TEGSEDI worse than tetramer stabilizer according to newly released EMA document

When Ionis presented data from the phase III NEURO-TTR study last year in Paris, they clung to numbers close to ‘zero’ to make the point that its TTR-lowering antisense drug TEGSEDI (aka inotersen) was 'stabilizing' and ‘halting’ disease progression.  According to a newly released document by the European Medicines Agency (EMA), this, however, does not seem to be truthful: TEGSEDI only delayed the progression of polyneuropathy compared to placebo, but patients on placebo still got worse over the 15 month study period.   

This not only widens the apparent distance in therapeutic efficacy between TEGSEDI and RNAi competitor ONPATTRO (which improved on disease parameters), but even puts it apparently behind generic tetramer stabilizer diflusinal.  Diflusinal also happens to be much better tolerated than TEGSEDI which has been plagued by platelet and renal issues.

EMA document suggests numbers were inflated

According to the ‘Summary of Product Characteristics’ document issued by EMA following its approval of antisense drug TEGSEDI for the treatment of TTR-related polyneuropathy, mNIS+7 after 15 months increased by +11 points vs 25 points for placebo.  By contrast, Ionis Pharmaceuticals (which has now licensed the drug to subsidiary Akcea Therapeutics) claimed a mere +5 point progression.  Curiously the placebo values haven’t changed.

This compares to an increase of +9.2 for diflusinal over 24 months and -6 for ONPATTRO over 18 months.

Similarly, on another measure of disease progression, the Norfolk Quality of Life questionnaire increased by only +0.99 per the Paris presentation last year, but by +4.38 per the EMA document.  Once again, the placebo numbers remained essentially the same.

Finally, what had been heralded as a TTR knockdown close to that of ONPATTRO, a median 75-79% TTR reduction vs 82% for ONPATTRO, now looks much different when considering that mean knockdown was only 68-74%, possibly reflecting the poor tolerability profile of TEGSEDI and missed doses.

I am sure that Akcea and Ionis will have eloquent explanations for the discrepancies which just so happens to  conveniently and selectively favor their drug when analyzed by them.  These new numbers, however, are not just minor adjustments, but represent substantial changes to the TEGSEDI narrative.

It should be noted that it is likely that tetramer stabilizers and TTR-lowering agents will be taken together by many patients.  The relative efficacy and tolerability numbers, however, put TEGSEDI in a very weak position with regard to direct competitor ONPATTRO, also as it comes to reimbursement decisions. 

ONPATTRO heart aches

In the phase III APOLLO study, patients treated with ONPATTRO were numerically less likely to die compared to those on placebo (~50% reduction in death rate).  Following the Paris meeting, I came away with the impression that the deaths in the ONPATTRO arm were largely due to cardiac failure and infection.

According tothe New England Journal of Medicine publication on the study, this seems to be a misunderstanding as infection was a main cause of death in the placebo arm while all deaths in the ONPATTRO arm were cardiac.  As has been pointed out by others on Twitter (@ionisdisrupts and @artkrieg), this could raise questions in the minds of regulatory bodies whether to include TTR cardiomyopathy applications on the label despite of ONPATTRO improving on related secondary endpoints.

In fact, considering that the recent study design agreement with the FDA for follow-up drug ALN-TTRsc02 also focuses on polyneuropathy endpoints, it is all but official that the label for the upcoming approval of ONPATTRO will be targeted at the polyneuropathy population only and that separate trials will have to address the patients mainly suffering from cardiomyopathy symptoms.

Disclosure: short AKCA, long ALNY.

Two Promising RNA Therapeutics to Face Off in Paris ATTR Amyloidosis Meeting

I’m en route a high-speed train to Paris to witness how RNA Therapeutics are starting to revolutionize the care of patients afflicted by ATTR amyloidosis.  Towards that end, the presentations on pivotal trials with Patisiran (APOLLO; RNAi) and Inotersen (NEURO-TTR; ASO) to an audience of key opinion leaders and patients at the inaugural European ATTR meeting will critically inform the adoption of these medicines.

Top-line data for these agents in the polyneuropathy-leaning form of the disease (FAP) have been disclosed previously (here and here).

This will only be the beginning though, with more potent, safe, and better tolerated follow-up RNA Therapeutics being developed and patient identification becoming more sophisticated.  Ultimately, I envision a world where, for the inherited version of the disease, patient identification based on genetics will be possible such that TTR lowering therapies can be initiated before organ damage through TTR deposition occur.

Patisiran seen leading

When Alnylam disclosed a month ago that intravenously infused Patisiran not only halted disease progression as had been reported for Ionis’ subQ Inotersen, but apparently improved symptoms compared to baseline, the stock shot up ~60% while Ionis stock dived ~15%. Furthermore, safety and tolerability looked solid with much less treatment discontinuations (7.4% vs 37.7%) and nominally less deaths observed in the Patisiran treatment arm versus placebo control (4.7% vs 7.8%). By contrast, Inotersen has been living under a safety shadow ever since deaths due to phosphorothioate ASO-dependent thrombocyte lowering wereseen in addition to renal toxicity.

Can Inotersen stage a comeback?

