Regulus Therapeutics RG-101 Continues to Have Potential in HCV Treatment Landscape

Having attended the International Liver Congress last week in Vienna, Austria, it has become clear to me that HCV is not going away soon.  Even in the US where progress towards its ‘eradication’ may be considered most advanced with about 1/5 of the known patient population treated last year alone (~250k), it will be an uphill battle to identify, treat, and pay for the millions more infected. Worse still, it is not enough to simply cure the existing pool of HCV patients, but also stop the cycle of re-infection (largely the result of injection drug use).

Treatment cost is one challenge and the current drug rationing approach leads to the counterproductive warehousing phenomenon where current medical intervention is focused on the patients with more advanced liver disease.  This is not only the hardest-to-treat population, but also allows the liver health of the previously less sick patients to deteriorate.  This obviously makes little sense also from a pharmaco-economical perspective when getting rid of HCV early on has now been shown over and over again to dramatically reduce HCV-related cirrhosis and liver cancer.

Another problem is the fractured treatment landscape that exists for the various patient populations (split up according to fibrosis/cirrhosis stage, genotype, co-morbidities, the rapidly growing concerns around drug-drug interactions, available/accessible meds etc) making it difficult for even the learned gastroenterologist to keep up with the latest developments and putting HCV treatment practically out-of-reach for the general practicioner.  

12-24 weeks remains the standard drug treatment duration with docs worrying about shorter treatment regimens being sub-optimal.  A triple regimen by Gilead after 4 weeks of treatment merely achieved a 27% SVR12 which in the DAA world is practically synonymous with a cure.  The best shot at shortening treatment duration may therefore come from Achillion with 6 week of DAAs achieving high cure rates in 'easy' patient populations.

While interferon is on the way out, it could make an at least transient comeback for the hard-to-treat genotype 3 where, in addition to cirrhosis, cure rates with the all-oral DAAs low (60-80%).

To sum it up, the liver community has expressed multiple times at ILC2015 that a short-acting pangenotypic regimen is an important goal in the development of new medications for HCV.   And if they paid attention at the oral late-breaker on Saturday, RG-101 is poised to play a critical role in filling this unmet treatment goal due to its long duration of antiviral activity following administration, regardless of genotype.

RG-101 update: more relapses, but thesis intact

The clinical investigators of Regulus Therapeutics presented a 20 week update on the phase I study in genotype 1, 3, and 4 patients with good to moderate liver health.  28 patients received study drug RG-101, 4 placebo.

At the primary endpoint on week 8 (reported in earlyFebruary), slightly more than half (15/28) of patients treated with RG-101 were below the level of quantitation (BLOQ).  According to the company, most of them were not only BLOQ, but undetectable (by sensitive PCR) at that.  This is a remarkable feat given that the GalNAc-conjugated phosphorothioate antisense molecule had been only given once.

According to the latest update, half of those patients eventually relapsed (7-8 depending on whether you count the patient that was lost to follow-up), most of them shortly after week 8.  Although the relapsers are slightly disappointing as in the short-acting DAA world undetectable virus for 8 (or better 12, SVR12) weeks following cessation of treatment is more or less equivalent to a full-blown cure.

Of course, the prognostic rules for a long-acting agent like RG-101 with a slower onset of antiviral knockdown ought to be different.  The notion that the viral rebounds were simply due to waning drug levels in the liver (and not due to viral escape mutations!), was supported by the biomarker analysis in the healthy volunteer part of the phase I study, also presented at ILC2015, where the trough in viral knockdown (~day 28) more or less coincided with maximal total cholesterol lowering as a predicted by miR-122 biology.

Of note, there was no apparent benefit of increasing the dose from 2 to 4mg/kg which was consistent with preclinical evidence that showed a declining liver/kidney drug ratio at 4mg/kg and maximal cholesterol lowering at 2mg/kg in humans.  This indicates that ASGPR receptor binding becomes saturated when too much GalNAc antisense is given at once.  The increased drug liver concentration at higher concentrations observed in earlier preclinical studies probably indicate uptake in non-productive compartments of the liver, including Kupffer and sinusoidal endothelial cells.

  

The hope is that with a second dose of RG-101 28 days after the first shot, maximal viral suppression can be maintained for at least another 4 weeks to stave off any viral comeback as seen in the single-dose study.  This is supported by both the healthy volunteer part of the study and the chimeric PXB mouse experiments presented which showed that such a second dose not only maintained drug potency, but in fact led to a step-up in efficacy.  I am therefore optimistic that with 2 doses of RG-101 monotherapy alone ~50% cure rates can be achieved in patient populations similar to that in the phase I study.

This, however, is not even the goal.  The ultimate goal would be to establish a simple pan-genotypic 4-week treatment regimen.  Accordingly, the combination of RG-101 with a DAA(s) (sandwich regimen) can be expected to result in a very, very deep viral knockdown by week 4.  At this point, a second shot of RG-101 would be administered to give the immune system another 6 weeks or so to finish off the virus.  I believe a very realistic scenario, and depending on which patient populations you are looking at a very compelling alternative to current HCV medications and those in development. 

PS: Open questions

Unfortunately, given that cholesterol lowering was still close to maximal at week 8, it would have been comforting to show a mutation analysis from the clinical study to confirm that viral relapse was not explained by the virus successfully developing resistance against RG-101.  This is such an obvious question that one wonders why Regulus did not present the data (yet). 

Another question mark around the current data set is why Regulus is not disclosing the differential effect of RG-101 on good and bad cholesterol and instead is reporting total cholesterol lowering.  The study investigator said that they are still analyzing the data from the multi-dose healthy volunteer study  (months after completing dosing???) and are planning to publish those.  I am mildly optimistic that this could unexpectedly bring to the fore the cardiovascular potential of miR-122 targeting, although in this case (à mostly chronic treatments) the liver cancer concern around miR-122 inhibition may be more valid than it is for the 2-shot HCV treatment goal. 

Reading the Tea Leaves on Regulus Insider Sales

Revelations Friday night that the CEO (here) and CSO (here) of Regulus Therapeutics had sold sizeable amounts of Regulus stock just days ahead of an important phase I data release, initially sent shivers down my spine I could soon be ridiculed a 'bagholder' on Twitter and by Benitec shareholders.  

What confidence does it betray in the upcoming results when the CSO sells what appears to be ALL his shares in the company (worth ~$1.5M) and the CEO about a third of his holdings in his Family Trust  slightly more than a quarter of his combined position, including his Family Trust (~$710M for original position).  

