Tuesday, June 23, 2015

The RNAi Therapeutics Blog is Taking a Break

When it feels that everything has been said, it may be time to be silent for a while.

This point has come for me and the RNAi Therapeutics blog and I look forward to take part in the conversation with renewed energy and ideas.  Until then, you can follow the 'light' version of this blog on Twitter @RNAiAnalyst. 

Thursday, June 11, 2015

There is No Doubt: Splice Modulator Drug for Spinal Muscular Atrophy Works

The fairy-tale story of the splice modulation for spinal muscular atrophy (SMA) continues.  This morning, Isis Pharmaceuticals provided an update on the phase II study of ISIS-SMNRx in type I SMA infants.  The data built on already highly promising data as of last September, showing that a doubling (~9 to ~18 months) of the median ‘event-free survival’ compared to the Natural History has now been reached with numbers still increasing as more than half the infants remain event-free.

Only one out of 12 infants still on study suffered an event (permanent ventilation) over the last 9 months.  This one in 108 month event rate compares to 6 events in ~200 months in the prior phase of the study, suggesting that if babies can be diagnosed and treated early enough so that they are covered during a critical period of development (e.g. maturation of the neuromuscular synapse) chances are that they will enjoy a very significant treatment benefit from ISIS-SMNRx.

This is thus consistent with the biomarker data showing that ISIS-SMNRx increases the missing functional full-length SMN protein by 2-3 times essentially turning a type I SMA infant (usually 2 copies of SMN2) with an 80% chance of dying or going on permanent ventilation by 18 months into a much milder form of the disease where patients have 4 or more copies of SMN2 and have an almost normal life expectancy (note: those with 3 copies, usually type II SMA, live into teens/early adulthood). 

While as a parent, I would almost do anything for my child to get access to the drug and I do understand there to be calls for immediate (à once diagnosed, the window of treatment opportunity may be quite narrow) regulatory action, the first consequence of today’s data should be getting SMA on mandatory genetic panels for newborn screening.  Only then will there be maximal benefit once the ongoing blinded phase III study reads out in late 2016/early 2017.

Wednesday, June 10, 2015

Alnylam Slams Dicerna with Trade Secret Complaint

How times have changed.  Four years ago, Alnylam found itself on the receiving end of a trade secret lawsuit regarding the delivery technology du jour, SNALP LNP then, in which it ended up paying near-bankrupt Tekmira ~$70M to settle the allegations.  As I opined back then, Alnylam seemingly used almost any means to get access to the know-how to make SNALP LNP delivery work in primates in an effort to rid itself of the reliance on Tekmira, the inventors.

At that time, all Alnylam's CEO had to say on the topic of honoring trade secrets: 'you pay for it, you own it'.

Tonight, Alnylam claims to be the victim of similar trade secret misappropriations surrounding RNAi delivery technology.  In this case, Alnylam alleges (see Complaint) that Dicerna had hired ex-Merck RNAi scientists to gain access to critical GalNAc trade secrets invented at Merck after Merck sold their RNAi assets to Alnylam and laid off related employees.

An interesting aside of this is that it appears, contrary to representations by Alnylam, that the GalNAc-ESC technology were invented at Merck, not in-house at Alnylam.

The Complaint makes it clear that Alnylam feels threatened by the technologically very direct competition.  In a way, Dicerna’s new strategy was to become Alnylam's clone.  What could be worse, given the differences in the RNAi trigger lengths (~19bp Tuschl-type siRNAs by Alnylam; 25/27 and longer Dicer-substrate versions by Dicerna) and the apparent importance of stability/degradation in GalNAc technology, there is the distinct possibility that Dicerna’s version, everything else being equal, would outperform (or underperform) Alnylam’s.

In light of recent apparently rapid progress at Dicerna on GalNAc technology and the timing of events, the idea that Dicerna may have benefited from the GalNAc know-how of ex-Merck scientists does not seem far-fetched.  

It is unclear to me, however, whether you can expect expert oligonucleotide chemists to suddenly forget everything about their former job. 

