RNAi is the Future of Cardiovascular Disease

At least, this is what Big Pharma and Biotech is saying right now following deals between pure-play RNAi companies Arrowhead Pharmaceuticals and Dicerna with Amgen and Eli Lilly, respectively, and the sale of The Medicines Company with its lead PCSK9 RNAi asset really being only a matter of timing.  Besides its new relationship with Eli Lilly announced yesterday, Dicerna has an ongoin CVD-related NASH/NAFLD collaboration with Boehringer-Ingelheim.  In addition, Wave Life Sciences and Akcea, the commercial Ionis spin-out, have been pursuing cardiovascular targets along with Pfizer and Novartis, respectively, using the competitive RNaseH antisense gene knockdown technology.

Drugging the undruggable

Part of the attraction of RNAi for CVD for the pharmaceutical industry is because the targets that come from large genetic studies (e.g. ApoCIII, Apo(a), ANGPTL3) based on chance alone are not readily druggable.  To make matters worse, amorphous lipid macromolecular aggregates are particularly difficult to target with either small molecules or antibodies.

Infrequent dosing

What a difference 10 years can make.  When Protiva (now Arbutus) was one of the first to enter a systemically administered RNAi therapeutic against LDLc-related ApoB into the clinic a decade ago, it often found itself ridiculed for using RNAi in such an indication.  Systemic RNAi back then required relatively frequent (1-3 weeks) intravenous administration which would make it an unlikely modality for widespread diseases that ideally require decade-long preventive treatment strategies.

Fast-forward to the present and now we have subcutaneously delivered RNAi with potential dosing frequencies of up to once-a-year as evidenced by the lead candidate of this crop, phase III asset Inclisiran by The Medicines Company.  If the remarkable safety profile holds up following about 2000 patient years of clinical experience, such a drug should be very widely prescribed, not least because it should enjoy great adherence, one of the major impediments of treatment success in cardiovascular disease.   

Undoubtedly, it has been the Inclisiran performance so far that has attracted the attention of players like Eli Lilly and Amgen, the latter of which, of course, should know particularly well about the competitive threat from RNAi having an antibody-based PCSK9 agent on the market (Repatha).  Beyond the upcoming slew of phase III read-outs with Inclisiran, it will equally be interesting to see the types of new targets being pursued and the clinical validation of targets like Apo(a) by the antisense competition.

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.

Alnylam Raises Another Half a Billion as It Rolls Out Cardiometabolic Program

There has been some confusion today why Alnylam would raise another half a billion dollars when it already has one billion in liquid assets.  The answer has probably to do with their newly formed cardiometabolic franchise (aka STAr), the first candidate from which, ALN-PCS, has just entered the clinic.

With a delivery platform that enables monthly to quarterly dosing for gene targets in the liver, RNAi can no longer be thought of as a mere second-line alternative in diseases with existing therapies or where there is direct competition with much-touted monoclonal antibodies for extracellular proteins.

For example, earlier this year, Alnylam reported early, but highly suggestive data for its subcutaneous hemophilia candidate ALN-AT3 which supported that it will work as beautiful as the genetic model behind it, and due to its monthly dosing regimen has to be considered a potential first-line therapy in a market where transitioning to weekly intravenous infusions with complex recombinant proteins is already considered progress.

Based on the non-human primate data, ALN-CC5 (going up against Alexion’s fabled Soliris) and ALN-PCS are no different.   

First cardiometabolic pearl: ALN-PCS

While all the focus in the PCSK9 space is currently on the monoclonal antibodies which are marching towards approval, ALN-PCS looks like it could shake up the market.  While up to 50-60% LDLc reductions can be expected with both the monoclonals and ALN-PCSsc, once-quarterly regimens appear feasible with ALN-PCS.  By contrast, the most advanced monoclonal antibody, alirocumab by Regeneron/Sanofi, struggles with achieving stable pharmacodynamics with just monthly dosing.  

Amgen’s evolocumab may be doing slightly better for the most part with monthly dosing, but there is still the challenge of patients with high starting levels of PCSK9- and it is still monthly and recombinant protein versus potentially quarterly and synthetic molecule.

Given that the target patient population for the PCSK9 class is expected to be in the tens of millions, clinical development for hard end points such as cardiovascular events would obviously cost a lot of money.

In the case of ALN-PCS, it is The Medicines Company that has to shoulder the costs for now.  This is because it exclusively licensed ALN-PCS from Alnylam around 2 years ago for just $25M and modest biobucks.  This deal was a great oddity because part of the reason why The Medicines Company had to pay so little is that the expectations was that ALN-PCS, at the time still the intravenously administered liposomal version ALN-PCS02, would only be used in select patient populations, such as those hospitalized with a need for rapid lipid lowering.

