RNAi Therapeutics Now a Commercial Reality

Last Friday, Alnylam received notification from the US Food and Drug Administration (FDA) that ONPATTRO (aka Patisiran) has been approved for the treatment of hATTR-related polyneuropathy.  This marks the culmination of an almost picture-book translation of a brand-new biotechnology into therapeutic reality.  20 years from worms to patients is nothing.

ONPATTRO development path

Much has been made in the press about the great uncertainty, reflected in supposedly unusually long timelines, of whether RNAi can be a therapeutic modality at all.  Of course, the challenges of delivering RNAi triggers in WoMan, staving off unwanted innate immune responses, and the question of how the transcriptional noise stemming from slightly modulating dozens of unrelated targets will affect safety were all daunting at the beginning.

But looking back, with the exception of a 2-3 year delay due to having to change from an insufficiently potent LNP chemistry to the MC3 lipid-based LNP underlying ONPATTRO and having to institute steroid pretreatment to minimize ‘infusion reactions’, all these challenges more or less dissolved in the development path of ONPATTRO.

A special shout-out here to Ian MacLachlan and his team at formerly Tekmira for solving the critical delivery challenge first.

A best-case scenario would therefore have seen an approval in 2015-6.  2018 is therefore not that bad at all.  Here a quick run-down of the milestones leading up to the approval:

1998: discovery of double-strand RNAs (dsRNAs) being the trigger for RNAi in worms

2001: finding that RNAi can be triggered in WoMan by short dsRNAs

2002: first demonstration of RNAi in mice

2005: first therapeutically relevant demonstration of RNAi in monkeys

2009: initiation of first clinical trial of first-generation LNP-RNA (SNALP-ApoB, aka PRO-040201; ALN-VSP02)

2012: start of ONPATTRO clinical development

2012: first solid clinical proof-of-concept for RNAi in WoMan from ONPATTRO phase I study

2012: start of ONPATTRO phase II study

2013: start of ONPATTRO phase III study (APOLLO)

2017: positive data read-out from APOLLO

2018: EU and US marketing approvals for ONPATTRO  

ONPATTRO is just the beginning

Since ONPATTRO had been conceived starting about a decade ago, there has been, of course, considerable progress in RNAi trigger design (safety, efficacy) and (conjugate) delivery technologies.  As a result, a slew of other RNAi drug candidates by Alnylam, including Givosiran for Acute Intermittent Porphyria (likely 2019 approval), Inclisiran for cardiovascular disease (likely 2020 approval), and Lumasiran for primary hyperoxaluria (likely 2020 approval), are about to be approved.  Especially with the adoption of off-target-minimizing chemical modifications, I am confident that the success rate of RNAi drug candidates for tissue types for which delivery is robust will only increase.

After the liver, for which the current crop of marketing candidates is the target organ, the CNS should be the next huge opportunity as Alnylam gears up to bring a first candidate into that organ over the next year.  In addition, Arrowhead Pharmaceuticals and Alnylam have also started to talk about opportunities in the lung and cancer, although here I am still hesitant about whether these are near-term clinical opportunities or something that will have to wait another 3 years or so.

RNAi shatters antisense competition

As the world is abuzz about the first full-blown marketing approval of an RNAi Therapeutic (note: formal marketing authorization in the EU is still pending), I would be remiss not to display a key graph illustrating the power of RNAi gene silencing versus competing approaches such as gene silencing by mass action RNaseH antisense (TEGSEDI by Akcea Therapeutics) and trying to keep bad proteins from acting out with small molecules (generic tetramer stabilizer diflusinal):  

If you were diagnosed with TTR amyloidosis and had an average life-expectancy of 2-5 years, which treatment would you like to be on?

Stock market reaction

When Alnylam opens for trading today, it will likely be down due to disappointment that the FDA label, unlike the anticipated case in the EU, will only specify TTR-related polyneuropathy for which the APOLLO study had been designed, and not cardiomyopathy with none of the exploratory cardiomyopathy data from APOLLO included.  While this is somewhat disappointing in light of biomarker-based accelerated approvals of Eteplirsen in DMD where target modulation and therapeutic hypothesis were enough to win the day, this should only be a minor hiccup in the overall history of RNAi Therapeutic.  In light of the recent Pfizer small molecule Tafamidis cardiomyopathy data, it is very likely that RNAi trials will show a benefit for cardiomyopathy symptoms as well in a dedicated study (à ALN-TTRsc02). 

Until then, it is possible that the cardiomyopathy data are being withheld until Alnylam and the FDA can come up with a way to include those in an amendment, or as part of an accelerated approval submission.  It is also likely that TTR patients will now more readily be referred from cardiologists to neurologist for an intense neuro check-up such that primary cardiomyopathy patients can access ONPATTRO (and get paid for it) at the slightest signs of polyneuropathy.