So even before Patisiran data were presented, the Big Pharma partner for Inotersen, GSK, dumped the drug (by not exercising the option).  Obviously, Ionis wants this to be seen as an act of Dumb Pharma throwing away highly valuable drugs under the directive of bean counters and smartly dressed corporate overhaulers (here: GSK leaving orphan drugs).  Nevertheless, it is difficult to believe that GSK gave rights to Inotersen back for free when it saw Inotersen competitive with Patisiran which easily accounts for roughly half of Alnylam’s  $11B market cap.

Still, while to many it is a foregone conclusion that today’s presentations won’t change much in the competitive dynamics between Patisiran and Inotersen, there are a few scenarios which could change it.

Firstly on efficacy, we still have to learn whether the disease improvement over baseline as reported for Patisiran by Alnylam is medically meaningful over the disease halt reported for Inotersen.  As such, it is possible that the (mean and median) mNIS+7 scores were barely negative (i.e. nominal improvement) as the phase II open-label extension trial results with Patisiran would have predicted.  And who knows, mNIS+7 values for Inotersen could actually be nominally negativ!

Somewhat complicating mNIS+7 matters is that the two companies are using slightly different scales, but I don’t expect this to have much impact on the discussion.

In addition to closing the gap on absolute efficacy, Inotersen could emerge as the winner in terms of treatment efficacy versus placebo.  Importantly, the placebo group in the Patisiran study received steroid treatment around the time of infusion since Patisiran treatment entails this to manage potentially dangerous reactions around the time of infusion and subsequent hours.  Although Patisiran clearly outperformed placebo, steroids, albeit given intermittently, should have some impact on perceived disease symptoms and I found it notable that while Inotersen was statistically better than placebo (no drug at all) at an intermediate time-point 9 months, Patisiran wasn’t yet at 8 months.

It’s therefore possible that Inotersen has the delta advantage over Inotersen which, of course, would influence how docs regard the inherent efficacy of Patisiran alone.

Finally, the placebo issue could also negate another apparent advantage of Patisiran over Inotersen: safety and tolerability. Notably, there was a ~40% SAE rate in both the Patisiran and placebo groups which are historically high for TTR amyloidosis clinical trials.  For example, an 18 month trial with TTR tetramer stabilizer Tafamidis had SAEs of less than 10%.  Is it therefore possible that steroid treatment accounts for the high SAE rate and that the overall SAE rate for Inotersen (to be disclosed) is much lower? 

 With the presentations being less than 8 hours away, we shall find out any time now as my train reaches the outskirts of Paris…

Extended Use of SNALP Delivery Technology Well Tolerated

On Monday, Alnylam revealed an update on their lead ALN-TTR02 drug candidate for the treatment of the FAP form of TTR amyloidosis. Given that this could be the first commercially meaningful RNAi Therapeutics to hit the market, a lot of attention is being paid to its progress in the clinic.  Success and failure of this program are expected to have widespread repercussions for the RNAi, if not Oligonucleotide Therapeutics field.

Importantly, the data from the phase II open-label extension study provided strong evidence that the underlying SNALP LNP delivery technology, licensed from Tekmira Pharmaceuticals, is safe and well tolerated with 19 of the 27 patients involved having now received ALN-TTR02 once every 3 weeks for at least 6 months.  After 282 doses administered, no drug-related serious adverse events were seen with infusion-related issues as expected the main source of adverse events.  Notwithstanding the 8 mild flushing events and infusion reactions, there have been no drop-outs in the study so far.

On the efficacy side, ALN-TTR02 continued to produce robust sustained 80-90% knockdowns with a trend towards increased knockdown efficacy with prolonged dosing.  This knockdown certainly puts ALN-TTR02 ahead of the competitor antisense drug from ISIS and GSK (ISIS-TTRRx) which is expected to be in the 70% range, but is probably ahead in terms of patient enrolment in their pivotal study.

The results presented at the ANA conference had been widely anticipated because it was the first time that Alnylam revealed measures of therapeutic efficacy beyond the gene knockdown.  Accordingly, at the 6-month time-point patients treated with ALN-TTR02 exhibited less neurological declines as would have been expected from the Natural History of the disease.  Unfortunately, in the absence of hard biomarker evidence indicating improved neurological and, for a subset of patients, cardiac functions, the apparent improvement in the well-being of the patients (mNIS+7) could easily be attributed to the open-label nature and the relatively early time-point of the study.

Therefore, despite of the fact that shares in Alnylam increased 20% on the results and the provider of the delivery technology, Tekmira, barely budged on the news, the most important take-home from the results was that SNALP LNP delivery technology and indeed extended robust RNAi has a remarkably good safety profile.

With Success, Pure-Play RNAi Therapeutics No More

As RNAi Therapeutics are charging forward towards first marketing approvals, it is time to consider how this will change the face of some of the pure-play companies involved.  Alnylam is set to become the dominant player in TTR amyloidosis, Arrowhead Research and Tekmira are vying to become just that in Hepatitis B, and Tekmira is increasingly isolating their biodefense division involving the formation of a filovirus alliance with non-RNAi modalities (prophylactic and therapeutic vaccines) as revealed yesterday.

Under normal circumstances, getting drugs approved that revolutionize the treatment of particular diseases provides great incentives to protect the resultant franchises.  Witness BiogenIdec .  BiogenIdec started out as a molecular biology pioneer and serendipitously established itself as the major player in multiple sclerosis, and is now considering all therapeutic modalities, including RNA Therapeutics, to build on that strength and further expand into neurology.  

