Monday, October 9, 2017

HBV RNAi 2.0

Gene knockdown, in particular RNAi and RNaseH antisense, holds great promise in the treatment of hepatitis B viral infection.  It is currently the only practical means to potently inhibit all viral gene products*.  It therefore is poised to become a cornerstone of future treatment regimens aiming at functionally curing HBV, an infection predisposing more than 200 million patients worldwide currently to liver failure and cancer.

Arrowhead- lessons learned

Unfortunately, the field took a big hit last year when HBV RNAi trailblazer Arrowhead Pharmaceuticals had to abandon its efforts due to preclinical toxicity resulting from its particular approach to releasing the RNAi triggers into the target cell cytoplasm (monkey deaths due to the DPC).
Nonetheless, after more than a dozen trials in WoMan, the company had learned a great deal about HBV and how to best tackle it by RNAi.  Chief among those lessons were the observations that RNAi can suppress viral genes, most notably the surface antigens HBsAg by sometimes more than 2-3 logs.  Moreover, in HBe-antigen negative and those HBe-antigen positive patients previously exposed to polymerase inhibitors (‘nukes’), Arrowhead painfully found that most HBsAg is derived from host genomically integrated HBV.  Consequently, RNAi trigger target sites placed downstream of the HBsAg ORF may be lost and RNAi rendered futile (ARC520àARC521 transition). 
Finally, consistent with the experience with nukes and interferons, it appears that RNAi treatment success (functional cure) should follow complex viral and host immune dynamics and while intriguing changes were observed in the clinic with ARC520/1 (e.g. new lower baselines following treatment cessation), it remains unclear how long an RNAi agent would have to be given.  This has implications for whether intravenous routes of administrations are practical or not.

The competition
Arrowhead Pharmaceuticals, however, has not been the only RNAi game in town developing HBV therapeutics.  Its main competitor in terms of scientific prowess has been Arbutus Biopharma (renamed from Tekmira after biotech wonder boy Vivek Ramaswamy of Axovant fame spectacularly raided the company in 2015).  Its lead RNAi candidate ARB-1467 comprises of 3 RNAi triggers which are formulated in lipids (LNP) and is given intravenously alongside steroids.

While I like the 3-trigger strategy for pangenotypic coverage and for minimizing the risk of the virus developing drug resistance (including by genomic integration), the more cumbersome intravenous route of administration- now reduced to short 2-week intervals in an effort to increase potency- and the steroids makes ARB-1467 uncompetitive in a world of more potent and less frequent simple subcutaneous competition.  The use of immune suppressive steroids, of course, in HBV patients is a dicey proposition and would also seem to run counter to the ultimate aim of achieving immune control of the virus.
Unless it turns out to promote a functional cure along with other agents in short order, say less than 6-12 months, ARB-1467 will likely end up as a science project without much clinical impact.

RNAi powerhouse Alnylam Pharmaceuticals meanwhile is the third RNAi company that has begun clinical development of an HBV RNAi agent.  Importantly, it has been the first company using a simple subcutaneous GalNAc-conjugate format, therefore positioning it to be useful even when more prolonged treatment will turn out to be necessary.
After review of the program, however, it appears that the company prematurely rushed the single trigger ALN-HBV into the clinic without thinking too much about resistance issues.  To start with, ~2% of tested HBV genotypes have mismatches with the trigger that mitigate targeting efficiency.  As a single trigger candidate, ALN-HBV will also have to be given alongside highly potent replication inhibitors (nukes) as one can easily see how ALN-HBV resistant genotypes would otherwise eventually take over.

ALN-HBV moreover targets a site downstream of the HBsAg ORF, around the DR2 repeat element with marks the integration hotspot that has bedeviled ARC-520 before.  While Alnylam has been going around claiming ALN-HBV doesn’t suffer from ARC-520-type issues, I would challenge them with two points:

1)     under selection pressure by ALN-HBV to maintain HBsAg expression and thus evade host immune detection, the virus may ‘choose’ to break up upstream the ALN-HBV target site without affecting the HBsAg ORF; 

2)      more troublesome, closer inspection of the very paper Alnylam points to for making its claim (Jiang et al. Genome Research 22: 593) and which analyzes HBV integration hotspots, shows that ~40% of DNA break points appear to be upstream of the ALN-HBV target site (compare ‘position 1600’ below).      

