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.

RNA Therapeutics Are Back in the Cardiometabolic Game

In the mid- to late 2000s, in the wake of Vioxx, I remember sounding the alarm bell on developing RNAi Therapeutics for cardiometabolic indications.  The FDA would simply refuse to approve cardiometabolic drugs even when strong data on widely accepted biomarkers such as blood glucose in diabetes and LDL-cholesterol levels in cardiovascular disease suggested that they should be efficacious.  Instead, the agency was demanding ridiculously expensive outcome trials for even the most underserved patient population, making cardiometabolic drug development difficult to justify financially.

Regulatory and technology changes

10 years later, the situation has changed dramatically due to a confluence of regulatory and technology changes.  In the regulatory arena, the staged approval process which involves a fast-to-market strategy for high unmet need orphan populations based on surrogate markers followed by the roll-out in larger patient populations, partly supported by the clinical experience gathered from the orphan indications, has been successful at rekindling interest in cardiometabolic drug innovation in general.

In terms of technology, both RNAi and antisense technologies have matured to a point that the risk:reward proposition looks highly promising not only for the most severe patient populations, but suitable for even the more general population.  The Old is exemplified by gen 2.0 RNaseH antisense oligonucleotide mipomersen for which it will be very difficult to break into markets beyond the ultra-orphan homozygous familial hypercholesterolemia one due to its weak drug activity and considerable side effects. 

In RNAi Therapeutics, the Old was represented by the need for intravenous administration with the former gold standard in RNAi delivery, 1^st and 2^nd generation SNALP liposomal nanoparticles (LNP), and their confounding effect on lipid metabolism (see the need for various normalizations in the phase I results of ALN-PCS02).  

Today, however, we not only have improved SNALP LNPs and 2^nd generation RNaseH antisense (2.2), but more importantly GalNAc-targeted RNAi and antisense technologies by Arrowhead Research, ISIS Pharmaceuticals, Regulus Therapeutics, and Alnylam.  Importantly, due to their highly specific targeting of hepatocytes in the liver, the therapeutic window has been widened considerably.  In addition, the surprisingly long duration of target engagement makes monthly, if not quarterly dosing conceivable, therefore not only erasing, but surpassing oral small molecules in terms of patient convenience.  And we have not even considered the superior therapeutic utility that they promise by their ability to go after all conceivable targets- individually or in combination.  This, after all, is what we all should care about most.

The attraction of cardiometabolic applications is also reflected by the recent establishments of related franchises by Alnylam (cardiometabolic STAr) and ISIS Pharmaceuticals (Akcea lipid commercial subsidiary), with development programs targeting ApoCIII (ISIS Pharmaceuticals), PCSK9 (Alnylam/The Medicines Company), Lp little a (ISIS Pharmaceuticals), and ANGPTL3 (ISIS/Alnylam) looking already very favorable.  In addition, ISIS Pharmaceuticals sports a couple of interesting diabetes-focused programs (targets: PTB, GCGR, GCCR) which are showing novel therapeutic/safety profiles that could be suitable for specific sub-populations in the enormous, but equally complex diabetes market (e.g. insuling sensitization, reduction of glucose production).

Competitive outlook

    

As ISIS Pharmaceuticals and Alnylam compete for some of the same targets, the most common pattern you will likely see is that ISIS has a first-mover advantage (à IP and experience) with non-GalNAc generation 2.2 candidates due to their formerly somewhat fool-hardy, but now genius-looking pursuit of the cardiometabolic area.  When there is direct competition, the gen2.2-based drugs will likely be outcompeted by Alnylam’s GalNAc-siRNA conjugates due to their a) longer duration of action, and b) their possibly superior safety profile.

However,  as ISIS Pharmaceuticals is giving their cardiometabolic franchise a GalNAc overhaul, the company will also likely have the once monthly dosing frequency and a safer alternative turning it into a head-to-head race between Alnylam and ISIS Pharmaceuticals with winners that could differ from target to target.  Long-term, ISIS Pharmaceuticals may another ace in the competitive race as the single-stranded phosphorothioate oligonucleotide approach currently seems more amenable to oral dosing than double-stranded RNAi approaches.