Let me be clear, whether the stock goes up or down and regardless of whether these sales occurred according to a 10b5-1 insider trading plan (which can be cancelled anyway and thus makes them a farce), such shenanigans are unwarranted and officers of publicly traded companies should refrain from such actions.

Nevertheless, since I am doing nothing but wait for the results, let me indulge in providing a timeline to provide context to these sales.

October 22, 2014

Regulus reports truly stunning results where they reveal that a SINGLE dose of 2mg/kg of RG-101 was able to knock down HCV virus by over 4logs, with each patient, no matter the genotype, responding to the drug.  The company says that dosing in the next higher dose cohort, 4mg/kg, was ‘ongoing’ and results therefrom would be reported in Q1 2015.

November 5, 2014

On the Q3 2014 conference call, the company updated investors that the 4mg/kg cohort had then been fully enrolled. Maintains guidance of providing results sometime in Q1 2015.

November 12, 2014

At the Credit Suisse Healthcare Conference, the company narrowed down data release to occur in January 2015.

November 25+26, 2014

The two persons most familiar with progress with the clinical progress of RG-101, the CEO and CSO of Regulus Therapeutics, set up 10b5-1 trading plans that apparently foresaw the selling of Regulus shares last week.  IF the January 2015 data release guidance was made in good faith two weeks earlier, this means that they likely hoped to cash in after the results. Fair enough and well deserved- even if the trial is open-label and they thus likely knew where the knockdown curves were headed by that time.

December 3, 2014

A week after setting up the automated trading plans, at the Piper Jaffray Conference, the time frame for data release was widened and shifted back with ‘January-February’ which means that the sales would either occur before or after the results.

January 8, 2015

Regulus Therapeutics announces 2015 goals under their ‘Clinical Map Initiative’ according to which 4mg/kg results would be announced in ‘early February’, i.e. right after the planned share sales.

According to the above, the stock sales can be interpreted both to portend good or bad results.  One scenario is that the CEO/CSO may have originally wanted to cash in on what they knew were good upcoming results, but then lawyers became involved and said that this could draw some unwanted attention and the data release was slightly pushed back.  If the results would be good and the stock were to go up, they would look like heroes anyway and countless bonus options would come their way in perpetuity to more than compensate for the loss.

Another scenario is that they were afraid of an impending stock drop triggered by the 4mg/kg data and simply wanted to get ahead of that train wreck.  Par for the course in biotech.  But in that case, I’m wondering why they wouldn’t just sell their shares well ahead of the event to avoid the attention they now have.

Until now, Regulus Therapeutics has been a comparatively credible and fairly low-key publicly traded biotech company to the degree that until October 2014 they had not even recognized the jewel that RG-101 could become for the company.  Besides the animal pharmacokinetics-human efficacy relationship, it is one of the reasons why I am long RGLS going into the results, believing the market is yet to appreciate the full value of RG-101.  Unfortunately, the insider sales have somewhat shaken this belief and I hope management will learn from it. 

RG-101 for HCV: Give Me 8mg/kg

Last October, Regulus Therapeutics announced stunning data from an ongoing trial of anti-miR122 RG-101 for the treatment of HCV infection.  Accordingly, 6 out of 14 patients administered a single injection of 2mg/kg of the GalNAc-conjugated antisense oligonucleotide dropped to what the company referred to as ‘below the level of quantitation’ (BLOQ) by day 30 and remained there as of the update (day 57 for those treated first in the study).

*BLOQ is not the same as 'undetectable'.  It is 'undetectable' for x number of weeks that technically defines a cure.

2mg/kg data looking ever better

The more I look at the data (here for the corresponding dataset), the more intrigued I get.  For starters, the 2mg/kg was only the starting dose in the patient cohort.  Moreover, a patient that had been more recently treated and had reached only 29 day in late October seemed to be on his way to BLOQ.  In fact, after his titers had dropped to below ~1000 IU/ml, viral decline seemed to accelerate as if a threshold had been reached. 

Overall, it seemed that as long as you got below ~1000 IU/ml, the virus would not rebound (at least until day 57).  Accordingly, the 5 patients that rebounded got close (1000-10000 IU/ml), but never below the apparent threshold.  The lack of overlap between the individual knockdown curves also suggest that viral rebound is not the result of stochastic escape mutations, as is often the case in HCV, but simply due to diminishing drug concentrations.

This leaves two patients which as of the update were still slowly declining as if the threshold rule was counterbalanced by declining oligonucleotide concentrations in the liver after day 30.

In summary:

Everybody responded irrespective of genotype and starting viral titers, of these…

…6/14 BLOQ;

…3/14 undecided;

…5/14 nadir of 1000-10000 IU/ml, then rebound.

A one-shot cure?

In the current marketplace, comprising of ~12M untreated HCV patients in the top 7 pharmaceutical markets plus hundreds millions more in the rest of the world, HCV treatment success has less become a function of viral cure rates achieved in clinical trials, but more one of compliance with the pill regimens.  Therefore, a therapy which would shorten current treatment regimens (say to 4 instead of 8-12 weeks), or even involve just one or two subcutaneous administrations in the physician’s office as part of routine checkup visits, would have great pharmacoeconomic impact.

The company is currently crunching the numbers for the next higher, 4mg/kg cohort.  In general, with RNAi and antisense therapeutics, what you see with increased doses is a slight acceleration of gene knockdown (thereby shifting the knockdown curves down), and, likely of more importance in this case, extended duration of drug activity.

The latter is supported by animal, including non-human primate data that showed that liver concentrations of RG-101 increase linearly with dose from 1-10mg/kg.  This means that for the 3 undecided patients in the 2mg/kg cohort, a doubling of the drug concentration could have easily pushed them BLOQ.  

Alternatively, a second dose of 2mg/kg on day 29 would have achieved that as also supported by animal data showing that viral nadir drops further when a second dose is given (on the left is an example from the challenging chimeric mouse model).

I am less sure whether the other 5 patients would have gotten there with 4mg/kg, but would be much more sanguine about it with a dose of 8mg/kg.

A mistake not to escalate to 8mg/kg

Unfortunately, Regulus Therapeutics stated last year that based on biomarker data which measures the activity of human genes naturally regulated by miR-122, 4mg/kg would be the highest dose to be tested in HCV.  This is because the biomarker response seemed to have saturated already by 2-4mg/kg.  This despite of the fact that they had established in the same phase I study that 8mg/kg is also safe and well tolerated in non-infected healthy volunteers.

