Non-RNAi Oligonucleotide Therapeutics Stocks

In the final instalment of the stock market-focused mini-series, I will turn my attention to the non-RNAi Oligonucleotide Therapeutics sector.  With last year’s approval of EXONDYS51 (Sarepta) and SPINRAZA (Ionis/Biogen), two highly impactful exon-skipping drugs, Oligonucleotide Therapeutics has finally gained widespread acceptance as a mainstream drug modality and arguably de-risked biotech investment vehicle.

Ionis Pharmaceuticals

This is a stock where tremendous value is waiting to be unlocked.  All it takes is a change in corporate strategy.  At present, Ionis needs ~4 groundbreaking medicines for every one developed by more traditional biotech companies such as Alnylam for it to reap similar market cap appreciation.  This is because it has readily given away ownership over its drugs regardless of needs, be they financial or related to a lack of disease expertise.

A striking recent example of this is the creation of Akcea as a subsidiary tasked with the commercialization of cardiometabolic drugs discovered by Ionis.  In addition to instantly giving up 1/3 of its ownership through an IPO of Akcea at very low prices, Akcea also partnered much of its assets with Novartis, thus further diluting Ionis’ ownership.

So what should have easily been a value of $3-4B to Ionis on the eve of the approval of the first important cardiometabolic antisense drug (triglyceride lowering Volanesorsen for FCS), Ionis’ stake in Akcea now probably accounts for barely $1B of Ionis’ ~$6.5B market cap.

To add insult to injury, Ionis this summer purchased close to $100M worth of real estate related to their R&D and manufacturing operations. $100M of valuable drug development monies!  This apparently they consider a better prospective return on investment than keeping full ownership of the cardiometabolic franchise or spending a few millions to just buy the marketing muscle they keep whining about lacking.

Not all may be lost though.  There are signs that Ionis, and perhaps even the CEO (Stan Crooke) himself who had been propagating the marketing-is-evil myth to justify Ionis’ business strategy, has started to realize that they need to change their ways to keep up with the market capitalizations of peers, including organizations driven by strong platform technologies (etc Alnylam, Regeneron).  With Brett Monia assuming the role of COO and Crooke’s right hand Lynne Parshall stepping aside, we are in the midst of a change of guards in this company.  But don’t hold your breath given that Dr. Monia, as a founding member (in his mid-20s!) of Ionis, still ought to be considered a part of status quo until proven otherwise.

Inotersen as an inadvertent opportunity

Just as Ionis was looking to be locked into its royalty play model with Volanesorsen (à Akcea) and GSK-partnered Inotersen for TTR amyloidosis as the next approvals on the 2018 horizon, GSK handed back full rights to Inotersen to Ionis.  Suddenly, Ionis is in full control of a drug competing for a market currently supporting ~$10B in market capitalizations between Ionis and Alnylam.  With peak sales expectations (even without the wild-type TTR cardiomyopathy opportunity) topping $5B, this number should only grow as the commercialization phase begins.   

If Ionis is smart, they will retain most marketing rights to Inotersen as any misstep by Alnylam around its first-generation TTR drug Patisiran could provide Ionis with an unanticipated upside (as an investor, I always look for the upside compared to market expectations).  Also, learning the TTR marketing ropes now will prepare them for the battle of the respective next-gen drugs between Alnylam and Ionis as this is where the TTR game will be won in the mid-term.

Chances are that Ionis will find commercialization less daunting and even rewarding, including to the R&D staff getting closer to the patient experience.  They should also then realize that through the exposure to the patients and medical community, they will gain a better understanding of the demands on follow-on products.  Drug discovery and commercialization in the orphan era is certainly a virtuous circle and Ionis may be the last one to find out.   

Better late than never.

In the interim, look to clinical results, especially from partnered CNS franchise drugs (Huntington’s, ALS) as tradable catalysts.  With a position in IONS that is approaching the size of my largest holding (ARWR) following the recent mini-sell-off in biotech, I also speculate that as the commercialization of Inotersen approaches and the market understands the impact of the SPINRAZA loading dose issue on sales numbers, IONS should be a solid outperformer in the biotech market. 

Strong buy.

