Developing Aerosolized TKM-EBOLA as Airborne Transmission of Ebola Likely

Knowing how a virus is spread, also from a cell biology point-of-view, is critical to curtailing its spread and devising effective treatment strategies.   

According to the World Health Organization (WHO), the first symptoms of an Ebola infection are ‘the sudden onset of fever fatigue, muscle pain, headache and sore throat’ (emphasis mine). Then also consider the following:

1)      Ebola once killed a number of monkeys are apparently spreading through the ventilation system in Reston, VA; 

2)      A nurse became infected in a reference hospital for infectious diseases in Spain despite the protective clothing she was wearing and her limited contacts with the infected patients she was looking after (taking temperatures twice);

3)      A single pregnant woman in Liberia infected atleast 10 people helping her as she came down with Ebola;

4)      Ebola virus can infect numerous cell types in the body (frequently cited are the liver, endothelial cells, and phagocytic cells) and is found in high amounts inthe respiratory tract in infected pigs with the virus spreading readily to cohabiting pigs in the colony;

If you still believe in the narrative, even propagated byotherwise fairly reliable sources such as the CDC, that Ebola is only transmitted by direct contact with body fluids, then you should start considering airborne transmission as a main route the infection is spread.

After all, since when are cough droplets not a bodily fluid?

If airborne is indeed an important route of transmission, this would not only raise concerns that just like in avian flu, a few mutations in the virus adapting it to better latch on to the human respiratory tract could further catalyze the spread of the virus, but would also mean that treating it at the respiratory stage could both prevent the virus from fully entering the body as well as limit its spread from person-to-person.

Enter TKM-EBOLA

An RNAi viral knockdown approach in the respiratory epithelium should obviously be able to achieve that goal.  All that would be required is to take the same RNAi triggers now part of the intravenous TKM-EBOLA formulation and incorporate it in something amenable for respiratory delivery.

Back in 2011, Tekmira revealed that it was developing aerosolized liposomal nanoparticles (LNPs) to deliver RNAi triggers to the respiratory epithelium.  A key challenge was to find formulations that not only could successfully transfect respiratory epithelial cells, but also withstand the shear forces involved in nebulizing them.  Initial structural and tissue culture RNAi knockdown results showed that this can be achieved.

The development was seemingly halted at the rodent preclinical stage as the company had to save financial resources as it was fighting off Alnylam in a trade secret case.  After coming out on top of the litigation in November 2012, the company was then able to once again expand the development of its LNP-based nucleic acid delivery technology, in addition to churning out clinical development candidates (e.g. the important HBV candidate to be revealed next week).

 

Given that the company established a separate biodefense unit headed by the ‘LNP-brain’ of the company, now Chief-Technology-Officer Ian MacLachlan, I would not be surprised if LNP nebulization was part of that effort with the next goal of showing efficacy in monkeys.

Such reformulation of TKM-EBOLA is just another example of the versatility of RNA Therapeutics, just as is the ability to rapidly adjust and optimize the medicine as the virus evolves (note: this is e.g. not possible with antibodies).  It also adds to the importance of scaling up the supply of the RNAi trigger now should airborne be recognized as a major route of transmission.  

Long-term, such developments would obviously benefit the development of LNP-delivered RNA Therapeutics for the lung epithelium in general, including mRNA delivery (e.g. for Cystic Fibrosis) and a universal RNAi agent against flu.   

Ebola Emergency Tests Oligo Manufacturing Readiness

With officials scrambling to put in place measures to contain the further spread of Ebola, it is highly likely that RNAi Therapeutic TKM-EBOLA will be on their shopping list.  This, however, requires the ability to manufacture the oligonucleotide-based medicine in quantities sufficient to treat at least 10 thousand or so either infected or potentially infected persons.  In the absence of commercial Oligonucleotide Therapeutics success stories this could prove to be a challenge, although in this case, I believe it's doable.

Manufacturing, an advantage of TKM-EBOLA over PMOs and antibodies

When the US Department of Defense selected TKM-EBOLA as its preferred Ebola development project a few years ago, manufacturing, and not just efficacy and safety should have been part of the equation.  The reason is that e.g. currently about 0.3mg/kg*70kg/day*7 days= i.e. approx. 140mg of TKM-EBOLA RNA oligonucleotide is required per treatment course.  Since its simple chemistry (a couple of spiked-in standardd 2’-O-methyls in an otherwise unmodified RNA) makes it one of the cheapest RNA oligonucleotides conceivable, let’s ballpark its manufacturing cost at $300 per treatment course at some of the largest possible manufacturing scales possible today (kilograms).  Note that the cost of the lipids in TKM-EBOLA is negligible compared to the oligo component.

