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.

Outcomes

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.

An RNAi Therapeutic Could Be Last Man Standing in PCSK9

PCSK9 has arguably become biotech’s hottest drug target as it promises to unlock much of the remaining unmet need in lowering ‘bad’ LDL cholesterol.  While monoclonal antibodies have been the predominant and most advanced modality to address PCSK9 (e.g  alirocumab Regeneron/Sanofi-Aventis and AMG145 by Amgen), RNAi Therapeutics have made tremendous, yet widely underappreciated progress in this area with predicted potencies equivalent to if not superior to monoclonal antibodies.

Alnylam’s ALN-PCS leads in this effort (preclinical 67% LDLc lowering without statins) and should have entered clinical development by the beginning of 2015.  It is partnered with The Medicines Company.

The news today that the FDA has become concerned about neurocognitive adverse events in the ‘PCSK9 class’ could mean that RNAi Therapeutics, despite their development delays, will carve out a nice junk of the PCSK9 market which is widely estimated to be a multi-billion dollar market in terms of annual sales.

But if it’s a ‘PCSK9 class’ issue, so how could this be positive for RNAi Therapeutics?  Wouldn’t this concern also apply to ALN-PCS?

Not necessarily.  Since by far the most clinical experience with PCSK9 has been obtained with monoclonal antibodies, the FDA may be inappropriately lumping all PCSK9 inhibitor agents in one bucket confusing a short-coming of a therapeutic target with a short-coming of monoclonal antibodies.

The reason why I have a good feeling that this turn of events could be very positive for RNAi Therapeutics is that RNAi is a genetic tool that reduces PCSK9 expression before any protein is made.  The approach therefore resembles populations that under-express PCSK9 for genetic reasons and which enjoy improved cardiovascular health compared to the general population without any apparent negative consequences of their PCSK9 deficiencies.  It is for this very observation that PCSK9 has become such a sought-after target and RNAi, a gene knockdown approach, best mimics human genetics.

Monoclonal antibodies don’t.  One mechanism by which antibody-specific toxicity might arise from is the fact that they form complexes with their target.  Such complexes could elicit adverse immune reactions in organs where they form and accumulate.  While I am not familiar with the binding sites of the particular Regeneron and Amgen antibodies to PCSK9, it might also be possible that the immune complexes form directly on neuronal cells expressing LDL-receptor-like proteins (note: PCSK9 binds the LDL-receptor).

Beyond PCSK9, today’s events emphasize yet another hitherto under-appreciated value proposition of RNAi Therapeutics, namely providing differentiation value when going head-to-head with the small molecules and monoclonal drug establishments.

Alnylam and The Medicines Company to Position RNAi PCSK9 Drug Candidate as Fast Follower

Yesterday, Alnylam made the somewhat surprising announcement that it partnered with the ~$1.6B market cap The Medicines Company to develop and commercialize its RNAi Therapeutic program targeting PCSK9 for hypercholesterolemia.   This program includes ALN-PCS02 which had completed a phase I study last year and contemplates subcutaneous formulations, too.  

This means that as a number of PCSK9 monoclonal antibodies are moving forward in clinical development at lightning speed, including phase III trials involving more than 20k patients, the ambition here is not to have a Big Pharma try and catch up (maybe they did try, but nobody was willing to partner), but to carefully study the experiences of the monoclonals and exploit the biological differentiation that an RNAi approach offers over antibody.  With The Medicines Company on board, some of that potential at least is seen in the hospital setting.   

Mechanism of Action of RNAi vs Antibody 

There are various points of differentiation which might translate into a clinical benefit for RNAi. Expect the companies to look hard for such evidence and, if found, beat the drum about it. These differences include: 1) reduction of both intra- and extracellular PCSK9 thus replicating human genetics from which PCSK9 emerged in the first place; antibodies merely bind existing extracellular PCSK9; 2) because antibodies form complexes with their targets and do not act catalytically, the percent target inhibition efficiency of antibodies depends on target abundance; therefore, in patients that have many more PCSK9 molecules than the number of antibodies you can fit in a subQ syringe, PCSK9 antibodies will not work well; RNAi, however, works with similar percent knockdown efficiency more or less regardless of target gene expression levels.

Efficacy

In general, the LDL cholesterol reductions with monoclonal antibodies have been between 40-70% in multi-dosing regimens.  In Alnylam’s single-dose phase I trial, the liposomal ALN-PCS02 achieved a ~30% reduction (area under the curve). 

Frankly, given the number of clinical trials involving PCSK9 monoclonals, I have given up tracking the results of each and every study.  Having said that, in reviewing the phase II trials of the candidate that may be viewed as the most advanced/exciting one, AMG145 by Amgen, it seems that the higher end of LDLc reduction was only achieved when given on top of statins.  Althought to me this seems a bit counterintuitive since statins are thought to act mechanistically essentially the same as PCSK9 inhibitors, namely via increasing LDL-receptors on hepatocytes, that's the way it looks right now, and the ALN-PCS02 trial may have been disadvantaged as it was mono-therapy.