This profile would have obviously matched a hospital specialty company like MDCO better than a drug with the profile of ALN-PCSsc. 

In terms of value, however, I believe that ALN-PCS already is worth more than MDCO’s market cap of ~1.6B which is a function of IP issues around lead drug Angiomax and some of the more recent hospital-focused niche products it has been frantically acquiring in an effort to fill the hole should Angiomax go generic this year.  

Therefore, should the phase I results in mid-2015 support a first-in-class profile for ALN-PCS, something will have to give: either The Medicines Company splits up into a PCSK9 company and a hospital-focused entity, or (more likely) it will dispose of ALN-PCS- how about to Alnylam which would love to have it back and become the heart of the new cardiometabolic franchise?

Note: I consider MDCO the best risk:reward opportunity in biotech 2015. 

NASH, diabetes, dyslipidemia

In addition to fighting bad cholesterol by knocking down PCSK9, some of the newly raised money will be directed at other large dyslipidemic opportunities, (type II) diabetes, and the increasingly hot non-alcoholic steatohepatitis (NASH) indication.  Given its central role in system-wide metabolism, the liver is rich in targets and being able to go after every protein-coding gene alone and in combination greatly increases the odds that Alnylam (or ISIS Pharmaceuticals) come up with category-busting drugs.

I believe Alnylam was right in doing the capital raise and it could well accelerate development of the new franchise and, partly depending on the outcome of the phase I study with ALN-PCS, result in another Genzyme-type billion dollar deal next year around JP Morgan.

Read the Xconomy timely interview with Alnylam's CEO John Maraganore which further details some of the thinking here. 

Alnylam’s Venture into Preeclampsia Exudes Confidence about Safety of RNAi Therapeutics

Last week, Alnylam disclosed yet another one of their development candidates (press release here, slide presentation here), this time ALN-AGT for the treatment of preeclampsia.  While most previously disclosed candidates address severe orphan diseases of high unmet medical needs such as TTR amyloidosis and complement-related diseases, some candidates such as ALN-PCSsc for hypercholesterolemia already have the potential to go after larger patient populations with less severe diseases.

With the preeclampsia indication, Alnylam has gone one step further, not in the sense that preeclampsia was not a very serious condition, but because pregnancy-related drug development is a largely shunned arena as the safety stakes are particularly high here.  Alnylam’s decision to go after this indication therefore must mean that the company has high confidence that RNAi Therapeutics, at least their particular breed in the form of GalNAc-siRNAs, should be very safe and succeed where small molecules have failed before.

Preeclampsia and current management

Preeclampsia affects about half a million pregnancies annually in the developed world and is a leading cause of pregnancy-related death (16% of maternal mortalities), frequently the result of stroke or end-organ damage such as in the liver and kidneys.  Because the disease can be the death sentence for a previously young, healthy woman (and her child), preeclampsia is a much dreaded condition where better diagnostics (esp. those that predict which preeclampsia cases will progress catastrophically) and new drugs are urgently needed.

Preeclampsia is characterized by high blood pressure (>140/90 mm Hg), frequently accompanied by protein in the blood (proteinuria).  It is a disease of the vasculature (Silence Therapeutics- listen up!) and while the causes are not fully understood, overexpression of VEGF/angiogenesis inhibitor sFLT may be a key early event in the disease.  It is probably the combination of vascular abnormalities and high blood pressure that ultimately can kill a woman.

The only cure for preeclampsia is delivery of the placenta.  Unfortunately, this may be much too early for the baby or mean delivery as early as 25 weeks of gestation with all the attendant infant mortality and developmental deficiencies. 

Although large randomized trials are lacking (because they would be difficult to justify), it is widely accepted that lowering blood pressure with antihypertensives lowers the risk of stroke and end-organ damage and thereby can help buy valuable extra weeks for the fetus to further mature. 

How RNAi can help

The management of high blood pressure is typically a multi-drug approach.  This means that for a given patient multiple antihypertensives are attempted sequentially or in combination until the desired control is achieved.

The drug cabinet for pregnancy-related hypertension, however, empties rapidly to a few somewhat trusted ones such as hydralazine and labetalol due to the suspected or known side effects (to the fetus) of most of them.   This includes otherwise widely prescribed antihypertensives which tackle high blood pressure along the renin-angiotensin-aldosterone system (e.g. ACE inhibitors). 

