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? 

Looking Ahead: Alnylam-Medtronic Alliance Stop-Go Decision Expected Soon

In early 2005, Alnylam and Medtronic announced a joint product development program to evaluate the use of Medtronic’s implantable drug delivery devices for RNAi Therapeutics applications of the central nervous system (CNS). If at the end of this development program a joint decision for the continuation of this program were made, Medtronic would take an equity position in Alnylam and additional investments following the achievement of certain milestones.

According to regulatory filings, the original decision making due date was April 2007, but was then postponed to July 2007. It is interesting to speculate that this delay may have been either caused by scientific uncertainties or is the consequence of drafting a comprehensive and therefore complicated co-operation agreement. Certainly, in development time-frames, 3 months do not seem to be sufficient to reasonably expect major new breakthroughs had there been fundamental scientific problems.

Medtronic realised early on the potential of RNAi as a new class of drugs that could be used with their drug delivery devices. Only shortly before the 2005 agreement, in August 2004, Medtronic published a patent on the treatment of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s, through intracranially delivered siRNAs using Medtronic’s implantable catheters (United States Patent 20040162255). Two years later, a similar patent was published for the treatment of neuropathic pain.

While pertinent in vivo data are lacking in these patents, it is clear that Alnylam already has amply tested Medtronic’s devices. Josephine Lai from the University of Arizona Health Sciences Center in Tucson, a Alnylam collaborator, for example has published strong in vivo data on intrathecally delivered siRNAs [Luo et al. Mol. Pain 1: 29 (2005)]. It is also of note that in this study, siRNAs were most efficient when formulated in the liposomal i-Fect transfection reagent from Neuromics. The same reagent was also successfully applied in rescuing mice from lethal flavivirus infection of the CNS [Kumar et al. Plos Med. 3: e96 (2006)].

One potential limitation with the local delivery of siRNAs and shRNA vectors such as AAV, however, is to achieve sufficient diffusion of the RNAi inducing agent to its target cells. That diffusion of macromolecules in the dense matrix of the CNS may also be an issue with a device from Medtronic similar to the one Alnylam is evaluating, is suggested by the failure of a phase II clinical experience of the neurotrophic factor GDNF for Parkinson’s [Salvatore et al. Exp. Neurol. 202:497 (2006)]. This particular experience, however, has to be taken with a grain of salt, as there appears to be some controversy about the interpretation of the trial results [Slevin et al. Annals Neurol. 59:989 (2006)]. A positive announcement on the Medtronic-Alnylam alliance may therefore indicate that it is possible to achieve sufficient siRNA diffusion.

Nevertheless, local delivery may not be sufficient for diseases where the whole brain has to be targeted, such as in viral infections and brain tumours. Here, systemic delivery solutions are needed. While the blood-brain barrier has historically been regarded as a major obstacle to achieving that goal, targeted approaches such as the rabies-peptide conjugation approach that I have highlighted in my June 19 Blog (“New Breakthrough in the Systemic Delivery of RNAi for the Brain”) and similar efforts make me hopeful that a range of both local and systemic delivery strategies will eventually prove successful in addressing a number of diseases of unmet medical need. These issues also highlight once more, that it will be critical to carefully tailor the delivery of an RNAi Therapeutic to its disease application.

Blog Watch: The ‘Old Vic’ blog talks about a possible takeover or significant RNAi Therapeutics alliance involving Silence Therapeutics: http://www.sharescity.com/2007/07/silence-therapeutics-takeover-rumours.html