I clearly think that stopping at 4mg/kg is a mistake.  First, I highly doubt that at least in terms of duration of biomarker activity, they did not see improvements with higher doses (show me the data).  Second, it is wrong in my opinion to assume that drug saturation with regard to microRNA activity against endogenously expressed genes is a good reflection of microRNA activity in the context of viral replication.  In this case, the rationale is further in question because of the special way miR-122 acts in HCV replication (increases, not decreases activity).

Tempering expectations

As we await the 4mg/kg data and an update on the 2mg/kg cohort in ‘early February’ according to recent company guidance, I should caution that the above scenario suggesting a one-shot monotherapy cure is within reach is obviously an unbelievably exciting best-case scenario.  There is a lot which could make the market react adversely to the upcoming data.  This includes emerging side effects, and responses that could even be worse than the 2mg/kg data, e.g. if some patients do not respond at all or if the company is right in their biomarker assumptions which due to chance could make the 4mg/kg data look worse numerically. 

Therefore, my base case for market-neutral data is that all patients will have to respond, and that the extent of the response will be similar to that seen with the 2mg/kg dose.  But then again, I’m looking at the data and keep thinking to myself…’8mg/kg might be the one-shot cure that could transform HCV treatment’.  In any case, the company has little to lose from dose escalating to 8mg/kg.

Predicting the Outcome of Regulus HCV microRNA Therapeutics Study

Regulus Therapeutics is on track to reveal phase I results of its anti-HCV compound by the end of the year according to a presentation at last week's OTS.  Although the phase I study is largely a healthy volunteer dose-escalating safety study, it does involve a cohort of HCV patients to assess the viral knockdown kinetics following a single dose of anti-miR122 RG-101. 

MicroRNA-122 is a small RNA host factor that had been identified to play an important role in HCV replication.  As a therapeutic target it promises a low risk of viral resistance, pan-genotypic activity, and entirely novel mechanism of action making it suitable for combination therapy.

Based on the experience with an LNA-based competitor compound by Santaris/Roche (Janssen et al. NEJM 2013), I predict a 2 to 3 log viral knockdown, with a 3 log viral knockdown setting the scene for RG-101 as a single shot in a 4-week treatment regimen in combination with other oral direct-acting antiviral agents (DAAs).  If viral reductions were on the low end of my expectations, it may require 2 or 3 doses within 4 weeks for GalNAc, cET-enhanced RG-101 to facilitate such a short treatment period which is considered a necessary attribute of future treatment regimens in an increasingly competitive market.

Miravirsen comparison

Earlier studies by Regulus competitor Santaris/Roche largely form the basis for my predictions.  In particular, a phase II study of 5 weekly doses of miravirsen at 3, 5, and 7mg/kg yielded 1.2log (3mg/kg) and ~3log (5 and 7mg/kg) viral knockdowns.  Miravirsen is an LNA-based antisense compound whereas RG-101 involves the analogous high-affinity cET chemistry.  Conservatively, miravirsen has a slight (1-3x) potency advantage over RG-101 without the GalNAc conjugation when considering non-human primate and clinical AldoA and cholesterol results which reflect anti-miR122 activity.

However, the GalNAc conjugate in RG-101 is giving it a great 10-30x boost in potency, meaning that overall RG-101 should be 3-30x more potent than miravirsen.  It is because of this and considering that RG-101 is given at 2 and 4mg/kg in the phase I trial in HCV patients, that I arrive at a predicted 2-3 log HCV reduction in the phase I study.  This also makes the conservative assumption that 3log viral reductions is all that an anti-miR122 treatment strategy may achieve based on the apparent plateauing of miravirsen at 5mg/kg.  The 3 log prediction would require that a single shot of RG-101 can already achieve super-therapeutic tissue levels of the oligo.  This, however, cannot be assumed given that for non-ligand-targeted phosphorothioate antisense technology at least this would normally require a multi-dose loading schedule.

But isn’t RG-101 late to the HCV game?

It’s long been thought that it’s game over for RG-101 given the dynamics in the HCV markets.  In particular, the already approved and soon-to-be-approved all-oral DAAs which typically achieve cures in >90% of patients in 8-12 weeks in well-supervised clinical trial settings, would make newer agents like RG-101 seem outdated.  On the other hand, especially given cost pressures (~$100K per average treatment and ~4 million infected in the US alone), the uptake of the new treatments has been relatively slow with only 1-2% treated thus far (according to some of the analyst reports that I have read).  And even then, the sales have been spectacular: Sovaldi e.g. is on track to become the most successful drug launch ever being on track for more than $10 billion in sales in its first launch year!!!

It is the cost pressures (pricing per pill, not per cure) and improved adherence that make a shortened 4-week treatment period so desirable.  A single or two subcutaneous injections in the doctor’s office during routine check-ups where blood is taken anyway should add to compliance.  Holding the subcutaneous route of administration of RG-101 against the drug is therefore wrong in my opinion and the ‘all-oral’ notion, a misnomer really, has only been so attractive because the former subcutaneous standard of care, interferon, was so unpopular not because of the needle injections, but because of its side effects.

So place your bets.  I believe RG-101 has value and will not only be superior to the Santaris/Roche drug, but has pretty much caught up with it in development terms given that miravirsen has only been tested with a DAA (telaprevir) that is already long outdated.  As to the necessary Big Pharma/Biotech licensee, Johnson&Johnson tops my list.

Disclosure: Long RGLS as an RNA Therapeutics stock waiting to be re-discovered with an increasingly broad and clinical-stage pipeline and good financials.  The RG-101 results should only be the trigger for the re-discovery of this ~$300M market cap company.   

Regulus Borrows from RNAi Delivery Technologies…5 Years Late

With the gift of birth of having access to all the technology toys from parent companies Alnylam and ISIS, Regulus Therapeutics in 2007 was poised to speed into the clinic a new class of RNA Therapeutics: microRNA Therapeutics.  Today, Regulus has yet to put a single compound into clinical development.  This not only reflects the increased biological complexity of microRNAs as opposed to for example single gene knockdown approaches such as RNAi Therapeutics, it also reflects a fear of breaking with the dogma that for microRNA inhibition ‘naked’ antisense technologies should be used.

It turns out that only now, Regulus finds that in order to optimize the product profile for their lead program, anti-miR122 for the pan-genotypic treatment of HCV infection, they really ought to borrow from RNAi delivery, in this case GalNAc-conjugates from Alnylam.  With this, they will achieve more potent miR-122 inhibition as well as increase the therapeutic window through the targeted delivery.  This is opposed to saturating the target organ along with the rest of the body with ‘naked’ phosphorothioate molecules, a concept I'm struggling to get comfortable with. 

