ISIS Will Become a Major, Major Drug Maker

I have been following ISIS Pharmaceuticals for a dozen years now and have heard Stan Crook, its CEO, promise his shareholders in as many years that profitability was just around the corner.  Over the last 4 years, he’s also been promising that KYNAMRO will be highly profitable, and indeed just at the R&D day yesterday, he said that KYNAMRO would make ISIS profitable or at least will be profitable for ISIS under the Genzyme agreement.

The reality has been that none of that has materialized and sales of KYNAMRO, which essentially is a placebo with serious safety issues, must be so enormous that ISIS has not had to break out its sales one year following its launch (my sense is that it’s been growing exponentially from 1 patient to 2, 4, and now perhaps 8 subjects with familial hypercholesterolemia). 

In fact, his delusion (he would probably call it his optimism) was on full display at the 2012 OTS meeting when he gave a keynote speech during which he celebrated himself for the first approval of a systemically administered oligonucleotide (KYNAMRO) which he said ‘had no side effects’.   

And, of course, the other perennial Stan classic: ‘partnership interest has never been greater’ -rain or shine.

People older and wiser than me will probably have the same story to tell, but going back not one, but close to 3 dozen years.  So the Street has stopped listening…

Why it’s different now

Today, however, I will make the case that the situation has changed and that ISIS Pharmaceuticals is set to become a major, major pharmaceutical company within a decade. Think $100B market cap and more.  In 20 years, it could be bigger than Apple is today with the only dilution being excessive stock option gifts to Stan and his management team.

The perfect storm is the result of improvements in 5 critical areas: platform technology, pipeline, target space, commercial and IP strategy. 

1.  Platform Technology

Phosphorothioate antisense oligonucleotides (ASOs) rely on saturating target- and non-target tissues with large amounts of potentially immunostimulatory sticky chemistry to achieve activity.  For KYNAMRO, the toxic tipping point was reached at 200mg per week with hardly any gene knockdown activity (first reported to be 40% and then seemingly coming down to 20% as drug development progressed).

For other candidates using the same 2^nd generation gapmer chemistry, the doses used in clinical development are not that different, but with improved 60-80% potency at 200mg, and much more robust knockdowns at 300mg and 400mg.    The safety profile also seems to have improved- although here I really want to first look at the briefing documents at the end of the development cycle based on the KYNAMRO history.

So at minimum, you have significantly improved potency with equivalent safety which would push open the technology to a number of additional applications beyond the extremely severe and rare populations such as those with homozygous familial hypercholesterolemia.

The potency improvements can be ascribed to just having the technology and capital to screen many more oligonucleotides for drug activity.  On the safety side, there may have been improvements by better understanding which sequences to avoid to minimize immune reactions.

Behind 2^nd gen chemistry, I’ve been quite impressed by the GalNAc-conjugation data revealed at AsiaTIDES which showed ~10x improvements in activity, and a re-direction of oligonucleotides from the kidney to the liver, both with major implications for the safety of phosphorothioate chemistry (see also supporting data by Regulus Therapeutics with its anti-miR122 candidate).  If now most of the oligonucleotides are in the target cell, many of the extracellular safety issues with the sticky chemistry will disappear.

And it does not have to stop here.  Since at least for RNaseH-mediated gene knockdown and the regulation of nuclear RNA, nuclear localization is required for ASO activity, how about attaching a little postcode to the ASO to get the oligonucleotide into the nucleus?  ASO is wasting a lot of its potential in the cytoplasm since most oligonucleotides, at least in non-cycling cells, remain in the cytoplasm.

In combination with higher-affinity chemistry, ligand-targeting and nuclear localization could make oral delivery a stroll in the park.

2.       Pipeline

Until early 2013, the claim by ISIS of having more than 2 dozen drugs in the pipeline was meaningless.  Most of these candidates were either commercially dead (KYNAMRO, Alicoforsen, Vitravene), had ceased active clinical development, belonged to other companies (!), or were in phase I. 

Today, this picture has changed dramatically.  Two major studies in the diabetes (ISIS-GCGRx) and blood clotting fields (ISIS-FXIRx) have read out positively over the last week. If the safety of these candidates is half as good as claimed in the press releases, they have be major blockbusters.  As the phase III planning is ramping up for these candidates, ISIS-SMNRx for spinal muscular atrophy and ISIS-ApoCIIIRx are promising compounds with significant commercial opportunities that will soon be in phase III.