1.4kg oligo and $3 million for 10,000 treatment courses.

Taking into account that these are the pure manufacturing costs when protocols have been established, and other monies will have to be spent when starting from sequence design---let’s say conservatively $5 million. I believe given the gravity of the current situation, this is a number we can live with (1/200 of investment in the response).

If you do the same Gedankenspiel for Sarepta’s Ebola therapeutic morpholino antisense candidate, you have to multiply the $3M number first by a factor of 30 for the much larger amount of oligonucleotide required and then by another factor of 6 or so for the greatly increased costs of making morpholinos over standard RNAà $500M+.  A non-starter not just for the increased costs, but also because the manufacturing capacities for that amount of oligonucleotides are not readily available today, let alone for the morpholino chemistry where Sarepta has experienced significant delays in obtaining sufficient oligo supplies for a relatively small (~100 patients on drug at 30mg/kg/week for 48 weeks) phase III program in an orphan diseases indication (DMD).

When we move to Tekmira’s antibody competition, in particular ZMapp, the situation is not all that different from Sarepta’s with the slight advantage that ZMapp could somewhat tap into the established know-how of monoclonal antibody production.  But in the end, we’d be talking about years of process development and scale-up compared to a few months TKM-EBOLA.

Wake-up call for oligonucleotide manufacturing

Although TKM-EBOLA should be within current oligonucleotide manufacturing capacities, the Ebola situation should get oligonucleotide manufacturers wondering whether they are ready for the upcoming surge in Oligonucleotide Therapeutics approvals and sales.  Following years of disappointment about the lack of big manufacturing requests, CMOs have been loath to build the plants that can churn out hundreds of kilos or even tons of oligonucleotides.

Consequently, I attribute the decisions of first ISIS and Sanofi/Genzyme, then Alnylam (for GalNAc conjugates), and more recently also Sarepta, to shift oligonucleotide manufacturing in-house, to this lack of outside manufacturing capacity.  While having manufacturing in-house may sound attractive for a number of reasons, spreading manufacturing risk across multiple vendors is an accepted risk reduction strategy in this and other industries. 

I am therefore hopeful that the ongoing Ebola outbreak will end up increasing oligonucleotide therapeutics manufacturing capacities to rule out a situation that manufacturing constraints could limit commercialization of agents like ISIS-ApoCIIIRx or the HBV agents with potentially very large patient populations. 

A Defining Month for Tekmira

As if Ebola has not showered Tekmira with enough attention, Tekmira will be front and center in the RNA Therapeutics industry in October.  It will be clinical results from two other drug candidates utilizing Tekmira’s RNAi delivery technology (TKM-PLK1 and ALN-TTR02) and pre-clinical data for TKM-HBV that will define Tekmira's trajectory as a 'normal' biotech company.  'Normal' as I have little idea how Ebola will change all this.

Accordingly, depending on the dataflow, Tekmira could finally be transformed into an established biotech company.  If there are serious disappointments, Tekmira risks being delegated to being 'the Ebola company'.

Event 1 (October 10-11): Do GI-NET patients respond to TKM-PLK1?

The first upcoming data event is the phase IIa update for TKM-PLK1 in gastrointestinal neuroendocrine tumor (GI-NET) and adrenocortical carcinoma (ACC) patients.  This one can be considered a bonus event for Tekmira as barely anybody has been paying attention to the potential of this first-generation SNALP-based product candidate.

 

Results from a  multi-dose escalating phase I study suggested a dose-dependent benefit with patients receiving 0.6mg/kg or more having an increased likelihood of showing ‘clinical benefit’ (stable disease or partial response) than those receiving less of the drug.  In particular, almost all (5/6) GI-NET and ACC patients in that trial with otherwise enrolled across a wide range of cancer types exhibited at least stable disease, with a partial response by RECIST and a 19.3% reduction in tumor size.

One aspect that I found particularly encouraging in these results was that TKM-PLK1 which involves a long-circulating form of SNALP achieved ‘several fold’ increased target tumor concentrations compared to an earlier, short-circulating SNALP product (ALN-VSP02 from Alnylam).   Unfortunately, the precise differences were not disclosed.