Wave Life Sciences

I consider the CNS where currently the most value is bottled up in antisense therapeutics whereas in the liver, RNAi in general holds the edge in terms of safety and convenience (long-term I believe the battle will be won based on off-targeting, one gene at a time).

Since Ionis has given up substantial rights to its CNS drugs through its broad partnership with Biogen and the next hot CNS candidate is partnered with Roche (for Huntington’s), consider Wave Life Sciences not primarily as a stereopure ASO investment, but an ASO CNS play with the company likely retaining significant commercialization rights.

Of most interest to investors should be its two early clinical-stage drug candidates specifically targeting the mutant alleles in Huntington’s disease.  Initially, I had been skeptical about the actual need for targeting mutant huntingtin specifically given that we are unlikely to see the 90%+ type knockdowns that *could* spark safety concerns if the degree of knockdown also applied to wild-type huntingtin. The observation by Ionis, however, that ASO knockdown in the various areas of the brain is uneven and that the deep brain structures thought to be most involved in Huntington’s pathology may be some of the least sensitive to ASO knockdown made me realize the potential value of the allele-specific approach.  This is because in order to drive substantial knockdowns in the deep nuclei, the corresponding drug doses might lower wild-type huntingtin to very low levels say in the cortical neurons.

Still, since the huntingtin knockdown concern remains theoretical and is largely based on animal models where huntingtin has been knocked out since around birth (please correct me if wrong), I still consider the allele-specific approach as a needlessly complicating measure.

With a healthy market cap of $1B, I feel that WVE is a very interesting ASO investment for the long-term, but that price-wise better buying opportunities could be ahead for this clinically nascent company.  Also, I am skeptical about Wave’s unforced fast-follower strategy and would like to see first-in-class candidates entering clinical development.

And yes, if stereopure chemistry can get around some of the safety issues of phosphorothioate oligos that will likely remain relevant (due to dose levels) for systemic applications outside the liver, additional competitive value is to be realized there.

Disclosure: no position as of November 29, 2017.

Sarepta Therapeutics

One of the fast-follower indications pursued by Wave is exon skipping for DMD- the domain of Sarepta Therapeutics.  Soon, Wave may not find themselves chasing a modestly potent EXONDYS51 and related PMO-chemistries for other exons, but what could emerge as a much more exciting exon skipping chemistry for the muscle: peptide-conjugated PMOs (PPMOs) which has recently cleared the preclinical safety hurdle to enter clinical development.

PPMOs easily outperform simple PMO chemistry in terms of potency, but arginine-rich precursors have suffered from unacceptable preclinical toxicity.  Sarepta now claims that it has found PPMOs with increased potency (see slide 16 of this presentation), but a much better safety margin.

If first clinical biomarker data support substantial exon skipping, then I believe Sarepta’s control over the DMD market will be cemented. Currently it somewhat hinges on confirmatory clinical evidence of therapeutic benefit for their mildly active PMO exon skippers entailing considerable clinical and competitive risk.  Add to this a number of other modalities in the quiver to treat DMD which Sarepta has acquired rights to more recently, Sarepta looks like a Vertex-/Alexion-type single orphan disease-focus play in the making.  Think $30-40B market cap (now: $3.6B).

Disclosures: long SRPT.

Regulus Therapeutics

After the miR-122 desaster in HCV and new management in place, it looks like a fresh start for Regulus Therapeutics.  The new mantra is quality over quantity as Regulus and partners alike have axed a number of microRNA Therapeutics programs.

As a result, it is clinical data from two development candidates that will most likely determine the shareholders’ fate in the years to come (note: I still think there could be tremendous opportunity in microRNA Therapeutics from addressing complex neurological diseases like Alzheimer's, but his seems of less interest to Regulus currently).  

One is RG-012 targeting miR-21 for the treatment of Alport Syndrome, an orphan disease impacting kidney health.  The advancement of this program into patients was recently slightly delayed by a few months after insights from a natural history study of the disease made the company re-focus on only X-linked cases of the disease for purposes of better stratification.

Instead of considering the change in study design as increasing the quality and therefore odds of success for the study, the market penalized this 3-6 month delay by selling off the stock from $1.4 to sub $1.  I call this a buying opportunity.