Alnylam obviously takes care of that problem by enforcing harsh non-compete and pay-for-silence practices against their former employees, meaning that if you are an RNAi scientist that job at Alnylam will be your last RNAi job in the industry, period. 

Looking forward, I predict that the outcome of the case will hinge less on the physical documents that were alleged to have been ‘misappropriated’, but on whether or not the ex-Merck scientists could have re-invented GalNAc-ESC based on their skills and publicly available information (including from Alnylam) at the time.  If so, then Alnylam only has Merck to blame that it does not force their employees to leave their profession when they lay them off.

Regardless, the GalNAc-ESC genie is out of the bottle.

Thursday, June 4, 2015

What to Watch for in RG-101 Post Regulus Therapeutics Executive Departures

As you will probably know already, Regulus Therapeutics surprised us this week with the sudden departures of both their CEO and CSO.  These two individuals also happened to be the insiders selling major positions in the stock earlier this year just days ahead of critical data to be released on their lead clinical candidate, RG-101 for the treatment of HCV ('Reading the tea leaves on Regulus insider sales').

While this would be a good reason for what looks like a sacking of the company’s two key executives (especially since the exodus came as a pair), for investors the all-important question is whether it is also related to bad news that we do not know about yet.  Most importantly, does this also have anything to do with the failure to report the viral resistance analysis which had been promised to us for the EASL meeting in April?

It is this analysis that will determine whether the miR-122 inhibitor can facilitate 4-week treatment regimens which must be the goal for this asset.  This is because RG-101 is the only serious long-acting agent out there in the HCV drug development arena and 4 weeks of oral, short-acting antivirals do not seem capable of getting rid of the virus. 

If there was no resistance to RG-101, based on the available data RG-101 given on week 4 would add ~6 weeks to deep viral suppression to the treatment regimen, in a way resembling a 10-week oral regimen which have much higher odds of viral clearance.  If viral resistance (and not waning drug levels as I am assuming) played a role in the rebounds seen in the single-dose study, then this would not necessarily be the case.  I say ‘not necessarily’ because even then, the risk of developing viral resistance to RG-101 should be much lower when given in combination with other agents as is the plan.

Take-home: I remain cautious (but not short any more) prepared to take advantage of another bout of panic selling that could come with the release of the resistance analysis.  The quality of the new leadership to lead the exciting microRNA platform will also indicate whether Regulus can finally live up to its original promise.  Long-term, whether precipitated by the insider sales or not, the changes should be good as morale at the company from what I can tell had been low.

PS: in more positive news, Regulus Therapeutics today reported that a first-in-man study with their second most advanced microRNA Therapeutic, RG-012 for the kidney-related orphan disease Alport Syndrome, has begun dosing.

Wednesday, May 27, 2015

RXi Pharmaceuticals Could Be Much More Than Skin Wound Healing

RXi Pharmaceuticals today commenced a secondary offering setting it on course to raise ~$10M, enough to finance the company for another year while expanding its pipeline and technology.  It could thus mark a new chapter in the life of this company which had shoe-boxed itself into a single-product (RXI-109 for dermal wound healing) company following a toxic 2012 financing that gave Tang Capital Partners de facto control over the company (pro tip: when you see the likes of Tang or Deerfield getting involved, it usually is not to the benefit of common stock holders). 

The news this morning that the preferred stock overhang (àTang Capital Partners) had finally been cleared, then paved the way towards the financing (amount and pricing to be determined).  

With RXI-109 winding its way through phase II studies, it became clear that RXi had to open itself up to new opportunities enabled by its promising self-delivering RNAi platform.  The financing will initially allow RXi to develop RXI-109 also for ocular (retinal and corneal) scarring-related indications such as wet AMD and cataract surgery.  First eye-related clinical trials with self-delivering RNAi triggers are expected to commence later this year.

The eye is an interesting application of sd-RNAi technology not only for the lucrative eye disease market (both genetic and age-related of considerable unmet medical need), but also because they seem to be able to penetrate throughout the eye (see image) whereas in the skin, distribution currently is limited to areas close to the injection site barring new delivery breakthroughs (patches, creams and the like).  In addition to cholesterol, it may also be interesting to test other ligands such as Vitamin A and E for enhanced uptake into certain ocular cell types.