The factor that makes me most optimistic about a positive update (--> multiple tumor responses) at the upcoming 7^th Annual NET Conference in Nashville is that there is evidence that SNALP LNP delivery should work particularly well in the GI-NET and ACC settings.  Not only did GI-NET and ACC patients seem to perform well in the phase I study, there have historically been apparent biological effects of other nanoparticulate cancer RNAi Therapeutics in neuroendocrine tumor patients, including cases of extended stable disease with Atu027 by Silence Therapeutics.  

Moreover, the adrenal cortex, and possibly other endocrine structures, seems to be a preferred target organ (next to liver) for SNALP LNP delivery.

What makes me less excited about this program is that TKM-PLK1 is based on fairly old SNALP LNP delivery technology, and wouldn’t it be nice to see the potent PLK1 RNAi trigger being utilized in the latest delivery formulation.

Event 2 (October 13): Does ALN-TTR02 show a therapeutic benefit in TTR amyloidosis?

At the upcoming American Neurological Association’s 2014 Annual Meeting, Alnylam will present first data from its high-profile ALN-TTR02 product candidate that will look not just at target gene knockdown (expected to be in the 80% range), but also whether this translates into an apparent therapeutic benefit.

ALN-TTR02 is an RNAi Therapeutic for the treatment of the FAP form of TTR amyloidosis and uses Tekmira’s delivery technology.  As a result, Tekmira stands to financially benefit from it in the form of development milestone payments and royalties (in the low to mid single-digit percent of revenues) which may reach ~$50-100M annually for this $500M market cap company if analyst projections as to the FAP market prove correct.

The data to be presented comes from the open-label extension (OLE) of the relatively short phase II study.  In this OLE study, Alnylam will look every 6 months how patients are doing according to the mNIS+7 functional score which will then be compared to data gathered from a Natural History study of the disease. 

It is expected that 20 patients that had been rolled over from the phase II study will now have reached the first 6 month time-point.  The phase II study was too short (2 doses spaced apart 3-4 weeks) to reasonably expect an obvious therapeutic benefit from the knockdown of the disease-causing transthyretin gene.

It is important to remember that a failure to see a therapeutic improvement after 6 months with ALN-TTR02 does not necessarily reflect badly on SNALP LNP delivery technology as long as the knockdown remains in the 80% range and is well tolerated.  In that scenario, target risk and an insufficient period of knockdown may be responsible instead and this is where each RNAi Therapeutic has its unique development risk.

My prognosis is that first divergences from the Natural History will be seen if the preclinical experiences and those from other amyloidotic diseases such as AA amyoloidosis are any guide (~50% knockdown and beyond should lead to a benefit).  From a Tekmira technology point-of-view, I will pay close attention as to the safety and tolerability of longer-term dosing, which so far looks quite good.

  

                Event 3 (October 15): Coming out for TKM-HBV

Possibly the dataset with the most impact on Tekmira is the revelation of the company’s RNAi candidate for HBV infection.  Based on data revealed earlier this year by Alnylam which showed a SNALP LNP-based RNAi compound to have multi-log viral knockdown and 2 log HBsAg knockdown in the challenging chimpanzee model with moderate amounts of drug, TKM-HBV is set to become most-potent and therefore hopefully best-in-class among the knockdown approaches by Arrowhead Research (ARC520, first-mover), ISIS/GSK, and Alnylam.

To facilitate cross-comparisons, Tekmira may wish to directly compare its candidate with Arrowhead’s ARC520 for which the structural identity is known.

One aspect that I will be paying particular attention to is whether the data support dosing without transient immune suppression.  This is because I am concerned that such a regimen, especially if it involved steroid use, would not be acceptable in the HBV setting. As you may remember, the company attempted to get away without immune suppression with TKM-EBOLA in a trial in healthy volunteers, but at moderate-to-high dose levels immune stimulations were seen prompting the FDA to put that program on Clinical Hold for the volunteer population. 

Having said that, TKM-Ebola is now being used in much more fragile patients actually infected with Ebola, and anecdotally even the most stringent dosing regimens such as 7x daily appear to be tolerated here, presumably without pre-medication.

As per the last quarterly conference call, Tekmira management seemed confident that TKM-HBV would not require pre-medication.  Since such immune stimulation is thought to be highly sequence-dependent, I do not fully understand their confidence, but maybe a little bit of immune stimulation is not that bad in the Ebola setting after all.

An IND for TKM-HBV is planned by the end of the year with first dosing starting in early 2015.

