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.
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When you pull an image from Wikipedia, please cite the source.
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