Lots of unexplored potential

Beyond the skin and eye, self-delivering RNAi strategies hold considerable promise for other tissue targets, both by direct/local and systemic delivery.  In terms of local delivery, I would be highly interested in the biodistribution of intrathecally administered sd-RNAi triggers in non-human primates.  This is because of their long phosphorothioated single-strand overhang and thus similarity to phosphorothioate antisense oligonucleotides which are starting to show amazing results in the clinic for CNS applications (watch out for update on the infant ISIS-SMNRx study by Isis Pharmaceuticals).

In terms of systemic delivery, sd-RNAi chemistry and structure may synergize well with conjugate-RNAi approaches, both in their simple (--> Alnylam GalNAc-type) and more refined form (--> Arrowhead DPC-type).  Even without further modification, RXi-type self-delivering RNAi has shown surprising knockdown efficacy in models of pre-eclampsia as shown by respected UMass scientists Melissa Moore and Anastasia Khvorova (formerly of RXi Pharmaceuticals).  

If RXi can get the backing from serious biotech investors and eventually a new management fit to lead a modern biotechnology company, the current $16M market valuation (for RXI-109 in the clinic for dermal scarring and soon in the eye; self-delivering platform potential; stake in MirImmune) of the company could make it an irresistible investment opportunity.  If management, however, continues to dig in their heels and refuses to listen to outside advice chances are that the financial death spiral will continue. 
Suspicious shorting into financing

It used to be common biotech practice that investors-in-the-know were allowed to short into financing resting assured that the offering will allow them to cover at a lower share price.  It is therefore remarkable that in the days and weeks before the financing, the short interest has sky-rocketed from virtually none to around 10% of the float and possibly much more by now due to the delays in reporting short interest.

Saturday, May 16, 2015

Aptamer-Targeted RNAi Trigger Delivery

In honor of 25 years of aptamers, or better the SELEX process which underlies the discovery of aptamers, I thought it might be a good time to revisit aptamers for the delivery of RNAi Therapeutics.

Aptamers are nucleic acids that have been selected to preferentially recognize a target, usually a protein, via their 3-dimensional structure in analogy to how monoclonal antibodies recognize their targets.  Aptamers are showing most promise in therapeutic development for the targeting of extracellular proteins in the eye for applications like wet AMD and diabetic macular edema (see Fovista from Ophthotech). 

Its success for systemic applications has been much more modest, however, with short circulation times and unexpected adverse events in a recent phase III study (likely due to the PEG portion of the aptamer drug) largely accounting for it.

Aptamers have also been considered as cell-targeting agents for RNAi Therapeutics.  Early reports suggested efficacy in HIV and cancer models.  Skepticism around the on-target mechanism in these examples was considerable though largely due to questions around how they were supposed to escape the endosomes.

I also fell into the camp of doubters (and still have some reservations), but have adjusted my view to a more productive one after it became clear that IF you had highly productive endosomal uptake like ASGPR/GalNAc and a highly stabilized RNAi trigger, gene silencing is possible even without explicit endosomal release chemistry.

Time to try the next iteration: Aptamer-DPCs

As there may not be another ASGPR-type receptor in the body and to compensate for lower drug exposure compared to the liver, in the quest to make aptamer-delivered RNAi Therapeutics more robust, the new learnings of RNAi trigger stability are probably best applied within the context of DPC delivery technology by Arrowhead Research.

Accordingly, the perhaps 10x lower uptake in say PSMA-expressing prostate cancer cells will be compensated by adding the RNAi trigger-aptamer complex (as one or separately) to a masked endosomal release polymer.  In case that the target cell receptor is only abundant, but does not support productive endosomal uptake, another aptamer may target a second co-receptor on the same cell (akin to some bispecific antibodies, co-receptors in viral cell uptake).

Following endosomal uptake, the masking groups come off, endosomal permeability increased so that the RNAi trigger may escape into the cytoplasm.  In certain configurations, a Dicer substract-type RNAi trigger structure may simplify design and increase stability.