The case for such a facilitated delivery strategy is even stronger for an antiviral anti-miR candidate such as this one because hitting the virus instantly instead of only slowly reaching effective drug concentrations in the target organ reduces the risk of drug resistance.

As a result, Regulus will enter the clinic with RG-101 at a time when the first all-oral HCV therapeutics with high cure rates will have hit the market.  This is a commercial catastrophe for an otherwise scientifically sound target.

One already has to be thankful that a small organization such as Regulus is able to show such flexibility at all (I don't even want to know in which antiquated terms Big Pharma is thinking about microRNA Therapeutics).  This achievement almost makes me afraid to ask why they have not thought it through to the logical end and adopted more structured, and much more potent anti-miR structures along with these delivery technologies?  This armchair CEO would have had a SNALP/structured anti-miR strategy tested in 2008.

However, Regulus Therapeutics has a chance to redeem itself- at least partly.  As it evaluates GalNAcs and LNPs (SNALP?) for an anti-miR program in liver cancer (HCC), it could for example help the RNAi Therapeutics industry understand whether the GalNac-receptor (ASGPR) is suitable for RNAi Therapeutics candidates for the attractive liver cancer indication.  So as Tekmira has followed Arrowhead Research into HBV, maybe Arrowhead Research may want to follow Tekmira (TKM-PLK1) into HCC.

Disclosure: The idea for this blog entry came after I started to look into RGLS ahead of the AASLD meeting (Nov1-5).  I concluded that there would be a good chance that with presenting a promising profile for RG-101 at AASLD and maybe some new data for the Alport Syndrome at the Kidney Week also in early November (Nov5-10), we could see RGLS bounce back into the $9-10 range by mid-November.

ISIS Claims Scalp of Santaris CEO

After noticing that the former President of the US operations of Danish LNA antisense company Santaris, Art Levin, had just joined muscle microRNA Therapeutics company miRagen, I was alerted that this has been in the wake of a major shake-up at Santaris. Most notably, it appears that the CEO of Santaris, Soren Tulstrup, either handed in his resignation, or, more likely, was let go.


Privately-held Santaris, of course, has been a fierce rival of ISIS for supremacy in the antisense space.  Having former ISIS insider Art Levin join Santaris 2 1/2 years ago was in fact a bit of a coup for that company.  Its LNA technology is probably the most potent/high-affinity in the space for many applications.  ISIS, however, has had the benefit of increased financial might and having built a large patent estate that it is (ab-)using to sue, preferably smaller competitors with the obvious intention of making it difficult, if not impossible for those to raise capital and pursue business development opportunities.  It is rumored that ‘partner’/satellite company Alnylam has probably paid the price in the tens of millions for the privilege of going public.   


Not long ago, ISIS sued Santaris for unduly hiding under the Research Exemption in its various relationships including Pfizer, Enzon, GSK, and Shire.  In parallel, ISIS and microRNA spin-off Regulus have been haunting Santaris by questioning Santaris’ ability to develop its exciting lead candidate, miravirsen, a miR-122 antagonist for the treatment of HCV.  As a result, Santaris was dumped by GSK in favor of Regulus’ miR-122 program despite having the superior data package, which is also born out by the clinical data so far (here for the latest update at EASL).


Regulus announced this week that it was awarded another HCV miR-122 patent, in Japan, concluding with the remark that it was continuing to pay 'attention to hepatitis C'- somewhat ironical given that its clinical entry seems to be delayed forever.  Seeing that announcement, I had thought that this was one of the unnecessary PRs that I often take as a sign of weakness. In hindsight, it was probably just a case of adding insult to injury.


I myself have had reservations about the wisdom of building the company’s financial future on a program for which it may be lacking access to some of the key patents in the space.  Although one may assume that in the wake of its scientifically leading efforts in miR-122/HCV, Santaris will have in turn built IP to which Regulus would need access if it were to develop its own miR-122 antagonist,  such a strategy has been a high-stakes gamble for sure.  Along with the ISIS lawsuit questioning Santaris’ fundamental business development strategy, I would therefore not be surprised if the CEO had faced some tough questions by Santaris' investors about his decisions and consequently was ousted. 


Clearly, an exit in the form of an IPO or takeover had long been overdue for that company.  The company’s technology, pipeline, and relationships, also in light of what’s out there already (i.e. ISIS and AVI Biopharma), should have easily supported this, if not for the lawsuit and threats thereof.

GSK Dumps Santaris, Chooses Regulus

Patents still matter. An impressive demonstration late last year by Santaris and collaborators from a primate center in Texas was not enough for GSK to exercise its option for SPC3649, Santaris’ lead microRNA therapeutics candidate directed at miR-122 for the inhibition of hepatitis C virus (HCV) infection (discussed on this blog here, and in a review by Mark Kay and myself here). Instead, Alnylam/ISIS-backed Regulus announced today that GSK has decided to side with them in the development of such an miR-122 antagonist for HCV. This is an amendment to an earlier inflammatory disease collaboration between Regulus and GSK with undisclosed upfront and ~$150M in potential milestones plus the usual tiered royalties on drug sales.

GSK’s decision not to exercise the Santaris option led to speculations, also on this blog, whether it is maybe the concern that miR-122 inhibition might be tumorigenic or could have other adverse effects on the liver. While one certainly ought to pay attention to such potential, the pre-clinical safety data and the expectation that any such therapeutic would not be administered chronically would have made this an unusually conservative decision.

It now appears, however, that GSK just could not ignore the fact any more that it is Regulus that got the exclusive license to the critically important miR-122/HCV Sarnow patents. The move can also be interpreted such that while LNAs are certainly an attractive approach to inhibiting microRNAs, there are alternative chemistries of similar potency. A new type of locked nucleic acid chemistry developed by ISIS that was inspired by and looks a bit like Santaris' LNAs but for a few adornments, that supposedly also make it less toxic, is one such chemistry that I could imagine Regulus-GSK to select for their IND-enabling studies. It is worth remarking that it is probably less the miR122-related Esau patent that was the swaying factor here, since as issued in the US, the Esau patent called for a fully 2’-MOE antisense molecule against miR-122…probably not a gate-keeping chemistry for microRNA antagonists.

It will be exciting to further monitor the race between Santaris (already in the clinic) and Regulus in developing a microRNA-based HCV therapeutic, including how the IP will be sorted out. In this context, I can only appeal to the players not to engage in big patent fights at this time and let the better arguments win, but outside the patent appeals courts and civil cases. To paraphrase related comments by the new CEO of Silence Therapeutics, Phil Haworth, yesterday, this is an utter waste of money and management attention. Time to wake up!

