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.

Ionis Pays to License TTR Drug

When it comes to reaping the financial benefits of its efforts, Ionis ranks at the bottom of the industry and last week provided a new low point in this ongoing saga.

Licensing drugs for commercialization purposes is normal in the biotech space, especially when a smaller company lacks the resources to do so.  In return, the licensor typically receives an upfront fee and other milestones in addition to a royalty on sales.

Ionis Pharmaceuticals has just broken with this sacred tradition.  In fact, it ended up giving $200M to Akcea Therapeutics for it to market TTR amyloidosis antisense drug candidate Inotersen for which regulatory approvals are expected this summer.  The two companies will share the profit/loss from the upcoming commercialization of Inotersen and the GalNAc-conjugated follow-on compound in early-stage development.

To put it in simple terms, Ionis is transferring billions of (stock) market value (à Alnylam’s ~$15 billions market cap largely rests on its TTR franchise) to Akcea in return for Akcea's recently established sales infrastructure for which it might have spent $50M.  As I’ve been saying all along: building commercialization capabilities does not involve magic and for orphan drugs certainly don’t require Big Pharma footprints.  All it requires is the will to just do it.

Unfortunately, Stan and his longtime followers at Ionis only feel comfortable playing in their early-stage sandbox and don't seem to really care about creating shareholder value.

No other takers?

  

Stating that they have just transferred billions of stock market value may also be partly wishful thinking. 

Last August, when GSK declined to license Inotersen, Ionis said that pharmaceutical companies had instantaneously started to line up to license the drug.  Then after nothing happened in the coming months, Ionis changed to wanting to keep the US to themselves and licensing rest of world.

And now this: it is ‘licensing’ the drug to its own spin-off company to which it already controlled more than 2/3 of the shares in addition to important veto powers regarding Akcea’s corporate development.

Ionis says that they were forced to give the nod to Akcea because the drugs were racing towards approval and other companies wouldn’t have been able to ready Inotersen for commercialization in time.  This, of course, doesn’t make any sense since why was Akcea more ready to do so?  Couldn’t Ionis have sent its TTR commercial team which it is transferring now to Akcea to just about any other company as well?   

Clearly, nobody was substantially interested in Inotersen and my guess is that this is not due to Alnylam’s Patisiran believed to have much better commercial prospects than Inotersen.  Instead, it is Alnylam's RNAi GalNAc compound which greatly limits the absolute value of both Patisiran and Inotersen as it looks like a vastly superior TTR knockdown drug (~quarterly subcutaneous dosing, much greater knockdown) and may be approved within the next 2 years already, much earlier than Ionis' GalNAc follow-on.  

  

RNAi Drug Trounces Antisense Rival in Paris ATTR Showdown

The audience gasped when Alnylam finally revealed the full dataset from the APOLLO trial in ATTR amyloidosis.  For the first time, patients and docs will have access to a drug that not only delays or just barely halts, but starts to actually reverse disease manifestation in a majority of patients afflicted by this debilitating, multi-systemic disease. 

Efficacy: reversal versus slow progression

A few minutes before the Patisiran RNAi data presentation, Dr. Benson, the lead investigator from the corresponding NEURO-TTR with rival antisense drug Inotersen was not met with nearly as much awe.  Yes, Inotersen did delay disease progression and was quite a bit better than the placebo control.  However, unlike Patisiran (-6 at 18 months), the mean change from baseline in the critical mNIS+7 score was well in positive territory (+5 at 15 months) indicating disease progression.

As such, Inotersen does not appear to be much better than TTR tetramer stabilizer diflusinal (given off-label in the US) which registered a +9.2 score in a trial over 24 months compared to +29.6 in the control.

Patisiran similarly came out ahead in the quality of life (QoL) assessment (improvement versus in this case a halt for Inotersen), although this was not a primary endpoint in the APOLLO trial. 

The NEURO-TTR trial could score some brownie points here as it not only made QoL a co-primary endpoint, it also scored positively in another patient-reported health score, SF-36.  Although investigators seem to prefer ‘hard’ outcomes measures such as the mNIS+7 and biomarkers, regulators and payors seem to prefer QoL endpoints according to comments at the meeting.

That the efficacy was better for Patisiran should probably not have surprised too much given that its knockdown was slightly better (82% mean median in APOLLO) than that of Inotersen (according to Benson: 75-79%, although I am a bit skeptical here as I do not understand what this range means).

As a side note and although everybody likes to see Patisiran versus Inotersen as an either-or issue, if you combined them both, you would easily exceed the 90% amyloid source protein reductions that amyloid researchers believe is necessary to allow tissue clearance exceed fresh amyloid deposition.

Safety: Patisiran once again exceeds, Inotersen disappoints expectations

If you still had difficulty deciding whether to take a drug that likely makes you better or a drug on which you will likely progress, the relative safety profiles should remove any remaining doubt.  Contrary to suggestions by the ‘counter-detailers’ at Ionis, Alnylam could not find any evidence that the steroid treatments to prevent untoward reactions around the time of infusion had any measurable adverse impact on patient health. 

Maybe this should not come as a surprise either given that immune suppression is given only transiently, every 3 weeks.  To make it clear, none of the many cardiologists in the audience voiced any concerns throughout the two days of the conference (where Patisiran was the star) about steroids in patients with cardiac disease manifestations.

If anything, the Patisiran group suffered from less adverse events compared to the placebo group, probably the result of addressing the disease.

