Friday, May 27, 2016

What the thrombocytopenia findings mean for Ionis Pharmaceuticals

Yesterday, Ionis Pharmaceuticals disclosed that severe reductions in platelets had been observed in phase III clinical trials of both IONS-TTRRx for the treatment of TTR amyloidosis and IONS-ApoCIIIRx for conditions related to highly elevated triglycerides.  Severe platelet reductions are dangerous since it can lead to occult, uncontrolled bleeding and poor blood clotting following injury.

Since the conference call was a PR disaster as the CEO of Ionis has major issues with speaking his scientific mind, and since competitor Alnylam has seemingly become the original source and interpreter of the Ionis thrombocytopenia issues (one wonders how they come into possession of these Ionis trade secrets...), I thought it may be useful to briefly come out of blogging hibernation and lay out my thoughts about what these events mean for the technology and the company.

Thrombocytopenia likely limited to systemically administered, unconjugated PS-oligos >200mg per injection

As a hematological abnormality that has historically been observed with phosphorothioate (a ‘sticky’ chemistry) oligonucleotides when given at high doses (>200mg/injection)  I’ve always considered it likely that such thrombocytopenia will be associated with measures of plasma exposure of the oligonucleotides.  Notable examples for thrombocytopenia with phosphorothioate oligos include the DMD exon skipper drisapersen by Biomarin/Prosensa (6mg per kg per week, i.e. around 300mg/week for 50kg boy) and telomerase inhibitor imetelstat by Geron (~10mg per kg per week, i.e. around 700mg/week for average adult).  Actually, isn’t it ironic, or maybe even curious that imetelstat is being developed for conditions where elevated thrombocytes is the problem (see related blog entry)???

Consistent with this notion, there was a study by Flierl et al. in 2015 that looked at the mechanism of platelet activation which may lead to platelet consumption and explain lowered thrombocyte counts.  Without going into the details of the mechanistic aspects of the study, the authors find a strong correlation with peak plasma exposure (c max) of the oligonucleotides and platelet activation.   

So why hasn’t Ionis seen severe cases of thrombocytopenia in the past (excluding use of PS-oligos in cancer patients which frequently suffer from potentially confounding bone marrow suppressions from other drugs)?  The most probable explanation is a) these events are quite rare events and b) that their experience with PS-ASOs at 300mg/week and above has been limited.  At 300mg and especially 400mg per week, safety has always looked a bit dicey such that the 300mg per week dose e.g. for TTRRx was only adopted after 200mg per week was not competitive with the knockdown results produced by ALN-TTR02 from Alnylam. 

Similarly, the initial studies with ApoCIIIRx did not include the 300mg per week dose and was adopted in favor of the very impressive triglyceride reductions seen at doses higher than 200mg.  Usually the dose escalation of the prototypical Ionis phase I studies involved 50, 100, 200, then 400mg per week with 400mg per week never being chosen for the phase II and/or pivotal studies.

What I find highly interesting is that the pharmacokinetics data from the healthy volunteer study of ApoCIIIRx reported by Graham and colleagues in 2013 (see only Table IV) reported a non-linear, 4.5x increase in cmax when doubling the dose from 200mg to 400mg per week.  This could mean that at doses of 200mg per week and higher, the risk of severe thrombocytopenia is dramatically elevated by going past the threshold where platelets become critically activated (à clotting cascade).  
If the cmax theory holds true, then the following should be the impact of the new findings on the Ionis platform.  The summary takes into account the clinical observations by Ionis that the platelet reductions are reversible upon stopping dosing and can be prevented and also treated by steroid use (just as ALN-TTR02 involves steroid use):

1)      Unconjugated, systemically administered antisense at 300mg per week and above (incl. phase III assets TTRRx and ApoCIIIRx): need for tight platelet monitoring.  May involve temporary halt of studies to amend protocols.  Commercially, need for tight platelet monitoring could be a problem for less severe diseases due to convenience and competitive issues.  

Note that for all the liver-targeted programs, backup GalNAc-conjugated versions are in development which should not suffer from thrombocytopenia (see below).  However, systemic programs targeting other tissues such as DMPKRx for myotonic dystrophy will have to be under continued scrutiny depending on the dose.

2)      Unconjugated, systemically administered antisense at 200mg and below per week and below: little impact.  Start collecting data more systematically to learn more about platelet interactions, otherwise no big impact.

3)      GalNAc-conjugated antisense: no impact. Essentially all the Ionis pipeline, including ApoCIIIRx, has been re-engineered for some time now to be GalNAc-conjugates.  This is because of their 10-100 fold increased potency over the unconjugated versions thus decreasing the doses to well below those expected to cause severe thrombocytopenia.  Even at the same doses, plasma exposures will be much reduced due to the rapid clearance into the hepatic compartment as demonstrated by Shemesh et al in one of the most recent publications by Ionis.  No thrombocytopenia events to my knowledge were seen with RG-101 (for HCV) by Ionis' 'satellite company' Regulus Therapeutics, where a up to 8 mg/kg of GalNAc-conjugated phosphorothioate oligonucleotide has been administered.

4)      CNS programs: no impact. Peak plasma exposures are insignificant for intathecally administered oligonucleotides as used in Ionis’ CNS franchise, a franchise which includes exciting drug candidates such as phase III asset nusinersen for the treatment of spinal muscular atrophy (SMA) and candidates for other severe neurodegenerative diseases.

