Friday, March 7, 2014

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.


Fontainebleau said...

So true Dirk, that is the beauty of the paradigm - already differentiating itself!

experiencedmentor said...

...and you didn't mention Alnylam's partner, even once! LOL

Steve_382 said...

Is there a chance that people with naturally occurring low levels of LDL have more neurocognitive issues than people with higher levels of LDL? This could open a lot of questions about what are the best levels of LDL. Maybe what's best for cardio is not what's best for neuro.

Anonymous said...

I think PCSK9 is dead for now. Monoclonal antibodies have killed the market for PCSK9. Even if RNAi doesn't cause this problem, it won't be easy to get FDA approval for this type of drugs. Most likely RNAi companies will be required to prove that they don't have this problem. This could mean further long and expensive clinical study. Not only that, but the RNAi companies developing PCSK9 will have to fight against negative publicity.

Richard Lund said...

We still have berberine. Not sure if it is active through PCSK9 but it has been noticed by the Norwegians in this play. I don't know if anyone has put down roots in IP for it here.

bion4maticist said...

"There are lots of issues with PCSK9 as a target and in fact the FDA has recently written a letter to IND holders of PCSK9 drugs expressing a great deal of concern about PCSK9 as a target, independent of modality, whether its monoclonal antibody or an siRNA or an antisense or a small molecule."
Stanley T. Crook 1/11/2012

Gleenjamin Allennewberry said...

Dirk what are your thoughts on Benitec and their TT-304 Hepatitis C trials going on currently.Looks very promising.

Anonymous said...

You shouldn't ask about Benitec on this blog. It would be nice to get objective insights regarding ddRNAi- anyone?
(Read the Voyager essay on this blog)

Anonymous said...

Benitec is a failure. However, some power brokers in Wall St have tipped some money in to it. They must know something. I suspect what they know is the necessary IP for BLT to actually carry some worth has been inlicenced. Or its life expectancy is short.
BLT is a faux biotech being managed on PR's and video puff pieces.

Dirk Haussecker said...

RE Stan's comments on PCSK9: don't you think it's ironic that it comes from somebody that has essentially killed ApoB as an approvable target?

RE Steve and whether too low LDLc could be bad for the brain: it would be great if you could find such evidence from studies on the PCSK9-deficient population. It is important that we don't jump to conclusions about PCSK9 as a class when all we have are cases linked to MAb-based trials.

PS: Don't Benitec investors know that it is extremely irritating that they litter each blog entry here with off-topic comments about Benitec?

Dirk Haussecker said...

Here is a recent study that argues against PCSK9 deficiency per se and lower cognitive impairment:

J Lipid Res. 2013 Feb;54(2):561-6.

PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population.
Postmus I1 et al.

Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10(-12)), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events.

Anonymous said...

bion4maticist said...

The paper you cite, J Lipid Res. 2013 Feb;54(2):561-6, shows that normal levels of a mutant protein, missense SNP R46L, does not appear to cause neurocognitive defects.
The paper to which you link, N Engl J Med 2006; 354:1264-1272, discusses 3 variants, R46L, Y142X, and C679X, only one of which (Y142X) is likely to cause nonsense-mediated decay. But the phenotypic effects of Y142X haven't been studied. So we really don't know much about the phenotype induced by the absence of the protein.
None of these "natural experiments" support your contention that an RNAi therapeutic is somehow going to be different, and that the FDA is going to approve one without large, lengthy, and expensive outcomes trials. On the contrary, there is every indication that the RNAi approach, just like the RNAseH approach, will trigger concern (whether or not it's justified). The Crooke quote was meant to highlight this likely outcome.

Dirk Haussecker said...

Right. I have full faith in Crook's unbiased conclusions such when he stated during the keynote address at the 2012 OTS meeting in Boston that 'mipomersen has no side effects'.

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