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.

Pfizer Study Clears Way for Broad Cardiomyopathy Label of TTR-lowering Drugs

TTR amyloidosis represents a major market opportunity for RNAi Therapeutics.  The pivotal trials underlying the expected approvals of Patisiran from Alnylam and antisense rival Inotersen from Ionis/Akcea were focused on the neuropathy aspect in the inherited form of the disease.  It is hoped, however, that approvals will be obtained that will also cover the cardiomyopathy spectrum of the disease. 

Nevertheless, the absence of a prospective study focused on cardiomyopathy raises the concern that the largely biomarker-related and post-hoc analyses conducted by Alnylam and Ionis/Akcea will not hold up when hard endpoints like mortality are considered.  This uncertainty could lead to resistance by payors to cover the drugs for cardiomyopathy uses.

Data released last week from Pfizer’s ATTR-ACT study should greatly aid in addressing this concern, paving the way for broad product labels and reimbursements not only for the familial form of TTR cardiomyopathy, but even to encompass those with wild-type TTR cardiomyopathy.

Evolving disease understanding

TTR amyloidosis is caused by the deposition and accumulation of misfolded tranthyretin protein in various tissues thereby poisoning them.  Historically, TTR amyloidosis was not considered a single disease, but either TTR neuropathy or TTR cardiomyopathy depending on where disease symptoms are most pronounced.

Over the last 5-10 years, however, it has become recognized that a given patient may suffer from a range of symptoms across organ systems.  Whether an individual patient suffers from largely neuropathic or cardiac symptoms or both to similar degrees is typically informed, but not entirely explained by the underlying mutation in the familial forms of the disease.

Cardiac symptoms can also be caused by wild-type TTR protein alone.  This is referred to as senile systemic amyloidosis (SSA).  This population has not been the subject of any rigorous, randomized trial in the development programs of TTR-lowering drugs, but based on my impressions from last November’s seminal Paris meeting on the disease, there is great anxiety in this particular patient community about access to TTR-lowering drugs.  

Tafamidis as an underappreciated TTR trailblazer

Pfizer, through its 2010 acquisition of Tafamidis, was the original trailblazer in this orphan disease.  Tafamidis falls in the class of (small molecule) TTR tetramer stabilizers (along with widely used off-label generic diflusinal) which prevent TTR tetramers to fall apart in the rate-limiting step to forming misfolded pathogenic TTR aggregates.

As is often the case in orphan disease drug development, being the first means that you have to do a lot of the heavy-lifting in terms of understanding the natural history of the disease to design adequately powered clinical trials with the appropriate endpoints.  Consequently, the first pivotal trial of Tafamidis in V30M early-stage neuropathy patients fell short of garnering FDA approval and only got a narrow label from European regulators. 

The problem was that, although the data strongly suggested efficacy, it turned out to be an underpowered study due to unexpectedly high drop-outs for patients undergoing liver transplants: starting from 125 intent-to-treat (ITT) patients, the efficacy evaluable (EE) number dropped to just 87 in this placebo-controlled study.  

Nevertheless, if you disregarded the liver transplant patients in the statistics (very reasonable in my opinion since a liver transplant throws everything off), the study would have met the quality of life and NIS-LL co-primary endpoints by greatly halting, although not stopping disease progression.  In addition, all key secondary endpoints were positive.

Given the improved understanding of TTR amyloidosis and a much more forgiving regulatory environment, this study, despite its limitations, would have ensured FDA approval today.       

Tafamidis succeeds in cardiomyopathy study

Last week's announcement by Pfizer represents another breakthrough for those living with TTR amyloidosis.  Its phase III ATTR-ACT trial in patients with pronounced cardiac symptoms, including those with wild-type TTR SSA with largely cardiac symptoms, has met the co-primary endpoints of reducing overall mortality (!) and cardiovascular-related hospitalizations.

Having learned their lesson, Pfizer went out of its way to make sure that this study would show a positive signal if the drug were active: instead of 18 months, 30; instead of 125 patients, 441; and instead of just one daily 20mg dose of tafamidis also 80mg.  Talk about not taking any chances!

Tetramer stabilizer and TTR lowering results mutually beneficial

When Pfizer announced late last trading week the ATTR-ACT results, the sponsors behind the TTR lowering RNAi and antisense drugs Alnylam, Akcea, and Ionis took it on the chin with 5-13% sell-offs in their stocks due to competitive concerns.

The main concern apparently is that while Tafamidis has now succeeded in a trial specifically targeted at the cardiomyopathy ‘population’, the APOLLO study of Patisiran and NEURO-TTR study of Inotersen have not specified this aspect as a primary endpoint.