Finally, with continued improvements in the potency of RNAi Therapeutics technologies, it should be possible to achieve similar LDLc reductions with RNAi as with PCSK9 antibodies. 

  

Acceptance

I like the fact that PCSK9 has become a small battleground between RNAi and monoclonal antibodies as this may be the best way for RNAi Therapeutics to work on its wider acceptance by the medical and investor community.  Notably, the often glorified monoclonals frequently suffer from injection reactions (some notable serious ones were observed in Regeneron’s PCSK9 trials), other immune-related issues and manufacturing challenges to name a few issues.  RNAi Therapeutics, of course, are facing some of the same challenges, but it irks me that when it comes to this technology, they suddenly are supposed to be show-stoppers.

Financials

The financials (including a $25M upfront, up to $180M in sales and commercialization milestones and double-digit royalties) were not all that exciting for Alnylam and reflect the fact that only one single-dose phase I trial had been conducted.  Also, as Alnylam cannot claim a blocking IP any more and has licensed hepatic targeting rights to other companies, including Roche/Arrowhead, the value of ALN-PCS as the only RNAi candidate for PCSK9 has been lost.

Still, $25M is serious money for a company the size of The Medicines Company and you do not turn this over just to help out an old friend.  

New Clinical Results Put ALN-PCS Firmly in Business in PCSK9 Race

Alnylam reported on Friday updated results from the phase I single-dose, dose-escalation trial of its hypercholesterolemia candidate ALN-PCS02.  Importantly, the data demonstrate that ALN-PCS can produce clinically meaningful 30-40% reductions in LDLc (the ‘bad’ cholesterol) for much of the 28 study days of the study after only a single infusion of the drug.  This bodes well that ALN-PCS may be useful for the millions of patients that cannot achieve their LDL cholesterol goals despite the availability of statins.

After presenting solid PCSK9 knockdown results in January from subjects receiving up to 0.25mg/kg of the PCSK9 siRNAs which are critically enabled by Tekmira's SNALP delivery technology, the latest data include the results from subjects receiving 0.4mg/kg PCSK9 siRNAs after the decision had been made to increase the top dose based on the favorable safety-efficacy profile thus far.  This was important because despite the solid plasma PCSK9 reductions seen up to 0.25mg/kg (roughly 50% mean reductions throughout the 28 days), both the peak and average mean LDLc reductions until then had been less than 30% and 20%, respectively.  Probably not enough to effectively compete in the hot PCSK9 field.  

Based on the latest data, which included impressive >80% target plasma PCSK9 reductions, it is reasonable that ALN-PCS will be able to achieve average (=sustained) ~45-50% LDLc reductions in a once-every-4-week dosing regime.  This would put it just slightly behind Regeneron’s PCSK9-targeting monoclonal antibody REGN727 in terms of LDLc lowering.  It may be more difficult for ALN-PCS to achieve the LDLc lowering efficacy of Amgen’s PCSK9-targeting antibody AMG145 which has been hailed at the recent ACCconference to produce LDLc lowering of ‘up to’ ~60-80% at apparently pristine safety and tolerability.  I should add, however, that the warts-and-all data on AMG 145 have yet to be made publicly available.

In light of the intense competition in the PCSK9 space and a possible potency disadvantage for this surrogate marker, it will be interesting whether, firstly, the pharmaceutical industry (note, a larger partner will have to be found to financially shoulder the unavoidable outcomes trial), and eventually the market-place will adopt this new class primarily for their absolute LDLc reducing ability or in order for patients to achieve their lipid goals.  Some LDLc proponents, of course, stress that the lower the LDLc, the better.  On the other hand, whether a drug can lower LDLc by 50% or 70% won’t matter for many patients when it comes to simply achieving standard LDLc goals of 100mg/dL or even 70mg/dL.  In that environment, the focus in making the choice between competing drugs would shift to factors beyond mere LDLc lowering potential, particularly safety.

While ALN-PCS is mainly suffering from the fact that it is given following pre-treatment with corticosteroids, something that also had important impacts on the PCSK9 and LDLc efficacy data, the once much-touted safety profile of the PCSK9 antibodies have taken a significant hit with the publication of phase II data from REGN727 (McKenney et al. 2012).  In addition to one serious adverse event, a case of potentially life-threatening inflammation of blood vessels (leukocytoclastic vasculitis) that, however, readily resolved after giving corticosteroids, there was an apparently dose-dependent, adverse event-related increase in the rate of discontinuations, with ~15-20% discontinuing treatment in the biweekly dose cohorts in study 11565.  Next to the case of vessel inflammation, the AE-related discontinuations involved cases of neutropenia, fatigue, injection site rashes, chest pain, and headache/nausea. 