Regulus Therapeutics stands out from the oligonucleotide therapeutics crowd in that also its second candidate, RGLS4326 for autosomal dominant polycystic kidney disease (ADPKD) now in the clinic, is also targeting cells in the kidney.  I don’t think that this was by design, but the result of the liver programs falling by the wayside for various reasons.

While the kidney is certainly an interesting organ for oligonucleotides due to its high exposure to this class of molecules, it is a complex organ and not all that much is known about cell type-specific pharmacodynamics outside the proximal tubule epithelial cells.  Add to this the uncertainty about the relevant therapeutic cell types that need to be targeted for a disease like Alport’s, and you end up with considerable target risk around these programs so that in the end we largely have to rely on the mouse models here being relevant to human disease.  

I am long RGLS given (1) that Alport Syndrome makes for a nice orphan market opportunity with some important groundwork laid by Regulus itself,  and (2) the fact that sentiment around Regulus can only get better and if targeting miR-21 does not have a measurable on fibrosis in the kidney, maybe it’s time to give up on microRNAs for therapeutics altogether.

RNAi Therapeutics Stocks (Part 2)

Having covered the most developed RNAi companies (Alnylam, Arrowhead, Dicerna) yesterday, this blog entry will discuss RNAi plays that are somewhat less established, but nevertheless could represent interesting investment opportunities.

Silence Therapeutics (SLN.L)

This London-listed company is roughly 2 years behind Arrowhead Pharmaceuticals and Dicerna.  Similar to those, Silence has set its sights on exploiting targets in liver hepatocytes using GalNAc conjugate technology.  Its first program targeting TMPRSS6 for iron overload disorders should enter the clinic in the first half of 2019.

The strength of Silence is partly its RNAi trigger IP position which, if the claims stand, should read on Alnylam’s 3-4 drug candidates that could come on the market over the next 2-3 years.  In my opinion, it would take a generous interpretation of what constitutes a ‘pattern’ for LNP-enabled Patisiran to fall under Silence IP, but it is much less of a stretch for the more stabilized GalNAc-enabled Givosiran, Fitusiran, and Inclisiran molecules in late-stage development.

Part of the potential upside could  therefore come from a settlement of the IP litigation that Silence has filed against Alnylam as it could hamper the commercialization of Alnylam's RNAi drug, especially as it ramps up for the launch of Patisiran. 

The reason why such revenues would be meaningful to the company is that Silence is run extremely well in financial terms such that these funds would neatly feed into Silence's operations as it is about to expand clinically all the while minimizing shareholder dilution. 

This, however, could also be viewed as a necessity since it is much more difficult for a London-based company to raise the kind of biotech ‘risk capital’ that allows companies like Alnylam in the US to really press down the gas pedal to pursue a grand vision without killing shareholders.   

Silence Therapeutics is an investment for those that value the pursuit shareholder return instead of mere market cap growth (=management bragging rights).  While I support this strategy, I am still largely on the sidelines as the company needs to address the anemic trading volume which makes it very costly to trade in and out.

RXi Pharmaceuticals (RXII)

Who doesn’t dream of striking it rich overnight?  If so, RXII is the type of stock that in the right biotech environment could be your daily biotech double in the not-so-distant future.

After all, which other biotech with a market cap of ~$15M can boast about 3 clinical data read-outs before year-end and one additional in early 2018?

1) Q4 2017: phase II results dermal scarring (RXI-109)

2) Q4 2017: phase II results warts (samcyprone, non-RNAi)

3) Q4 2017: UV-induced hyperpigmentation results, consumer testing (RXI-231)

4) Q1 2018: phase I/II results retinal scarring (RXI-109)  

It is possible that the first 3 data read-outs could show that the agents are active and well tolerated, but where there will be a discussion about the commercial adoption of these agents in the real world.  Therefore, the real fireworks may occur following the results from the retinal scarring phase I/II trial in early 2018.  Here, the self-delivering RNAi trigger technology is tested for the first time in the eye where for reasons of technical feasibility (more equal biodistribution throughout eye than in the skin) and clinical application I see the most potential for this technology.