    

Behind the growing late-stage pipeline, there is a whole bunch of earlier-stage candidates addressing exciting targets from the common (e.g. Apo little a) to the rare/severe disease spectrum (e.g. Huntington’s, myotonic dystrophy type I).  This pipeline is starting to look stronger and more diverse than any in the industry (hence the above projection of ISIS becoming a, if not the major pharmaceutical company).

3.       Commercial strategy

The most advanced candidate of commercial potential in the ISIS pipeline is ISIS-TTRRx for the treatment of TTR amyloidosis.  Leaving aside the inferior potency compared to Alnylam’s RNAi competition, this candidate with ~70% knockdown of the toxic, disease-causing gene in its own right has solid therapeutic prospects.  However, the financial windfall as that from the next most advanced candidate, ISIS-SMNRx, will fall to a pharmaceutical partner. 

You only need to consider the relative market capitalizations of ISIS ($3B) and TTR competitor Alnylam ($4.5B) when you understand that in order to become a major pharmaceutical company, you need to retain significant commercialization rights for commercially attractive drugs and not cap your upside in phase I or even at the preclinical stage as happened with SMNRx and TTRRx.

This picture, however, is changing, and with ISIS-ApoCIII, ISIS-GCGRx, and ISIS-FXIRx, the company now has exciting 3 phase III-ready candidates which it still owns 100%.  

4.       Expanding target space

In addition to improvements in gene knockdown, ISIS Pharmaceuticals is also firing on all cylinders as it comes to exploiting additional mechanisms and targets that only antisense oligonucleotides can address such as modulating splicing in a sequence-specific manner (àe.g. ISIS-SMNRx) or reducing toxic RNAs (à type I myotonic dystrophy).  So in addition to applying ASOs to the 75% of the undruggable protein-coding genome, ISIS can take advantage of the exploding insights into the involvement of RNAs in disease and exploit modulating RNA processing to a therapeutic end.

In sum, ISIS Pharmaceuticals has the largest druggable target space at its disposal in the industry.  When you are the only game in town, often addressing the root cause of a disease, there is not much to convince regulators and payors to approve and pay for your drug.

5.       IP ever-greened

When you have invented a method to invent, you can make life (freedom-to-operate) difficult for your competition.  But beyond asserting questionable claims against the competition, the fact that ISIS is continually improving on their technology and is filing for new patents can have profound impacts on their partnering and commercial strategy. 

This is because one concern with the broad partnerships that ISIS has entered with the likes of BiogenIdec, GSK, and AstraZeneca is that they are giving away too many attractive targets.  Although this is pure speculation at this point, it would be interesting to think that these licenses have not given the partners perpetual rights to the targets involved and that at some point, for example once ISIS has developed oral versions for these targets, ISIS could compete with these older drugs and retain full commercial value.

In general, the IP ever-greening strategy means that even if the target space stayed the same, ISIS could continue to draw value from it and overtake the Big Pharma that have been feeding it.

Ebola Update Questions Whether SNALP Ready to Wean Off Transient Immune Suppression

At the annual gathering of the gene therapy community today, Tekmira presented  an update on their ongoing phase I trial with TKM-Ebola, the company’s biodefense candidate for the treatment of Ebola infection developed with funding by the US government (press release here, presentation here).  I have long considered this to be a 'thankless' trial, a real ‘Haertetest’ of SNALP delivery because a) Tekmira took the risk of not employing transient immune suppression as it otherwise does, and b) the multi-ascending dose schedule (5x daily) would be as intense as in no other setting.  While taking on all these safety risks, the company would not be able to balance any safety findings with efficacy/knockdown data in this safety trial.

Indeed, what we got today was an update from the single-ascending dose part of the study which showed a dose-limiting toxicity (DLT) in the form of immune stimulation resulting in the potentially serious condition of hypotension at the top, 0.5mg/kg dose level.   

From the many emails I have received and message board postings that I have read on InvestorVillage, it seems that a common misinterpretation of the data was that they reflected poorly on the safety of 3^rd gen SNALP delivery, the most recent and most potent version of SNALP. 

