RNAi Therapeutics Now a Commercial Reality

Last Friday, Alnylam received notification from the US Food and Drug Administration (FDA) that ONPATTRO (aka Patisiran) has been approved for the treatment of hATTR-related polyneuropathy.  This marks the culmination of an almost picture-book translation of a brand-new biotechnology into therapeutic reality.  20 years from worms to patients is nothing.

ONPATTRO development path

Much has been made in the press about the great uncertainty, reflected in supposedly unusually long timelines, of whether RNAi can be a therapeutic modality at all.  Of course, the challenges of delivering RNAi triggers in WoMan, staving off unwanted innate immune responses, and the question of how the transcriptional noise stemming from slightly modulating dozens of unrelated targets will affect safety were all daunting at the beginning.

But looking back, with the exception of a 2-3 year delay due to having to change from an insufficiently potent LNP chemistry to the MC3 lipid-based LNP underlying ONPATTRO and having to institute steroid pretreatment to minimize ‘infusion reactions’, all these challenges more or less dissolved in the development path of ONPATTRO.

A special shout-out here to Ian MacLachlan and his team at formerly Tekmira for solving the critical delivery challenge first.

A best-case scenario would therefore have seen an approval in 2015-6.  2018 is therefore not that bad at all.  Here a quick run-down of the milestones leading up to the approval:

1998: discovery of double-strand RNAs (dsRNAs) being the trigger for RNAi in worms

2001: finding that RNAi can be triggered in WoMan by short dsRNAs

2002: first demonstration of RNAi in mice

2005: first therapeutically relevant demonstration of RNAi in monkeys

2009: initiation of first clinical trial of first-generation LNP-RNA (SNALP-ApoB, aka PRO-040201; ALN-VSP02)

2012: start of ONPATTRO clinical development

2012: first solid clinical proof-of-concept for RNAi in WoMan from ONPATTRO phase I study

2012: start of ONPATTRO phase II study

2013: start of ONPATTRO phase III study (APOLLO)

2017: positive data read-out from APOLLO

2018: EU and US marketing approvals for ONPATTRO  

ONPATTRO is just the beginning

Since ONPATTRO had been conceived starting about a decade ago, there has been, of course, considerable progress in RNAi trigger design (safety, efficacy) and (conjugate) delivery technologies.  As a result, a slew of other RNAi drug candidates by Alnylam, including Givosiran for Acute Intermittent Porphyria (likely 2019 approval), Inclisiran for cardiovascular disease (likely 2020 approval), and Lumasiran for primary hyperoxaluria (likely 2020 approval), are about to be approved.  Especially with the adoption of off-target-minimizing chemical modifications, I am confident that the success rate of RNAi drug candidates for tissue types for which delivery is robust will only increase.

After the liver, for which the current crop of marketing candidates is the target organ, the CNS should be the next huge opportunity as Alnylam gears up to bring a first candidate into that organ over the next year.  In addition, Arrowhead Pharmaceuticals and Alnylam have also started to talk about opportunities in the lung and cancer, although here I am still hesitant about whether these are near-term clinical opportunities or something that will have to wait another 3 years or so.

RNAi shatters antisense competition

As the world is abuzz about the first full-blown marketing approval of an RNAi Therapeutic (note: formal marketing authorization in the EU is still pending), I would be remiss not to display a key graph illustrating the power of RNAi gene silencing versus competing approaches such as gene silencing by mass action RNaseH antisense (TEGSEDI by Akcea Therapeutics) and trying to keep bad proteins from acting out with small molecules (generic tetramer stabilizer diflusinal):  

If you were diagnosed with TTR amyloidosis and had an average life-expectancy of 2-5 years, which treatment would you like to be on?

Stock market reaction

When Alnylam opens for trading today, it will likely be down due to disappointment that the FDA label, unlike the anticipated case in the EU, will only specify TTR-related polyneuropathy for which the APOLLO study had been designed, and not cardiomyopathy with none of the exploratory cardiomyopathy data from APOLLO included.  While this is somewhat disappointing in light of biomarker-based accelerated approvals of Eteplirsen in DMD where target modulation and therapeutic hypothesis were enough to win the day, this should only be a minor hiccup in the overall history of RNAi Therapeutic.  In light of the recent Pfizer small molecule Tafamidis cardiomyopathy data, it is very likely that RNAi trials will show a benefit for cardiomyopathy symptoms as well in a dedicated study (à ALN-TTRsc02). 

Until then, it is possible that the cardiomyopathy data are being withheld until Alnylam and the FDA can come up with a way to include those in an amendment, or as part of an accelerated approval submission.  It is also likely that TTR patients will now more readily be referred from cardiologists to neurologist for an intense neuro check-up such that primary cardiomyopathy patients can access ONPATTRO (and get paid for it) at the slightest signs of polyneuropathy.