   

While Tekmira’s SNALP LNP technology may be competitive when it comes to multiplexing targets, it is Arrowhead Research that is best positioned to surpass both Alnylam and ISIS Pharmaceuticals should they succeed in progressing their single-molecule subQ DPC technology into the clinic as indicated in last quarter’s conference call.  The endosomal release chemistry gives it a potency, and potentially also dosing frequency advantage over Alnylam’s simpler GalNAcs. 

Expect the CEO of Alnylam to increasingly attack the Arrowhead competition by raising safety concerns as he did in the recent RBC Healthcare conference presentation. I find this remarkable given that Arrowhead Research has not released the full safety data from its phase I study of ARC520.  But if you don't think you can win on potency, it may be best to sow seeds of safety doubt based on innuendo.

  

So watch this space. Next up are results from ISIS-GCCRRx (diabetes) and ISIS-ANGPTL3Rx (lipid disorders), clinical results from which are imminent.  Head-turning ALN-PCSsc results could be out in Q3. 

ISIS-GCGR on Path to Become Important Diabetes Drug

At this year’s ADA diabetes meeting, ISIS presented the full dataset for ISIS-GCGR for the treatment of advanced diabetes patients having failed oral options and who are on the way to taking insulin.  After having presented top-line data a few weeks earlier claiming more than 2 percentage point reductions (on top of metformin) in HbA1c, enthusiasm around the results was limited given concerns about liver enzyme elevations that were not much further characterized and ISIS' history of being parsimonious when it comes to sharing safety data. 

Data indicate that good risk:reward will be found

A placebo-adjusted 1 percentage reduction of HbA1c reduction, the gold standard for measuring glucose control, is generally considered to be quite meaningful.  HbA1c stands for glycated hemoglobin and essentially integrates blood sugar levels over time. 

In type II diabetes, blood sugar is elevated either due to insufficient insulin-mediated uptake of sugar (glucose) into liver, muscle, and adipose tissue and/or due to excessive release of glucose from the liver stores due to the action of glucagon.

Due to the time-dependent nature of hemoglobin glycosylation, it takes at least 2-3 months for HbA1c to reflect the full impact of an antidiabetic medication on blood glucose levels.  Because it takes another 1-1.5 month for a PS-based ASO like ISIS-GCGR to promote full target knockdown and in the case of GCGR work its way downstream biologically, it will be about 4-5 months before the full extent of HbA1c lowering will be seen with ISIS-GCGR.

This is borne out by the HbA1c curves (slide 37) which appeared to be still declining after the 3 months of dosing in the study. Importantly, coincident with plateauing fasting plasma glucose levels, a more proximate measure of the drug effect, liver enzyme elevations, markers of liver injury, plateaued after ~1.5 months. 

This not only further supports that the liver enzyme elevations, the main safety concern with ISIS-GCGR, were due to on-target pharmacology rather than a flaw of the ASO platform, it also suggests that HbA1c lowering on the order of 1.5 percentage points or greater can be achieved without triggering liver safety concerns.

At the 200mg dose where more than 2 percentage points reductions were reported, liver enzyme elevations as measured by ALT were 2.7 times the upper limit of normal (ULN).  Although the variability of these ALT elevations was remarkably small, consistent with on-target toxicity, a 2.7 ULN is a non-starter for a drug in this population when in the drug world instances of 3x ULN are often a show stopper.

At the 100mg dose things become much more tolerable with 1.6 times ALT elevations and little variability all the while 1.35 percentage reductions in HbA1c were achieved.  I therefore expect more than 1.5 percentage reductions in HbA1c following more prolonged dosing without a further increase in liver enzyme levels.  Additional dosing optimizations and potentially drug combinations will be the subject of future phase II studies.

Best-in-class profile

Merck and Eli Lilly have also been developing GCGR inhibitors, but using small molecules to inhibit the proteins instead of oligonucleotides to inhibit glucagon receptor synthesis.  Apparently, these drugs have not only seen liver enzyme elevations in humans, again consistent with the on-target toxicity hypothesis of the ALT elevations, but more importantly cardiovascular safety signals such as increases in blood pressure.  Whereas Merck seems to have given up on further development of MK-0893, clinicaltrials.gov shows that development is ongoing for LY2409021, including a safety-related study to characterize its effect on blood pressure.