It is important to emphasize that the reason why we saw this DLT in this study, but not in the various, preceding SNALP-enabled studies such as TKM-PLK1 (1^st gen), ALN-TTR01 (1^st gen), ALN-TTR02 (2^nd gen), or ALN-PCS02 (2^nd gen), is because Tekmira did not employ the transient immune suppression around the time of dosing that has become routine for SNALP technology following a similar finding of immune stimulation in the first-ever trial with SNALP-RNAi, TKM-ApoB (2009/2010).

What it means for the pipeline

This means that if the company re-adopted transient immune suppression for their other pipeline candidates, there would not be all that much to worry about with regard to encountering this type of immune stimulation again.  Transient immune suppression will not matter much for most of the diseases of high unmet need and severity pursued by Tekmira and partners (e.g. cancer, TTR amyloidosis). 

The reason why Tekmira likely did not employ transient immune suppression for TKM-Ebola is because the help by the immune system is thought to be an important adjunct mechanism to achieving cures with an RNAi approach to this highly severe, acute infection.  Moreover, suppressing the immune system might actually make the Ebola infection worse than it already is.

For other viral infections, especially HBV, the issues become more complex.  For example, it is known that with immune suppression such as steroids or certain monoclonal antibody therapies, HBV may dangerously reactivate.  However, if the immune suppression was only transient (~1 day versus an RNAi duration of activity of weeks), I am not aware that the same risks exist.  Moreover, doing something to get the virus out of its hiding place and then coming in to knock it down may actually result in the highest cure rates just as the likelihood of e-antigen seroconversion increases in immune active versus immune silent patients.   

Another part of the equation would be whether doses anywhere near 0.5mg/kg would be required for 3^rd generation SNALP-based TKM-HBV.  If say 0.15mg/kg or less would be enough, transient immune suppression may not need to be considered.

What it means for TKM-EBOLA

Today’s data raises most uncertainty with regard to TKM-EBOLA and the timeline of potential stockpiling.  In the non-human primate studies, it was the 0.5mg/kg dose that resulted in 100% protection in a post-exposure treatment setting.  If the 0.5mg/kg dose level would have been clean in the current trial, I would have been very optimistic about the prospect of accelerated stockpiling, even before full FDA approval.  At 0.2mg/kg in the NHP studies, protection was incomplete with 2/3 of the animal surviving.

In their presentation, Tekmira points to pharmacokinetic data, especially the maximal drug concentration in serum that was higher in humans than the monkeys at the same mg/kg dose levels.  In other words, Tekmira makes the case that a 0.24mg/kg dose in humans would be therapeutically equivalent to the therapeutic 0.5mg/kg dose in the monkeys.

It is true that under the Animal Rule, you have to demonstrate sufficient safety in humans at doses that are pharmacologically equivalent to those found to be therapeutic in the animal models, and these do not have to be numerically the same on a mg/kg basis.

However, based on the limited monkey-human PK-PD bridging data provided, I am yet to be fully convinced by this argument.  Ideally, there would be knockdown efficacy data for 3^rd gen SNALP available already, data showing that on a mg/kg basis, 3^rd gen knocks down genes slightly more efficiently in humans than in non-human primates. 

The best sign that Tekmira is getting crucial buy-in from the FDA and DoD would be if these agencies were in support of the dose levels chosen by Tekmira for the multi-ascending dose part of the study that is planned to start next month (0.06mg/kg, 0.12mg/kg, 0.24mg/kg).  The presentation indicated that the single-ascending dose data is under review by the FDA, and the MAD going ahead could be a positive sign with regard to agency support.

Long-term  research challenge: new modifications

Long-term, it is still desirable for SNALP to fully wean itself off from any transient immune suppression at any dose and in any indication to maximize the therapeutic opportunities.  One avenue which I have not seen Tekmira adequately explore is the use of chemical RNAi trigger modifications beyond 2’-O-methyl.  Although Tekmira scientists have nicely shown that 2-O-methylation can be very effective in dampening the innate immunostimulatory potential of an RNAi trigger sequence, comparative chemistry studies by ISIS and the clinical experience by Prosensa indicate that larger modifications on the 2’ position are even more effective in circumventing recognition by innate immune sensors such as toll-like receptors.  