Alnylam Slams Dicerna with Trade Secret Complaint

How times have changed.  Four years ago, Alnylam found itself on the receiving end of a trade secret lawsuit regarding the delivery technology du jour, SNALP LNP then, in which it ended up paying near-bankrupt Tekmira ~$70M to settle the allegations.  As I opined back then, Alnylam seemingly used almost any means to get access to the know-how to make SNALP LNP delivery work in primates in an effort to rid itself of the reliance on Tekmira, the inventors.

At that time, all Alnylam's CEO had to say on the topic of honoring trade secrets: 'you pay for it, you own it'.

Tonight, Alnylam claims to be the victim of similar trade secret misappropriations surrounding RNAi delivery technology.  In this case, Alnylam alleges (see Complaint) that Dicerna had hired ex-Merck RNAi scientists to gain access to critical GalNAc trade secrets invented at Merck after Merck sold their RNAi assets to Alnylam and laid off related employees.

An interesting aside of this is that it appears, contrary to representations by Alnylam, that the GalNAc-ESC technology were invented at Merck, not in-house at Alnylam.

The Complaint makes it clear that Alnylam feels threatened by the technologically very direct competition.  In a way, Dicerna’s new strategy was to become Alnylam's clone.  What could be worse, given the differences in the RNAi trigger lengths (~19bp Tuschl-type siRNAs by Alnylam; 25/27 and longer Dicer-substrate versions by Dicerna) and the apparent importance of stability/degradation in GalNAc technology, there is the distinct possibility that Dicerna’s version, everything else being equal, would outperform (or underperform) Alnylam’s.

In light of recent apparently rapid progress at Dicerna on GalNAc technology and the timing of events, the idea that Dicerna may have benefited from the GalNAc know-how of ex-Merck scientists does not seem far-fetched.  

It is unclear to me, however, whether you can expect expert oligonucleotide chemists to suddenly forget everything about their former job. 

Alnylam obviously takes care of that problem by enforcing harsh non-compete and pay-for-silence practices against their former employees, meaning that if you are an RNAi scientist that job at Alnylam will be your last RNAi job in the industry, period. 

Looking forward, I predict that the outcome of the case will hinge less on the physical documents that were alleged to have been ‘misappropriated’, but on whether or not the ex-Merck scientists could have re-invented GalNAc-ESC based on their skills and publicly available information (including from Alnylam) at the time.  If so, then Alnylam only has Merck to blame that it does not force their employees to leave their profession when they lay them off.

Regardless, the GalNAc-ESC genie is out of the bottle.

First RNAi Therapeutic Nearing Finish Line

ALN-TTR02 for the treatment of TTR amyloidosis is the most advanced RNAi Therapeutic in clinical development and has been carrying the torch for the field as whole. Expectations are therefore high and a stumble in this program as a result of the therapeutic hypothesis underlying the program not panning out would likely trigger a temporary*, but steep sector-wide sell-off.  

* it should be clear, however, that with the current ability to robustly knock down genes in the liver, RNAi Therapeutics will result in a number of successful treatments.

It therefore came as a relief yesterday when Alnylam presented (press release here, data slides here) 12-month data from an open-label extension phase II study of ALN-TTR02 in the polyneuropathy form of the disease (FAP) showing

a)      continued robust gene knockdowns for more than a year (88-80% reductions peak/trough in 3-week cycle);

b)      disease stabilization (if not improvement) when the Natural History of the disease would have predicted marked deterioration (predicted mNIS+7 at 12 months of +18 in Natural History vs ~-2.5 on ALN-TTR02).

Furthermore, the safety of this liposomal formulation enabled by Tekmira seemed more than sufficient for a disease as severe as FAP TTR amyloidosis (5-15 year survival following diagnosis) with the most significant adverse events being related to the intravenous route of administration meaning that ALN-TTR02 should be given under trained medical surveillance.

There are some questions that remain open, some of which should be answered by the ongoing phase III APOLLO study which should complete sometime in 2016 (with an 18 month primary endpoint).

Firstly, it will be important to show disease stabilization to be strictly related to ALN-TTR02.  In the phase II study, most patients (20 of 27) were on tetramer stabilizers which have previously shown to result in very modest (tafamidis) to moderate (diflusinal) therapeutic benefits.  While neither tafamidis nor diflusinal have shown disease stabilization after 12 months, the concern remains that they could have contributed to the apparent therapeutic benefit seen in the phase II study.