Buckle up for an exciting month with Tekmira, and if all that weren’t enough, it unfortunately looks like we are still in the early innings with Ebola as being ahead of the curve is a concept foreign to the governing authorities.

Disclosure: long Tekmira.

Regado Biosciences Should Trade Up Over 30% within 3-5 Months

Sometimes Wall Street just needs a bit help to see all the free money around it.  The current share price of Regado Biosciences is one example of that.

As discussed in an earlier blog entry, aptamer company Regado Biosciences recently was forced to permanently hold development of their only asset to speak of, the antithrombotic Revolixys kit, aka REG1.  As a result of that, the company disclosed yesterday that it would wind down all activities associated with this program and conduct a strategic review of the company’s future which the company says ‘could maximize returns for Regado shareholders in the near future’.  

At the end of that re-organization period, projected to be at the end of 2014, the company should have $50-55M in cash and no liabilities to speak of.  The company has 34 million shares outstanding, and given its spectacular 90% drop in valuation over 6 months, there is little risk that this will be diluted much from the exercise of options and warrants.

In other words, the company will have $1.47-1.62 cash per share and is currently trading at $1.17 per share.  That is, the shares are trading at a 20-28% discount to the cash it will have when it can start over its biotech adventure with a clean slate (meaning the shares would have to rise 26-38% to equal cash on hand). 

This 26-38% upside is my base case that I am confident that RGDO will achieve over the next 3-5 months with relatively little risk- just as the result of investors realizing that the discount does not make any sense.  The upside should be much more if management and the Board could find a new biotech asset that can generate some excitement. 

The major risk to this free money scenario would be that class action lawsuits by disgruntled shareholders (who, of course, knew all about the risks involved in biotech investing) will cost the company a significant amount of cash, but in this instance it should be relatively easy to thwart off the ambulance chasers given all that had been known about Revolixys kit, including the rare acute immune reactions seen in phase II.

(Following paragraph added on Sep26, 2014)  A lesser risk (because that only happens once in a blue moon in biotech) to the numbers would be in case the company actually decided to return its cash to shareholders and close up shop.  Under that scenario, the Series F Convertible Preferred Stock Holders would claim and thereby take off $10M from the cash balance.  

You would not believe it, but with the valuations of small biotech companies being quite depressed right now, it is a buyers’ market again for numerous assets.  Given that in similar situations (lead drug has failed, pipeline otherwise weak), biotech companies like Celsion and Oncothyreon have recently opted for RNA Therapeutics assets, and not least because Regado Biosciences is already an RNA Therapeutics company, chances are that the asset will be an RNA Therapeutics one.

Maybe Marina Biotech would be an interesting shop to visit, given that it has a lot of different technologies on offer, has a history of giving away their assets for cheap, and since Marina could use some cash.  Another target might be the RNAi assets of Novartis.

Disclosure: I had been long RGDO at sub $1, but went longer still today after management provided more clarity last night on the Revolixys close-down costs.  It certainly beats the 0.2% interest you might get these days in a savings account. But remember: do your own due diligence before investing.

TKM-EBOLA Making RNAi History

Today, Tekmira disclosed that an acceptable regulatory pathway has been found with US and Canadian regulators to use its RNAi Therapeutic against Ebola infection, TKM-EBOLA, in the current outbreak.  In fact, the company added that 'TKM-Ebola, has been administered to patients on an emergency basis and the repeat infusions have been well-tolerated'.

While not going into specifics, it is more or less a confirmation that Dr Sacra who was said to have received multiple courses of a treatment was indeed treated with TKM-EBOLA (he seems to have pulled through).  Further substantiating that suspicion was a comment by a relative that subsequent administrations of the experimental drug were better tolerated:

'He also tolerated the research drug well – better than he had the previous doses he was given.”'

This is consistent with infusion reactions of many intravenously administered drugs being a particular problem during the first administration only.

Then there was another report that a number of suspected, early cases had been evacuated from Western Africa to the US with the intention of giving them experimental treatments.  This, in fact, would be the ideal setting for using TKM-EBOLA, or for that matter most other experimental treatments against Ebola.  It should be remembered that while in the preclinical monkey studies, the efficacy of TKM-EBOLA started to wane if treatment was delayed for more than 3 days following infection of the animal, this experimental setting is more akin to a needle stick accident in the lab given the large amount of virus involved in the innoculum.