One can therefore easily see why the project leader behind ALN-HBV, Laura Sepp-Lorenzino, has recently left the company to join Vertex Pharmaceuticals.  One has to get the impression that ALN-HBV, just like ALN-GO1 have only been rushed to the fore as a front in order to keep a lid on their competition by creating doubt about the ability of Arrowhead Pharmaceuticals and Dicerna, respectively, to compete with juggernaut Alnylam. 

It is yet another lesson that in drug development, a detailed understanding of the disease is as important as the technology used to tackle it.  Half-hearted side projects typically lead nowhere.

Lastly, I would be remiss if I did not mention the RNaseH antisense efforts by Ionis along with partner GSK, and those of Roche.  Ionis/GSK are not only developing an unconjugated fully phosphorothioated antisense molecule, which I believe has little chance of competing in the market due to predictable safety and potency issues, but also a more interesting GalNAc-conjugate version (IONIS-HBV-LRx).  Although I currently see RNAi ahead of antisense in gene knockdown in hepatocytes (potency, frequency of administration, and safety), the GalNAc-conjugate version potentially has the advantage of also being able to access the pregenomic RNA directly, while direct pgRNA cleavage by RNAi of this non-mRNA remains to be shown.  My prediction is that  while RNAi can to some degree access pgRNA, this is not as effective compared to its cleaving mRNA.  What all of this means biologically remains to be seen.

Arrowhead HBV RNAi 2.0

Therefore, after all the drama and competitive noise, Arrowhead is poised to recapture the HBV RNAi lead with its new GalNAc-based candidate.  ARO-HBV is poised to enter the clinic in the first half of 2018.   It is subcutaneously administered and involves 2 RNAi triggers that are claimed to cover the viral resistance bases, including HBsAg derived from genomically integrated HBV.
The company expects the agent to be used once a month or less frequently, an attribute valuable should functional cures take longer to emerge.

Given knowledge leadership in HBV gene knockdown and prior practical experience, Arrowhead should also be able to navigate through the HBV clinical development maze faster than its competition.  As can be seen from its resurging stock price, this view is also shared by an increasing number of investors. 
Arrowhead has paid for taking some short-cuts when it was compelled to push ARC-520 into the clinic to give it a shot of becoming a serious player in RNAi before it ran out of capital.  It took some risks and failed, but that failure could well be the soil from which future success will emerge. 

Disclosure: long Arrowhead Pharmaceuticals







* it is unclear whether RNAi can directly cleave pregenomic RNA, whereas RNaseH antisense should be able to do that.

Friday, September 29, 2017

Oligonucleotide Strategies beyond the Liver

As the first major wave of pivotal trial successes involving gene knockdown in the liver has reached the shores, oligonucleotide therapeutics are quickly establishing themselves as the dominant modality in this important target organ for new drug development.  While the industry is milking this organ for therapeutic applications, my thoughts are directed towards the next tissue opportunities that should further feed this revolution in drug development we are witnessing now.

After not having been part of the conference circus for 2 years, this week’s Oligonucleotide Therapeutics Society annual meeting in Bordeaux, France, was just what the doctor ordered for me to get a clear perspective on this issue.  Importantly, lessons learned from GalNAc-targeted oligonucleotide delivery to hepatocytes, but also LNP delivery to the liver prior to this, now allow the field to take the next step in extending delivery beyond the liver.

Chemical stability

All these efforts essentially share their use of highly modified oligonucleotides which have particularly changed the philosophy around the RNAi modality.  This allows the oligonucleotide to not only reach the target tissue intact, but also to remain trapped in endosomal compartments which serve as slow-release depots for long duration of action.

Chemical modification also has greatly reduced the immunogenicity of RNAi triggers and obviated the need for protective nanoparticle formulations.  These often came with the added liability of amplifying the immunostimulatory potential of these molecules.  Consequently, decade-old approaches are now being revisited with more fully modified RNAi trigger versions (e.g. self-delivering RNAi trigger structures as pursued by RXi Pharmaceuticals and the Khvorova group at UMass).