Although it breaks my scientific heart, I do not expect that to be any different for RNAi Therapeutics companies.  HBV is a great example since an immune de-repressing RNAi Therapeutic alone is unlikely to facilitate the 100% cure rates now seen with combinatorial HCV treatments.  Instead, the addition of a direct immune-activating agent such as a TLR agonist should enhance cure rates and shorten treatment durations.  For an acute fatal infection such as Ebola, you also do not want to limit yourself to one treatment, but recruit multiple mechanisms to save an infected person, or start vaccinating populations around areas of viral outbreaks.

To extract maximal value from such disease indications, it is often best to combine the various options under one roof.  It may be partly this fear of moving away from your roots that is responsible for ISIS Pharmaceuticals giving up marketing rights early on for a few cents on the dollar worth (SMN, myotonic dystrophy, TTR).

Having said that, just like BiogenIdec with recombinant proteins and monoclonal antibodies, most of these RNAi Therapeutics companies will continue to focus their internal R&D efforts on RNAi Therapeutics.  In special cases such as Ebola and other biodefense opportunities, a spin-out may create most shareholder value without damaging the platform technology value of the parent company.

Nothing of what I just said is revolutionary.  It is, however, worth keeping in mind as the first major RNA(i) Therapeutics wave will make landfall in 2-3 years. 

Alnylam Comments Suggest SubQ Tech Failed to Achieve Efficacy Goal

At today’s Morgan Stanley Healthcare Conference, the President and COO of Alnylam, Barry Greene, told the audience to assume that it took a dose of 5 to 10mg/kg of ALN-TTRsc to achieve the 80% knockdown that had been reported in July.  This suggests that ALN-TTRsc has failed to meet the stated goal of limiting the subcutaneous injection volume to 1ml or less as this is predicted to correspond to a dose of 2.5mg/kg.

If it holds up, this would have a number of important implications.  Firstly, it would affect the profile of ALN-TTRsc itself.  I don’t believe it to be necessarily terminal in a disease like the FAC form of TTR amyloidosis for which ALN-TTRsc is being developed.  Nevertheless, squeezing 2 or even 4ml into the subcutaneous space, or alternatively administering multiple 1ml shots in one sitting, could put some needle-phobic patients off, especially as TTR amyloidosis is set to become a competitive marketplace.

Secondly, such doses would not bode well for Alnylam’s GalNac delivery platform on which the company has pinned its future.  For example, one of the big draws of the hemophilia drug candidate ALN-AT3 which is about to enter clinical development was supposed to be its subcutaneous, instead of intravenous route of administration. However, as I speculated last week (Alnylam's GalNAcs as Cholesterol-siRNA 2.0), I believe ‘GalNac-siRNAs’ have advanced somewhat since ALN-TTRsc with the addition of lipophilic moieties such as cholesterol and the jury could therefore still be out regarding the capabilities of the GalNac delivery platform.

And finally, a weak potency of ALN-TTRsc would further increase the value of competing delivery technologies, especially SNALP (Tekmira) and the subcutaneous version of DPCs (Arrowhead Research). In fact, if the full results that are to be presented in about a week at the American Heart Failure Meeting confirm the 5-10mg/kg doses, it would explain why Alnylam chose not to have ALN-TTRsc compete with and potentially replace SNALP-based ALN-TTR02. Instead, the intravenous ALN-TTR02 will likely be applied to the earlier onset, more rapidly progressing form of TTR amyloidosis (FAP), whereas the subcutaneous ALN-TTRsc will be used for the more slowly progressing, later onset form of the disease (FAC).

Arrowhead Research: The Next Two Years

Over the last year, Arrowhead Research has undergone a corporate transformation putting it into a position to develop important drugs and create sustained shareholder value.   After what must be a decade of chasing after the latest and hottest in nanotechnology, the company finally appears to have realized that it is in possession of a platform technology that can deliver not just dreams, but actual life-changing products: Dynamic Polyconjugates.

In the following, I will describe how I see the company go about creating value over the next 2 years.

ARC520, ARC520, ARC520

The current corporate messaging is clear: it’s all about the company’s potential cure for chronic hepatitis B, ARC520 (for review, follow this blog and Arrowhead's investor day).  ARC520, of course, is enabled by DPC delivery.  However, as its own experience and that of fellow Tekmira, Silence Therapeutics, and others have shown, the financial markets do not care much about valuing the key enabling delivery technologies in RNAi Therapeutics.  As a result, the company is focusing public attention on its lead product candidate which by now probably has commenced dosing in the first clinical study.

ARC520 has the makings of the start of an enormous franchise (note: I expect ARC520 to be followed by other versions should initial clinical results bear out the immune reactivation hypothesis).  Chronic HepB, a disease affecting over 300 million globally, has to be considered an incurable infection and there has not been an experimental medicine that can knock down the key surface antigen (HBsAg) as rapidly and potently as ARC520.  By knocking down HBsAg, it is hoped that the immune system can be reawakened to seroconvert against HBsAg which would be considered a functional cure.

We should find out whether the hypothesis is correct with the results from the first multi-dose phase IIb study which I expect to come in by the end of 2014/early 2015.  There is a slight possibility, however, that first functional cures may be observed in the single-dose phase IIa Hong Kong study with results in less than a year.

