patient. I’m sure we’ll witness similar debates raging once the first RNAi Therapeutics get approved. Hopefully, a winning combination like RNAi and whole genome sequencing can contribute to keeping the financial cost of personalized medicines low by increasing drug development success rates through better targets and RNAi platform efficiencies and keeping waste to a minimum by only treating people genetically predicted to respond to the therapeutic.

Disclosure: I do not hold GNOM (Complete Genomics), and unless it drops by 30% for no good reason, do not have plans to buy over the next week.


Anonymous said...

Dirk, what is your assessment of Wafergen's "Smart Chip" system which can process 5,000 genes on a single chip? The company also projects that, by the end of the year, they will market a chip that can process 30,000 genes at a time.

Anonymous said...

Vertex is the manufacturer of the Cystic Firbrosis drug. I wasn't aware that Genzyme had an interest in this drug.

Dirk Haussecker said...

You are absolutely correct. Sorry for mixing up the two Cambridge biotechs. I guess Vertex will be interested in such data as well.

Wafergen- I did not know about it. Seems like they are doing gene expression analysis, correct? Definitely, adding dynamic data to the more static genome data would add value. Probably a bit more complicated though to get the proper samples.

Anonymous said...

What does it mean that the USPTO has issued an allowance for Alnylam's novel new lipid formulations including the highly potent ones contested by Techmira?

Dirk Haussecker said...

It just means that the USPTO granted the patent claiming the specific MC3 lipid based on the information provided to it by Alnylam and based on the prior art at the time the invention was made.

It does not, however, mean that the USPTO has made any statement with regard to the contested ownership of this lipid, which, of course, is subject to at least one of the various accusations made by Tekmira against Alnylam. The 'surprising' thing is that Semple and Madden e.g. are missing as inventors on the patent despite having functioned as LNP 'consultants' to Alnylam during the supposed time of invention. Very strange indeed. Instead, the list of inventors is stuffed with a bunch of other scientists that one would have thought were much less versed in the art of LNP delivery. Strange again. Well, the USPTO has no way of determining whether Alnylam gave them the correct inventorship information or not. Wilfull misrepresentation of inventorship information, of course, is against the rules. Since I believe that Alnylam mgmt is a highly ethical (!) one, one must believe that it was an honest mistake. If not, MC3 could become available to everybody- and this would not even to Tekmira any good...

Gene genie said...

Sequencing and gene based therapies will be the next big arm of medicine , understanding the genetic basis of disease ie the roll of intracellular infection the the genesis of malignancy and the autoimmune disorders will be the result of mass sequencing , I suspect we will see more corporate activity in this area.

Anonymous said...

Dear Dirk, I appreciate your thinking on GNOM and it mirrors mine. If you dont mind my asking, did you open up a position in it yet. I did after what I felt was validation with the recent Mayo clinic contract. Although, I am in at a much higher price than current price per share, I am confident that this is a long term 600 pound gorilla one day. Why not start acquiring now ? So what are your thoughts? Appreciate your erudite understanding of both the science and biz of biotech my friend.

Dirk Haussecker said...

No, I have not bought GNOM since I wrote this blog despite my belief that human WGS will be huge and GNOM has a good shot at becoming a major, profitable player once the industry has matured.

To me, it will be important to see that GNOM can continue to grow revenues at present pace so that they can reach profitability with one more financing at most. As the market cap is currently quite depressed, but cash needs still high, I would probably prefer to wait until the financing. Before that, due to the volatility, GNOM is probably a good trading stock.

bion4maticist said...

I'd recommend caution when investing in WGS players. This field has had a record of disruptive technologies completely changing the game every few years for the last decade. Latest instance: Oxford Nanopore's announcement a month ago at AGBT. Check it out.

BTW, I'd also recommend caution in investing in Tekmira, for similar reasons -- it, too, could be rendered irrelevant overnight by an unanticipated breakthough.

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