This concern is lessened, however, due to the recognition of TTR amyloidosis as a single disease with the relative degree of various symptoms varying between patients.  Of course, let’s be frank and admit that this is also a self-serving agenda that has been mainly promoted by Alnylam so as to increase the market size of Patirisan without having to wait for another 3-4 years. 

On the other hand, since the root cause of the various manifestations is the same, TTR aggregation and tissue accumulation, a drug that works in addressing it should be beneficial for all these manifestations.  In fact, strong evidence on improved cardiac outcomes has come from the APOLLO and NEURO-TTR study as well as an open-label investigator-instigated study of Inotersen specifically in the cardiomyopathy indication (both mutant and wild-type forms; ‘Benson study’).

Similarly, since the mechanism of action of TTR stabilizers and TTR-lowering drugs are essentially the same, lowering the pool of aggregation-prone TTR, success in ATTR-ACT is highly supportive of the cardiac benefits of Patisiran and Inotersen as much as APOLLO and NEURO-TTR strengthen the case for Tafamidis use in addressing TTR-related neuropathy. 

All this mutually reinforcing data should ultimately help in Inotersen and Patisiran getting a very broad label and helping with reimbursement, perhaps even in the SSA indication which I believe the market could not have priced in yet.  Having said this, we have yet to see the SSA vs hereditary subgroup analysis from the Pfizer study.

Relative drug efficacy

Finally, in terms of drug efficacy, Tafamidis is unlikely to challenge Patisiran even in the cardiomyopathy indication, since Patisiran improved outcomes in the APOLLO study while Tafamidis stabilized or merely delayed disease progression.  

The efficacy of Inotersen based on Quality of Life data should end up being somewhat ahead of Tafamidis (QOL in EE population vs placebo of -9 for Tafamidis in the neuropathy study vs -12 for Inotersen in NEURO-TTR and -20 for Patisiran in APOLLO), although its safety profile appears to lag that of Tafamidis.  Because of the new data indicating efficacy similar to diflusinal, but with better safety, Tafamidis ought to replace generic diflusinal which has dominated the tetramer stabilizer market until now.  

Ultimately, if patient welfare was a top concern, TTR stabilizers probably ought to be used on top of TTR-lowering drugs to prevent any TTR protein that survived TTR knockdown from misfolding.

The Wait is Finally Over

For some time now, I’ve been fascinated by how the RNAi Therapeutics sentiment cycle has been progressing in 3-year intervals.  Before I left off for my baby-break, I referred to 2014-17 as The Wait. The Wait was a reference to the ‘market’ having been convinced by early clinical data that RNAi can bring about deep and sustained gene knockdowns in WoMan, but that the ultimate clinical utility and subsequent commercial value remained to be proven.

We are now on the cusp of finding out with results from the registrational phase III study of the TTR-lowering Patisiran in familial amyloidotic polyneuropathy (FAP) imminent.

The wind is clearly in RNAi’s back with supporting developments in the related oligonucleotide therapeutics and, indeed, drug regulatory spaces.  In particular, the successful commercial launches of splice modulators EXONDYS51 (for Duchenne muscular dystrophy) and SPINRAZA (for spinal muscular atrophy) and promising phase III data from the triglyceride-lowering Volanesorsen (gene target: ApoCIII) should have removed the long-held doubt that oligonucleotides can be clinical practice-changing and profitable drugs.  And boy, are EXONDYS51 and SPINRAZA changing the clinical practice of two devastating, previously orphan diseases!

Equally important, drug regulation is strongly moving infavor of patient choice and access.  As a result, we are going to see many more drug candidates benefiting from accelerated approval pathways similar to EXONDYS51.  A number of RNAi Therapeutics programs such as Givosiran by Alnylam (àmetabolite ALA lowering as reasonably predictive endpoint) and DCR-PHXC by Dicerna (àoxalate lowering) are poised to benefit from this development.

But let’s not get ahead of ourselves and await the Patisiran APOLLO study outcome for which sponsor Alnylam has guided a ‘late September/summer’ read-out.  Drug development is full of surprises, so despite all the data* pointing towards a positive outcome, a number of variables (e.g. steroid use, lipid nanoparticle delivery) remain unknown in how they impact overall outcomes.  I for one will breathe a big sigh of relief should Patisiran be able to overcome this Make-or-Break event for RNAi Therapeutics.

 *

à positive open-label extension data from phase II Patisiran;

à positive phase III data from IONS-TTRRx targeting same gene and indication;

à the high roll-over rate into the open-label extension) indicating a positive outcome