The same, namely exceeding expectations, could unfortunately not be said for Inotersen: in addition to the previously disclosed renal and platelet SAEs, there was a 5:0 death imbalance against the drug candidate.  While the drug-related thrombocytopenia case had already been known and the 4 other deaths were attributed to disease progression, one cannot but notice that strangely, when it comes to safety, all the disease-related, random events always end up going against the Ionis drugs. What a coincidence!  And given that Ionis partner GSK had abandoned Inotersen even before the APOLLO trial were announced, I am wondering what other safety findings (in addition to thrombocytopenia, renal AEs, pyrexia, chills, and nausea) will come to light with the FDA briefing documents next year.

Take-home

Alnylam and the RNAi field could not have hoped for better outcomes from the high-profile APOLLO trial.  If anything, the full results presented at this first European combined patient-doc ATTR conference are more impressive than first indicated by the topline data a month ago.

And regarding the competitive profile compared to the antisense rival, it makes me wonder about the magic of feeding into a biological mechanism that has evolved to do just that: gene silencing.

There are still some questions around the label that these data will support.  Importantly, how much credit will be given to the positive cardiac outcomes since these were not the primary focus of the studies?  But since this is a multi-systemic disease and given the totality of the data, a number of doc presenters made it clear that they will be looking hard for polyneuropathy manifestations in ATTR patients to justify (to payors) treating them with the new agents.

Disclosure: I am short ALNY since the stock may be gasping for air up here, at least in the short-term; long IONS since this public humiliation by the fiercest rival may make them realize that in the orphan drug age, commercialization is a must.

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…

RNAi Therapeutics Become Real

It’s been a long ride.

The lives of quite a few of us has been consumed now for close to two decades dreaming about a world in which RNAi Therapeutics have real-world clinical impact.  Yesterday, that dream has officially materialized.

TTR knockdown improves disease state

With the conclusion of the most comprehensive clinical study conducted to date in the severe orphan disease ATTR amyloidosis, Alnylam and investigators have found that prolonged knockdown of the causative transthyretin (TTR) gene improved both objective (mNIS+7) and subjective (quality of life) measures of the main manifestation of the disease, peripheral neuropathy.

There is no doubt that this was the result of on-target TTR gene knockdown since this was a strictly controlled study in which the only difference to the placebo group was the administration of the RNAi formulation.  Furthermore, results from a similar study for this indication (NEURO-TTR) by Ionis earlier this year in which related RNaseH antisense oligonucleotide technology was utilized for TTR knockdown also demonstrated disease benefit, albeit a ‘mere’ halt of neuropathy progression in QoL as opposed to the improvement seen here (note: mNIS+7 was reported only with regard to placebo, not versus baseline).

Importantly, this extra benefit is likely explained by the fact  that the Patisiran RNAi formulation had been shown to be slightly more potent than antisense drug candidate Inotersen in earlier-stage studies (here and here).  While considering a ~80-85% vs ~70-75% knockdown may not seem much at first glance, protein deposition, clearance and in particular misfolding that is at the root of the disease are higher-order concentration-dependent processes (think about crystallization) so a difference of ~17.5% vs ~27.5% (>50% more remaining than with Patisiran) remaining insulting protein may well be highly meaningful. 

Of note, phase II data from Patisiran have demonstrated that the ~80-85% knockdown was able to somewhat tilt the tables in favor of TTR tissue clearance, but also that it was not able to fully do so.

It is therefore of utmost importance to push forward with the development of the even more potent GalNAc-enabled RNAi candidate ALN-TTRsc02.  Preliminary phase I data from that candidate suggest that it should be able to reduce TTR levels to 5% or less with subcutaneous dosing as infrequently as every 3-6 months (Patisiran: intravenous every 3 weeks; Inotersen: weekly).

Why this is such a big deal for RNAi Therapeutics

As I had indicated in last week’s post, the phase III APOLLO results represented a make-or-break moment for RNAi Therapeutics.  If it turned out that RNAi- and delivery-related side effects were to outweigh the benefits of gene knockdown at the conclusion of this decade-long, high-visibility program, the financial markets would have reacted violently and starved the industry of the cash necessary to more fully develop the technology (Alnylam with its cash reserves at least would have mounted a comeback eventually).

If it’s one thing I’ve learned about biotech money matters over the last 15 years of riding the RNAi rollercoaster, it is that the perception of a technology is as important for its continued development as its intrinsic technological validity.

Personally, I am most relieved in that the small, but often pervasive transcriptomic off-target changes introduced by an RNAi trigger (à microRNA-type off-targeting) did not have an apparent detrimental effect on the target organ (here: liver) after prolonged, 18-months treatment.  This should not be entirely surprising based on what we’ve learned about microRNA biology- not all targets of a microRNA are biologically relevant- but is still a great relief to see play out in practice.

To wit, the RNAi industry has been overly focused on potency when selecting RNAi trigger sequences for clinical development and mostly relied on bioinformatics for specificity. Indeed, Alnylam has paid the price for this negligence in that certain RNAi triggers, such as the one for its original alpha-1-antitrypsin program, have caused liver tox most likely due to microRNA-type off-targeting.  It is therefore finally employing chemical strategies such as the incorporation of modified nucleotides in the seed region of the trigger to bias the RNAi apparatus towards RNAi cleavage instead of microRNA-type message destabilization. 

This strategy was first reported by Rosetta Inpharmatics (now Merck) and had then been developed further in the commercial realm by Marina Biotech which then licensed the IP to Roche (then acquired by Arrowhead) and possibly others. 

It will be some time until we have complete certainty that microRNA-type off-targeting won’t rear its ugly head again, but the odds should be getting better and better with the employment of best practices. More generally, Patisiran is only the beginning of a long string of real-world impactful RNAi Therapeutics.