Busy Week in Oligonucleotide Therapeutics

Ionis-Akcea ApoCIII Panel

Alnylam CNS Aspirations

Arrowhead Cardiovascular Data 

Dicerna Deal Pre-Announcement

It’s been a very busy week in the Oligonucleotide Therapeutics space, so I thought to memorialize the most important events of last week with this blog entry. 

Difficult Volanesorsen Panel

The highlight of the week certainly was the Advisory Committee on Volanesorsen (VLN; commercial name WAYLIVRA) for the treatment of Familial Chylomicronemia Syndrome (FCS) hypertriglyceridemia.  Here, the FDA, experts in the field, and sponsor Akcea Therapeutics were struggling to assess the risk:benefit of the ApoCIII-targeting phosphorothioate antisense gapmer. I had previewed the panel here.  

As I had expected, the majority voted yes on whether VLN should be approved for FCS.  

While following a very strict diet can be a powerful risk mitigator in FCS, it greatly affects quality of life and alone cannot absolve patients from the risk of pancreatitis attacks, abdominal pain and a range of other morbidities related to having very high triglyceride levels in the blood.  Because VLN is by far the most effective agent for lowering triglyceride, I would have been very surprised in this era of patient choice if a panel of experts wanted it to be out of reach for them.

Unfortunately, aside from on-target pharmacological efficacy, VLN performed very poor in terms of safety and tolerability.  Moreover, the trial was too small and ill-designed to tease out real disease benefits such as a lower pancreatitis attack rate and improved quality of life.  Not even a trend in favor of VLN could be discerned here.

As a result, the discussion was mostly centered around what an effective risk mitigation program (REMS) could look like to prevent dangerous bleeding events caused by the thrombocyte-(= platelet-) suppressing activity of VLN, the adverse event that was singled out as most concerning. 

Unfortunately, the practical experience with VLN showed that even closely following platelet counts and stopping VLN administration or adjusting dosing frequency in response to dropping levels are not able to stop such bleeding risk from continuing.  As such, it is to be expected that VLN will get onto the market without a really satisfactory REMS and that patients may have to accept the bleeding risk, knowing that treating physicians will be ready to administer steroids and/or IVIG should platelets drop to extremely low levels.

Due to thrombocytopenia and the range of other safety and tolerability issues and safety monitoring demands, there is a real possibility that VLN will mostly be a placeholder until safer ApoCIII-lowering alternatives can get approved.  In light of what we have learned from mipomersen and TTR-lowering drug Inotersen, the most negative impact of the VLN data is probably on the potential of systemically administered phosphorothioate antisense oligos outside of the liver.  While GalNAc for the liver and potentially GLP-1 peptides for pancreatic beta cells should keep required ASO levels substantially below the 200-300mg/week dose known to cause the tox and tolerability issues, the prospect for tissues, including muscle, that require systemic ASO administrations is less bright.

Having said that, there could be very simple solutions such as minimal reductions in the extent of phosphorothioation that miraculously can get rid of most of these side effects.  In the absence of a reliable animal model system, however, learning the rules in the clinic could take quite a few more years.  

Alnylam announces CNS aspirations

Another highlight of the week in Oligonucleotide Therapeutics was Alnylam’scoming out in applying RNAi for gene knockdown in the central nervous system (see presentation here). 

While CNS had been an area of interest of the company in its early days (Huntington’s Disease collaboration with Medtronic, a Parkinson’s program), the direct intrastriatal injection results and delivery approaches with old RNAi trigger formats were far from promising for clinical translation.  Not surprisingly, CNS had dropped off the corporate radar.

With the lesson learned from GalNAc-RNAi for the liver, most notably that of the importance of high chemical stabilization and ligands to maximize both oligonucleotide concentration and cellular uptake, and the surprisingly broad CNS biodistribution seen following intrathecal administration of antisense oligonucleotides by Ionis, it was only a matter of time that companies in the RNAi space would re-visit ‘old tissues’ for RNAi.  So with Arrowhead stoking interest in its RNAi efforts in the lung and Alnylam now in the CNS, RNAi is on the cusp of shedding its perception that it is ‘only for the liver’.  And unlike Ionis and Akcea, the RNAi space has street cred so that the capital markets are likely to buy into those claims.

