Review of Recent RNAi-Related Developments

The last 2 weeks have been busy ones in the lands of RNAi Therapeutics.  Here, I would therefore like to offer my take on the most important developments.

Alnylam’s Primary Hyperoxaluria Drug Breezes Through Clinic

With 20 subjects on Lumasiran, a GalNAc-RNAi targeting glycolate oxidase, for a median of 7 months, the investigational treatment for type I primary hyperoxaluria (PH1) ismore and more looking like a solid drug.  If the data presented last week at a Paediatric meeting in Turkey hold up in another 30 patients, it should fly through approval onto the market by the end of 2019.

While the relatively small numbers in each cohort has caused a bit statistical noise, it seemed like 3mg/kg monthly gives you an advantage over 1mg/kg monthly or 3mg/kg monthly in terms of the key biomarker urinary oxalate.  Interestingly, the company has chosen 3 times 3mg/kg monthly as the loading dose regimen in the now ongoing pivotal ILLUMINATE-A trial to be followed by dosing every 3 months. , the initiation of which the company has just announced.    

The core double-blind portion of the trial runs for only 6 months, so I am a bit puzzled how much the trial can inform on the value of the loading dose regimen and whether quarterly maintenance doses are sufficiently effective.   In any case, the trial design apparently was blessed by the FDA (incl. the urinary oxalate lowering primary endpoint), so surely they will know (e.g. based on preclinical animal data).

Regarding the competition with the primary hyperoxaluria drug candidate from Dicerna, the approximately 2/3 lowering of urinary oxalate and essentially all patients getting into a range considered safe and an unremarkable safety profile sets a high hurdle for the upcoming data presentation of DCR-PHXC at ASN later this month.

Arbutus HBV-RNAi Drug About to Die   

Yesterday, Arbutus provided an update on its LNP-enabled RNAi drug candidate for the treatment of chronic HBV (ARB-1467) and it does not bode well.  Similar to most other drug candidates attempted and barely tried, ARB-1467 should be canned in the not-too-distant future. 

In a combination study testing ARB-1467 in chronic HBV patients on nucleoside reverse transcriptase inhibitor tenofovir, probably only 1 in 6 patients hit a pre-defined criteria in terms of HBsAg lowering that would allow the patient to then receive immune booster PEG-Interferon.  The not very forthcoming revelation and the fact that the data was mentioned even after dropping another shoe that its small molecule HBV RNA destabilizer is also biting the dust makes it clear that not even the company sees much value in ARB-1467.

What an utter disaster this company has been since its inception as a HBV solutions entity.

Arrowhead Early HBV Deal Further Validates

Last week, shareholders in Arrowhead Pharmaceuticals got a lesson in biotech investing as it shares have given up ~1/3 of its value following a nice deal with Johnson&Johnson for the leading HBV knockdown asset in the space, ARO-HBV.

The deal gives Arrowhead a solid $250M in financing, including a $175M upfront fee and a $75M investment in company stock at a premium of ~50% to current trading.  While this avoids an imminent dilutive secondary share issuance- the company had been running low of cash- the ‘up to 15%’ in royalties from future sales of early phase II-stage ARO-HBV is clearly disappointing.  The relatively low royalty despite of it having confirmed strong HBsAg knockdown in patients can be explained with the fact that Arrowhead has avoided bearing the full risk of having to show proof-of-concept of HBV control.  This despite of having earlier paraded results obtained with an earlier DPC-based RNAi candidate (ARC-520) as strong evidence that RNAi can achieve such immune control.

While Arrowhead got punished for playing it safely, it can now focus on commercial home-run indications with highly validated targets and transition to being a broad platform company with a wholly owned attractive lead candidate in ARO-AAT.  Indeed, Arrowhead may emerge as the leading RNAi company as Alnylam, with a market cap ~8x that of Arrowhead, is still burdened by late-stage RNAi drugs with suboptimal specificity.