PS: Another milestone in the deepening relationship between GSK and Alnylam, and GSK’s move into innovative, high-value medicines.

Anti-miR122 Antagomir Successful in Fighting HCV in Chimpanzees

I just wanted to post this video by KENS 5 on the anti-miR122 studies in HCV-infected chimpanzees by Danish LNA company Santaris and researchers from the San Antonio Southwest Foundation for Biomedical Research. The study, just published online in Science, shows surprisingly potent reduction of HCV levels (2 1/2 logs) with an miR-122 antisense inhibitor and, at least equally important, without the emergence of viral escape mutants. While this study only involved four chimpanzees and human studies are still in the early phases (phase I, healthy volunteers), these results justify hopes that such a first-in-class agent could be a valuable component of future combination therapies with increased cure-rates, shortened treatment times, and maybe without the need for current standard-of-care component ribavirin.

Curiously in light of these promising results, it appears as if GSK let an option to the Santaris compound expire. While Big Pharma may have multiple reasons why it does not want to pursue a certain compound aside from the science (e.g. the fact that HDL-cholesterol was lowered as a result of miR-122 inhibition could warrant caution), for example product portfolio considerations, one possibility is that IP concerns and GSK's relationship with Regulus were important factors: Regulus has an exclusive license to the IP surrounding the fundamental work by Jopling and Sarnow on the role of miR-122 in HCV replication. While this may be good news for Regulus, I was made aware that the broad Esau and Tuschl patent applications on microRNAs as therapeutic targets and held by Regulus are being narrowed down considerably by the patent offices.

Note: For a more detailed discussion of this paper, please read the review by Mark Kay and myself in Molecular Therapy (click here).

Santaris Initiates First Clinical Trial for a MicroRNA Therapeutic

Another notable milestone has been reached in the history of small RNA-based therapeutics. Yesterday, Santaris announced that it had commenced a clinical trial for SPC3649, an LNA-based antisense molecule against miR-122 for the treatment of Hepatitis C. The phase I trial will be a double-blind, randomized dose-escalation study involving 48 healthy male volunteers.

MiR-122 has been shown to facilitate HCV replication as well as to have a role in cholesterol synthesis. Because of these potential applications and its expression in the liver, the tissue that can be best addressed with today’s systemic delivery technologies for nucleic acid-based therapeutics, miR-122 has become the favorite target for first generation microRNA-based development programs.

Santaris has made rapid progress and appears to be leading anti-miR-122 efforts, at least based on the published literature, with most prominently a recent Nature study demonstrating miR-122 antagonism in non-human primates, but also a nice transcriptomic study looking at changes in gene expression following miR-122 inhibition in mice. Santaris is using so-called LNA-“mixmers” which consist of a combination of interspersed DNA and LNA nucleotides and a phosphorothioate backbone and appear to act by sequestering the microRNA in the cytoplasm.

In mice, this LNA-antimiR-122 was quite a bit more potent than a competing technology developed originally by Alnylam and now owned by Regulus Therapeutics (‘antagomirs’) which were thought to induce the degradation of miR-122, possibly by RNase H. While these differences may also relate to the tissue concentrations and tightness of hybridization achieved by the various chemistries, my impression is that sequestration rather than RNaseH is the more promising approach to antagonizing microRNAs while for mRNA inhibition by antisense the opposite may be the case (e.g. morpholino versus gapmers). Moreover, the exact mechanism of action of the antagomir is still somewhat controversial, and I am curious to learn about the potency of antagomirs in vivo when formulated into SNALP-like particles.

A remarkable aspect of the LNA-antimiR-122 studies in non-human primates was the long duration of activity, up to 100 days after 3 loading doses of the antisense as judged by the lowering of plasma cholesterol. However, at this time point, the shift in the Northern blots which was taken to directly reflect microRNA sequestration, was not observed at this point. This could either mean that the Northern blot shift may represent an experimental artifact due to hybridization of antisense to miR-122 following sample preparation, and/or that the cholesterol lowering had persisted after LNA-antimiR-122 has ceased to sequester miR-122.

Of course, while the speedy technological progress is encouraging, there are a number of risks associated with this program. One is that it is unclear whether successfully inhibiting miR-122 in a chronic hepatitis C infection in man will have a meaningful effecgt on HCV burden. Compared to targets in RNAi Therapeutics trials, little is known about the actual role of miR-122 in HCV replication. Unlike in tissue culture liver cell lines which generally express less miR-122, miR-122 is a very abundant microRNA in the liver and may not be as rate limiting for HCV repliation in vivo. The argument, however, that this drug candidate lacks in vivo validation could be applied to a range of other HCV therapeutic programs, some of which have proven to be successful. The development of more convenient animal models for HCV infection over the next 5 years should change this and benefit not only the development of miR-122-based HCV therapeutics, but particularly RNAi-based HCV antivirals.

The Nature studies have also shown that anti-miR-122 may have limited utility for the treatment of hypercholesterolemia as its inhibition downregulated the “good cholesterol” even more than it did the “bad cholesterol”. On the other hand, given its abundance in the liver, it is likely that other indications for miR-122 antagonism will emerge and for which the Santaris phase I trial could be leveraged.

As far as the business strategy is concerned, maybe Santaris ought to solve the IP issues surrounding miR-122 for HCV once they initiate HCV-specific studies, as related IP fundamental to such an application has been exclusively licensed to Regulus and may thus limit the partnership value of this promising program.

The Race to Knocking Down Cardiovascular Disease

Given the burden of cardiovascular disease in the Western world representing a multibillion dollar drug market, finding a drug to complement statins in reducing complications due to high levels of bad cholesterol is naturally high on the priority list of many drug developers. The recent OTS Meeting and a Press Release by Alnylam emphasising their leadership by having obtained first-ever data on safely and effectively knocking down PCSK9 with RNAi in non-human primates, illustrate home the promise of RNA-based therapies for CVD. The interest is largely rooted in the fact that targets such as PCSK9, ApoB100, and potentially microRNA-122, well known determinants of blood cholesterol levels, but which have proven impossible to target by traditional small molecule approaches. Moreover, these targets are expressed in the liver, and it is clear by now that current systemic oligo delivery technologies allow them to be knocked down in vivo. Hence, the race is on to who will be first to develop a safe and efficacious oligonucleotide-based therapy for hypercholesterolemia and stand to reap the benefits of a potential blockbuster in the first phase of RNA-based drugs.