Beefing up the DPC-enabled pipeline

While ARC520 has enormous potential for which spelling out the market size would yield ridiculously high numbers, there are two main risks that need to be overcome. 

The first one is the safety of a DPC-enabled RNAi Therapeutics.  DPC has never been tested in Man before, so you always cross your fingers as it enters the clinic.  Nevertheless, the company has repeatedly reported in the peer-reviewed literature and otherwise that the safety profile, from rodents to a chimpanzee, is looking clean.  This gives me confidence that safety might actually be a strong point of the liver-targeted, short-circulating DPCs.

The second one is about the validity of the HBsAg immune reactivation hypothesis.  Key opinion leaders in the chronic HepB field support it, but as long as the direct link has not been demonstrated, it remains a risk.

As a result, the company would not do justice to DPC technology or itself by making ARC520 multi-dose results a binary event.  Instead, Arrowhead Research should add one or two additional DPC candidates to the pipeline by the end of 2014 when critical results for ARC520 are to be expected.

The first one is expected to be announced in 2013.  This should be another liver-targeted, two-molecule, intravenously infused DPC RNAi Therapeutics.  As Alnylam’s efforts show, there are numerous attractive, often orphan indications that involve gene expression in the liver.

In 2014, I would hope that a liver-targeted candidate based on their newly developedsubcutaneous DPC technology will be added to the pipeline.  Arrowhead presented first such subQ data in late 2012 so that with a few CMC refinements and gene specific development work, they might have a candidate in 2014.

Adding a subcutaneously administered DPC candidate to the pipeline would not only be progress in that this route of administration opens up new therapeutic opportunities, it would also mean that Arrowhead succeeded at where it historically has struggled with: making a single-molecule DPC at high enough yield and which can be properly analyzed.  Remember, Merck at the 2012 OTS meeting more or less announced single-molecule DPCs to be their RNAi delivery dream.  This means that Big Pharma will be and probably are already queuing up for the technology.  Big Pharma loves single-molecule solutions.

Going after the TTR cake: a proven path of value creation

Going by the analyst reports, more than half of Alnylam’s market capitalization ($2.4B) rests on their TTR amyloidosis pipeline: intravenous SNALP-based ALN-TTR02 in mid-stage phase II, and GalNAc subcutaneously delivered ALN-TTRsc in early phase I.  I believe that Arrowhead can create a candidate that is superior to both of them and thus claim a good part of that ~$1.5B in a relatively short period of time (~1.5 years from first IND to generate ALN-TTR02-type data).  Compared to ALN-TTR02, the subcutaneous mode, but equal potency could make it the preferred RNAi Therapeutic.  On safety, we have to wait, but this could be another differentiator.  Compared to ALN-TTRsc, improved efficacy and less frequent administration with lower injection volumes would make an ARC-TTRsc the winner in the market place.  Compared to phosphorothioate antisense-based ISIS-TTRsc, the winning differentiators would be potency and safety.

Arrowhead is a $70M market cap company.  It would seem like a no-brainer to go after the $1.5B market cap attributed to early-stage TTR amyloidosis data for their first subQ IND.  With a superior product and quite different molecular composition (delivery chemistry, possibly Dicer-substrate RNAi trigger) and superior clinical performance, no orphan drug designation by Alnylam or ISIS could hold it back.

Price Target: $30

In summary, by H2 2015, the time current funding is expected to last, Arrowhead Research could have demonstration of functional cure for chronic HepB (I won’t even start trying to value that), two additional product development candidates in the clinic one of which likely with a value between $1-2B, and a potent single-molecule delivery platform that will attract much attention in the industry. 

The achievements of these goals do not assume heroic operational feats.  Even in a worse-case scenario, namely that the immune reactivation hypothesis fails to live up to its expectations, ARC520 should add to the evidence of DPCs being a strong delivery platform thereby also de-risking the other two pipeline candidates.

Anybody laughing at a price target that is 15x that of its current price, by somebody who has put most of his stock market investment in that company at that, should perform an apples-to-apples comparison of clinical programs (ARC520 vs ALN-TTR) and delivery technologies (DPC vs GalNAc) with $2.4B market cap Alnylam.  Could it be that Wall Street has it all wrong?  Of course, Arrowhead Research is not the chosen one in RNAi Therapeutics on Wall Street, but I believe that clinical data on chronic HepB could lower Arrowhead’s cost of capital such that by mid-2015, a financing or business development deal would be on much improved terms.

Alnylam Moves to Increased Dosing Frequency as Knockdown Duration Shortens

The ALN-TTR02 phase II results have finally been announced.  The results are consistent with the view that ALN-TTR02 is a strong candidate for becoming RNAi’s first marketed drug.  Having said that, the knockdown efficacy results came short of what one could have expected based on the phase I and non-human primate results and explain why the company has amended the protocol to test increased dosing frequencies.

Non-human primate studies show cumulative dosing

Alnylam had long telegraphed the results for the phase II studies.  They stated that we should expect the clinical results to be essentially the same as what they are seeing with the drug in non-human primates.  I understand that non-human primates are an immensely insightful model system in RNAi Therapeutics development.  Still, making such strong suggestions just weeks before clinical data release seemed a bit odd in that it risked stealing its own thunder.

