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.