In data presented at the 2011 ADA meeting, MK-0893 achieved HbA1c reductions of ‘0.6 to 1.5 percentage points’ in a 12-week study, with 0.8 and 0.5 drops observed in the metformin and placebo control groups, respectively.  As presented at the 2011 European diabetes meeting, an up to 1 percentage point reduction was achieved with the Lilly drug LY2409021 in a study of shorter duration.  I am not sure whether results from longer studies are known, but it is probably a good assumption that the reductions will fall in a range similar to the Merck drug.

In sum, the ISIS drug is at least as potent, if not more potent (à on top of metformin) as the small molecule competitors, but without the additional safety issues, particularly the blood pressure increases.  In addition, being an oligonucleotide, it should be much easier to combine them with other antidiabetic medications.  On the competitive downside, the small molecule inhibitors are orally available, whereas ISIS-GCGR is administered subcutaneously.

Given the central importance of glucagon signaling in glucose homeostasis, a GCGR inhibitor will have its place in the enormous and fractured diabetes market.

Metabolic Disease Drug Development Anxieties Highlight Benefit of Diversified RNAi Therapeutics Pipeline

Like the commodity bubble, it seems that the regulatory hurdles to drug development are mounting just when we thought we had reached the top. This is the impression one gets from the vote taken by an FDA advisory panel this week that can be essentially boiled down to the presumption that lowering blood sugar increases the risk of heart attack. The prospect of longer and more expensive clinical trials has certainly caused a few mini heart attacks to a number of drug companies developing medicines for diabetes and other metabolic diseases thinking that the obesity epidemic in the prosperous half of the world was bad enough such that regulatory agencies, politicians, and certain clinicians involved in drug development would have a keen interest in new treatment options. Don’t get me wrong here, I see very well the problem of millions of real patients and maybe not-so-needy folks taking drugs from which they do not derive any benefit, but there certainly are other ways of ensuring drug safety and efficacy without rendering drug development, and eventually the cost of drugs just unaffordable to anybody, and often without good reason.

Now that I got this off my chest, what does the broad attack on metabolic disease drug development mean for RNAi Therapeutics?

Metabolic disease, because of the ability of current systemic delivery methods to effectively knock down genes in the liver which is critically involved in regulating blood sugar and lipid levels, is one of the main therapeutic focus areas of current RNAi Therapeutics development. It shares this position with cancer, followed by respiratory, ocular and CNS-related disease. It may therefore be tempting, if you have the ability to target a range of hot metabolic disease targets, to create a development pipeline based on metabolic disease and little else. ISIS Pharmaceuticals from the related field of antisense therapeutics is probably the best example here as it has very much limited their internal drug development activities on metabolic disease, while handing off some of the more challenging targets such as for cancer to one of their many satellite companies.

Of course, if you don’t have the capability to diversify, concentrating on building a franchise around a single, but potentially very lucrative market may be the most efficient way of maximizing shareholder value given the many synergies derived from largely having only to exchange the siRNA inside and comparatively few other changes. However, if you can afford it and you are interested in establishing RNAi Therapeutics as a broadly applicable drug development platform, you probably would want to spread your risk more widely even if all the programs added up individually would yield a higher valuation. The fact that the regulatory environment may change overnight while drug development is a 12-15 year effort being one reason.

Next to insuring from regulatory risk, diversification also means that failure of one drug candidate such as for a given organ does not necessarily have to impact the perceived probability of success for candidates aimed at other organs. In the same vein, it may also be wise not to be too dogmatic about delivery technologies, siRNA modification or DNA-directed RNAi methods and structures. For example, if your entire IP claim depends on just one siRNA modification pattern even without so much as functional validation in a non-human primate, you may have ended up totally reliant on clinically non-viable chemistries. Related technologies have shown that developing chemistries in generations rather than multiple chemistries in parallel may mean that if your chosen chemistry generation turns out to be either inefficient or unsafe, it may take another 7 years to get a shot with the next generation.
Meanwhile, all bets are off what steps the FDA will take next.