Downside risk comes from management that is pitifully ignorant about the workings of the financial markets and shareholder value creation.  If RXi fails to ignite investor interest in the wake of any of these 4 shots on goal, we could well see a continuation of the financial death spiral that has seen RXII lose 98-99% of its value in the last 3-4 years!!!

I own approximately 3% of the outstanding shares of RXII and will try to add on any weakness ahead of data release.

Arcturus Therapeutics (ARCT)

In sharp contrast to RXi, I view management of Arcturus as far more savvy when it comes to the financial markets and building a biotech company of decent size.

Arcturus, which has recently gone public via a reverse merger, has its roots in RNAi technology, largely by copying liposomal delivery technology from Tekmira (now Arbutus) and then licensing related RNAi IP from Marina Biotech.  In light of the Patisiran APOLLO results, you could view the platform as fundamentally de-risked.

In fact, its lead program was an RNAi program to address TTR amyloidosis.   Since then, however, Arcturus has largely re-tooled itself as an mRNA Therapeutics company using LNP delivery technology.  Although its pipeline is not as prolific as that of much-better known Moderna, it appears impressive for a company with a market cap of still less than $100M just as its partnering activities.

Therefore, Arcturus is a bet on a management that can take average science to build a significant biotech as it talks the language of Wall Street and Pharma deal makers.  It was one of my early biotech investment mistakes to undervalue big-mouthed management relative to science. The best science can always be acquired once you have lowered your cost of capital by growing market cap.

I have a starter long position in ARCT as I wait for it to be discovered by larger hedge fund manager.

The final instalment of this series will cover oligonucleotide therapeutics companies Ionis Pharmaceuticals, Wave Life Sciences, Regulus Therapeutics, and Sarepta.

RNAi Therapeutics Stocks (Part 1)

According to the RNAi calendar, a calendar characterized by 3-year sentiment cycles, we are coming to the end of the first third of another RNAi Therapeutics stock bull market. 

The current cycle follows one (2014-7) that I had referred to as The Wait when the stock market had priced in the ability of RNAi to knock down genes in humans, yet still needed confirmation that this would translate into overall therapeutically beneficial drugs to justify a further increase in the valuation of RNAi companies.  As you know, the phase III APOLLO study of Patisiran in hATTR amyloidosis has provided us with just that.  Expectedly, this has not only lifted the stock price of Alnylam (+70% since results 1 ½ months ago), but positive sentiment has trickled down to 2^nd tier companies like Arrowhead Research and Dicerna vying to be the next Alnylam.

The following blog entries will give you a quick run-down on my thoughts about the most bona fide, publicly-listed RNAi companies and stocks as well as the most interesting plays in the oligonucleotide therapeutics arena at large.

 

Alnylam (ALNY)

Love them or hate them, this company and management has stuck to their belief that RNAi is a major drug development platform to support the development of major biotech companies.  Such belief is shown by the fact that Alnylam has long chosen to retain main commercialization rights to their drug candidates while building 100 million $ manufacturing and sales operations around that.  Talk about planning for success!

While this company has recently received most recognition for the outstanding APOLLO data, it has another three (!) drug candidates (Fitusiran for hemophilia, Givosiran for Acute Hepatic Porphyria, and MDCO-partnered PCSK9 inhibitor Inclisiran) for which pivotal phase III data will read out over the next 2 years.

Nevertheless, I suspect that their share price will be largely driven by the launch of Patisiran in 2018. While the base case of ~10k patients on drug seems to be baked into its $13B market cap, there is an upside from the identification of more TTR amyloidosis patients which I feel is quite likely.  And if the amyloidosis, largely heart disease, from wild-type TTR becomes more widely recognized as a significant disease in the elderly along with diseases like Alzheimer’s, TTR amyloidosis alone should be able to support the $30-40B market caps enjoyed by similar niche players like Alexion (àsevere complement-related diseases) and Vertex Pharmaceuticals (àcystic fibrosis).

The main risk is that the competitor TTR drug Inotersen by Ionis will gain a larger market share than is currently widely anticipated, partly because patients prefer the convenience of a simple at-home injection to a day spent in an infusion center every 3 weeks.

I currently view ALNY as the RNAi stock in most need of a breather and am playing the stock from the short side as a hedge for temporary dips in the oligonucleotide and wider biotech stock market.