While humiliating, this serves Alnylam as a good reminder to also value innovation by the direct competition (note: specificity-enhancing technology now adopted by Alnylam has been available for a decade and could have been had for peanuts, e.g. from now defunct RNAi play mdRNA/Nastech).  Fittingly, today long-time archrival Silence Therapeutics issued a press release indicating that Alnylam is playing hard-ball with regard to Silence-owned IP purportedly covering ONPATTRO.

My guess is that Alnylam would rather risk an injunction and deprive patients of a very good medicine than to submit to what appear to me legitimate demands of a competitor.

Akcea’s antisense drug for TTR amyloidosis gets FDA nod

Last Friday, Akcea’s TTR drug TEGSEDI (licensed from Ionis) finally got FDA marketing approval for patients suffering from TTR-related polyneuropathy.  As expected from the delay in the approval process, TEGSEDI’s approval is accompanied by hefty black box warnings highlighting thrombocytopenia and renal risks of the (non-GalNAc) phosphorothioate oligonucleotide.  

Furthermore, the REMS program calls for frequent blood monitoring, essentially negating the claimed at-your-home convenience advantage over competing RNAi drug ONPATTRO.  Add to the poor safety profile clear efficacy disadvantages and pricing at parity with ONPATTRO, ONPATTRO should clearly win out in the marketplace.

Having said that, the TTR community is relatively small and key opinion leaders with relationships to a given drug company tend to support the drugs from the same company.

Anti-MiR122 Therapeutic Stuns HCV World with Single-Dose Efficacy Results

This morning, Regulus Therapeutics greeted us with amazing results from a phase I study of RG-101, an anti-microRNA 122 oligo for the treatment of HCV infection.  The results show that in the exploratory HCV-infected patient subgroup, a single dose of 2mg/kg of RG-101 resulted in a mean viral load reduction of 4.1log on day 29.  All responded with viral declines, with 6 and 3 of the 14 patients with viral levels below the level of quantitation on days 29 and 57, respectively.   

These results even exceed my own wildest imaginations (as discussed here yesterday) and I’m amazed how much this virus, in all patients, seems to have come to rely on this host-derived microRNA for replication and/or genome stabilization.

It is not clear whether increasing the dose to 4mg/kg, the pre-planned upper dose in the HCV-infected cohort for which dosing is ongoing will bring any additional benefit given that the biomarker data (host genes targeted by miR-122) from the healthy volunteers showed a plateau already at 2mg/kg, indicating the power of this GalNAc chemistry approach.  My guess is that the main benefit from a higher dose would be a decrease in response variability.

Interestingly, IL-28 status, frequently a predictor of treatment success, did not influence the results, nor did HCV genotype seem to have an impact (small numbers).  This further supports that RG-101 could fill some of the more attractive opportunities in the current HCV market.   

Regarding safety, mild and transient injection site reactions seemed most significant with no serious adverse events in the entire study, including the healthy volunteer cohorts (up to 8mg/kg).  This is also consistent with data for Alnylam’sALN-TTRsc which uses a similar GalNAc chemistry and where multiple doses up to 10mg/kg had been tolerated, with injection site reactions, especially at 10mg/kg, being the main safety finding.   

So what’s it all worth?  The results position RG-101 to facilitate a 4-week HCV dosing regimen (compared to typically 8-12 weeks currently), potentially in combination with a single direct-acting antiviral such as Olysio by Johnson&Johnson.  One or two injections maximum.  Great compliance, potentially pan-genotypic, ideal for the busy practicing physician who does not have the time nor inclination to know the ins and outs of each DAA.

In dollar terms, I’d like to think that with this drug profile, this overlooked compound and company are worth as much as what Merck recently paid for HCV drug developer Idenix: $3.85B. The market valuation of Regulus before the news: $300M.  Needlessly to say that I'm long the stock.

PS: GSK once had rights to a precursor compound of RG-101 which it did not exercise.  Importantly, at the time, Regulus’ anti-miR122 compound was not GalNAc-enabled.  This would have necessitated much more frequent dosing and higher dosages and resulted in less potent and more protracted viral declines, i.e. something that would not have been competitive in the current HCV marketplace.  But as often the case with Big Pharma and cutting-edge technology, today’s data clearly shows them wrong.  It has to be said though that GSK more or less got out of HCV which also would have explained GSK’s decision RE anti-miR122.