Ironically, after all the song and dance by RNAi bellwether Alnylam about the utility of exotic modifications in their conference presentations (one can also call it willful misleading of the field- not really the purpose of scientific conferences), the strong trend is towards maximizing 2’-O-methyl content, in addition to some 2’-F and phosphorothioation at the RNAi trigger termini.

PK enhancers

One of the reasons why the liver became the first major oligonucleotide target organ is that it is readily accessible from the blood.  This allows it to soak up oligonucleotides before they get removed by renal filtration.  In an effort to fight this tendency, the use of PK enhancers, in particular lipophilic groups is frequently seen.  Ionis and Alnylam are testing these for example for getting better distribution to the muscle and potentially also better functional uptake.


PK enhancers, however, are largely about shifting around biodistribution, but it is hepatocyte ASGPR-type receptors that are the most valuable assets the industry is striving to identify.  My highlight of the conference therefore was a talk on a collaboration by AstraZeneca and Ionis demonstrating strikingly selective and effective targeting of beta cells in pancreatic islets. Think diabetes! 

It is the GLP1-receptor that does the magic here and which can be targeted by GLP1-peptides for effective oligonucleotide uptake.  While the in vivo validation was limited to rodent models, including an elegant GLP1-receptor knockout mouse model, I am convinced that the findings will translate to larger animals and humans.  It is one of those things you just know when seeing such data.

This example illustrates the value of knowing your target cell type really well, as this may allow you to identify additional ASGPR-type receptors which had been thought of elusive.  But even if they are lacking in some tissues, a nice, yet simple strategy to overcome this was illustrated by MPEG LA and Axolabs: by linking more than one RNAi trigger to a small scaffold, they were able to show that cellular oligonucleotide uptake capacity can be increased beyond the limits of receptor amount on the cell surface.
While the liver certainly does not need this strategy, it should definitely be applied to new targets like the beta cells.  Let free market competition do its magic and have oligonucleotide therapeutics solve diabetes now that you can effectively reach hepatocytes, adipocytes, and now also beta cells. Yes, I love the free markets, but I digress… 

After beta cells, it was a collaboration between Alnylam and Johnson & Johnson on overcoming the long-held dream of oligonucleotide therapeutics addressing gene regulation in cancer cells.  Here, small and stable ~2nm peptide scaffolds referred to as centyrins were coupled to the RNAi trigger and directed towards different receptors like PSMA and EGFR.  Perhaps the most striking aspect of centyrin-siRNA conjugates was their effective tumor penetration where prior RNAi delivery attempts like LNPs had fallen short.

Endosomal release

Sometimes getting to the endosomes alone is not enough when the rate of cytosolic release therefrom is insufficient.  So despite of the DPC fiasco last year and despite of aborted arginin-based endosomal release attempts prior to this, active endosomal release is still embraced in some delivery efforts.  Most notably, Sarepta has shown dramatic increases in dystrophin exon skipping in non-human primates with new peptide-PMOs (PPMOs) compared to their unconjugated parent molecules.

Of course, everybody now wants to know what the therapeutic window really is.  While the Sarepta representative at OTS was a bit cagey when asked about it, Sarepta’s CEO noted in a recent investor presentation that the filing of an IND by the end of the year would be a major positive signal in that regard.

Finally, all of the above developments are aided by more general progress in technologies interrogating biology such as single cell technologies (cell type isolation from complex tissues like the kidney), reduced chemistry costs allowing for much larger numbers of oligonucleotides to be screened, and ubiquitous low-cost and high-throughput sequencing.

Sometimes I pinch myself asking whether all this is real and not just a figment of my imagination, but at least in my mind the stars just keep aligning allowing for RNAi and oligonucleotide therapeutics to take the next step up the value ladder.

Thursday, September 21, 2017

RNAi Therapeutics Become Real

It’s been a long ride.

The lives of quite a few of us has been consumed now for close to two decades dreaming about a world in which RNAi Therapeutics have real-world clinical impact.  Yesterday, that dream has officially materialized.

TTR knockdown improves disease state

With the conclusion of the most comprehensive clinical study conducted to date in the severe orphan disease ATTR amyloidosis, Alnylam and investigators have found that prolonged knockdown of the causative transthyretin (TTR) gene improved both objective (mNIS+7) and subjective (quality of life) measures of the main manifestation of the disease, peripheral neuropathy.