Anyhow, the non-human primate studies showed the peak and the terminal knockdown (terminal knockdown defined as the knockdown just before repeat dosing) increased with each additional dose administration.  Whereas the peak/terminal knockdown in cycle 1 was ~85%/47% at 0.3mg/kg, they were ~90%/58% in cycle 2 and so on.  This is what Alnylam refers to as with ‘cumulative’ efficacy.

Unfortunately, this was only partially repeated in humans.

Knockdown not as sustained with repeat dosing

The ALN-TTR02 phase II study represented the first opportunity to rigorously test gene knockdown of a SNALP-delivered RNAi Therapeutic following repeat dosing.  Whereas the phase I study in healthy volunteers was a one-dose study, this phase II study was a 2-dose repeat-administration trial in European patients with TTR amyloidosis (FAP form).  In both studies, target gene knockdown could easily be determined by measuring TTR levels in the blood.

In my analysis of the data, I will stick with slide 10 of Alnylam’s slide set which seems to provide the clearest overview of the data.  At the critical 0.3mg/kg dose level, the peak knockdown either remained +/- the same (~80à80% for once-every-4-weeks) or showed evidence of cumulative activity (~80à88% for once-every-3-weeks) when comparing the first with the second dose administration.  While this looks quite good, albeit somewhat less than what was observed in the phase I study, slide 5), the downside surprise comes with the terminal knockdown values.  Here, the knockdown for cycle one (day 28; n=6) was around 75% with tight error bars, but dropped to 60% for cycle two (day 56; n=5) with much more considerable inter-patient variability.  The same was observed for the 0.15mg/kg dose level with ~53% and ~45% reductions after cycle one and two, respectively.

I have no idea where Alnylam is getting the 93% knockdown from that is so prominently mentioned in the press release.  Are they referring to a single patient that achieved such knockdown?    

Once-every-3-weeks to stay on top of competition

You can safely assume that reduced knockdown duration and the fact that the critical phosphorothioate antisense competitor by ISIS/GSK has a ~70% knockdown have driven Alnylam’s decision to amend the ongoing phase II study by including once-every-3-week regimens.

Data for the first such cohort was provided.  As noted above, once-every-3-weeks showed evidence of cumulative peak knockdown activity thus staying on top of the antisense competition.  It is a shame though that the data provided coincidentally ended on day 35, only a week before the important repeat terminal knockdown point.  It is thus not possible to tell whether diminished terminal knockdown is also an issue for the once-every-3-week regimen.

Safety findings largely related to route of administration  

Safety findings were only reported at the 0.3mg/kg level (4 events in 9 patients).  The infusion-related reaction and the 'nuisance' side effect of fever/chills are known for SNALP delivery, but do not appear to be prohibitive.   Unfortunately, there was a serious adverse event due to a misplacing of the infusion needle.  New to me is the finding of polyuria (peeing a lot). 

Based on this profile, Alnylam will try to lower the amount of immune suppression given with the drug.  Immune suppression is given as a precaution to avoid hypersensitivity reactions seen with SNALP-enabled TKM-ApoB.  It seems to me that in introducing the once-every-3-week regimen, Alnylam wants to dial up the product profile by lessening the burden of the immune suppression.

The future of ALN-TTR02

Given the high unmet medical need for FAP patients, ALN-TTR02 should remain on track of making it to the market provided reduced TTR levels indeed translate into a clinical benefit (a low risk at 80% knockdowns).  Some additional warts, however, have been added to the product profile and my main interest as to the future data will be how efficacy and safety is maintained not after just two, but after 3, 4, 5 doses and so on.  

It would also be good to find an explanation for the diminished knockdown duration (e.g. some neutralizing antibodies or a peculiarity of TTR gene regulation?).  Tekmira, the delivery partner which should receive a $5M milestone on the initiation of ALN-TTR02 phase III studies at the end of this year, would be an important ally in answering this question.  This could therefore be an important test of whether the two companies can put aside past differences.

  

The ALN-TTR02 Phase II Results...Abstract Today, Presentation Tomorrow

The abstracts for the Peripheral Nerve Society Meeting in France have been published.  The abstract on ALN-TTR02 does not reveal the results, but I post them anyway as a warm-up for tomorrow.  You can notice though that there is a relative shift towards the once-every-3-week regimen and the dose escalation started at the same point as the phase I study did (0.01mg/kg).  Check back for more tomorrow.

INTERIM RESULTS FROM PHASE II TRIAL OF ALN-TTR02, A NOVEL RNAi THERAPEUTIC FOR THE TREATMENT OF FAMILIAL AMYLOIDOTIC POLYNEUROPATHY

Adams D1, Coelho T 2, Suhr O3, Conceicao I4, Waddington-Cruz M5, Schmidt H 6, Campistol J7, Pouget J8, Buades J9, Falzone R10, Harrop J10, De Frutos R10, But- ler J10, Cehelsky J10, Nochur S10, Vaishnaw A10, Gollob J10. 1Centre Paris-Sud, APHP, Hopital de Bicetre, INSERM U788, Service de Neurologie, and Centre de Reference des Neuropathies Amyloides Familiales Le Kremlin-Bicetre, France; 2Unidade Clinica de Paramiloidose, Hospital de Santo Antonio, Porto, Portugal; 3Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden; 4Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon, Por- tugal; 5Hospital Universitario Clementino Fraga Filho, Rio de Janeiro,Brazil; 6TheUniversityHospitalofM¨unster,M¨unster, Germany; 7Hospital Clinic, Barcelona, Spain; 8Centre de Ref- erencedesMaladiesNaueromusculairesetdelaSLA,Hopital de la Timone, Marseille, France; 9Hospital Son Llatzer, Palma de Mallorca, Spain; 10) Alnylam Pharmaceuticals, Cambridge, MA, USA.