In summary, the only programs which could be significantly impacted by the thrombocytopenia findings are the programs that target tissues outside the liver and which involve systemic administration.  The liver franchise remains intact especially with the new GalNAc versions although there could be some minor delays and increased competitive impact in those diseases that Alnylam is free to go after according to the Ionis-Alnylam IP agreements.  The important CNS franchise remains fully intact. 

Disclosure: long Ionis and doubled down yesterday.

Monday, August 31, 2015

Cholesterol-lowering RNAi Therapeutic Shocks Monoclonal Antibody Establishment

Not too long ago, RNAi Therapeutic got dumped by Big Pharma in a big way not least because of the monoclonal/recombinant protein pedigree and corresponding bias among the top dogs of these organizations.  This was most obvious with Roche and Merck when changes in their overall R&D organizations led to the loss of their last internal RNAi champions.

How times have changed. Yesterday, The Medicines Company (who have now become a natural acquisition target) and Alnylam presented data (press release here, data here) strongly suggesting that an RNAi Therapeutic will push aside the temporally more advanced monoclonal antibody competition to become the best-in-class agent in the potentially top pharmaceutical category over probably the next two decades: the inhibition of PCSK9 for the prevention of cardiovascular morbidity and mortality.

The data in support of this claim were presented yesterday at the 2015 ESC congress in London that in retrospect was apparently named in honor of the delivery technology underlying ALN-PCSsc, a so-called Enhanced Stabilization Chemistry-based RNAi conjugate.

Treatment adherence

Importantly, the single-dose part of the study showed that starting with a dose of 300mg of ALN-PCS, PCSK9 levels were flat-lined to ~25% of normal levels for at least 4-5 months and haven’t started to perk up yet by the data cut-off date for this presentation.  It is to be expected that the knockdown will be even more pronounced with repeat dosing as supported by the initial repeat-administration data (2/3 doses) showing mean PCSK9 reductions to ~15% of normal.

Since in the PCSK9 category, it is PCSK9 that is driving LDLc lowering, the ultimate aim of this therapeutic approach, similar kinetics were seen in terms of LDLc levels in the blood with reductions (and safety/tolerability profiles) comparable to that seen with the recently approved monoclonal antibodies PRALUENT (by Regeneron/Sanofi) and REPATHA (by Amgen), ~55-60%.

In the case of the monoclonal antibodies, dose administrations every two weeks is really what it takes to consistently suppress PCSK9/LDLc because their inhibitory ability is directly correlated to their amount in the blood which declines rather precipitously after drug administration.  In the case of RNAi, however, you only need minute amounts to clamp down gene expression and at least for the liver, it appears that quarterly/semi-annual dosing schedules are realistic (it also depends on target and how much it needs to be repressed; e.g. with CC5 you may need much more target gene knockdown than 58-90%).

Sticking a needle into you just 2 or 4 times a year instead of 26 times, of course, has great advantages when it comes to treatment adherence. Keeping patients on drugs is a major issue for such life-long therapies especially since the disease is not felt acutely.  This point was made repeatedly by cardiovascular disease thought leader Dr. Kastelein on the companies’conference call.  By being able to co-ordinate drug administration with routine doctor visits, it would be possible to achieve very high compliance rates thereby preventing intermittent LDL cholesterol spikes that are believed to be particularly harmful.

In other words, assuming cardiovascular outcomes to be almost entirely driven by LDLc lowering, ALN-PCSsc would/should be best-in-class in the PCSK9 category.  There are numerous examples such as Eylea in the wet AMD space where injection frequency is the main competitive driving force among competing agents (here VEGF inhibitors) that exemplify how being a best-in-class follower can be very profitable.  Let the monoclonals build the PCSK9 market for ALN-PCSsc to then take it.


Last but not least, the ultimate value from being different will come from the results of the cardiovascular outcomes (and actually overall survival) studies that will really unleash the wide adoption of the PCSK9 class.  Due to their similarities, there is every reason to believe that the results from the monoclonal antibodies will cluster tightly.  By contrast, for better or worse, the outcome studies from ALN-PCSsc should be notably different and given that an RNAi agent mimics the compelling human genetics behind the PCSK9 story (extreme LDLc lowering in PCSK9-mutant individuals without other apparent untowards effects such as elevated liver triglycerides etc) much more closely, I like my chances here.  

We all know about the intricate feedback mechanisms of lipid biology so that binding a player merely in the serum as the monoclonals do as opposed to removing it from both inside and outside the cell could have unanticipated consequences.  Albeit early, the preliminary data from ALN-PCSsc support that in that the percent LDLc knockdown is the same whether in the presence or absence of high-dose statins whereas that of the monoclonal antibodies becomes muted.

Having said that, expect the monoclonal antibody establishment to play the 'RNAi is different from monoclonal antibody card' lest ALN-PCS piggy-backs on the MAb CVOT results expected to come out starting in 2017.

Back to my self-imposed exile, but I couldn't resist on commenting on what could be a perfect Oligonucleotide Therapeutics storm that is building. Next up is (maybe) ARC-520 for HBV.  And yes, I'm long MDCO as if that's not obvious.

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.
By Dirk Haussecker. All rights reserved.

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