Assuming that it is a safe bet that cholesterol levels can be reduced with oligo-based strategies, what will determine regulatory success? Given that low cholesterol is a life-long effort, any drug taken over a long period of time, even before disease onset, will have to be safe first of all. Risk can be largely grouped into four categories: target risk, risks inherent to the therapeutic platform, sequence risk, and risks associated with route of delivery and drug formulation. Arguably the target best validated on the grounds of human genetics is PCSK9, a protease that degrades LDL-receptors and therefore inhibits clearance of bad cholesterol from circulation. Research mostly from the University of Texas Southwestern has shown that mutations that increase the activity of PCSK9 increase cholesterol levels, whereas individuals with nonsense mutations in PCSK9 that reduce PCSK9 activity have lower cholesterol levels and, importantly, a much reduced risk for cardiovascular events. Moreover, the absence of any functional PCSK9 throughout life has no obvious adverse side-effect while retaining the health benefits of low cholesterol.

Before PCSK9 came to the fore, ApoB100, a protein required for the assembly of LDL-cholesterol, used to be the target of choice. Indeed, the development of PCSK9-based treatment strategies have extensively made use of ApoB100 as a marker protein for evaluating RNAi delivery and knockdown in the liver. Pioneering research mostly by ISIS Pharmaceuticals has shown that indeed ApoB100 knockdown has the ability to lower LDL-cholesterol. Although ISIS has not seen fatty liver in clinical trials and preclinical research of their lead antisense compound ISIS 301012 (currently in late phase II) to be a problem, various other groups have observed this side-effect following ApoB100 knockdown, which would not be that surprising given the role of ApoB100 in fat metabolism. However, even if fatty liver will be observed in larger phase III trials and post-approval, ISIS has made the right decision to test 301012 first for patient populations most at risk for CVD.

Similar to ApoB100 and PCSK9, inhibition of microRNA-122 by antisense technologies has been now shown numerous times to also have LDL-cholesterol lowering effects. Strangely, despite the fact that this is by far the most abundant microRNA in the liver, no obvious toxicities have been associated with miR-122 inhibition. Consequently, a number of groups such as Regulus and Santaris hope to develop this into a treatment for hypercholesterolemia.

Taken together, my bet is on PCSK9 knockdown to lead the way in oligo-based therapies for the long-term treatment of hypercholesterolemia. New targets, however, should emerge, partly as a result of now being able to apply RNAi itself for target identification, for example by transiently targeting essentially any gene of interest in the liver in vivo and the use of transgenic RNAi mice (Artemis), a combination of the two latest Nobel prize-winning technologies.

Next to target choice, the nature of the knockdown technology, antisense versus RNAi, itself will also have important safety implications. As I am quite fascinated about the prospect of RNAi for various reasons, please keep in mind that my natural inclination is to favour RNAi any time. In terms of potency, once equal amounts of oligos get delivered into the cell, RNAi has been shown frequently to be generally superior to antisense oligos (ASO), although antisense technologies can be quite diverse. Lower dosages will not only reduce cost of a treatment that has to be taken long-term, but, more importantly, allow for dosages that fall well within therapeutic windows. Moreover, in the case of RNAi, I feel quite comfortable with a technology where the risks such as immuno-stimulation, off-targeting, and potential interference with the endogenous microRNA pathway are reasonably well understood, intensely studied, bioinformatics- and chemistry-based solutions devised, and well taken into account in current RNAi-based drug development efforts. This in fact reflects a new awareness in RNA-targeted therapies, largely driven by the renewed interest generated by the discovery of RNAi. Accordingly, the therapeutic utility of any two RNAi compounds, or antisense compounds for that matter, may differ dramatically due to sequence-dependent toxities.
These toxicities may also be linked to route of delivery and related oligo formulation. A technically quite uncomplicated approach, as taken by 301012, is to simply administer relatively large amounts of unformulated oligos (200mg/week in the case of 301012) to make sure that enough of it ends up in the liver. By contrast, liver uptake of siRNAs is thought to require additional formulation. Indeed, liposomal formulations that are set to enter the clinic within the next year increase liver uptake of siRNAs from less than 1% of injected material to over 30%, allowing for lower dosages to be used. Some toxicities, however, were observed at relatively high dose levels with some of the cationic liposomes, and it remains to be seen whether lipidoids and other “not-so-cationic” liposomes will come to dominate the liver delivery field. Also, while most of the disclosed liposomal delivery vehicles efficiently enhance liver uptake, they are often not specific for uptake into the hepatocyte population in the liver, the cell type of interest. Particularly uptake into Kupffer cells, a type of immune cell in the liver, can lead to dosing and safety complications, and ultimately the path taken recently by scientists from Mirus, which by the way has an RNAi delivery collaboration with Pfizer, to specifically target formulated siRNAs to hepatocytes, but not other liver cell types, may substitute non-specific liposomes in the second wave of RNAi-based therapies for hypercholesterolemia. While delivery is often described as the Achilles Heel for RNAi therapeutics, the charge (ironically) and chemical similarity of siRNAs as a class makes them ideally suited to devise drug targeting strategies that can be broadly applied and should lead to safer therapies, something that is nearly impossible for say small molecules.

ISIS’ ApoB100-targeting antisense 301012 has good chances of becoming the first oligo-based therapy for CVD, at least for people with familial hypercholesterolemia and for whom statins don’t work. Although only a fraction of the overall market, the sheer size of the cholesterol market makes this a lucrative goal nonetheless. I am somewhat surprised that, to my knowledge and despite potential target risk, there is little talk of other ApoB100-targeting therapies. It will be interesting to see what companies like Merck, which has clearly stated their admiration for 301012 at the last OTS Meeting, are willing to pay for rights to 301012. PCSK9-targeting therapies are in late preclinical development and therefore about 3 years behind 301012, but I believe these to be the safest bet for a widely applied oligo-based drug for hypercholesterolemia with a number of organisations ramping up their PCSK9 programs.

Alnylam appears to be leading this race with the recent announcement of first-ever non-human primate data of an RNAi compound that safely and effectively knocked down PCSK9 with concomitant reductions in total and LDL-cholesterol. An IND is planned for the end of this year, or early next year, and probably will depend on finding the delivery solution that most importantly is safe for long-term administration. Importantly, Alnylam enjoys a particularly strong IP position and know-how in targeting PCSK9 by RNAi, due to their own position in fundamental RNAi technology, and important collaborations on the biology of PCSK9 with UT Southwestern, which has been leading in the genetics of PCSK9, as well as in delivery with the Anderson/Langer lab at the MIT and exclusive access to Tekmira’s cationic liposomal delivery IP for RNAi. Sirna-Merck may want to dispute this with an patent on targeting the same PCSK9 by RNAi that issued recently and was filed in July 2006 as part of their brute-force approach to patenting genes for RNAi. Alnylam, however, presented their first PCSK9 RNAi data in mice at last year’s 2nd Annual OTS Meeting, and it is anybody’s guess when their or rather UT Southwestern’s first lab-book entry on PCSK9 RNAi occurred. Probably at a similar stage to Alnylam is the PCSK9-antisense collaboration of ISIS with Bristol-Myers Squibbs for which mouse data have been published earlier this year. Santaris’ antisense compounds for PCSK9/ApoB100 and miR-122 should also be heading soon towards the clinic.