Familial amyloidotic polyneuropathy (FAP) is a fatal, autosomal dominant, multi-system disease caused by abnormal tissue deposition of mutant and wild-type transthyretin (TTR). Almost all circulating TTR is synthesized by hepatocytes, and in FAP this liver-derived TTR is responsible for amyloid accumulation in the main target organs, including peripheral nerves, gastrointestinal tract and heart. Treatment approaches have focused on reduction of amyloidogenic TTR monomer either through elimination of hepatic production of mutant TTR (liver transplantation) or stabilization of the TTR tetramer (tafamidis). While both of these approaches have been shown to slow neuropathy progression in a limited subset of FAP patients with the V30M mutation and early disease, there remains a significant unmet need for new therapies that can impact FAP patients with different TTR mutations across a broader range of disease severity. ALN-TTR02 is a systemically administered lipid nanoparticle (LNP) formulation of a small interfering RNA (siRNA) targeting wild-type and all mutant forms of TTR. This formulation predominantly delivers the siRNA to the liver, thereby inhibiting synthesis of TTR at the primary site of production. In non-human primates, repetitive dosing with ALN-TTR02 every 3–4 weeks at doses up to 0.3 mg/kg resulted in an average relative TTR suppression of up to 90% with no tachyphylaxis of the pharmacodynamic effect. In a randomized, placebo-controlled, Phase I dose-escalation trial in healthy volunteers, a single intravenous infusion of ALN-TTR02 administered over 60 minutes was shown to be safe and well-tolerated, and potently suppressed serum TTR levels by 82-94% at doses of 0.15–0.5 mg/kg. TTR reduction of up to 67% was observed out to 28 days post- dose, suggesting that sustained TTR knockdown could be achieved with a monthly dosing schedule. Based on these promising results, a multi-national Phase II trial of ALN-TTR02 in FAP patients was initiated in mid-2012 to evaluate the safety/tolerability and pharmacodynamic effect of multiple doses of ALN-TTR02. Patients receive two doses of ALN- TTR02 administered every 3–4 weeks at dose levels ranging from 0.01 to 0.3 mg/kg, with a total anticipated enrollment of approximately 27 patients. In this presentation, we will provide an update on the results of this ongoing clinical trial.

ALN-TTR02 Phase II Results Preview

Although the phase I results for ALN-TTR01 in late 2011 and ALN-PCS02 in first half of 2012 should have caught the attention of the diligent biotechnology investor, it was the highly potent knockdown (>90%) reported for ALN-TTR02 in July of last year that put the spotlight back on RNAi Therapeutics. The results for the TTR amyloidosis drug candidate not only benefited Alnylam, they were a blessing to the entire field of RNAi Therapeutics allowing it to raise ~$300M over the ensuing 12 months.  It is therefore an understatement that the phase II results for ALN-TTR02 to be disclosed in about two weeks will be closely watched across the industry and investors.

Possibly hoping to relieve some of the tension around the event, Alnylam has long telegraphed what we should expect the results from this open-label study to be: just look at the multi-dose non-human primate data and this is what you will see repeated in humans.  Nevertheless, I doubt that the generalists are buying the argument that non-human primates studies are highly predictive of clinical results, at least in terms of gene knockdown.   Just witness the valuations of other RNAi Therapeutics companies that have reported impressive non-human primate data (one could call that a buying opportunity).

Study primarily designed for safety…

The phase II study for ALN-TTR02 is primarily one of safety for repeat administration of ALN-TTR02.  The initial two-dose study design seems an overly cautious approach given that products enabled by Tekmira’s SNALP delivery technology have already been dosed for several months in patients with cancer.  This could be due to differences in how the different divisions within the FDA view the safety of SNALP and/or RNAi product candidates. 

With regard to hypersensitivity reactions, which are probably the most critical hurdle ALN-TTR02 needs to overcome, multi-dosing should actually the lower the incidence of infusion reactions (desensitization) which were the major safety issue in the phase I single-dose study.  With regard to spleen toxicity, multi-dosing is predicted to increase risk (cumulative).

Overall, given the dose (study geared towards the 0.3mg/kg dose) and history of ALN-TTR02, I am quite optimistic that no nasty surprises will emerge on the safety front.  This would also be consistent with plans by Alnylam to reduce the use of immune suppressants in the extension phase of the study.

…but efficacy could drive volatility

Although we have already been told what the efficacy results should look like and that Alnylam is aiming for an 80% knockdown, I expect analysts to pay close attention to efficacy given that Alnylam is in an arms race with ISIS/GSK.  As a reminder, in the 300mg/week regimen that has been chosen for the ongoing phase II/III study, a ~70% knockdown was reported with the ISIS/GSK antisense compound.  However, while a phosphorothioate antisense compound for liver-targeted gene knockdown given weekly has a sustained knockdown effect over time, there are wider fluctuations between peak and trough knockdowns for a SNALP-delivered RNAi Therapeutics administered only once a month.  In other words, watch the time-course of the knockdown, especially after Alnylam announced that it is considering a once-every-3-weeks regimen for the extension phase of the study.