Dicerna (DRNA)

Long a neglected laggard in RNAi stocks, DRNA has been catching up with the competition with a solid ~200% increase over the last 3 months.

The bullish view of why you might want to ride up the stock further (note: unlike you constantly luck out on binary events, riding a stock up in bull markets is your best bet to make outsized stock market returns) is that DRNA sits now where Alnylam was in 2011/12 when it first demonstrated solid gene knockdown in humans.  It’s been a ~20x return since then. 

Actually, Dicerna’s technology is more advanced than Alnylam’s was back then.  On the other hand, there is now more competition for knocking down genes in the liver which is where Dicerna is focused on almost exclusively.  Still, I love Dicerna as they have a chance to bring two distinct, impactful drugs for severe orphan diseases towards marketing application by 2022 (for primary hyperoxaluria and an undisclosed one).  

A currently diluted market cap of slightly more than $300M is attractive given this realistic opportunity, and in hindsight their widely poo-poo’d March 2017 convertible stock offering now looks like genius as they keep hitting on all the milestones for lowering the inherent cost of the convertible. 

Some of the main 2018 potential catalysts will be (1) the conclusion of the litigation with Alnylam, (2) the disclosure of the second orphan drug candidate and subsequent IND/CTA filing, and (3) positive clinical biomarker data from the hyperoxaluria program.

DRNA is my second largest position along with IONS. 

Arrowhead Pharmaceuticals (ARWR)

While the discontinuation of their DPC-based pipeline was certainly a setback, for the long-term development of the company it wasn’t nearly as dramatic as its once ardent supporters, now harshest critics make it out to be. 

DPC, as illustrated by the cardiovascular deal with Amgen preceding the DPC fiasco, was on its way out and simpler conjugates on their way in as enhanced RNAi trigger stabilization chemistry has been able to close the potency gap with DPC and is now able to provide more sustained gene knockdown.

To play in that area, Arrowhead has been assembling an able, integrated drug development team with a proven track record of quickly advancing drug candidates towards the clinic using best RNAi practices.  Pair that with one, if not the industry’s most commanding IP estates and a proven ability to deal with Big Pharma (à partnering opportunities), I consider Arrowhead as the most likely ‘2^nd tier’ company to achieve or even exceed Alnylam greatness.

Look for continued progress of them getting back into the clinic and advances of achieving robust gene knockdown outside the liver.

ARWR has been my largest position for the last few months.

To be continued…

Artificial Intelligence for RNAi Gene Target Discovery Still Early

It’s not every day that you can see a person like chess playing legend Gary Kasparov at a biotech company’s Investors Day.  And if you did, you might wonder whether this was  some kind of stunt.

I was therefore pleasantly surprised to find that Kasparov was indeed a very fitting appearance investor event by Silence Therapeutics this week (for presentation here).  In the 80s, Kasparov apparently gained an edge over the competition by analyzing opponents’ playing habits using ‘big data’ at a time that personal computers were only about to take off.  As a former professional chess player himself, the CEO of Silence (Ali Mortazavi) therefore believes that there similarly must be ways to more efficiently take advantage of the realms of genomic data being generated to gain an edge over the pharmaceutical competition in finding attractive targets and indications for RNAi gene silencing.

Herd mentality

One of the main reasons I used to look down at Big Pharma  with disdain was their herd mentality especially with regard to the targets and indications they are pursuing.  You can bet that if there is general hype around a certain target, or that once a target has been validated for a commercially attractive indication in a clinical proof-of-concept study, almost all Big Pharma companies will be pursuing corresponding programs.

Unfortunately, such herd mentality is not restricted to Big Pharma, but can also be observed in the biotech space (see PD/PD-L1 for cancer etc etc), even in the subsector dearest to my heart: oligonucleotide therapeutics.  Be it TTR, AAT, DMD, or HBV: once there is a compelling therapeutic rationale for pursuing a gene target, multiple companies will be on its case.

It is for this reason, particularly the fear that an Alnylam or Ionis will scorch the earth around these targets, that many companies now delay disclosing the nature of their most promising preclinical programs.  This is remarkable since small biotechs like Dicerna typically rely on disclosure of their of these programs to garner the necessary investor interest.