By contrast, in the current outbreak in Western Africa, not every contact obviously leads to a successful transmission of the virus, a reflection of the fact that the starting viral population will be much less compared to the experimental setting.  This means that it would take the virus more than 3 days to overwhelm the capacity of TKM-EBOLA and the immune system to stall the infection in its tracks.  Hopefully, Tekmira is conducting analogous innoculum-window-of-opportunity studies in monkeys to get a better sense of how much treatment can be delayed when infectious doses are quite low.

With this in mind, I am more or less convinced that RNAi Therapeutics is saving patient lives for the first time.  I personally would risk an anaphylactic shock in a closely supervised clinical setting any day over the prospect of not getting specific treatment when infected with Ebola. #RNAiHistory

ProQR Therapeutics- an RNA Therapeutics IPO to Be Enjoyed Responsibly

This week, a new RNA Therapeutics company went public: mRNA repair company ProQR Therapeutics.  This Dutch company from genetics hotbed Leiden sets out to cure severe diseases that are caused by small mutations by repairing the mutations at the messenger RNA level.  First on the list is a treatment for Cystic Fibrosis caused by the 508 deletion.

If Only Science Were Always That Way

The repair is thought to be mediated by the provision of at least two synthetic RNA oligonucleotides (CF4 and CF6 in the image above), a long, modified one (~30nt) with complementarity to the area around the mutation, and a shorter (~10nt), 5’ and 3’-phosphorylated, but otherwise unmodified one of the desired sequence.  Add this to living cells, and hocus-pocus, mutant mRNA is converted into good mRNA.

What makes the publication by Zamecnik et al. from 2004 on which PRO-010 for Cystic Fibrosis is based so amazing, is that by just wishing to repair an RNA and without knowledge of an mRNA repair pathway (note: I’ve considered myself an RNA molecular biologist for close to 10 years, but never came across even the notion of such a mechanism), they obtained the desired results wanted.  Unfortunately, this is not how science works—never. 

In fact, even they considered themselves somewhat lucky, as they had initially thought that the repair first required a third oligonucleotide which by acting via RNaseH mechanism would cleave the target mRNA so that it becomes more amenable to repair ligation reactions.  But when they tried it, it did not make a difference (I would have expected a knockdown), so they stuck with the 2 oligo approach.  Equally amusing was the fact that the phosphorylations were just added for good luck, without any investigation on whether they were useful or necessary.  But as they say, never change a winning team.

Molecular Mechanism Supported Only by Tricky PCR

Most bothersome to me was the fact that the claimed mRNA repair could only be supported after trying out a bunch of PCR amplification reactions, with some reactions suggesting that something might have occurred to the target mRNA. 

As anybody who’s ever work with PCR knows, a lot of strange products are generated during most PCR reactions, either in tiny amounts or less tiny amounts (the infamous PCR artefacts that make lab meetings a fun event).  A related problem is that no conclusions can be drawn from end-point PCRs as used in that seminal paper regarding the amount of these products.  This would have answered the question of whether the phenotypic changes that were reported could be explained by the x % of wild-type CFTR mRNA being generated.

At the minimum, the generation of wildtype CFTR mRNA should have been shown through a hybridization method, not PCR.

Biology’s Best-Kept Secret

As you might imagine, the ability to repair mRNAs with simple oligonucleotides would generate a lot of interest, the type of interest for example that the discovery of RNAi received.   In the case of RNAi, the seminal findings by Tuschl and colleagues that RNAi gene silencing worked in mammalian cells were instantly followed by an explosion of publications harnessing this technology.  Strangely, however, according to GoogleScholar, only 9 papers have cited the mRNA repair publication by Zamecnik et al.  This is explained by most scientists just shaking their heads on reading the publication and then move on, with the more gullible ones failing to reproduce the results.

Laughing All the Way to the Bank

I know that as a scientist I have to be open-minded, but as described above my BS-recognition system, is lighting up bright red.  I  am therefore upset that such science was able to raise $90M in the IPO, valuing ProQR Therapeutics at 300 million dollar- US, not Zimbabwean ones!  On the one hand, I should be glad that financial interest in orphan diseases and RNA Therapeutics is so big right now that this was even possible.  And if you invest according to relative valuations, you will probably do quite well in RNA Therapeutics (Regulus e.g. is worth around the same $300M).  On the other hand, I am always afraid about backlashes from the failures of such companies.  It is therefore important to remember that the qualities of RNA technologies differ vastly in quality from company to company.

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.