Wall Street ascribes most of Alnylam’s value to TTR amyloidosis program

The reason, of course, why the TTR amyloidosis data is expected to cause major volatility is because two thirds if not more of Alnylam’s market value is based on a discounted cashflow analysis for ALN-TTR02 and ALN-TTRsc in the polyneuropathy and cardiomyopathy markets, respectively.  It is estimated that with premium orphan pricing (you will be surprised how precisely Alnylam’s pharmacoeconomic models will arrive at a fair price of $300,000 per patient year), peak sales revenues for Alnylam’s TTR products will be somewhere between $1.3-$2.0 billion.

I am optimistic that the TTR product candidates will make it to market and dominate over any phosphorothioate-based antisense competitor.  However, there remain important uncertainties as it relates to pricing and reimbursement, especially in some of the European markets where many of the FAP patients reside.  Furthermore, there is always an element of chance when it comes to avoiding prohibitive toxicities from sequence-specific off-targeting in a chronic treatment setting.

Over time, however, it does look like the rest of Alnylam’s pipeline is finally gathering steam.  With the porphyria and AAT deficiency candidates ALN-AS1 and ALN-AAT, respectively, and the intriguing complement inhibitor program, additional differentiated, high-value orphan opportunities are emerging.  It remains to be seen, however, whether the GalNAc-siRNAs are potent enough to exploit the potential of RNAi Therapeutics for these diseases or whether other delivery technologies enabling deeper knockdowns would have been appropriate.  This concern e.g. applies to the hemophilia program where my feeling is that only deep knockdowns will allow you to see clinically meaningful improvements in clotting times.  Unfortunately, I am still trying to find results from clotting assays (which are standard in the field) and not just the thrombin measurements that Alnylam is providing.

Trading the event

As Alnylam's share price has tripled since last year's announcement of phase I results and given that the two-dose design won't do that much for additional de-risking, I am speculating that only in a very bullish, confident biotech market that seizes on every news opportunity there is much upside from the phase II top-line results.  Because of the nervousness that has been creeping into the markets the last two weeks, I am taking a small bearish position ahead of the event, in a way hedged by much larger long positions in other RNAi Therapeutics companies (Arrowhead Research, Tekmira, RXi Pharmaceuticals) which are more attractively valued on a relative basis and should benefit from renewed RNAi Therapeutics investor interest as a result of the data release.

Last reminder that the GTC RNAi Therapeutics conference will start this week.  Don't forget to mention 'RNABLG13' for 20% discount on registration.

Genzyme Taps RNAi Therapeutics for TTR Amyloidosis

Orphan disease gold miner Genzyme has just partnered Alnylam’s promising TTR amyloidosis drug candidate, giving it the right to commercialize resulting medicines in Japan and ‘other Asia-Pacific countries’.  In addition to a healthy $22.5M upfront, Alnylam stands to receive the customary development milestones and actually high royalties for a post-phase I program, plus Genzyme bears responsibility for the regulatory process in the licensed territories.

The basis for this deal, as also expressly stated in the press release, were the potent, ~90% knockdown efficacies obtained in the (single) dose-ranging ALN-TTR02 phase I study (for review, see 'Simply SNALP').  Critically, it was Tekmira’s SNALP delivery technology that made these results possible and catapulted Alnylam’s market cap by ~300M (50% increase in share price) at the time the phase I results were announced this summer.  I should add, however, that in addition to ALN-TTR02, the preclinical subcutaneously administered candidate ALN-TTRsc has been included in the deal. 

Clearly, if they are really serious about the competitiveness of the subcutaneously administered GalNAc-siRNA conjugate, Genzyme has got to be hoping that there won’t be a repeat of the mipomersen (antisense) injection site reaction fiasco which, in addition to the liver fat and immune stimulation issues, is endangering the approval for mipomersen even in the very high unmet medical need population of homozygous familial hypercholesterolemia.  In this case, the adverse event that could drastically lower the deal value soon after its close comes in the form of the Tekmira litigation risk (note: Genzyme is ISIS' partner on mipomersen and should know, also about the strength of the competing subQ ISIS-TTRRx program which is partnered with GSK).  

In case you are wondering what I am alluding to: less than a month after Genzyme invested more than $300M in ISIS and their hypercholesterolemia candidate mipomersen, the FDA issued a Partial Clinical Hold due to significant safety signals with the systemic phosphorothioate oligonucleotide, according to last week’s Briefing Documents for the mipomersen Advisory Committee meeting.   The risk in the TTR case, of course, is the pending litigation with Tekmira, involving the critical RNAi delivery technology enabling the ALN-TTR02 results, its manufacturing and other (e.g. 2’-O-methyl) IP associated with the TTR amyloidosis program.  You would expect that Genzyme would have at least waited for another month or so before closing the deal (trial date in November).  

I doubt that the deal value would have been much higher without the overhang given the size of the Asian TTR market.  But then, of course, nothing can surprise me here any more and a resolution to the Alnylam-Tekmira troubles may already have been hammered out.  A clue may be how Tekmira responds to the news.  If there is tonight a we-are-pleased-that-Genzyme-has-partnered-ALN-TTR02-for-which-we-provide-the-delivery-technology-PR, then it's probably nothing to get excited about.  But if there is silence, then maybe the real news may come with a slight delay.  

