AstraZeneca Selects MicroRNA Development Candidate, Blazes Innovative Trail

When it is screaming into your face that your business model has failed you and the young competition is running circles around you, only then you might be compelled to change. 

This certainly is true for Big Pharma which have lost sight that their business is to make a buck while increasing the health of their customers instead of wasting time and energy on challenges like turning a twice-a-pill into a once daily therapy.  In its quest to optimize their business processes, it has thus thrown out of the window revolutionary, innovative technologies that just would not fit into those loved models.

Case in point, Merck writing off their multi-billion dollar investment in RNAi Therapeutics and selling it to Alnylam for $175 in largely equity and some cash. Alnylam then turned around and made at least a 10x return on the RNAi trigger stabilization chemistry by Merck in little more than a year.

This is a rough estimation of how much the Merck RNAi assets have approximately contributed to increasing Alnylam’s market cap.

AstraZeneca leading the way for Big Pharma in RNA Therapeutics

Not long ago, AstraZeneca was widely vilified for being the worst of the worst in terms of R&D productivity.  Their labs just would not produce new compounds that mattered to patients.

After a corporate shake-up, things certainly have changed on the innovation front.  AstraZeneca has fully emerged as a real risk-taker when it paid Moderna $240M in upfront monies alone for access to a comparatively early-stage mRNA Therapeutics platform in 2013. 

Before that, however, it already got active in the RNA Therapeutics in a less visible manner, notably with a much smaller, but possibly more profitable deal with microRNA Therapeutics platform company Regulus Therapeutics.

In the 2012 deal, AstraZeneca made a $25M equity investment in addition to a token $3M cash hand-out in the then privately-held Regulus Therapeutics.  In exchange, AstraZeneca received 3 microRNA target picks in the cardiovascular, metabolic, and/or oncology areas.

The best part of the deal for AstraZeneca (and the reason why I took money off the table today at what I considered an outsized reaction) was that it only has to pay $2.5M per target/candidate pick and Regulus Therapeutics has to pay for part of the work involved in generating the candidate at that.  There would, of course, be the milestones and royalties, but they should also be modest, in-line with the $2.5M payment due now. 

Oh, those were the good old times of abusive (because they could) Big Pharma biotech business development deal right on par with the steal that The Medicines Company got from Alnylam with regard to the PCSK9 target.

But still, you have got to credit AstraZeneca that unlike its brethren they not only sealed the deal, but actually advanced one of the first clinical candidates involving a fundamentally new molecular target class.  It will be interesting whether they will do the same in mRNA Therapeutics.

Anti-miR103/107 antagonism for improving liver health in diabetes

Initially, the focus  of the partnership had been on what looked like a very promising HDL-augmentation strategy by inhibiting miR33 in the liver, but this candidate has apparently taken a backseat in favor of the insulin-sensitizing strategy by inhibiting miR103/107.

It had been known that in type II diabetes, there is an inverse correlation between insulin sensitivity and miR103/107 expression.  Supporting a causal involvement, inhibiting miR103/107 in mouse models of diabetes with (unconjugated) antisense oligonucleotides increased not only insulin sensitivity, but also had positive effects on a couple of other diabetes-related parameters not only in the liver (e.g. triglyceride levels), but also body fat (adipocyte size/differentiation).

One puzzling aspect, somewhat akin to Regulus’ Alport’s program (--> miR-21), in exploiting anti-miR103/107 for pharmacological intervention is that it was initially uncertain what the target cells ought to be: adipocytes and/or hepatocytes?  A role for miR103/107 expression in adipocytes was particularly supported by the observation that its steady-state level there is higher than in the liver and the fact that single-strand phosphorothioate oligonucleotides also distribute to body fat.

However, with the adoption of GalNAc conjugation technology where most of the oligonucleotides now accumulate in hepatocytes it seems that AstraZeneca and Regulus have come to the conclusion that it is the liver that once again is calling the shots here as it usually does in diabetes.  You can deduce this from the fact that a GalNAc version was selected as the clinical candidate (AZD4076) slated to enter the clinic later this year.

Taking advantage of the observation that anti-miR103/107 has positive effects on liver triglyceride levels, the clinical development of AZD4076 will at least initially be geared towards treating non-alcoholic steatohepatitis (NASH) in diabetes patients.