PPS: Congrats to Peter Sarnow and Catherine Jopling who in 2005 made the mind-boggling discovery that HCV relies on a microRNA for its replication.  I hope they will be handsomely rewarded for it.

Johnson & Johnson Likely Tekmira’s Next Official SNALP RNAi Delivery Partner

Since I know that many readers of this blog share a keen interest in Tekmira and the fate of SNALP delivery, one if not the leading systemic delivery technology for RNAi gene knockdown in the liver, and likely with use for solid cancers and immune-related diseases as well, you may like what I dug out today from the long-neglected junk mail pile on my desk: An abstract for the 6th Annual CHI conference on ‘RNAi for Therapeutics’ (Boston 22-23 October) by Pieter Peeters from the Johnson&Johnson company entitled ‘LIVER-SPECIFIC KNOCKDOWN USING SNALP-FORMULATED siRNAs TO STUDY PATHWAYS IN LIPOPROTEIN SECRETION AND STEATOSIS’.

The abstract body, which can also be found online here, as follows:

“As the application of RNA interference in vivo further develops, we are pursuing several promising technologies for systemic delivery. The goal of the current study was to evaluate the SNALP (“Stable Nucleic Acid Particles”) systemic RNAi delivery platform to knockdown genes encoding for key enzymes in triglyceride synthesis. SNALP-Formulated siRNAs were found to effectively knockdown mRNA levels by >90% in liver compared to a SNALP-Delivered scrambled siRNA control. The effect knock-down in liver was further investigated following a 3-week high-fat feeding challenge. The results demonstrated the efficient in vivo SNALP-mediated delivery of siRNA by systemic route and the utility of targeting novel targets to reduce fat storage in liver and improve hepatic steatosis.”

It is thus apparent that J&J is one of the as yet undisclosed SNALP evaluation partners of Tekmira, and has extensively used the delivery technology for target discovery/validation purposes as well as with a view of using it as a therapeutic modality itself. Given the obvious success of their efforts (note that J&J chose to present SNALP from among the other 'promising' delivery technologies it has evaluated), I would not be surprised for J&J to soon join the ranks of Alnylam, Merck, Takeda, Bristol-Myers Squibbs, and Roche, as the next major Tekmira SNALP RNAi delivery partner.

While I do not say that SNALP is the end-all, be-all for gene knockdown of the liver with new technologies likely to emerge over time, the extensive successful use of the technology by third-parties is great validation of its reproducibility and clinical relevance for advancement into the clinic at this time, and a testament to not just the liposomal patent position of Tekmira, but also the RNAi-related know-how of its scientists (see also Tekmira’s publication on the immunostimulatory potential of siRNAs and how to avoid it here).

Beyond the use of SNALP-RNAi in target validation, where will J&J likely be interested in applying the technology clinically? My first bet certainly would be on the treatment of hepatitis C infection. Not long ago, we learnt from a report in RNAiNews that J&J was about to contribute to a $25M fund-raising round for the DNA-directed RNAi company Nucleonics before the deal was called off on questions about scientific misconduct. I honestly could not believe that J&J would even consider collaborating with a company that has entered an RNAi phase I clinical trial for hepatitis B that was so patently destined to fail because of the known inefficiency of liposomal plasmid (not siRNA) delivery.

Developing an RNAi Therapeutic for HepC has also to be seen within the context of building upon J&J’s imminent franchise in this hard-fought market. Together with marketing and development partner Vertex Pharmaceuticals it is currently conducting phase III studies for telaprevir, a protease inhibitor that has all the looks of becoming the next big breakthrough drug in HepC (my other favorite biotech drug story is Tysabri, in case you wanted to know). With predicted cure rates of 60-70% for type I after the introduction of protease inhibitors, RNAi antivirals should be able to enhance cure rates due to their complementary mechanism of action.

Two years ago, J&J awarded RNAi discoverer and Nobel Laureate Craig Mello the Dr. Paul Janssen Award for Biomedical Research. This alone leads me to believe that J&J should have broad ambitions in RNAi as a platform technology. As the number of conference abstracts related to RNAi in the liver (especially fibrosis, metabolic disease) suggests, the liver alone should yield sufficient targets to keep SNALP scientists busy for now.