Talking of Tekmira, this company, as it is customary in biotech sub-licensing, is likely to receive a partial payment out of the $22.5M upfront (plus a cut of the future income stream related to ALN-TTR02).  Another partnership implication is that Alnylam has talked to Takeda, and Takeda declined on ALN-TTR.  As you remember, in 2008 Takeda forked over $150M to Alnylam, also for being the exclusive Asian partner for 5 years with a right of first refusal for Alnylam drug candidates in the Asian territories.   You’ve got to wonder how comfortable that conversation was, especially after handing over some of that for the ‘technology transfer’.  There might be even less room to hide from Genzyme, as I believe Genzyme and Alnylam may be sharing one building now.

Simply SNALP: RNAi TTR Knockdown Data Impress

Clearly, RNAi Therapeutics is back in fashion.  Well, almost.

Alnylam’s announcement of profound gene knockdown in the ALN-TTR02 phase I study for the treatment of TTR amyloidosis was greeted with an over 50% jump in the stock price on very high volume.  Various observers pointed out that this might have been an over-reaction given the early nature of the data.  On the other hand, considering that the over 80% peak knockdowns achieved with only a single dose of 0.15mg/kg are representative of a widely applicable delivery strategy, namely Tekmira’s SNALP technology, and considering that an accelerated approval path  should be possible for this orphan disease, determining the fair value of a SNALP-based company like Alnylam becomes difficult.

Yes, this was a study that enrolled just 17 subjects, healthy volunteers at that.  But it may be this that makes the tight variability in the pharmacodynamic response (=TTR knockdown) even more remarkable so: less than 5% relative standard deviations in the 0.15mg/kg and 0.30 mg/kg 3-person dose cohorts, the relevant groups for this analysis.  

When I had mentally listed the technical risks of SNALP-mediated delivery several years ago when I did my fundamental research on SNALP delivery, intersubject knockdown variability was one of the major ones.  However, given the present results and those from the recent hypercholesterolemia study (ALN-PCS02), I am much less concerned about this now, also in patient groups where liver health may be affected.

Moreover, the dose-related TTR knockdown in humans was essentially what has been seen in non-human primates.  Although a number of analysts were apparently puzzled by the importance of this observation, its value to a scientist is obvious: you can essentially eliminate the risk that an SNALP program fails in phase I due to lack of knockdown efficacy (and if you are one of those scientists that also dabble in the stock markets, you can start investing in the stock based on the monkey data that you’ll see presented at an informal presentation).   

The safety profile with ALN-TTR02 in this study was good.  There was one infusion reaction seen in other SNALP studies before and that was managed by slowing the infusion rate.  This was said to be possibly related to the pre-treatment with corticosteroids, and not the liposomal formulation itself.  In any case, while corticosteroids and other transient immune suppressions will not be an issue for the initial patient populations in diseases like TTR amyloidosis, Tekmira and Alnylam should start to try and wean themselves of it.  The improved, more predictive immune stimulation assays may form a sound scientific basis for this.

The reason for why the study was limited to 17 healthy volunteers was mostly due to competitive concerns.  In particular, the ISIS/GSK TTR antisense compound is said to skip phase II studies altogether and go straight into a pivotal phase III.  In data presented in May of 2011, this antisense compound was reported to effect a 44% mean TTR reduction at the 200mg/week dose level when given for four weeks, and 81% knockdown at 400mg which was the next higher dose tested.  400mg/week, however, is a dose that I believe is too high for chronic phosphorothioate oligonucleotide administration.  Although ALN-TTR02 should thus be 100- to 200-fold more potent on a weight basis than the antisense drug candidate, being the first-to-market is seen by some as an important factor for the commercial success in this orphan market, especially since these compounds work by the same mechanism of action.

The value of SNALP delivery

Some readers of this blog may be tiring by now of reading me sing the praises of SNALP delivery technology and Tekmira.  Yes, I’m invested in the technology via my Tekmira shares.  In all fairness, however, it is the clinical data from the SNALP compounds, really starting last November with the ALN-TTR01 data (SNALP Works!) that are reviving the RNAi Therapeutics field: ALN-VSP, ALN-PCS, and ALN-TTR.  We have heard a lot about exciting new, revolutionary RNAi delivery technologies, often claiming to solve the putative problems with  SNALP technology.  However, in the end, it is SNALP that is set to unlock the first wave of RNAi Therapeutics value creation.

Even Arrowhead Research and Benitec which develop competing delivery and RNAi trigger technologies, respectively, admitted so much in congratulating Alnylam to the results.  Sadly, they missed the opportunity to also congratulate the real innovator behind SNALP technology, Tekmira.  It seems that since Alnylam is getting all the media attention, it was probably not a good PR strategy to do so.

RNAi delivery technologies are tough to develop and rare to find, but when they work, they open up a range of therapeutic opportunities.   

Preview: For my next post, I am planning to write something about last week’s MC3 paper and how it reveals that covering all the tracks is hopeless when a scheme is that elaborate (RE Tekmira-Alnylam litigation), and why Alnylam the stock may be a great short here.