TEGSEDI worse than tetramer stabilizer according to newly released EMA document

When Ionis presented data from the phase III NEURO-TTR study last year in Paris, they clung to numbers close to ‘zero’ to make the point that its TTR-lowering antisense drug TEGSEDI (aka inotersen) was 'stabilizing' and ‘halting’ disease progression.  According to a newly released document by the European Medicines Agency (EMA), this, however, does not seem to be truthful: TEGSEDI only delayed the progression of polyneuropathy compared to placebo, but patients on placebo still got worse over the 15 month study period.   

This not only widens the apparent distance in therapeutic efficacy between TEGSEDI and RNAi competitor ONPATTRO (which improved on disease parameters), but even puts it apparently behind generic tetramer stabilizer diflusinal.  Diflusinal also happens to be much better tolerated than TEGSEDI which has been plagued by platelet and renal issues.

EMA document suggests numbers were inflated

According to the ‘Summary of Product Characteristics’ document issued by EMA following its approval of antisense drug TEGSEDI for the treatment of TTR-related polyneuropathy, mNIS+7 after 15 months increased by +11 points vs 25 points for placebo.  By contrast, Ionis Pharmaceuticals (which has now licensed the drug to subsidiary Akcea Therapeutics) claimed a mere +5 point progression.  Curiously the placebo values haven’t changed.

This compares to an increase of +9.2 for diflusinal over 24 months and -6 for ONPATTRO over 18 months.

Similarly, on another measure of disease progression, the Norfolk Quality of Life questionnaire increased by only +0.99 per the Paris presentation last year, but by +4.38 per the EMA document.  Once again, the placebo numbers remained essentially the same.

Finally, what had been heralded as a TTR knockdown close to that of ONPATTRO, a median 75-79% TTR reduction vs 82% for ONPATTRO, now looks much different when considering that mean knockdown was only 68-74%, possibly reflecting the poor tolerability profile of TEGSEDI and missed doses.

I am sure that Akcea and Ionis will have eloquent explanations for the discrepancies which just so happens to  conveniently and selectively favor their drug when analyzed by them.  These new numbers, however, are not just minor adjustments, but represent substantial changes to the TEGSEDI narrative.

It should be noted that it is likely that tetramer stabilizers and TTR-lowering agents will be taken together by many patients.  The relative efficacy and tolerability numbers, however, put TEGSEDI in a very weak position with regard to direct competitor ONPATTRO, also as it comes to reimbursement decisions. 

ONPATTRO heart aches

In the phase III APOLLO study, patients treated with ONPATTRO were numerically less likely to die compared to those on placebo (~50% reduction in death rate).  Following the Paris meeting, I came away with the impression that the deaths in the ONPATTRO arm were largely due to cardiac failure and infection.

According tothe New England Journal of Medicine publication on the study, this seems to be a misunderstanding as infection was a main cause of death in the placebo arm while all deaths in the ONPATTRO arm were cardiac.  As has been pointed out by others on Twitter (@ionisdisrupts and @artkrieg), this could raise questions in the minds of regulatory bodies whether to include TTR cardiomyopathy applications on the label despite of ONPATTRO improving on related secondary endpoints.

In fact, considering that the recent study design agreement with the FDA for follow-up drug ALN-TTRsc02 also focuses on polyneuropathy endpoints, it is all but official that the label for the upcoming approval of ONPATTRO will be targeted at the polyneuropathy population only and that separate trials will have to address the patients mainly suffering from cardiomyopathy symptoms.

Disclosure: short AKCA, long ALNY.

Taking Stock of RNAi Therapeutics

Though currently vacationing, this summer is starting to get quite busy for the RNAi Therapeutics space, so I thought a quick update summary might be warranted.

RNAi Therapeutics on the eve of commercialization

Following a positive opinion by the CHMP in the EU and an upcoming US decision next week, preparations for the first commercialization of an RNAi Therapeutics, ONPATTRA (aka Patisiran) are in full swing.

The financial markets are full of worry that the label could be a narrow one for ONPATTRO, mainly focusing on the polyneuropathy manifestation of TTR amyloidosis that has been the primary focus of the phase III APOLLO study.  While this is to be taken for granted given the trial design, since many TTR patients have overlapping polyneuropathy and cardiomyopathy symptoms and given the strong cardiomyopathy secondary endpoint data in APOLLO, it has been voiced again and again by physicians at last years European ATTR meeting that patients will be put on an TTR lowering therapy at the slightest indication of cardiomyopathy.

Interestingly, this label worry has had no impact on Akcea’s stock marching to a $3B market cap despite the antisense competitor TEGSEDI clearly having inferior efficacy and a worrisome safety profile.  The choice is: ‘for the convenience of an at-home needle injection (mind you, you'd still have to go to the doctor's office frequently for safety check-ups), do you want to have something that is likely to only delay disease progression instead of reversing it and that might even shorten your life expectancy versus prolonging it if you did nothing?  To help you make this decision, be reminded that your life expectancy from diagnosis is around 5 years.’