There is no doubt that this was the result of on-target TTR gene knockdown since this was a strictly controlled study in which the only difference to the placebo group was the administration of the RNAi formulation.  Furthermore, results from a similar study for this indication (NEURO-TTR) by Ionis earlier this year in which related RNaseH antisense oligonucleotide technology was utilized for TTR knockdown also demonstrated disease benefit, albeit a ‘mere’ halt of neuropathy progression in QoL as opposed to the improvement seen here (note: mNIS+7 was reported only with regard to placebo, not versus baseline).

Importantly, this extra benefit is likely explained by the fact  that the Patisiran RNAi formulation had been shown to be slightly more potent than antisense drug candidate Inotersen in earlier-stage studies (here and here).  While considering a ~80-85% vs ~70-75% knockdown may not seem much at first glance, protein deposition, clearance and in particular misfolding that is at the root of the disease are higher-order concentration-dependent processes (think about crystallization) so a difference of ~17.5% vs ~27.5% (>50% more remaining than with Patisiran) remaining insulting protein may well be highly meaningful. 

Of note, phase II data from Patisiran have demonstrated that the ~80-85% knockdown was able to somewhat tilt the tables in favor of TTR tissue clearance, but also that it was not able to fully do so.

It is therefore of utmost importance to push forward with the development of the even more potent GalNAc-enabled RNAi candidate ALN-TTRsc02.  Preliminary phase I data from that candidate suggest that it should be able to reduce TTR levels to 5% or less with subcutaneous dosing as infrequently as every 3-6 months (Patisiran: intravenous every 3 weeks; Inotersen: weekly).

Why this is such a big deal for RNAi Therapeutics

As I had indicated in last week’s post, the phase III APOLLO results represented a make-or-break moment for RNAi Therapeutics.  If it turned out that RNAi- and delivery-related side effects were to outweigh the benefits of gene knockdown at the conclusion of this decade-long, high-visibility program, the financial markets would have reacted violently and starved the industry of the cash necessary to more fully develop the technology (Alnylam with its cash reserves at least would have mounted a comeback eventually).

If it’s one thing I’ve learned about biotech money matters over the last 15 years of riding the RNAi rollercoaster, it is that the perception of a technology is as important for its continued development as its intrinsic technological validity.

Personally, I am most relieved in that the small, but often pervasive transcriptomic off-target changes introduced by an RNAi trigger (à microRNA-type off-targeting) did not have an apparent detrimental effect on the target organ (here: liver) after prolonged, 18-months treatment.  This should not be entirely surprising based on what we’ve learned about microRNA biology- not all targets of a microRNA are biologically relevant- but is still a great relief to see play out in practice.

To wit, the RNAi industry has been overly focused on potency when selecting RNAi trigger sequences for clinical development and mostly relied on bioinformatics for specificity. Indeed, Alnylam has paid the price for this negligence in that certain RNAi triggers, such as the one for its original alpha-1-antitrypsin program, have caused liver tox most likely due to microRNA-type off-targeting.  It is therefore finally employing chemical strategies such as the incorporation of modified nucleotides in the seed region of the trigger to bias the RNAi apparatus towards RNAi cleavage instead of microRNA-type message destabilization. 

This strategy was first reported by Rosetta Inpharmatics (now Merck) and had then been developed further in the commercial realm by Marina Biotech which then licensed the IP to Roche (then acquired by Arrowhead) and possibly others. 

It will be some time until we have complete certainty that microRNA-type off-targeting won’t rear its ugly head again, but the odds should be getting better and better with the employment of best practices. More generally, Patisiran is only the beginning of a long string of real-world impactful RNAi Therapeutics.

Friday, September 15, 2017

The Wait is Finally Over

For some time now, I’ve been fascinated by how the RNAi Therapeutics sentiment cycle has been progressing in 3-year intervals.  Before I left off for my baby-break, I referred to 2014-17 as The Wait. The Wait was a reference to the ‘market’ having been convinced by early clinical data that RNAi can bring about deep and sustained gene knockdowns in WoMan, but that the ultimate clinical utility and subsequent commercial value remained to be proven.