To my surprise, the 7 patients not taking tetramer stabilizers on top of ALN-TTR02 seemed to do even better, at least numerically than those taking them (-6.5+/-9.2 vs -1.1+/2.5).  Although the number was quite small, the fact that this is the opposite result from what one might have expected, it is possible that a slight placebo effect may have played a role in this open-label study: those for which ALN-TTR02 was the only medical intervention might have had a greater ALN-TTR02-driven placebo effect.

Other more complicated explanations based on TTR lowering affecting the PK/PD relationship of tetramer stabilizers are also possible if this phenomenon is for real.

Fortunately, the blinded phase III APOLLO study will compare ALN-TTR02 to patients taking no tetramer stabilizers to treat their FAP.  Finally, it would be of interest to look at the effect of ALN-TTR02 on the spleen in the APOLLO study as spleen toxicity due to lipid stability might be the most important safety parameter with chronic dosing.    

In summary, yesterday’s 12-month data removed important overhangs over the RNAi sector and we are on track for the first commercial RNAi drug in 2017. Seeing is believing.

RNA Therapeutics Are Back in the Cardiometabolic Game

In the mid- to late 2000s, in the wake of Vioxx, I remember sounding the alarm bell on developing RNAi Therapeutics for cardiometabolic indications.  The FDA would simply refuse to approve cardiometabolic drugs even when strong data on widely accepted biomarkers such as blood glucose in diabetes and LDL-cholesterol levels in cardiovascular disease suggested that they should be efficacious.  Instead, the agency was demanding ridiculously expensive outcome trials for even the most underserved patient population, making cardiometabolic drug development difficult to justify financially.

Regulatory and technology changes

10 years later, the situation has changed dramatically due to a confluence of regulatory and technology changes.  In the regulatory arena, the staged approval process which involves a fast-to-market strategy for high unmet need orphan populations based on surrogate markers followed by the roll-out in larger patient populations, partly supported by the clinical experience gathered from the orphan indications, has been successful at rekindling interest in cardiometabolic drug innovation in general.

In terms of technology, both RNAi and antisense technologies have matured to a point that the risk:reward proposition looks highly promising not only for the most severe patient populations, but suitable for even the more general population.  The Old is exemplified by gen 2.0 RNaseH antisense oligonucleotide mipomersen for which it will be very difficult to break into markets beyond the ultra-orphan homozygous familial hypercholesterolemia one due to its weak drug activity and considerable side effects. 

In RNAi Therapeutics, the Old was represented by the need for intravenous administration with the former gold standard in RNAi delivery, 1^st and 2^nd generation SNALP liposomal nanoparticles (LNP), and their confounding effect on lipid metabolism (see the need for various normalizations in the phase I results of ALN-PCS02).  

Today, however, we not only have improved SNALP LNPs and 2^nd generation RNaseH antisense (2.2), but more importantly GalNAc-targeted RNAi and antisense technologies by Arrowhead Research, ISIS Pharmaceuticals, Regulus Therapeutics, and Alnylam.  Importantly, due to their highly specific targeting of hepatocytes in the liver, the therapeutic window has been widened considerably.  In addition, the surprisingly long duration of target engagement makes monthly, if not quarterly dosing conceivable, therefore not only erasing, but surpassing oral small molecules in terms of patient convenience.  And we have not even considered the superior therapeutic utility that they promise by their ability to go after all conceivable targets- individually or in combination.  This, after all, is what we all should care about most.

The attraction of cardiometabolic applications is also reflected by the recent establishments of related franchises by Alnylam (cardiometabolic STAr) and ISIS Pharmaceuticals (Akcea lipid commercial subsidiary), with development programs targeting ApoCIII (ISIS Pharmaceuticals), PCSK9 (Alnylam/The Medicines Company), Lp little a (ISIS Pharmaceuticals), and ANGPTL3 (ISIS/Alnylam) looking already very favorable.  In addition, ISIS Pharmaceuticals sports a couple of interesting diabetes-focused programs (targets: PTB, GCGR, GCCR) which are showing novel therapeutic/safety profiles that could be suitable for specific sub-populations in the enormous, but equally complex diabetes market (e.g. insuling sensitization, reduction of glucose production).

Competitive outlook

    

As ISIS Pharmaceuticals and Alnylam compete for some of the same targets, the most common pattern you will likely see is that ISIS has a first-mover advantage (à IP and experience) with non-GalNAc generation 2.2 candidates due to their formerly somewhat fool-hardy, but now genius-looking pursuit of the cardiometabolic area.  When there is direct competition, the gen2.2-based drugs will likely be outcompeted by Alnylam’s GalNAc-siRNA conjugates due to their a) longer duration of action, and b) their possibly superior safety profile.