The toxicity here is due to the small molecules entering fetal circulation and consequently interfering with blood pressure regulation in the fetus thereby causing often fatal cardiac and renal defects as well as a general failure to thrive.

By contrast, an RNAi therapeutic would allow you to target the angiotensin pathway in the mother only.  The target of ALN-AGT, angiotensinogen, for example is expressed in the liver and both angiotensinogen as well as a GalNAc-siRNA would be restricted to the circulation of the mother.   Given the biodistribution of oligonucleotide therapeutics, I could also imagine RNAi Therapeutics to go after targets in the kidney with the same benefit of being limited to the mother.

ALN-AGT good for both (rat) mom and baby

In data presented last week at High Blood Pressure Research 2014, GalNAc-enabled ALN-AGT was shown to inhibit angiotensinogen of the mother by 90% in rodent models of preeclampsia.  Importantly, this was accompanied by a 20mm Hg reduction of mean arterial pressure, in addition to a reduction in proteinuria.

Such a 20mm reduction is clinically meaningful, given that reducing blood pressure from 160 and 140mm Hg can be the difference of highly likely stroke to no stroke.

Interestingly, not only did the maternal manifestations of the disease improve, the placental blood supply and architecture was improved, too, resulting in considerable benefits to the fetus as seen by increased birth weights and normalized brain:liver weight ratios.  

Safety and future development path

The data provided little discussion of the potential drawbacks and safety concerns around ALN-AGT.  One concern would be hypotension (lowering blood pressure too much) and related to this the reversibility and/or half-life of ALN-AGT.  Given that RNAi Therapeutics targeting genes expressed in the liver are typically active for weeks, close attention needs to be paid to hypotensive potential.

 

Encouragingly, the rat data indicate that the effect of ALN-AGT on blood pressure is more pronounced when blood pressure is high and medication is indicated (delta of 20mm Hg) compared to when it is normal (delta of 5mm Hg).  Another parameter that would be useful to consider in this context would be the dose/knockdown-blood pressure relationship and intrapatient/intra-rat variability.  E.g. would increasing the knockdown from 90% to 95% have a dramatic effect on blood pressure lowering or would it make little difference?

It will be safety that will guide the future clinical development path of ALN-AGT.  I can imagine Alnylam to first address women with a high likelihood of developing the devastating consequences of preeclampsia, perhaps with the help of a companion diagnostic.  Alternatively, it is not farfetched to think that ALN-AGT will first be used on top of other antihypertensives when they alone are not able to sufficiently control blood pressure.

Albeit little-loved by the pharmaceutical industry, once having been validated by proper clinical development in pregnant women, a drug like ALN-AGT would be poised to immediately become a mainstay in this indication.  From there, ALN-AGT could take on the rest of the $30-40B antihypertensive market.

Wild speculation

A drug like ALN-AGT is unlikely to be commercialized by Alnylam, both in the focused, likely hospital-based preeclampsia setting and in the wider antihypertensive market.  For preeclampsia, it would seem like a good addition to the portfolio of The Medicines Company, Alnylam’s partner for ALN-PCS in hypercholesterolemia.  

It is my suspicion that Alnylam rues the day it gave away ALN-PCS when times were hard. I don't believe Wall Street is anywhere close to grasping the potential of ALN-PCS to become a well-differentiated best-in-class in what is predicted to be a very large market.   And since Alnylam is known for its zeal to exploit all the RNAi value there is, with licensing and collaboration partners (usually referred to as 'friends') regularly turning into fierce 'competitors', it could be just a matter of time before Alnylam will claw back control over ALN-PCS.  ALN-AGT looks like the perfect trade-in. 

Alnylam GalNAc Improvements Incremental, but Likely Enough to Beat PCSK9 Antibodies

Over the last week, Alnylam presented pre-clinical data for their new development candidates for the treatment of hypercholesterolemia (ALN-PCSsc) and liver disease related to forms of alpha-1 antitrypsin deficiency (ALN-AAT).  These candidates are based on second-generation GalNAc-conjugate chemistry that the company is now dubbing ESC (Enhanced Stabilization Chemistry).  They involve the increased use of chemical nucleic acid modifications for stability with attendant improvements in knockdown potency and duration over first-generation GalNAc conjugates such as ALN-TTRsc.  ALN-TTRsc is the lead GalNAc candidate and currently in phase II development.

Borderline first-generation GalNAcs

In a phase I study of ALN-TTRsc, potent knockdowns were achieved with about:

-60% knockdown at 2.5mg/kg;

-80% knockdown at 5.0mg/kg (ED80), and

-90% knockdown at 10.0mg/kg.