We are now on the cusp of finding out with results from the registrational phase III study of the TTR-lowering Patisiran in familial amyloidotic polyneuropathy (FAP) imminent.

The wind is clearly in RNAi’s back with supporting developments in the related oligonucleotide therapeutics and, indeed, drug regulatory spaces.  In particular, the successful commercial launches of splice modulators EXONDYS51 (for Duchenne muscular dystrophy) and SPINRAZA (for spinal muscular atrophy) and promising phase III data from the triglyceride-lowering Volanesorsen (gene target: ApoCIII) should have removed the long-held doubt that oligonucleotides can be clinical practice-changing and profitable drugs.  And boy, are EXONDYS51 and SPINRAZA changing the clinical practice of two devastating, previously orphan diseases!

Equally important, drug regulation is strongly moving infavor of patient choice and access.  As a result, we are going to see many more drug candidates benefiting from accelerated approval pathways similar to EXONDYS51.  A number of RNAi Therapeutics programs such as Givosiran by Alnylam (àmetabolite ALA lowering as reasonably predictive endpoint) and DCR-PHXC by Dicerna (àoxalate lowering) are poised to benefit from this development.

But let’s not get ahead of ourselves and await the Patisiran APOLLO study outcome for which sponsor Alnylam has guided a ‘late September/summer’ read-out.  Drug development is full of surprises, so despite all the data* pointing towards a positive outcome, a number of variables (e.g. steroid use, lipid nanoparticle delivery) remain unknown in how they impact overall outcomes.  I for one will breathe a big sigh of relief should Patisiran be able to overcome this Make-or-Break event for RNAi Therapeutics.

à positive open-label extension data from phase II Patisiran;
à positive phase III data from IONS-TTRRx targeting same gene and indication;
à the high roll-over rate into the open-label extension) indicating a positive outcome 

Friday, May 27, 2016

What the thrombocytopenia findings mean for Ionis Pharmaceuticals

Yesterday, Ionis Pharmaceuticals disclosed that severe reductions in platelets had been observed in phase III clinical trials of both IONS-TTRRx for the treatment of TTR amyloidosis and IONS-ApoCIIIRx for conditions related to highly elevated triglycerides.  Severe platelet reductions are dangerous since it can lead to occult, uncontrolled bleeding and poor blood clotting following injury.

Since the conference call was a PR disaster as the CEO of Ionis has major issues with speaking his scientific mind, and since competitor Alnylam has seemingly become the original source and interpreter of the Ionis thrombocytopenia issues (one wonders how they come into possession of these Ionis trade secrets...), I thought it may be useful to briefly come out of blogging hibernation and lay out my thoughts about what these events mean for the technology and the company.

Thrombocytopenia likely limited to systemically administered, unconjugated PS-oligos >200mg per injection

As a hematological abnormality that has historically been observed with phosphorothioate (a ‘sticky’ chemistry) oligonucleotides when given at high doses (>200mg/injection)  I’ve always considered it likely that such thrombocytopenia will be associated with measures of plasma exposure of the oligonucleotides.  Notable examples for thrombocytopenia with phosphorothioate oligos include the DMD exon skipper drisapersen by Biomarin/Prosensa (6mg per kg per week, i.e. around 300mg/week for 50kg boy) and telomerase inhibitor imetelstat by Geron (~10mg per kg per week, i.e. around 700mg/week for average adult).  Actually, isn’t it ironic, or maybe even curious that imetelstat is being developed for conditions where elevated thrombocytes is the problem (see related blog entry)???

Consistent with this notion, there was a study by Flierl et al. in 2015 that looked at the mechanism of platelet activation which may lead to platelet consumption and explain lowered thrombocyte counts.  Without going into the details of the mechanistic aspects of the study, the authors find a strong correlation with peak plasma exposure (c max) of the oligonucleotides and platelet activation.   

So why hasn’t Ionis seen severe cases of thrombocytopenia in the past (excluding use of PS-oligos in cancer patients which frequently suffer from potentially confounding bone marrow suppressions from other drugs)?  The most probable explanation is a) these events are quite rare events and b) that their experience with PS-ASOs at 300mg/week and above has been limited.  At 300mg and especially 400mg per week, safety has always looked a bit dicey such that the 300mg per week dose e.g. for TTRRx was only adopted after 200mg per week was not competitive with the knockdown results produced by ALN-TTR02 from Alnylam. 

