The $28M AstraZeneca-Regulus MicroRNA Therapeutics Deal

Yesterday, it was announced that AstraZeneca is paying microRNA Therapeutics company Regulus $28M for three preclinical-stage microRNA targets.  This is certainly good news not only for the field of microRNA Therapeutics, but also oligonucleotide therapeutics in general which is well on the day to be the third major drug development engine after small molecules and monoclonal antibodies.  

After GSK and Sanofi-Aventis, it is the third of its kind for Regulus and there were similar ones between Miragen and Servier late last year and Santaris and GSK before that.  The number of such deals, each usually involving a number of microRNAs, illustrates how far the field of microRNA biology has come in just 10 years from the discovery of microRNAs in humans to yield promising therapeutic targets that number in the dozens.  In fact, microRNA Therapeutics has been more successful than the more straight-forward RNAi Therapeutics approach in attracting the partnering interests of Big Pharma lately.

On the other hand, it’s been now five years since the founding of Regulus Therapeutics, and still no program has made it into the clinic.  Such a performance is certainly not good enough to support an IPO these days for which the company, based on job postings, appears to have had ambitions for for some time now.  With remaining ~25M in cash and an annual burn rate of around that, the revenues recognized from the AZ deal may well be the substitute for a public offering.  

As it was not disclosed how much of the $28M was for equity in Regulus, other than the cash added to Regulus’ balance sheet it is really difficult to tell whether the dealmakers at Regulus will be all smiles about it.  What’s more, the miR-33 atherosclerosis program which had yielded exciting data (including in non-human primates) in enhancing reverse cholesterol transport with a subsequent reduction in plaque size seems to be spoken for already at this early stage (before the magical phase II value-inflection point).

It is unclear what is causing the apparent delay of Regulus progressing programs into the clinic.  Is it the complexity of microRNA biology where each microRNAs often has dozens of targets, or has it something to do with the concern that the 2'-fluoro modification initially favored by the company may be genotoxic?

AstraZeneca’s Return to ‘Proper’ RNA Therapeutics

When AstraZeneca, in its farewell to Silence Therapeutics in January, said that the Silence effort was ‘part of its overallstrategy to explore this important therapeutic approach [i.e. RNA Therapeutics]’, I took it to mean that the Silence projects may not be their top priority in this regard and that it already had other oligonucleotide technologies and companies in mind.  

Confusingly, half a year before that AstraZeneca entered into a ‘small molecule RNA Therapeutics’alliance with PTC.  Beware of companies, particularly prevalent in the (cancer) stem cell field it seems, which claim to be pursuing new platforms and treatment paradigms, when the innovation actually rests on just tying pre-existing molecules to new biological rationalizations.  

Classic Big Pharma I thought then: advertising innovation, but really sticking to its old, rusty guns; and if AstraZeneca is widely thought to have the industry’s worst productivity, you have to look no further for its causes.

Yesterday’s news was therefore quite encouraging in that AstraZeneca has not given up on developing ‘proper’ RNA Therapeutics by which I mean that nucleic acids are the therapeutic agents.  Whether the stream of positive clinical results in oligonucleotide therapeutics (and vaccines) have provided AZ encouragement to go down this path is unclear, but they certainly did not hurt.  Maybe it will even make AZ re-energize its RNAi Therapeutics efforts (e.g. for oncology or respiratory disease).

Want to learn more about microRNAs?  Register for the 2012 Janssen Award Symposium in New York.

Next post: Tekmira's very busy quarter.

Targeting MicroRNA to Increase Good Cholesterol

In back-to-back publications in the journal Science, researchers from Boston and New York demonstrate that microRNA-33 (miR-33) is part of the complex control system regulating cholesterol metabolism (Najafi-Shoushtari et al. and Rayner et al.). The research further suggests that miR-33 is an attractive target for increasing ‘good’ HDL-cholesterol and continues to add to the intriguing possibilities how microRNAs may be exploited for the treatment of a range of major diseases.

Most pharmacologic strategies in cardiovascular risk management today aim at lowering the ‘bad’ LDL-cholesterol, including oligonucleotide therapeutics targeting ApoB and PCSK9 currently in development. It is, however, actually the ratio of the bad to good cholesterol and associated proteins in the blood that provides a better measure of the cardiovascular risk compared to the absolute levels of bad cholesterol alone.

The reason HDL-cholesterol is good for you is because it promotes reverse cholesterol transport from atheromatous plaques in blood vessels back to the liver and excretion via bile. If you come across a colleague in your workplace with an intensely red head, chances are that they have just taken niacin, the most widely used drug to increase HDL-cholesterol. Partly because of the side-effects of niacin and also to even more increase HDL levels, the medical community is extremely interested in additional drugs that can complement the LDL-lowering drugs such as statins with those that elevate HDL-cholesterol. Despite the failed high-profile billion $ gamble by Pfizer on small molecule Torcetrapib, appetite for such agents continues to be high also in the pharmaceutical industry.

Ever since the work by Brown and Goldstein, lipid metabolism has become the prime example for complex, yet robust regulatory networks in biology with lots of built-in feedbacks and redundancies. It is therefore probably not surprising that encoded within an intron (the part of an RNA transcript that is cut out during messenger RNA processing) in one of the master regulators of this network, the SREBP transcription factors, was encoded a microRNA, miR-33, that was co-expressed with SREBPs and similarly functioned in cholesterol regulation. While SREBPs contribute to the synthesis and cellular uptake of cholesterol, miR-33 redundantly works to increase cellular cholesterol levels by targeting members of the ATP-binding cassette transporter family involved in the transport of cholesterol out of cells (loading of cholesterol onto HDL apolipoproteins).

In other words, inhibiting miR-33 function should enhance cholesterol efflux from cells. This would be particularly beneficial for macrophages that by overfeeding on LDL-cholesterol play a central role in forming plaques and clogging up arteries. Indeed, the researchers were able to show that the inhibition of miR-33 with antisense would do just that: increase cholesterol efflux from macrophages. Preliminary data showing the predicted increase in HDL-cholesterol following systemic administration of miR-33 antisense molecules were presented as well.

Although encouraging, in order to firmly validate mir-33 as a therapeutic target for increasing HDL-cholesterol, a more thorough understanding of the consequences of miR-33 inhibition is required as are strategies aiming at targeting miR-33 preferentially in the atherogenic macrophages and possibly also hepatocytes. This, however, should be a quite realistic goal given that phosphorothioate antisense molecules alone as well as a number of oligonucleotide nanoparticle delivery systems are preferentially taken up by these cells anyway.

It is quite exciting to see so many microRNAs emerge as potentially high-value therapeutic targets. It is a testimony to the intense interest these small RNAs have attracted in the scientific community as they are involved in very likely almost all biological pathways. This should both help to establish microRNA Therapeutics as a vibrant industry able to stand on its own feet due to the many therapeutic opportunities, and also benefit RNAi Therapeutics by contributing to our understanding of the molecular mechanisms and functions of the natural counterparts of RNAi triggers.