Amgen has yet to publicize more detailed data for AMG145.

Next to multi-dosing and the safety and efficacy impacts of omitting corticosteroids in future studies, another important question for ALN-PCS that remains to be answered in the upcoming trials will be testing the candidate in patients on statins.  REGN727 encountered problems here as patients concomitantly taking statins experienced an LDLc rebound effect after around 2 weeks.  Whether this is a class effect of agents merely blocking extracellular PCSK9 (such as antibodies), instead of inhibiting the synthesis of both intra- and extracellular PCSK9 such as ALN-PCS is an interesting question.  

This mechanistic difference could also be the big wildcard when it comes to the ultimate arbiter of clinical utility, the outcome trials: despite the clear evidence that LDLc levels are inversely related with cardiovascular events, with all the complicated feedback loops of lipid biology and related diseases, mechanistic differences could easily erase 20% differences in LDLc lowering.  An indication that these theoretical considerations are translating into the clinic may be deduced from the observation that (in Alnylam's words) ‘importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor.’

For Alnylam, the near-term challenge will be thus to find a large partner, probably without a stake in PCSK9 yet, willing to take the risk with RNAi Therapeutics mainly for the differentiation it offers over the other PCSK9 approaches.  A stumble of the monoclonal antibody class could easily mean that ALN-PCS becomes the lead candidate in the PCSK9 market, estimated by many to be a multi-billion dollar one. 

Can RNAi Therapeutics do a Better than Monoclonal Antibodies in RSV Infection?

Arguably, the next main proof point that looms for RNAi Therapeutics is proof-of-concept that RNAi can be made to work in humans. Alnylam takes its first shot at this in their randomised, placebo-controlled, double-blinded phase II study for the treatment of respiratory syncytial virus (RSV) infection. In this study, volunteers infected with an attenuated form of RSV will be treated with ALN-RSV01, an siRNA targeting a conserved region of the nucleocapsid (N) protein mRNA, and its effect on viral load and symptoms evaluated. Results from this trial, initiated last month (see Blog from 25 June 07: “Alnylam Progresses RSV RNAi Program into Phase II Clinical Studies”) are expected by the end of this year.

Currently, the only effective drugs in addressing RSV are neutralising antibodies that were developed by MedImmune (now AstraZeneca). These monoclonal antibodies (MAb) are directed against the F-protein on the surface of RSV and block cellular entry of the virus. Importantly, whereas these MAbs are used for the prevention of RSV infection in a small at-risk population, premature infants, ALN-RSV01 is geared towards the treatment of RSV.

Numerous studies have shown that the effect of RNAi, and probably any type of drug, on viral replication is most potent when given around the time of infection. I therefore wondered why ALN-RSV01 should succeed in the treatment of RSV when other drug classes such as MAbs have failed. Indeed, my own literature research confirms that MAbs have been tested in animal models for the treatment of RSV, but were found to lack sufficient therapeutic activity.

A study by Mejia et al. [Antimicrobial Agents and Chemotherapy 49: 4700 (2005)] compares 50mg/kg of the latest generation of anti-RSV MAbs when given either before or after viral infection in mice, and finds that on almost all accounts (viral load, inflammation, lung pathology) MAbs were only effective when given shortly (24 hours) before infection. The only assay that showed an effect when MAbs were given 48 hours after infection was a viral plaque forming assay which may reflect the presence of neutralising antibodies in the assay.

Bitko et al. [Nature Medicine 11:50 (2005)] on the other hand showed in an almost identical mouse model that intranasally delivered siRNAs had a profound effect on RSV replication even when given after viral infection. Moreover, 3.5mg/kg doses already proved very effective. Importantly, siRNAs were able to limit viral replication even when given up to 5 days after viral infection, the time when the acute phase of RSV peaks in this particular model. This is crucial in the clinical setting where the treatment benefit will likely be optimal if RNAi therapy can be initiated before acute infection has peaked. The authors then go on to show that on a number of counts (respiratory rate, pathology score, leukotriene production), anti-RSV siRNAs almost abolished any pathological signs of the disease.

These results suggest that while current MAbs are potent in reducing the initial infection by neutralising the interaction of the virus with the host cell, they are ineffective in preventing the subsequent spread of the virus. This could be due to the kinetics of viral re-infection in close proximity to the next host cell. By contrast, unless they target host surface receptors, siRNAs will not be able to prevent viral infection. The can, however, prevent and limit the ability of the viral genomic RNA to replicate and/or inhibit virion formation. Although Bitko et al. have not measured viral RNA levels directly, it is very likely that these were also reduced, and treatment with siRNAs even after the acute phase of infection may have a clinical benefit on RSV co-morbidities such as asthma/wheezing later in life.