Similarly, the initial studies with ApoCIIIRx did not include the 300mg per week dose and was adopted in favor of the very impressive triglyceride reductions seen at doses higher than 200mg.  Usually the dose escalation of the prototypical Ionis phase I studies involved 50, 100, 200, then 400mg per week with 400mg per week never being chosen for the phase II and/or pivotal studies.

What I find highly interesting is that the pharmacokinetics data from the healthy volunteer study of ApoCIIIRx reported by Graham and colleagues in 2013 (see only Table IV) reported a non-linear, 4.5x increase in cmax when doubling the dose from 200mg to 400mg per week.  This could mean that at doses of 200mg per week and higher, the risk of severe thrombocytopenia is dramatically elevated by going past the threshold where platelets become critically activated (à clotting cascade).  
If the cmax theory holds true, then the following should be the impact of the new findings on the Ionis platform.  The summary takes into account the clinical observations by Ionis that the platelet reductions are reversible upon stopping dosing and can be prevented and also treated by steroid use (just as ALN-TTR02 involves steroid use):

1)      Unconjugated, systemically administered antisense at 300mg per week and above (incl. phase III assets TTRRx and ApoCIIIRx): need for tight platelet monitoring.  May involve temporary halt of studies to amend protocols.  Commercially, need for tight platelet monitoring could be a problem for less severe diseases due to convenience and competitive issues.  

Note that for all the liver-targeted programs, backup GalNAc-conjugated versions are in development which should not suffer from thrombocytopenia (see below).  However, systemic programs targeting other tissues such as DMPKRx for myotonic dystrophy will have to be under continued scrutiny depending on the dose.

2)      Unconjugated, systemically administered antisense at 200mg and below per week and below: little impact.  Start collecting data more systematically to learn more about platelet interactions, otherwise no big impact.

3)      GalNAc-conjugated antisense: no impact. Essentially all the Ionis pipeline, including ApoCIIIRx, has been re-engineered for some time now to be GalNAc-conjugates.  This is because of their 10-100 fold increased potency over the unconjugated versions thus decreasing the doses to well below those expected to cause severe thrombocytopenia.  Even at the same doses, plasma exposures will be much reduced due to the rapid clearance into the hepatic compartment as demonstrated by Shemesh et al in one of the most recent publications by Ionis.  No thrombocytopenia events to my knowledge were seen with RG-101 (for HCV) by Ionis' 'satellite company' Regulus Therapeutics, where a up to 8 mg/kg of GalNAc-conjugated phosphorothioate oligonucleotide has been administered.

4)      CNS programs: no impact. Peak plasma exposures are insignificant for intathecally administered oligonucleotides as used in Ionis’ CNS franchise, a franchise which includes exciting drug candidates such as phase III asset nusinersen for the treatment of spinal muscular atrophy (SMA) and candidates for other severe neurodegenerative diseases.

In summary, the only programs which could be significantly impacted by the thrombocytopenia findings are the programs that target tissues outside the liver and which involve systemic administration.  The liver franchise remains intact especially with the new GalNAc versions although there could be some minor delays and increased competitive impact in those diseases that Alnylam is free to go after according to the Ionis-Alnylam IP agreements.  The important CNS franchise remains fully intact. 

Disclosure: long Ionis and doubled down yesterday.

Monday, August 31, 2015

Cholesterol-lowering RNAi Therapeutic Shocks Monoclonal Antibody Establishment

Not too long ago, RNAi Therapeutic got dumped by Big Pharma in a big way not least because of the monoclonal/recombinant protein pedigree and corresponding bias among the top dogs of these organizations.  This was most obvious with Roche and Merck when changes in their overall R&D organizations led to the loss of their last internal RNAi champions.

How times have changed. Yesterday, The Medicines Company (who have now become a natural acquisition target) and Alnylam presented data (press release here, data here) strongly suggesting that an RNAi Therapeutic will push aside the temporally more advanced monoclonal antibody competition to become the best-in-class agent in the potentially top pharmaceutical category over probably the next two decades: the inhibition of PCSK9 for the prevention of cardiovascular morbidity and mortality.