Tuesday, May 12, 2015

Dicerna Keeps Searching for Its Identity

Dicerna Pharmaceuticals recent move from Watertown to Cambridge is symbolic for its continued search for a place in the RNAi Therapeutics landscape.  Following some setbacks in its cancer and home-brew LNP efforts, the company now pins its hope on that it can compete head-on with Alnylam in the development of GalNAc-RNAi trigger conjugates for gene knockdown in the liver.

Oncology on hold

Like others in the field, confidence in its cancer program (DCR-MYC in phase I/II studies for solid cancers and HCC) seems to be low.  In the absence of clear-cut early development-stage cancer responses and confirmation of bona fide tumor-wide gene knockdown, cancer drug development remains a hit-and-usually-miss for the Oligonucleotide Therapeutics industry.

As a result, Dicerna seems to view their own mouse data with skepticism just as I myself have yet to see data supporting tumor penetration and bona fide knockdown in well-controlled studies.  The company has to be credited that it is now setting the bar for DCR-MYC quite high when clinical data from higher-dose cohorts is expected to emerge around year-end.  If DCR-MYC does not make the cut, Dicerna will likely cut its losses in cancer drug development and LNP research in general.

DCR-PH1 close call

Dicerna management was also surprisingly frank about their hesitations about the technical success of their most interesting current program, namely DCR-PH1 for the treatment of hyperoxaluria type I. 
After reviewing the latest non-human primate studies, it now appears that at least an 85% mRNA knockdown of the HAO-1 target gene will be required to see the key oxalate biomarkers ‘move’, and over 90% for more robust movement.  Based on rodent data, the company had thought that 75% might be sufficient.

In NHP studies of DCR-PH1, an 84% average peak knockdown was seen following a single dose of 0.3mg/kg of a Tekmira SNALP LNP formulation with 68% knockdown remaining at week 4.  0.3mg/kg seems to be the current well-tolerated upper dose of Tekmira’s LNP formulations and almost identical (protein) knockdowns were observed with 0.3mg/kg of Tekmira LNP-formulated ALN-TTR02. 

In clinical 3-weekly multi-dose studies of ALN-TTR02, this translated into sustained 80-85% target gene knockdowns.  This means that Dicerna now relies on the safety of DCR-PH1 to allow for doses of around 0.5mg/kg.  Not impossible, but probably a close call given the history of SNALP LNP and further exposes DCR-PH1 to competitive threats.

GalNAcs coming

Given the stage of their internal cancer and LNP efforts, Dicerna is now pinning its hopes on taking on Alnylam with GalNAc-RNAi trigger.  This is where Dicerna is currently investing most of its R&D efforts in.

It has now disclosed non-human primate data from those efforts, with 5 consecutive daily doses of 2.5mg/kg GalNAc-Dicer substrates resulting in ~70% knockdown of HAO-1 2-3 weeks after this loading dose.  Given the larger molecular size of the extended Dicer-substrates versus Tuschl-type siRNAs, this corresponds on a molar basis to ~1.5mg/kg of Alnylam’s GalNAc-siRNAs.  

This is somewhat less than what Alnylam presented for their PH1 program at OTS 2014 (ED80s in rodents of ~2.5mg/kg weekly) and Dicerna's GalNAcs would seem to require some further refinements to be competitive.

But in this case, they will end up with something that has little pharmacological distinction, is 3-4 years behind Alnylam, which in turn is not shy to put legal/IP pressure on its competition.

In my opinion, Dicerna management and Board need to put in quality time to find their true identity.

Disclosure: I am short DRNA as a relative valuation short for my ARWR long position. DRNA has a slightly larger market cap than ARWR, but ARWR has a distinguished, more mature DPC pipeline with ARC-520 and ARC-AAT two attractive candidates in the clinic whereas DRNA has nothing in the clinic it apparently has confidence in.  It's possible that both stocks are grossly undervalued, but relative valuation is one of my main RNAi investment methods and this is why I'm applying it here. Nothing personal.
By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.