Market uptake among cardiologists should also be a catalyzed by the Pfizer tetramer stabilizer Tafamidis data later this month.  Following news that Tafamidis had a positive impact in a phase III trial geared towards the cardiomyopathy symptoms, Alnylam's share price took a hit.  By contrast, the impact on ONPATTRO commercialization should be positive if the upcoming data presentation shows a mere disease stabilization for Tafamidis given that ONPATTRO has clearly beaten Tafamidis in polyneuropathy (there is no reason to believe a priori why cardiomyopathy should respond differently to tetramer stabilizer vs TTR knockdown).  Ultimately, increased awareness of TTR-targeting medicines in the cardiology community by players like Pfizer should only help ONPATTRO commercialization there.

Importantly, the star medicine among this new crop of TTR drugs, GalNAc-based TTRsc02, is on track to start a 9-month pivotal phase III study by the end of year and a cardiology-focused trial shouldn’t be far behind.  

Onwards and upwards RNAi.

Disclosure: long Alnylam as the clear value play in Oligonucleotide Therapeutics these days with a number of significant catalysts in the back half of the year, especially over the next month; short Akcea since not only do their most important medicines, TEGSEDI and WAYLIVRA, s.ck in terms of safety/efficacy, the revenues of their medicines has to be shared with Ionis, Novartis, and now also PTC Therapeutics.  One would therefore have to multiply their market cap by a factor of 3 or so (--> ~$9B) for comparison purposes with more typical biotech market caps.

Amgen misleading secrecy around AMG-890

Not only would Akcea have to share revenues for its most exciting drug candidate, a GalNAc-targeted Lp(a)-antisense in phase II, with Novartis, it now has serious and likely superior RNAi competition in the guise of AMG-890.  To wit, the rights to GalNAc-RNAi AMG-890 were licensed 2 years ago from Arrowhead Pharmaceuticals to Amgen and despite it having been the lead GalNAc-RNAi candidate at Arrowhead until then, HBV and AAT candidates by Arrowhead seem to have beaten AMG-890 to the clinic by a year or so.  This and the early trial termination of the ARO-AAT trial in my mind raised serious concerns that Arrowhead was willing to take far more risks with its current technology than Amgen wanted to, raising questions over the general quality of the Arrowhead pipeline in light of their otherwise amazing execution speed.

Now that Amgen has disclosed that they must have filed the AMG-890 IND/CTA-equivalent months ago, but already dosed their first subject with it, more positive interpretations are warranted.

Disclosure: Since the Arrowhead cult has attacked me on my stock trading potentially influencing my view of their technology, here a more detailed summary of my trading strategy: I started pursuing a ‘covered short’ strategy following the strong run-up in the wake of the ARO-AAT early termination and first knockdown data news releases (July puts expiring worthless, then writing new puts for August and September largely in the $14-16 range) and consider myself lucky to have covered my short on the stock route from $17 to $12.5 last Friday and this Monday leaving me short a bunch of puts.  As Arrowhead has strongly rebounded from the sell-off, I have been gradually re-shorting it starting from the ~$14.5 level to lock in some of the windfall profits; by now, the short covers ~1/3 of my puts (note: ‘covered short’ is actually a misnomer as the short portion of the trade could still bankrupt you).

RXi biting the dust no matter the (ocular) data

Self-delivering RNAi Therapeutics company RXi Pharmaceuticals reported encouraging data this week from a small study of anti-scarring candidate RXI-109 for retinal scarring.   In important news to the RNAi Therapeutics space at large, no serious drug-related adverse events were seen with these highly modified oligonucleotides.  On the efficacy side, numerical improvements were seen over placebo, but clearly need to be regarded as preliminary.

For a sub-$10M market cap company, such news should have strongly propelled the stock under normal management.  In this case, the clinical results look like a mere note on their way to impending bankruptcy.  It is a timely reminder that the number 1 job of a CEO is actually investor relations and making sure adequate capital is available when needed.  It seems like RXi’s CEO has believed that operational execution is all that was needed and that investment funds will start knocking on their door.  This was a serious miscalculation, especially since after the split from CytRx, a biotech that many would consider a scam, the entire pre-existing financing mechanics (I spare you the gory mechanics) of RXi fell away.

Disclosure: I hold a small long position in RXII (<1 a="" and="" be="" been="" believe="" bit="" company="" course="" different="" it="" management.="" more="" much="" of="" portfolio="" s="" should="" span="" style="mso-spacerun: yes;" technology="" the="" under="" value="" valued="">  I cannot, in good conscience, recommend this stock as a buy under current circumstances.

 Note: a proof-read version with links will follow as time permits.