Target scarcity?

The fact that the lead programs of RNAi therapeutics companies frequently overlap also beckons the question of whether there is a biological scarcity of targets available.  This would be in contrast to Alnylam which have limited themselves to GalNAc-RNAi trigger conjugates for gene knockdown in the liver, claiming- in the flowery languish of its CEO- to be ‘drinking from a firehose of opportunities’ in just the hepatocyte.

To Alnylam’s credit, it has not only duplicated some of the programs initiated by antisense competitor Ionis Pharmaceuticals and that of its smaller RNAi competitors, they have done some of the heavy lifting themselves.  It was e.g. Alnylam that realized the true value of going after transthyretin for TTR amyloidosis and it was Alnylam that selected a target as unorthodox, but promising as antithrombin for the treatment of a protein deficiency: hemophilia (à ALN-AT3/Fitusiran). 

Other companies like Dicerna and Arrowhead Research can also be complimented for unearthing gene target nuggets for orphan indications like primary hyperoxaluria and liver disease due to certain mutations underlying alpha-1-antitrypsin disease.

Mining for targets

I am not concerned about a dearth of suitable targets that could inhibit the continued growth of RNAi Therapeutics.  This is because there are thousands of rare and severe diseases for which there should be straight-forward genetic solutions and because genetic/genomic information continues to explode.  Still, there is certainly tremendous value if you are the first to gain high conviction around a new target and it was the CEO of Silence who bemoaned what seemed to him like an archaic, manual process of sifting through the genetic ideas one by one.

The panel discussion largely cautioned that human curation will remain dominant for the foreseeable future.  I am slightly more optimistic (or pessimistic, depending on your attitude towards AI) and give AI 5 years or so until it will become a more and more compelling means for driving gene target discovery.  This delay relative to areas like the internet is largely explained by the fact that whereas genomic information has exploded, databases that link them to careful, systematic medical phenotyping are still in their infancy. 

In the meantime, some low-hanging fodder for oligonucleotide drug development may come as a by-product of genetically diagnosing rare diseases when often the last hope for getting a grip on a condition is to genome sequence the patient.

There are beneficiaries already from the recognition of the importance of pairing phenotype with genotype databases such as 23andMe which is said to be getting quite a bit interest from pharmaceutical companies and investors. This comes after the pioneer of sifting through genomic/phenomic data for target discovery, deCODE of Iceland, was acquired by Amgen in 2012.  deCODE rose to fame by linking population-wide genetic information to national health-record databases.  I would think that we will see quite a few more similar endeavors linking existing (à nations with a high level of social bureaucracy such as the Nordic countries) or IT-driven newly generated (à Google, wearables) health records to genome and transcriptome databases. 

And as these databases grow and become more intelligent, it will be those that first understand to harness them that will gain a Kasparov-style edge over the competition.  But don’t be afraid: AI should not make human gene target discoverers/evaluators redundant any time soon and their cost relative to the cost of developing drugs is too low.  If anything, they will be needed to make the ultimate decision of whether to pursue a proposed target as each disease is unique and it will take a long time until enough billion-$ clinical experiments will have been run to provide sufficient feedback for the AI to improve.

 Silence Therapeutics: Ready for Take-off

I usually do not attend biotech companies’ Investors Days, but since London is not too far away from home, I took advantage of the proximity to get a feel for how the company has matured. 

Silence Therapeutics has long been a player in the area of RNAi trigger design and IP (see also their claim on Alnylam products), but has struggled to come up with compelling therapeutic programs.  It was as if they never really tried.  This can probably be attributed to them having lacked the personnel with the experience of taking an idea through the clinic and onto the market.

It now seems as if they not only got the technology (à focus on GalNAc-RNAi) to the point of clinical maturity, but also have assembled the management with the skill and will to succeed in developing game-changing RNAi drugs.  First up will be SLN124 targeting TMPRSS6 for iron overload disorders with a projected CTA/IND filing in Q4 2018.