To make matters worse for Ionis, Alnylam is now predicting that (similar to the liver), knockdown with its RNAi molecules should be longer-lived and much better tolerated than the phosphorotioate competition (from Ionis and Biogen): 

'Expect superior potency, duration and systemic safety profile vs. ASOs'

In light of the limited though promising public data (single rat intrathecal injection of 0.9mg of RNAi trigger causing substantial, ~75% target gene lowering for at least 1 month, the latest time point measured), it is too early to decide whether that’s true.  More information on this subject should, however, emerge over the next 2 years by which time Alnylam plans to file its first IND for the CNS.

Arrowhead highlights cardiovascular pipeline

Arrowhead Pharmaceuticals seems to have repaired relationships with investors following its DPC Waterloo and is increasingly getting credit for its GalNAc-based turnaround.  Outside of its lead programs in HBV and AAT-related liver disease, it is cardiovascular disease indications that are the focus of these efforts.

So at ATVB, the company presented an update on these programs with a focus on ANGPTL3 for the treatment of a range of lipid-related abnormalities, especially hypertriglyceridemia.  Of note, first monkey data showed that the administration of therapeutically relevant 3mg/kg triggered robust, 80% target gene knockdown lasting for more than 4 weeks. 

With INDs/CTAs planned for both ANGPTL3 and ApoCIII as well as potentially Lp(a) by partner Amgen anticipated before the end of the year, 2019 promises to be a clinical data-rich year for RNAi in cardiovascular disease.

Dicerna kind of pre-announces AAT-deal as investors get ready to sell shares

Much of what is going on behind the scenes at Dicerna is currently only being reflected by its SEC filings.  

On May 4, large shareholders who had supported the company throughout its litigation with Alnylam and now stand to be richly rewarded for it (~5x gain currently) had their shares registered for sale in an S-3 filing.  These shares account for a whopping roughly half of the shares outstanding.

To bring all investors up to speed, such a registration necessitates the filing of a prospectus.  Interestingly, this document was very specific in that the company now expects to partner the mystery orphan-disease candidate it has been talking about for quite some time this quarter:

‘We plan to seek a risk-sharing collaborator for this program before we file an IND and/or CTA, which we expect to be prepared to file in the second quarter of 2018.’

The document also removes any doubt that the secret target of that program is alpha-1-antitrypsin:

‘The protein causes progressive liver damage and fibrosis, in some cases leading to cirrhosis and liver failure, and we believe that silencing of the disease gene will prevent production of the abnormal protein and thereby slow or stop progression of the liver fibrosis. Greater than 100,000 people in the United States (“U.S.”) are believed to be homozygous (i.e. having identical pairs of genes for any given pair of hereditary characteristics) for the mutation that causes the liver disease, and at least 20% of those people, and potentially a significantly higher fraction, are believed to have liver-associated disease as a consequence.’

So if you were mesmerized by the stocks recent strong performance on modest volume, here’s a conspiracy theory: the company is helping supportive investors to get out on a high volume day that an AAT deal announcement would precipitate.  And spending a few bucks to run the shares up is well worth the investment. 

If the events unfolds as I speculate, it is yet another powerful reminder it is not sufficient for investors to merely follow the press releases, but carefully read the regulatory filings, even if they may seem dry and overly long. 

Addendum 15May18: on its quarterly conference call, Dicerna clarified its convoluted statement in the prospectus regarding the timing of partnership and IND of the mystery candidate. Accordingly, the candidate will be ready for IND/CTA filing by the end of Q2. An actual filing, however, will have to await a partnership which the company now guides for the second half of this year.  Apparently, they are currently in talks with 'more than two' potential partners.

Another focal point of the conference call Q&A session was the rationale behind the single-dose trial with DCR-PHXC for primary hyperoxaluria and how they want to use that as the basis for designing a pivotal registrational, multi-dose trial in 2019.  In this regard, contradictory statements were made.  On the one hand, the CMO contended that as seen with the more advanced program by Alnylam, most of the oxalate lowering can be seen following a single dose already so the company will have a good idea as to the necessary dose and dosing frequency for the pivotal trial.  On the other hand, the CEO predicted that repeat dosing is likely to be necessary to get an idea as to the actual oxalate-lowering potential of a given dose.  Here, I side with the CEO, but keep asking myself why on earth are they taking so much scientific and regulatory risk with a single-dose trial? 

