Alnylam Indicates that 80% Subcutaneous TTR Knockdown Achievable with Magic 2.5mg/kg Dose

This morning, Alnylam announced a milestone in the development of subcutaneously administered, systemically acting RNAi Therapeutics.  A ‘more than 80%’ knockdown was achieved in a phase I trial of ALN-TTRsc, the GalNAc-siRNA conjugate for the treatment of TTR amyloidosis.  It is the first time that a meaningful knockdown in Man was reported using the subcutaneous route of administration.

The key question as to the clinical attractiveness of the liver-specific GalNAc delivery platform versus intravenous alternatives such as SNALP (compare to just reported ALN-TTR02 clinical results) relates to injection volume and frequency of administration.  The hurdle to overcome here would seem a once weekly regimen with dosages of 2.5mg/kg or less.  2.5mg/kg is widely considered to be a threshold as this amount of drug can be accommodated in a 1ml syringe.  Higher injection volumes would likely be quite painful and possibly increase the risk of injection site reactions.  Higher dosing frequencies in order to stay within the 2.5mg/kg limitations would reduce the convenience factor.

Unfortunately, these data points were left undisclosed in today’s announcement.  Instead, we were given a riddle.  The company first stated that the results were in-line with observations in non-human primates.  At another point, they say that 80% knockdown with ALN-TTRsc were achieved in non-human primates with the magic 2.5mg/kg dose.  Logically, Alnylam stated that in humans 80%’ knockdowns were seen with the 2.5mg/kg dose. 

Curiously, the company also stated that dose escalation was continuing.  It makes, of course, sense to push the degree of knockdown.  The difference between an 70% knockdown (e.g. ISIS-TTRRx), an 80% knockdown (current ALN-TTRsc results), and 90% knockdowns (e.g. ALN-TTR02) is that compared to a 90% knockdown, the amount of remaining insulting protein (here: mutated TTR) is twice (80%) and 3x (70%) as high which could result in dramatic differences in the clinical outcome, or even whether a knockdown approach would even work for a disease like TTR amyloidosis.

Maybe we will get more clarity on dose and dose frequency at today’s R&D day.  If not, more detailed results are to be presented at the Annual Scientific Meeting of the Heart Failure Society of America (HFSA), September 22-25.

RNAi and Antisense Targeting the Same Gene: Not a Zero-Sum Game

Transthyretin-mediated amyloidosis has become the single-most important factor for the 3-5 year valuation of certainly Alnylam, and possibly ISIS Pharmaceuticals as well. After TTR, Z-alpha-1-antitrypsin (Z-AAT) is gearing up as the next Alnylam(RNAi)-ISIS(antisense) battleground. Expect to hear competitive language from the two camps why their approach will prove superior over the other.  It is, however, worth keeping in mind that having two candidates race towards approval can also have significant pie-enlarging benefits.

Raising Awareness and Pressuring Regulators

A good competition will attract attention, from patient groups, physicians, regulators, and the investor community.  Patient groups and physicians will be primed that after years of lacking treatment options, the time for change has come.  We have seen this with the trifecta ofweight-loss drug candidates, two of which have recently been virtually willed into approval.  Given the enormous problem of obesity, it became politically untenable to further withhold treatment options.  Eventually, the regulators were forced to give in to the pressure despite their original objections over safety.

Closer to home, similar awareness and pressure is being brought to bear on getting exon-skipping oligonucleotides approved for the treatment of Duchenne Muscular Dystrophy, stoked by the competition between Prosensa/GSK and Sarepta .  If you caution about hurried, aka accelerated approval, then you are readily labeled as a heartless misanthrope.  Similarly, the homozygous familial hypercholesterolemia population has already been educated, targeted, and friended by both patient-access specialist Genzyme and competitor Aegerion and probably strongly expect the new drug approvals.  

Understand that these comments are not meant to be judgments on the respective drug candidates, but just the way I view current dynamics.  In fact, I agree that developing drugs for many of the rare and severe (orphan) diseases requires more risk-taking, usually biomarker-based approaches, and that not too long ago patient needs were not sufficiently considered in a highly risk-averse regulatory climate.

The TTR Amyloidosis Race

Given that Pfizer’s drug candidate tafamidis does not appear about to revolutionize the treatment of TTR amyloidosis, I see similar pressure building for the approvals of gene knockdown approaches ALN-TTR02 and ISIS-TTRRx in 2015-6.  The intense competition between ISIS and Alnylam will provide good fodder for the press (just as it does for this blog), engage the minds and pad the pockets of key opinion leaders and consequently raise the expectations of the public and hopes of those suffering from the disease.