RNAi Drug Trounces Antisense Rival in Paris ATTR Showdown

The audience gasped when Alnylam finally revealed the full dataset from the APOLLO trial in ATTR amyloidosis.  For the first time, patients and docs will have access to a drug that not only delays or just barely halts, but starts to actually reverse disease manifestation in a majority of patients afflicted by this debilitating, multi-systemic disease. 

Efficacy: reversal versus slow progression

A few minutes before the Patisiran RNAi data presentation, Dr. Benson, the lead investigator from the corresponding NEURO-TTR with rival antisense drug Inotersen was not met with nearly as much awe.  Yes, Inotersen did delay disease progression and was quite a bit better than the placebo control.  However, unlike Patisiran (-6 at 18 months), the mean change from baseline in the critical mNIS+7 score was well in positive territory (+5 at 15 months) indicating disease progression.

As such, Inotersen does not appear to be much better than TTR tetramer stabilizer diflusinal (given off-label in the US) which registered a +9.2 score in a trial over 24 months compared to +29.6 in the control.

Patisiran similarly came out ahead in the quality of life (QoL) assessment (improvement versus in this case a halt for Inotersen), although this was not a primary endpoint in the APOLLO trial. 

The NEURO-TTR trial could score some brownie points here as it not only made QoL a co-primary endpoint, it also scored positively in another patient-reported health score, SF-36.  Although investigators seem to prefer ‘hard’ outcomes measures such as the mNIS+7 and biomarkers, regulators and payors seem to prefer QoL endpoints according to comments at the meeting.

That the efficacy was better for Patisiran should probably not have surprised too much given that its knockdown was slightly better (82% mean median in APOLLO) than that of Inotersen (according to Benson: 75-79%, although I am a bit skeptical here as I do not understand what this range means).

As a side note and although everybody likes to see Patisiran versus Inotersen as an either-or issue, if you combined them both, you would easily exceed the 90% amyloid source protein reductions that amyloid researchers believe is necessary to allow tissue clearance exceed fresh amyloid deposition.

Safety: Patisiran once again exceeds, Inotersen disappoints expectations

If you still had difficulty deciding whether to take a drug that likely makes you better or a drug on which you will likely progress, the relative safety profiles should remove any remaining doubt.  Contrary to suggestions by the ‘counter-detailers’ at Ionis, Alnylam could not find any evidence that the steroid treatments to prevent untoward reactions around the time of infusion had any measurable adverse impact on patient health. 

Maybe this should not come as a surprise either given that immune suppression is given only transiently, every 3 weeks.  To make it clear, none of the many cardiologists in the audience voiced any concerns throughout the two days of the conference (where Patisiran was the star) about steroids in patients with cardiac disease manifestations.

If anything, the Patisiran group suffered from less adverse events compared to the placebo group, probably the result of addressing the disease.

The same, namely exceeding expectations, could unfortunately not be said for Inotersen: in addition to the previously disclosed renal and platelet SAEs, there was a 5:0 death imbalance against the drug candidate.  While the drug-related thrombocytopenia case had already been known and the 4 other deaths were attributed to disease progression, one cannot but notice that strangely, when it comes to safety, all the disease-related, random events always end up going against the Ionis drugs. What a coincidence!  And given that Ionis partner GSK had abandoned Inotersen even before the APOLLO trial were announced, I am wondering what other safety findings (in addition to thrombocytopenia, renal AEs, pyrexia, chills, and nausea) will come to light with the FDA briefing documents next year.

Take-home

Alnylam and the RNAi field could not have hoped for better outcomes from the high-profile APOLLO trial.  If anything, the full results presented at this first European combined patient-doc ATTR conference are more impressive than first indicated by the topline data a month ago.

And regarding the competitive profile compared to the antisense rival, it makes me wonder about the magic of feeding into a biological mechanism that has evolved to do just that: gene silencing.

There are still some questions around the label that these data will support.  Importantly, how much credit will be given to the positive cardiac outcomes since these were not the primary focus of the studies?  But since this is a multi-systemic disease and given the totality of the data, a number of doc presenters made it clear that they will be looking hard for polyneuropathy manifestations in ATTR patients to justify (to payors) treating them with the new agents.

Disclosure: I am short ALNY since the stock may be gasping for air up here, at least in the short-term; long IONS since this public humiliation by the fiercest rival may make them realize that in the orphan drug age, commercialization is a must.

