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.