While I have 2015-6 approvals baked into my projections of the RNAi Therapeutics story, I wouldn’t mind a year’s delay if the competitive dynamics would allow for it.  In fact, I expect the FDA to manipulate the process in a way that both drug candidates will come before an AdCom panel together, making the obsession with speed over good science even more so nonsensical.

My problem with ISIS and GSK speeding straight into a phase III study after a single phase I study is that they do not seem to have identified a suitable dosing regimen: 400mg/week good efficacy (-81% knockdown), but probably too high a dose from what we know about the safety of phosphorothioate oligonucleotides; 200mg/week could fare better in terms of safety, but has shown only modest knockdown efficacy (-44% knockdown).  In my opinion, another dose-finding study would be in order under normal circumstances.

[Update 29Nov2012: The Clinicaltrials.gov entry for the upcoming phaseII/III ISIS-TTRRx trial shows that the companies have chosen the stab-in-the-dark 300mg/week dose.  Although the January 2012 phase I results press release made no mention of such a cohort, the June 2012 Annual Shareholder Meeting TTR poster shows data from a 300mg cohort (~70% knockdown).  Unlike all the other cohorts were 90+ day data, the 300mg cohort data was less than 50 days.  It thus looks like a 300mg cohort was included post-hoc. Unfortunately, ISIS has chosen not to list the phase I trial on clinicaltrials.gov.]

This concern over uncertain dosing schedules also applies to Alnylam's ALN-TTR02 (-87% peak knockdown, -67% knockdown after 28 days following single dose) where the current ‘multi-dose’ phase II study only seems to cover two doses.  You would hope that Alnylam presses hard to amend the study to include further doses to gain more experience with the repeat-dosing pharmacology of ALN-TTR02 before betting their house on a single pivotal phase III trial.

Once approvals are obtained, however, the beneficial aspects of competition should disappear quickly especially when small orphan disease populations are involved.  But until then, the race towards approval should free energies allowing TTR amyloidosis to become the first real commercial success story of either RNAi Therapeutics or RNaseH antisense.

Who do you think will win the TTR race? Take part in the survey (upper right hand corner).   

ISIS TTR Results Show 1st Gen SNALP Already on Par with RNase H Antisense

ISIS today reported knockdown results from a phase I trial with its RNase H antisense compound ISIS-TTRRx against the transthyretin gene for the treatment of TTR amyloidosis. The results show that while high 81% knockdowns can be achieved, very large amounts of oligonucleotides (400mg weekly for 4 weeks) had to be given. When clinically more relevant doses were given (200mg as in mipomersen and the next lower dose from 400mg), a mean knockdown of 44% was achieved.

As you will remember (SNALP Works!), the RNAi Therapeutics candidate ALN-TTR01 last November showed a mean reduction of 41% of serum TTR from baseline following a single 1.0mg/kg infusion. In light of yesterday’s results with ALN-PCS02 where a supposedly less potent RNAi trigger was employed and a ~60% knockdown was achieved with 0.25mg/kg, it seems likely that the Tekmira SNALP-enabled ALN-TTR02 which is about to enter clinical development and which employs a formulation similar to PCS02 will show the type of 70-80% knockdown at 0.25mg/kg.

We have yet to learn more about the safety profile of ISIS-TTRRx which is being developed under an option agreement with GSK. ISIS stated in their press release that they were planning to enter pivotal studies with this compound soon. If it is with the 400mg dosage, they may be tempting fate. It might be interesting to try 300mg.

As you know, these days I’m strongly advocating RNAi Therapeutics as the technology is currently being sold at much below the worth of the science which has progressed steadily over the years despite the up and downs in public perceptions. Today’s results by ISIS show that the new darling in nucleic acid therapeutics can certainly knock down genes in the liver (and some other tissues). They also show, however, that even the initial SNALP formulations are already on par with it in terms of efficacy at the higher end of tolerability (not talking about other aspects such as absolute differences in dosage or route of administration).

Phase I Study of ALN-TTR01 in Transthyretin Amyloidosis- A Preview

(For a discussion of the phase I results, see here).

Alnylam is about to reveal results from its phase I study with ALN-TTR01 for the treatment of transthyretin amyloidosis (ATTR) at the Nov20-22 FAP meeting in Kunamoto, Japan. This blog provides a brief overview of the rational for RNAi Therapeutics in this disease and the importance of this particular study for the field of RNAi Therapeutics.