PS: Since I know that this blog is also read by some larger investment companies, despite the apparently low volume of Tekmira on the Toronto Stock Exchange, it should be possible to acquire shares in size without moving the price too much as the overhang of Protiva stock following the merger is noticeable. End of advertisement.

The Wall Street Journal Reports that ‘Big Pharma Faces a Grim Prognosis’- In what Form will it take its RNAi Pill?

As I am procrastinating about what to write in a review about the ‘Business of RNAi’, I have tried to get more into the heads of Big Pharma rather than seeing the world from the RNAi company’s point of view as I used to. In a nice front-page article of the Wall Street Journal this week (http://online.wsj.com/article/SB119689933952615133.html?mod=googlenews_wsj), Barbara Martinez and Jacob Goldstein vividly painted a dark portrait about looming patent expirations and generic competition, declining drug approval rates, and a research enterprise that has just gotten too bureaucratic to respond to the new pressures.

To go biotech, which is now producing many of the most innovative and high-margin drugs and which has so far largely avoided similar pressures and proven quite profitable if you invested in the right platforms such as monoclonal antibodies and recombinant proteins, appears to be one of the last options left for Big Pharma to survive. As the likes of Merck, Pfizer, and AstraZeneca jostle to become the leading biotech company of the future, RNAi as one of the few broad technology platforms with a unique mechanism of action has to be up very high on their priority list. So how will Big Pharma get into the game?

There are the early adopters such as Merck, Novartis, and Pfizer which have been quite public about their RNAi efforts. Merck initially played the nice guy that wanted to help companies like Alnylam translate the science of RNAi into drugs. However, with the acquisition of Sirna Therapeutics and later difficulties with Alnylam, it is clear that Merck had grander ambitions than just being a humble licensee. Pfizer on the other hand has been trying this and that as if they first wanted to confirm the clinical viability of RNAi and then make their move. Eventually, unless of course RNAi fails (which I tend not to believe), they will all have to, because even though you are now allowed to use patented technologies with the intent of developing commercial drugs, the moment you hit the market, you have to pay in one form or another, and it is common practice that the earlier you license the less it will cost you.

As I’ve been trying (in vain) to find out which Prior Art was cited in the EPO decision as a reason to restrict the scope of Kreutzer-Limmer to 15-21 base-pair double-strand RNA in 2006 (if somebody can help me here, please contact me), I have come across a webpage on the EPO site where some of the opposition history of K-L is documented. I found it quite interesting that initially, the opposition included the likes of ISIS Pharmaceuticals, now Alnylam’s modification partner for RNAi Therapeutics, and Novartis, the second Big Pharma after Merck to take a broad license from Alnylam. Both of them dropped their opposition and instead joined Alnylam. On the other side there are the likes of Sanofi-Aventis, AstraZeneca, and Atugen (now Silence Therapeutics), and we know that AstraZeneca eventually took a license from Silence, probably the cheaper option.

It therefore appears that in the not-so-distant future we will see Big Pharma split into two camps- those with Alnylam, and those against Alnylam. The rationale for the latter either being the belief that they can find a way around Alnylam’s IP estate, or at least avoid some of the royalties by trying blunt-end dsRNA of longer than 21 base-pairs should K-L’s scope not stand. Of course, the higher the going rate for the license fees, the more the temptation to go that route, and maybe Alnylam bravely does not even mind it that way too much, since a sense of exclusivity probably makes the terms of the licenses more attractive for them. Nevertheless, for somebody with the balance sheet of many in Big Pharma, this would not only appear to be scientifically quite risky, but also penny-wise and pound-foolish. As the WSJ documented so well, the times have probably come to realize that a lot of the innovation has happened outside their research labs and no matter the correlation between wallet size and ego, being humble at the right time may help you survive the next 10 years. The same EPO website also says that Janssen Pharmaceutica, a subsidiary of Johnson and Johnson, has dropped their opposition- what do you conclude?