New delivery technologies, including oral formulations, and targets should ensure that the oligo-CVD field will remain lively in the years to come. Also, since there have been a number of recent data demonstrating efficient targeting of RNAi to the endothelia of blood vessels, new RNAi strategies aimed directly at the atherosclerotic plaques may emerge.

It would not be the first time that several similar compounds, small molecule, antibody or recombinant protein, with essentially the same molecular targets, would co-exist in a market, a concept also very familiar to the hypercholesterolemia field. IP, careful clinical development involving the best scientists in both oligonucleotide technology, delivery and the biology of the drug targets, together with a bit of luck, will decide who will reap the largest benefits from the potentially first knockdown blockbuster.

Impressions from the 3rd Annual Meeting of the Oligonucleotide Therapeutics Society: Day 1

The 3rd Annual Meeting of the Oligonucleotide Society (OTS) got under way in the stylish Langenbeck-Virchow Auditorium situated in the centre of a culturally vibrant Berlin. The OTS brings together the many disciplines in the rapidly expanding field of oligonucleotide-based drug development, ranging from aptamers, ribozymes, antisense, immunostimulatory nucleic acids to RNAi. Reports from clinical studies of these treatment modalities and oligonucleotide chemistries were at the centre of today’s lecture sessions.

Brett Monia from ISIS Pharmaceuticals chaired the first session and set the stage by reporting that while there are only four approved oligo-based therapies, more than 50 are currently in clinical development. Many of these are designed for cancer applications, but infectious, metabolic, and inflammatory disease applications are emerging as major new focus areas. This may not only be due to considerable unmet medical needs, but also because these may offer better success rates for clinical development. A few talks on cancer therapies with ASOs (antisense oligos) documented the challenges of designing smooth clinical trials for cancer therapies. One problem is the heterogeneity of cancers and matching the gene target with the right cancer. Early trials on a given compound typically involve small patient numbers with a wide spectrum of cancer manifestations. Although safety trials, almost anecdotal evidence of biological activity in a few patients then often guide the design of later phases of clinical development. Clearly, for cancer, there is a need for the development of more reliable biomarkers as early indicators of therapeutic efficacy and for patient stratification, which may be something that Rosetta Genomics’ microRNA diagnostics may be able to facilitate.

Focusing on diseases like viral infection and metabolic disease where efficacy can be routinely evaluated in early stages of clinical development (viral titers, LDL-cholesterol, glucose) should therefore be lower hanging fruits for the next wave of oligonucleotide-based therapeutics. This transformation in the industry is illustrated by ISIS’ new focus on metabolic disease and its out-licensing of the more challenging ASO applications. Rosanne Crooke recounted the clinical experience with 301012, ISIS’ lead compound for the treatment of hypercholesterolemia. As I wrote earlier, one major concern with targeting ApoB100 is the risk of steatosis of the liver due to inhibition of a protein required for the export of triglycerides and which has indeed been observed by a number of groups targeting ApoB100 by RNAi. Possibly motivated by the existence of individuals with null mutations for PCSK9, the new target of choice for hypercholesterolemia, with no evidence for adverse effects due to lack of the LDL-receptor processing protein, a conference participants asked about the existence of ApoB100 knockout mice. Interestingly, no such mice exist, because ApoB100 would have additional roles during development.

Despite reports of steatosis due to knockdown of ApoB100 with RNAi, Sirna Therapeutics is yet another biotech company interested in targeting it for lowering cholesterol. In a talk about siRNA delivery to the liver, Barry Polisky, CSO of Sirna Therapeutics/Merck also noted that in Sirna’s experience, there are genes that can be knocked down extremely well (e.g. ApoB100) and some that are relatively refractory to knockdown by RNAi. Although anecdotal, given the extensive experience of Sirna Therapeutics with screening for effective siRNAs by tiling them across entire genes, and similar findings by Qiagen and others, it will be interesting to determine what makes a gene a good target for RNAi, particularly whether it involves its normal regulation by microRNAs.

Polisky further focused on the need for siRNA modifications to make RNAi therapeutics a reality. Currently, Sirna’s standard siRNA design seems to involve si(R)NAs that lack essentially all 2’OH groups, except for the three 5’ nucleotides of the guide strand, while the passenger strand has 5’ and 3’ modifications that avoid it to be loaded into RiSC to reduce off-targeting. Other speakers and posters also noted that since most nucleotide modifications had been developed with antisense therapies in mind, new modifications may exist for optimal RNAi efficacy, particularly in vivo. Indeed, new synthesis strategies are being developed that will allow this to be tested, such as the 6-membered carbohydrate substitutions of ribose reported by Piet Herdewijn from the University of Leuven, Belgium.

Polisky further characterized siRNA delivery to the liver as efficient, albeit not optimal. Progress is clearly illustrated by the fact that >30% of siRNA formulated into liposomal nanoparticles now end up in the liver with first-pass kinetics with no evidence for toxicity in the 1-9mg/kg range (mostly rodent studies), whereas >99% of unformulated siRNAs are rapidly filtered out by the kidney.

The liver is also the organ where the first microRNA-based therapies are likely to be targeted. Like Regulus and Rosetta, I was amazed, or maybe not, at how many groups are currently working at abrogating miR-122 function for treating either hypercholesterolemia or HCV infection. LNAs, owned by the privately held Danish company Santaris, appear to be a particularly promising oligonucleotide class for achieving potent microRNA down-regulation in vivo. Similarly, antisense strategies based on LNA appear to rival siRNA potency in a number of settings, and it will be interesting to learn more about the toxicologies of these compounds, which would certainly be facilitated if Santaris decided to enable to field by allowing better access to their technology. It also highlights the need for specialized chemistries for therapeutic targeting of microRNAs which in my mind is something that Regulus ought to consider.