ATTR is an autosomal dominant amyloidotic disease due to point mutations (>100 possible) in the TTR gene. These mutations cause protein misfolding and aggregation into fibrils that, depending on which tissues they accumulate in, can cause various organ dysfunctions, most notably polyneuropathy (FAP), cardiomyopathy (FAC), and gastrointestinal/nutritional defects. For those that develop the disease, death is common 5-15 years following the emergence of disease symptoms (usually between 30 and 50 years of age). Although there is genotype-disease phenotype overlap, the most common mutation, Val30Met, strongly predisposes to FAP, while the Val122 is associated with FAC. About 10,000 patients suffer from FAP and 40,000 from FAC. As a rare genetic disease, it occurs in clusters, with FAP cases for example concentrated in Portugal, Sweden, and Japan.

Until recently, the only accepted treatment has been liver transplantation for FAP where removing the source of the mutant TTR in blood serum can reverse the polyneuropathy. Pfizer just got European approval for FAP with its small molecule TTR conformational stabilizer Vyndaqel based on slowing the rate of peripheral neuropathic impairment.

There exists, however, great need for additional therapies as Vyndaqel actually missed the primary endpoint in its pivotal study (the FDA did not accept the NDA for review earlier this year), and because liver transplantation is ineffective for FAC. The latter seems to be due to wildtype TTR still being able to deposit into pre-existing plaques, for example in heart tissue, at a rate that is higher than the turnover of the amyloidotic plaque. In fact, the amyloidotic potential of wildtype TTR is illustrated by the fact that it frequently causes spontaneous amyloidosis in elderly people (senile ATTR).

RNAi Therapeutics Approach to ATTR

The contribution of both wildtype and mutant to disease pathology, the dynamic turnover of plaques, and the fact that TTR knockout mice have the same life expectancy and fertility as their wildtype littermates and are otherwise essentially asymptomatic, makes RNAi Therapeutics a highly attractive treatment approach for this disease. TTR is involved in the transport of vitamin A and thyroxine in the blood, but it appears that in the absence of TTR these carrier functions are compensated for by other carrier proteins in the serum. What is more, essentially all the life-limiting pathologies are caused by TTR that is expressed in the liver, and with Tekmira’s SNALP delivery technology, RNAi can address the relevant gene expression.

TTR01 vs TTR02

One source of confusion that I expect to affect the financial markets tomorrow stems from Alnylam developing two candidates for ATTR, ALN-TTR01 and ALN-TTR02, the difference between the two candidates being in the SNALP lipid composition. TTR01 is the subject of the present trial and is based on an early DLinDMA lipid-containing formulation. It was shown to be effective in knocking down TTR in non-human primates with an ED50 of around 0.3-0.4mg/kg. As the highest dose in the phase I study was 1mg/kg it is reasonable to expect there to be evidence for TTR knockdown in the ALN-TTR01 trial. I should warn, however, that because of the small patient number in each dose cohort and the natural intra- and inter-patient variability of TTR levels in the serum, the pharmacodynamic outcome measure in this trial, the pooled numbers may not give us a straightforward 'stat-significant' answer.

Because of the rapid developments in improving the efficacy and tolerability of SNALP technology, it is therefore almost assured that Alnylam will drop TTR01 and prioritize TTR02 which takes advantage of these developments and for which the filing of an IND is imminent.

Consequently, the importance of tomorrow’s results for the RNAi Therapeutics field lies in providing proof-of-concept for RNAi knockdown following systemic delivery at OKish tolerability. That’s it. It also sets up the results from the phase I studies with ALN-PCS02, the PCSK9-targeting hypercholesterolemia candidate, which are expected to be reported by the end of this year. As PCS02 uses one of the more recent SNALP formulations, this will be the SNALP candidate that has to shine both in terms of knockdown efficacy and safety/tolerability.

ATTR Economics

If you had any doubts as to the commercial potential of ATTR, it is worth noting that Vyndaqel, Pfizer's just-approved TTR drug, is expected to be priced at more than 100,000 Euros per patient year and that most (known) FAP patients are in healthcare systems that will still bear such costs. Pfizer last year paid $200M in upfront considerations for FoldRx, the original developer of Vyndaqel, with another $200M in contingent milestones. Although FoldRx has a mission of developing other protein folding-based drugs, this price tag was essentially for a drug with results from a pivotal trial that failed to meet the primary endpoint and for which approval was far from certain. Considering Alnylam’s cash position, this one registrational drug candidate valued FoldRx higher than all of Alnylam- although you might justify that with the mounting existential risks stemming from Alnylam's alleged theft and misuse of Tekmira's SNALP technology.

Given these economics, it is not surprising that other companies have similarly recognized the commercial potential of ATTR. Importantly, ISIS Pharmaceuticals will also present progress with its antisense candidate for ATTR (ISIS-TTRRx) at the meeting. This candidate entered clinical development in May and is financed by GSK which retains an option for its exclusive license.

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