The data in support of this claim were presented yesterday at the 2015 ESC congress in London that in retrospect was apparently named in honor of the delivery technology underlying ALN-PCSsc, a so-called Enhanced Stabilization Chemistry-based RNAi conjugate.

Treatment adherence

Importantly, the single-dose part of the study showed that starting with a dose of 300mg of ALN-PCS, PCSK9 levels were flat-lined to ~25% of normal levels for at least 4-5 months and haven’t started to perk up yet by the data cut-off date for this presentation.  It is to be expected that the knockdown will be even more pronounced with repeat dosing as supported by the initial repeat-administration data (2/3 doses) showing mean PCSK9 reductions to ~15% of normal.

Since in the PCSK9 category, it is PCSK9 that is driving LDLc lowering, the ultimate aim of this therapeutic approach, similar kinetics were seen in terms of LDLc levels in the blood with reductions (and safety/tolerability profiles) comparable to that seen with the recently approved monoclonal antibodies PRALUENT (by Regeneron/Sanofi) and REPATHA (by Amgen), ~55-60%.

In the case of the monoclonal antibodies, dose administrations every two weeks is really what it takes to consistently suppress PCSK9/LDLc because their inhibitory ability is directly correlated to their amount in the blood which declines rather precipitously after drug administration.  In the case of RNAi, however, you only need minute amounts to clamp down gene expression and at least for the liver, it appears that quarterly/semi-annual dosing schedules are realistic (it also depends on target and how much it needs to be repressed; e.g. with CC5 you may need much more target gene knockdown than 58-90%).

Sticking a needle into you just 2 or 4 times a year instead of 26 times, of course, has great advantages when it comes to treatment adherence. Keeping patients on drugs is a major issue for such life-long therapies especially since the disease is not felt acutely.  This point was made repeatedly by cardiovascular disease thought leader Dr. Kastelein on the companies’conference call.  By being able to co-ordinate drug administration with routine doctor visits, it would be possible to achieve very high compliance rates thereby preventing intermittent LDL cholesterol spikes that are believed to be particularly harmful.

In other words, assuming cardiovascular outcomes to be almost entirely driven by LDLc lowering, ALN-PCSsc would/should be best-in-class in the PCSK9 category.  There are numerous examples such as Eylea in the wet AMD space where injection frequency is the main competitive driving force among competing agents (here VEGF inhibitors) that exemplify how being a best-in-class follower can be very profitable.  Let the monoclonals build the PCSK9 market for ALN-PCSsc to then take it.


Last but not least, the ultimate value from being different will come from the results of the cardiovascular outcomes (and actually overall survival) studies that will really unleash the wide adoption of the PCSK9 class.  Due to their similarities, there is every reason to believe that the results from the monoclonal antibodies will cluster tightly.  By contrast, for better or worse, the outcome studies from ALN-PCSsc should be notably different and given that an RNAi agent mimics the compelling human genetics behind the PCSK9 story (extreme LDLc lowering in PCSK9-mutant individuals without other apparent untowards effects such as elevated liver triglycerides etc) much more closely, I like my chances here.  

We all know about the intricate feedback mechanisms of lipid biology so that binding a player merely in the serum as the monoclonals do as opposed to removing it from both inside and outside the cell could have unanticipated consequences.  Albeit early, the preliminary data from ALN-PCSsc support that in that the percent LDLc knockdown is the same whether in the presence or absence of high-dose statins whereas that of the monoclonal antibodies becomes muted.

Having said that, expect the monoclonal antibody establishment to play the 'RNAi is different from monoclonal antibody card' lest ALN-PCS piggy-backs on the MAb CVOT results expected to come out starting in 2017.

Back to my self-imposed exile, but I couldn't resist on commenting on what could be a perfect Oligonucleotide Therapeutics storm that is building. Next up is (maybe) ARC-520 for HBV.  And yes, I'm long MDCO as if that's not obvious.

Tuesday, June 23, 2015

The RNAi Therapeutics Blog is Taking a Break

When it feels that everything has been said, it may be time to be silent for a while.

This point has come for me and the RNAi Therapeutics blog and I look forward to take part in the conversation with renewed energy and ideas.  Until then, you can follow the 'light' version of this blog on Twitter @RNAiAnalyst. 
By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.