With the healthy cash balance, I would expect Tekmira to reinvigorate their efforts in identifying even better immune-reducing RNAi trigger chemistries.  It could also be a worthwhile endeavor to be funded under the EBOLA contract as it has been a very successful program so far in furthering the platform while at the same time developing a biodefense agent.

Dicerna Should Focus on Conjugate Delivery

Barely 3 months a public company, Dicerna has yet to emerge as a distinct RNAi Therapeutics player similar to the likes of Alnylam (à subQ GalNAc), Arrowhead Research (receptor-targeted DPCs), and Tekmira (àhigh potency liposomal RNAi).  Without leveraging the potential advantages of its Dicer-substrate RNAi triggers on which it had been founded, Dicerna will be remembered by the market as not much more than an IP workaround play.

Currently, Dicerna is utilizing liposomal delivery for its lead programs in cancer and orphan disease primary hyperoxaluria 1 (PH1), a highly versatile approach, but a niche that might be better left to Tekmira.  At least for the greater good of RNAi Therapeutics investment dollars.

Instead, Dicerna should compete more directly with both Alnylam and Arrowhead in conjugate delivery.  This is because Dicer substrates allow for the liberation of the active small interfering RNA from the conjugated ligand and/or polymer backbone by Dicer directly chewing off the conjugate.  By contrast, for conjugates like current GalNAc-siRNAs or DPCs, removal of the ligand/backbone has to be accomplished via more complex or difficult-to-work-with linker chemistries including protease-sensitive linkers or disulfides.  Such removal is usually necessary to allow for efficient incorporation into the RNAi effector complex RISC. 

In fact, it may be this chemical attachment challenge that has delayed Arrowhead’s single-molecule DPCs which I am so keen seeing progress into the clinic.

Of course, similar to adopting liposomal delivery, becoming expert in conjugate delivery probably won’t happen overnight and requires the hiring of appropriate talent.  Competition for such talent ought to be fierce with both Arrowhead and and particularly hometown rival Alnylam well cashed up and even antisense company ISIS entering the field.

We have now well crossed the point that RNAi Therapeutics is ready to churn out drugs.  If each of the players were to focus on its core strengths, it would ensure that the reach of the technology will grow in a most efficient manner.  

GalNAc 2.0 with Greatly Improved Single-dose Efficacy and Duration

Last night, Alnylam kicked off a week of what promises to be exciting disclosures about continued progress in therapeutic gene silencing of genes expressed in the liver.  In a presentation by oligonucleotide star chemist Mutiah Manoharan at TIDES, the company provided a more thorough chemistry and pharmacology background behind the apparent improvements of the GalNAc delivery platform (Enhanced Stabilization Chemistry).

Journey along a hostile environment

The improvements are based on the observation that the 5’ ends of both the guide and passenger strands are subject to degradation by 5’-3’ exonucleases.  These may act at various stages during the relatively long journey of a subcutaneously administered RNAi trigger-conjugate: in the subcutaneous space, the circulation and lymphatics, and finally along the nuclease-rich endosomal/lysosomal uptake pathway in the target cell itself. 

Accordingly, by adding undisclosed chemical modifications to the 5’ (but also 3’) termini of the RNAi trigger strands, ~5 times the amount of RNAi trigger reaches the liver, and 10-100x RNAi trigger is found in the liver over time compared to first-generation chemistry as exemplified by ALN-TTRsc.  This means that single digit microgram per gram liver tissue can now be achieved at steady-state.  For comparison, gen 2.0 and 2.5 RNaseH ASOs (--> ISIS) depend for activity on ~100-300 microgram per gram liver tissue steady-state concentrations of phosphorothioated oligonucleotides. 

There obviously is a balance between maintaining high drug concentrations for efficacy and avoiding excessive concentrations for fear of causing inflammation and subsequent tissue scarring.  In that regard, Alnylam reports a wide therapeutic index, including in non-human primates which, laudably, were generally extensively used in these studies.

Great benefit for single-dose efficacy and duration

The new pharmacological profile is somewhat counter to a critical advantage of the RNAi platform over single-strand RNaseH technology: achieving great and sustained efficacy with minimal tissue exposure.  