FDA Cautious on Triglyceride-Lowering Antisense Drug WAYLIVRA

Today, the FDA released review material for the Advisory Committee Meeting on Volanesorsen (trade name WAYLIVRA) this Thursday.  WAYLIVRA has been developed for the lowering of serum triglyceride level in patients with a genetic form of severely elevated triglycerides, familial chylomicronemia syndrome (FCS).  Briefing Docs provide valuable insights as to the safety of drug candidates which are often glossed over by sponsor companies leading up to such regulatory events.

Echoes of KYNAMRO

The last time we had this opportunity in the phosphorothioate antisense space was in 2012 when the subject was the ApoB-lowering KYNAMRO.  Like KYNAMRO, WAYLIVRA is a second-generation 2’-MOE phosphorothioate-backbone oligonucleotide that was given at high doses in the registrational trials (200mg for KYNAMRO, 300mg for WAYLIVRA). 

It should therefore not come as a surprise that the safety and tolerability of WAYLIVRA was quite poor. In particular, not only did the at times drug-induced severe thrombocytopenia cause considerable bleeding concerns, the sponsor Akcea and parent company Ionis Pharmaceuticals have no idea about how to mitigate such risk.  Dose adjustments and increased platelet monitoring apparently did not change the thrombocytopenia risk substantially and apparently are still being made to this date without much rhyme or reason.   

In addition, there were the flu-like symptoms, liver enzyme elevations, renal tox, even a case of anaphylaxis causing around half of what should be highly motivated patients with FCS to drop out from the clinical studies.

This time it’s potent though

Fortunately, unlike KYNAMRO, WAYLIVRA has robust potency.  For those that managed to stay on the 300mg weekly dose, serum triglyceride lowering in excess of 70% was seen (reflecting ~90% target ApoCIII-lowering; cf. ~20% target-gene lowering with KYNAMRO).  Even the FDA had to acknowledge here that this is an unparalleled achievement.

But the positives end here already, with the FDA noting that in contrast to Akcea’s/Ionis’ claims there is no reliable reduction in measures of actual morbidity of FCS patients such as pancreatitis attacks, abdominal pain, and general well-being.  In fact, on most measures there was not even a numerical benefit favoring WAYLIVRA.  This, the FDA agrees, is also a function of the low number of patients available for such ultra-orphan disease studies.

The FDA admits that lowering of the biomarker serum triglyceride, even to much lesser extents than WAYLIVRA, has formed the basis for approving other drugs for hypertriglyceridemia-related disease.  In light of this, I expect WAYLIVRA to receive a favorable panel vote on Thursday on the condition that access to WAYLIVRA is strictly limited and safety tightly monitored (à REMS).  It apparently scares the FDA that while FCS has an estimated prevalence of 1 to 2 in a million, up to 1 in 600 have very high triglycerides resembling FCS.

Having said this, I am not quite clear why there should be different risk/benefit threshold with regard to the triglyceride-related morbidity for FCS and conditions resembling FCS as long as these other patients have exhausted options to treat the underlying causes for their particular hypertrigliceridemia.  As such, I believe the market potential estimates ought to be dramatically increased for WAYLIVRA.

WAYLIVRA competition

It is already clear, however, that WAYLIVRA will have a limited shelf-life.  Hot on its heels is a GalNAc-conjugated in-house competitor (ApoCIII-LRx) which has shown triglyceride lowering approaching that of WAYLIVRA, but at 5-10x lower dose levels, less frequent dosing and, crucially, with supposedly none of the worrisome safety issues of WAYLIVRA.  A phase III study of that compound is planned for 2019.  By that time, an RNAi GalNAc compound by Arrowhead should also be well in the clinic setting up ApoCIII-lowering to become a substantial market for oligonucleotide therapeutics by expanding the market well beyond the FCS population.