With regard to delivery outside the liver following systemic administration, PEI-formulated siRNAs (see recent PolyPlus-Alnylam deal) are now being used successfully by a number of groups for lung delivery. Other interesting delivery data was presented by a Portuguese group in a poster on RNAi in the brain. By non-covalently adding transferrin protein to cationic liposome-siRNA particles, they were able to efficiently target neuronal cells both in vitro and in vivo which, similar to cancer cells (see Calando’s cancer cell targeting with transferrin), are studded with transferrin receptors.

PS: A nuisance to most scientists in the field, immunostimulation by oligonucleotides is exploited by Dynavax as an adjuvant for vaccines. Poor adjuvants activity lead to insufficient immune responses and the need for multiple booster injections affecting compliance. HBV vaccination is a case in point, and as a consequence around 50% of patients in the US fail to successfully complete vaccination. Very high HBsAg antibody titers after only two injections of recombinant HBsAg with an immunostimulatory oligo from Dynavax as adjuvant, instead of alum, suggests that they may be able to greatly improve on those numbers.

Regulus Rx, Where One and One Equals Five

One has to be impressed by the way John Maraganore, chief astronomer and CEO of Alnylam, and his team are maximising the value of their company’s scientific know-how and intellectual property. Last week’s launch of Regulus Therapeutics, a joint venture with ISIS Pharmaceuticals focussed on the development of microRNA-based therapeutics, is the latest in a string of strategic decisions that positions Alnylam to lead and participate in the very promising field of RNAi-related therapies while wisely managing the company’s resources and respecting the scientific challenges ahead. The scientific and financial results speak for themselves and are starting to catch the attention and respect of Wall Street and beyond.

Forming this joint venture not only consolidates and complements much of the IP in microRNA-based therapeutics, it also allows the respective companies to focus on their core operations in RNAi and antisense while giving the new company a distinct identity and independence that should incentivise their employees and help attract 3rd party funding, particularly in the form of alliances with larger partners. The joint venture also acknowledges the fact that microRNA therapeutics sets a new paradigm for treating disease with its unique set of challenges and risks.

Based on pioneering work by Regulus SAB member David Bartel and his group at the MIT, it is now believed that the approximately 1000 human microRNAs regulate around one third of our genes, “that is one third of our genes” (Stanley Crooke). It follows that each microRNA targets multiple genes. Targeting a microRNA for therapy is therefore based on the premise that the functions of these genes are linked to a common biological process hence limiting the potential for unwanted side-effects by disturbing unrelated pathways. In this sense, microRNA- and RNAi-based therapies are opposite philosophies where siRNAs seek to surgically target single disease-associated genes, whereas microRNAs are aimed at whole networks. Genetic research supports both approaches, and a number of microRNAs have been shown in animal models and human cells to specifically affect discrete regulatory pathways, a fact that is arguably best understood by two key SAB members of Regulus Rx, namely David Bartel and David Baltimore. A recent catalogue of microRNAs established by yet another Regulus SAB member, Thomas Tuschl from the Rockefeller, however, suggests that many microRNAs are constitutively expressed in a number of tissues, thereby slightly questioning whether this is the case for most microRNAs. Although a truly exploding field of research, compared to RNAi Therapeutics where there are already an abundance of well-defined targets, the development of Regulus Rx will heavily depend on progress made in elucidating the exact role of specific microRNAs.

Regulus Rx’s first development program, targeting miR-122 for the treatment of Hepatitis C Virus (HCV) infection is a particularly interesting case. This program has been licensed from Stanford University where Catherine Jopling from Peter Sarnow’s group has shown that miR-122 specifically interacts with part of the HCV genome and thereby stimulates HCV replication. MiR-122 is by far the most abundant microRNA in the liver, and it is surprising that no obvious toxicities have been associated with its inhibition in vitro or in vivo, as demonstrated by work from both Alnylam and ISIS scientists. It is even thought that inhibiting it may have applications in managing cardiovascular disease. Earlier this year, Alnylam and ISIS were issued a patent covering miR-122 as a therapeutic target. I am quite curious to learn whether last week’s announcement of HCV miR-122 as the first development program of Regulus is also based on results targeting HCV replication by miR-122 inhibition in vivo. In this regard, it is notable that a leading group in HCV biology, the Rice group at Rockefeller only recently confirmed miR-122’s importance in HCV replication in a paper jointly published with Thomas Tuschl from the same institute.

Regulus Rx will be based in Carlsbad, CA, not only because of the better weather, but also because this is where ISIS Pharmaceuticals is located. This acknowledges the fact that antisense technology, pioneered and long dominated by ISIS, is the key enabling technology for antagonising mature microRNAs many of which are processed out of introns of RNA Polymerase II transcripts and therefore not a target for RNAi. This underscores the importance Alnylam has attributed to ISIS’ patent estate, also demonstrated by their exclusive licensing ISIS’ oligonucleotides modification patents for the use in double-stranded RNAi Therapeutics. It also sends out the subtle message that as Alnylam respects other parties’ IP it expects anybody interested in RNAi Therapeutics to follow this example by licensing from Alnylam.

The 50:50 joint venture also speaks volumes to the negotiating leverage Alnylam has gained in recent years, made possible in large part by its solid financial position. Only 3 months ago, the financial strength of Alnylam has allowed it to revise a partnership agreement with Medtronic that has given Alnylam a larger stake in the financial success of any drugs coming out of that collaboration in return for increased funding by Alnylam. Unlike ISIS which not long ago had to repeatedly issue debt to fund their operations and is biting its nails to gain financial freedom by partnering its ApoB100 antisense program, Alnylam could easily pay the $10M to equal the companies’ stake in the new venture. In addition to its financial muscle and Tuschl III which gives Regulus exclusive access to some of the most important microRNA targets, Alnylam further brings to the table its invaluable access to leading scientists in academia and Big Pharma alike.

Finally, it is notable that the otherwise wide-ranging technology access licenses that Alnylam has granted Novartis and Roche did not include microRNAs. It would therefore be appropriate that following last week’s development the newco be put on a solid financial footing through a significant partnership. But let’s give them some time for this as although the day may never end on Alnylam, on earth their day still has only 24 hours.

(For more on the scientific rationale for microRNA therapeutics, please read my Blog from 26 May, 2007: “MicroRNAs as Therapeutic Targets”)


PS: Once the dust has settled, we should learn more about the exact scope of Regulus Rx. Specifically, it is not clear to me yet whether in addition to antagonising microRNAs by antisense, the scope of Regulus will encompass the microRNA agonist approach as well where microRNAs mimics are introduced for therapeutic purposes. While this would strengthen Regulus’ portfolio, it would be a significant contribution of Alnylam IP since such mimics would essentially be based on siRNA technology.