Two Promising RNA Therapeutics to Face Off in Paris ATTR Amyloidosis Meeting

I’m en route a high-speed train to Paris to witness how RNA Therapeutics are starting to revolutionize the care of patients afflicted by ATTR amyloidosis.  Towards that end, the presentations on pivotal trials with Patisiran (APOLLO; RNAi) and Inotersen (NEURO-TTR; ASO) to an audience of key opinion leaders and patients at the inaugural European ATTR meeting will critically inform the adoption of these medicines.

Top-line data for these agents in the polyneuropathy-leaning form of the disease (FAP) have been disclosed previously (here and here).

This will only be the beginning though, with more potent, safe, and better tolerated follow-up RNA Therapeutics being developed and patient identification becoming more sophisticated.  Ultimately, I envision a world where, for the inherited version of the disease, patient identification based on genetics will be possible such that TTR lowering therapies can be initiated before organ damage through TTR deposition occur.

Patisiran seen leading

When Alnylam disclosed a month ago that intravenously infused Patisiran not only halted disease progression as had been reported for Ionis’ subQ Inotersen, but apparently improved symptoms compared to baseline, the stock shot up ~60% while Ionis stock dived ~15%. Furthermore, safety and tolerability looked solid with much less treatment discontinuations (7.4% vs 37.7%) and nominally less deaths observed in the Patisiran treatment arm versus placebo control (4.7% vs 7.8%). By contrast, Inotersen has been living under a safety shadow ever since deaths due to phosphorothioate ASO-dependent thrombocyte lowering wereseen in addition to renal toxicity.

Can Inotersen stage a comeback?

So even before Patisiran data were presented, the Big Pharma partner for Inotersen, GSK, dumped the drug (by not exercising the option).  Obviously, Ionis wants this to be seen as an act of Dumb Pharma throwing away highly valuable drugs under the directive of bean counters and smartly dressed corporate overhaulers (here: GSK leaving orphan drugs).  Nevertheless, it is difficult to believe that GSK gave rights to Inotersen back for free when it saw Inotersen competitive with Patisiran which easily accounts for roughly half of Alnylam’s  $11B market cap.

Still, while to many it is a foregone conclusion that today’s presentations won’t change much in the competitive dynamics between Patisiran and Inotersen, there are a few scenarios which could change it.

Firstly on efficacy, we still have to learn whether the disease improvement over baseline as reported for Patisiran by Alnylam is medically meaningful over the disease halt reported for Inotersen.  As such, it is possible that the (mean and median) mNIS+7 scores were barely negative (i.e. nominal improvement) as the phase II open-label extension trial results with Patisiran would have predicted.  And who knows, mNIS+7 values for Inotersen could actually be nominally negativ!

Somewhat complicating mNIS+7 matters is that the two companies are using slightly different scales, but I don’t expect this to have much impact on the discussion.

In addition to closing the gap on absolute efficacy, Inotersen could emerge as the winner in terms of treatment efficacy versus placebo.  Importantly, the placebo group in the Patisiran study received steroid treatment around the time of infusion since Patisiran treatment entails this to manage potentially dangerous reactions around the time of infusion and subsequent hours.  Although Patisiran clearly outperformed placebo, steroids, albeit given intermittently, should have some impact on perceived disease symptoms and I found it notable that while Inotersen was statistically better than placebo (no drug at all) at an intermediate time-point 9 months, Patisiran wasn’t yet at 8 months.

It’s therefore possible that Inotersen has the delta advantage over Inotersen which, of course, would influence how docs regard the inherent efficacy of Patisiran alone.

Finally, the placebo issue could also negate another apparent advantage of Patisiran over Inotersen: safety and tolerability. Notably, there was a ~40% SAE rate in both the Patisiran and placebo groups which are historically high for TTR amyloidosis clinical trials.  For example, an 18 month trial with TTR tetramer stabilizer Tafamidis had SAEs of less than 10%.  Is it therefore possible that steroid treatment accounts for the high SAE rate and that the overall SAE rate for Inotersen (to be disclosed) is much lower? 

 With the presentations being less than 8 hours away, we shall find out any time now as my train reaches the outskirts of Paris…