Mechanistically, this fundamental capacity is explained by the fact that once loaded onto the RNAi effector complex, RISC, the duration of RNAi trigger activity in non- or very slowly dividing tissues such as the liver is largely limited by the slow (weeks) natural turnover of RISC.  By contrast, although RNaseH is a catalytic mechanism, too, no such sustained holding on to the antisense oligonucleotide is known for RNaseH such that the guide oligonucleotide has to be constantly available.

According to this model, an important determinant for the efficacy and very feasibility of traditional RNAi approaches is the size of the unloaded pool of RISC during the short period of time that an otherwise unstable RNAi trigger is available.  By contrast, unstable RNAi triggers are ill suited to take advantage of newly synthesized RISC complexes as part of natural RISC protein turnover.   

This is where GalNAc2.0 comes in: by extending the presence of the RNAi trigger, RNAi triggers can now also be loaded into newly synthesized RISC, thus extending the duration of gene silencing by replenishing the pool of RISC that gets lost during its turnover.  As discussed last week, in the case of ALN-PCSsc for the treatment of hypercholesterolemia, GalNAC2.0 can achieve sustained potent gene silencing of PCSK9 for 2-3 months following a single dose compared to only days/weeks with the old chemistry.  Moreover, when it comes to single-dosing schedules, GalNAc2.0 is also vastly (~10x)  in terms of maximal knockdown potency compared to GalNAc1.0 which relies on a loading dose schedule (5x daily injections) for efficient loading of free RISC.

ESC less transformational in multi-dose regimens

Somewhat lost in Alnylam’s press release was the fact that for multi-dosing, the benefit of GalNAc2.0 is less dramatic in terms of the amount of RNAi trigger required to achieve say a 80% target gene knockdown.  For example, for TTR, the ED80 with weekly GalNAc1.0 in non-human primates was ~2.5mg/kg, the same as that now reported for the ED80 with a GalNAc2.0-chemistry improved version in rodents.

This confusion was not helped by the fact that direct comparisons between GalNAc1.0 and 2.0 were only shown for single-dose studies or by the fact the efficacy summary slide compares GalNAc1.0 for TTR with GalNAc2.0 for PCSK9.

Therefore, when the goal is to enhance the target product profile of your RNAi therapeutic by minimizing the frequency of subcutaneous administration (e.g. PCSK9 in light of the monoclonal antibody competition), then GalNAc2.0 certainly represents a very valuable advance, albeit at the cost of (still) relatively large injection volumes (10mg/kgà 4ml).  However, when it comes to the maximal potency against a given target gene, similar results may be obtained with GalNAc1.0 with possibly an improved safety profile.

Of course, more potent and at least equally sustained efficacy following subcutaneous administration may be achieved by Arrowhead's single-molecule DPCs.  If and when they can finally be translated into the clinic, is an important and open question.  I hope we see more data on that this week, also from the TIDES.

Alnylam GalNAc Improvements Incremental, but Likely Enough to Beat PCSK9 Antibodies

Over the last week, Alnylam presented pre-clinical data for their new development candidates for the treatment of hypercholesterolemia (ALN-PCSsc) and liver disease related to forms of alpha-1 antitrypsin deficiency (ALN-AAT).  These candidates are based on second-generation GalNAc-conjugate chemistry that the company is now dubbing ESC (Enhanced Stabilization Chemistry).  They involve the increased use of chemical nucleic acid modifications for stability with attendant improvements in knockdown potency and duration over first-generation GalNAc conjugates such as ALN-TTRsc.  ALN-TTRsc is the lead GalNAc candidate and currently in phase II development.

Borderline first-generation GalNAcs

In a phase I study of ALN-TTRsc, potent knockdowns were achieved with about:

-60% knockdown at 2.5mg/kg;

-80% knockdown at 5.0mg/kg (ED80), and

-90% knockdown at 10.0mg/kg.

At the risk of insulting medical geneticists for oversimplifying, assume that an RNAi technology that can safely achieve an 80% target gene knockdown provides for a solid platform.  In the case where a subcutaneous route of administration is desired and/or necessary, this should ideally also fit into a 1ml injection volume which in the case of GalNAc conjugates would correspond to a 2.5mg/kg dose.