At the risk of insulting medical geneticists for oversimplifying, assume that an RNAi technology that can safely achieve an 80% target gene knockdown provides for a solid platform.  In the case where a subcutaneous route of administration is desired and/or necessary, this should ideally also fit into a 1ml injection volume which in the case of GalNAc conjugates would correspond to a 2.5mg/kg dose.

There is some controversy around acceptable injection volumes and as often is the case, increased standards are applied to RNAi Therapeutics.  I say this because drugs and drug candidates such as expected mega-blockbuster PCSK9 antibody from Amgen, AMG-145, has been administered at 2ml volumes.  In fact, to achieve once-every-4-week dosing, 6ml (3x2ml) have been administered (see Giugliano et al. 2012).

In light of this, ALN-TTRsc has failed the 1ml test, but 80% are certainly possible with this first-generation GalNAc chemistry.  There is therefore room, and in some cases a competitive need (àcompetition with more potent delivery technologies such as Tekmira’s SNALP LNPs and Arrowhead’s single molecule DPCs) for improvements in GalNAc conjugation technology.    

Second-generation data could indicate progress

In agreement with this, Alnylam is now advertising the ESC second-generation GalNAc and has presented critical non-human primate data for their new development candidates ALN-PCSsc and ALN-AAT.  Non-human primate data are ‘critical’ because the RNAi knockdown observed in monkeys typically closely predicts what will be seen in humans based on the experiences with ALN-PCS (SNALP), ALN-TTR (SNALP), and ALN-TTRsc. 

In interpreting the newly presented data, it should be noted that in the case of ALN-TTRsc, an 80% knockdown was already observed at 2.5mg/kg (and 5mg/kg) in non-human primates, but that this shifted to 5mg/kg in humans.  Numerically a relatively small difference, in practical terms an important one.   

ALN-PCSsc achieved 80% PCSK9 target gene knockdowns at 2mg/kg in a weekly multi-dose study in non-human primates.  This resulted in a highly competitive 60% LDLc lowering in the absence of statins.  Similarly impressive in light of the monoclonal antibody competition was that 80% PCSK9 knockdown and 50-60% LDLc reductions were achieved and sustained for over 3 months (!) when a single dose of 10mg/kg (2x2ml) was given.  Compare this to 57% LDLc lowering with AMG145 in a once-every-4 week regimen in the MENDEL-2 phase III study of AMG145:

-ALN-PCSsc (RNAi): 50-60% LDLc reduction, 2x2ml subcutaneous, once-every-3-months

-AMG145 (monoclonal antibody): 57% LDLc reduction, 3x2ml subcutaneous, once-every-4-weeks (phase III MENDEL-2 monotherapy study)

(Yes, I do keep an eye on cash-rich, sub-$2B market cap The Medicines Company, Alnylam’s licensee for ALN-PCSsc for this reason).

Before I get carried away with all the advantages of the RNAi platform over monoclonal antibodies for even extracellular targets such as PCSK9, in terms of GalNAc improvements, these knockdown results are very much in line with what was seen for TTR in non-human primates. 

The same applies for ALN-AAT where a single dose of 3mg/kg translated into a 60% knockdown which, based on TTR and PCSK9, will likely translate into a weekly multi-dose ED80 of 2.0-2.5mg/kg in non-human primates.

However, with the caveat of different half-lives for different target genes, the durability of the PCSK9 knockdown is quite impressive and more than what is typically seen with e.g. SNALP LNPs which have historically utilized minimally modified RNAi triggers.  Such triggers may be turned over more rapidly in liver cells.

Similarly, the RNAi trigger sequence in the TTR development candidate is an extraordinarily potent one with low single-digit picomolar EC50 potency in tissue culture.  It is therefore possible that equivalent animal potencies have now been achieved with less potent sequences meaning that the underlying delivery technology has improved.

It’s been fascinating to watch the various delivery platforms, and indeed RNaseH antisense, compete over the years and pushing each other to new heights.  In this context, I am anxiously waiting for Arrowhead’s presentation at next week’s TIDES meeting with the intriguing title:  “Next Generation Dynamic Polyconjugates for siRNA Delivery in vivo,”

Market commentary: I remain mostly on the sidelines.  Years ago, these scientific data would have made me jump head-first into the market with me buying all I could in the opening minutes.  These days, however, I view them as ensuring the long-term value of RNAi stocks, but fail to see how they will support share prices in the current, growth-to-value rotating trading environment for more than a trading week or so.  I am therefore speculating on a capitulation event before some of the important clinical data read-outs roll in.  

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.