There is some controversy around acceptable injection volumes and as often is the case, increased standards are applied to RNAi Therapeutics.  I say this because drugs and drug candidates such as expected mega-blockbuster PCSK9 antibody from Amgen, AMG-145, has been administered at 2ml volumes.  In fact, to achieve once-every-4-week dosing, 6ml (3x2ml) have been administered (see Giugliano et al. 2012).

In light of this, ALN-TTRsc has failed the 1ml test, but 80% are certainly possible with this first-generation GalNAc chemistry.  There is therefore room, and in some cases a competitive need (àcompetition with more potent delivery technologies such as Tekmira’s SNALP LNPs and Arrowhead’s single molecule DPCs) for improvements in GalNAc conjugation technology.    

Second-generation data could indicate progress

In agreement with this, Alnylam is now advertising the ESC second-generation GalNAc and has presented critical non-human primate data for their new development candidates ALN-PCSsc and ALN-AAT.  Non-human primate data are ‘critical’ because the RNAi knockdown observed in monkeys typically closely predicts what will be seen in humans based on the experiences with ALN-PCS (SNALP), ALN-TTR (SNALP), and ALN-TTRsc. 

In interpreting the newly presented data, it should be noted that in the case of ALN-TTRsc, an 80% knockdown was already observed at 2.5mg/kg (and 5mg/kg) in non-human primates, but that this shifted to 5mg/kg in humans.  Numerically a relatively small difference, in practical terms an important one.   

ALN-PCSsc achieved 80% PCSK9 target gene knockdowns at 2mg/kg in a weekly multi-dose study in non-human primates.  This resulted in a highly competitive 60% LDLc lowering in the absence of statins.  Similarly impressive in light of the monoclonal antibody competition was that 80% PCSK9 knockdown and 50-60% LDLc reductions were achieved and sustained for over 3 months (!) when a single dose of 10mg/kg (2x2ml) was given.  Compare this to 57% LDLc lowering with AMG145 in a once-every-4 week regimen in the MENDEL-2 phase III study of AMG145:

-ALN-PCSsc (RNAi): 50-60% LDLc reduction, 2x2ml subcutaneous, once-every-3-months

-AMG145 (monoclonal antibody): 57% LDLc reduction, 3x2ml subcutaneous, once-every-4-weeks (phase III MENDEL-2 monotherapy study)

(Yes, I do keep an eye on cash-rich, sub-$2B market cap The Medicines Company, Alnylam’s licensee for ALN-PCSsc for this reason).

Before I get carried away with all the advantages of the RNAi platform over monoclonal antibodies for even extracellular targets such as PCSK9, in terms of GalNAc improvements, these knockdown results are very much in line with what was seen for TTR in non-human primates. 

The same applies for ALN-AAT where a single dose of 3mg/kg translated into a 60% knockdown which, based on TTR and PCSK9, will likely translate into a weekly multi-dose ED80 of 2.0-2.5mg/kg in non-human primates.

However, with the caveat of different half-lives for different target genes, the durability of the PCSK9 knockdown is quite impressive and more than what is typically seen with e.g. SNALP LNPs which have historically utilized minimally modified RNAi triggers.  Such triggers may be turned over more rapidly in liver cells.

Similarly, the RNAi trigger sequence in the TTR development candidate is an extraordinarily potent one with low single-digit picomolar EC50 potency in tissue culture.  It is therefore possible that equivalent animal potencies have now been achieved with less potent sequences meaning that the underlying delivery technology has improved.

It’s been fascinating to watch the various delivery platforms, and indeed RNaseH antisense, compete over the years and pushing each other to new heights.  In this context, I am anxiously waiting for Arrowhead’s presentation at next week’s TIDES meeting with the intriguing title:  “Next Generation Dynamic Polyconjugates for siRNA Delivery in vivo,”

Market commentary: I remain mostly on the sidelines.  Years ago, these scientific data would have made me jump head-first into the market with me buying all I could in the opening minutes.  These days, however, I view them as ensuring the long-term value of RNAi stocks, but fail to see how they will support share prices in the current, growth-to-value rotating trading environment for more than a trading week or so.  I am therefore speculating on a capitulation event before some of the important clinical data read-outs roll in.