However,  as ISIS Pharmaceuticals is giving their cardiometabolic franchise a GalNAc overhaul, the company will also likely have the once monthly dosing frequency and a safer alternative turning it into a head-to-head race between Alnylam and ISIS Pharmaceuticals with winners that could differ from target to target.  Long-term, ISIS Pharmaceuticals may another ace in the competitive race as the single-stranded phosphorothioate oligonucleotide approach currently seems more amenable to oral dosing than double-stranded RNAi approaches.

   

While Tekmira’s SNALP LNP technology may be competitive when it comes to multiplexing targets, it is Arrowhead Research that is best positioned to surpass both Alnylam and ISIS Pharmaceuticals should they succeed in progressing their single-molecule subQ DPC technology into the clinic as indicated in last quarter’s conference call.  The endosomal release chemistry gives it a potency, and potentially also dosing frequency advantage over Alnylam’s simpler GalNAcs. 

Expect the CEO of Alnylam to increasingly attack the Arrowhead competition by raising safety concerns as he did in the recent RBC Healthcare conference presentation. I find this remarkable given that Arrowhead Research has not released the full safety data from its phase I study of ARC520.  But if you don't think you can win on potency, it may be best to sow seeds of safety doubt based on innuendo.

  

So watch this space. Next up are results from ISIS-GCCRRx (diabetes) and ISIS-ANGPTL3Rx (lipid disorders), clinical results from which are imminent.  Head-turning ALN-PCSsc results could be out in Q3. 

Tekmira Merges to Create HBV Powerhouse as ex-Pharmasset Geniuses Seek an Encore

Last night, Tekmira startled the RNA Therapeutics world by announcing that they would combine with OnCore Biopharma in a merger-of-equals to create the HBV drug development powerhouse.  With eight investigational HBV assets in the pipeline, this model follows the HCV space where combination therapies and companies with a single-minded focus on HCV were able to create tremendous shareholder and patient value.

Most often cited here is Pharmasset which gave Gilead HCV wonderdrug Sovaldi for an at the time (2011) unprecedented $11B.  Of note, OnCore Biopharma was founded by ex-Pharmasset people, including the inventor of Sovaldi.

This also makes it clear that despite paying lip service to the combined Tekmira to continue to value their other liposomal RNA Therapeutics assets ex TKM-HBV1/2, it is a good guess that the RNA Therapeutics platform will not have a long life in the merged company.  This is also because with $100M in cash, the company will have to look for ways to raise capital, some of it in a non-dilutive manner.

Combination and speed

Before the merger, OnCore had already started sweeping up a number of HBV-related assets intended to tackle chronic HBV infections at multiple stages: 1) replication and gene expression; 2) promoting, by stimulating and de-repressing, an immune response against the virus; and 3) even removing cccDNA, thus aiming not only at an already extremely valuable ‘functional cure’, but complete cure.

It is likely that only a multi-pronged approach will be able to achieve that.  The two RNAi candidates by Tekmira which have just entered the clinic are expected to form the cornerstone of that since they target ALL the viral genes.  Moreover, in the challenging chimeric mouse model, TKM-HBV1/2 had an unexpected impact on cccDNA abundance. 

The fact that TKM-HBV is administered intravenously is acceptable for this disease as long as a (functional) cure is achieved after a finite treatment period which, of course, is the goal. By contrast, the other assets contributed by OnCore are largely, if not all oral, including agents designed to inhibit immunosuppressant HBsAg secretion. 

Unlike TKM-HBV, these are at the pre-clinical stage, at least regarding their use for chronic HBV (the TLR9 agonist has already been tested in humans for non-HBV applications).  It is expected that many of them will enter the clinic this or next year. 

Regarding clinical development, the initial goal is to establish the safety of these agents individually before combining members from the three different classes pairwise and in triplicate in phase II.

The fact that all modalities are now under one roof will also greatly accelerate development timelines as, again in analogy to the HCV experience, it would otherwise have made necessary protracted partnering negotiations, sometimes with direct competitors.

Merger a good deal for Tekmira shareholders

Although I bemoan the loss of Tekmira as an RNA Therapeutics platform company, creating the strongest drug developer in the hot HBV space is the more attractive alternative also given the importance of TKM-HBV to Tekmira even before the merger. 

Accordingly, it is more likely that this setup will yield Pharmasset-type returns (say 10x in 3 years), e.g. following an acquisition after showing >40% cure rates in phase IIb, compared to a more balanced RNA Therapeutics platform play which has faced considerable competition from increasingly potent and more convenient technologies. 

Congrats to Tekmira management and Directors. The seeming investor relations breakdown recently has now been explained. Well played!

Tekmira Enters 2015 a Different Company

Today is the last official day for Chief Technology Officer Ian MacLachlan at Tekmira.   While scientifically a great loss to Tekmira, the change marks the end of Tekmira as a technology development company and the official beginning as a commercially focused clinical product development company.  From the clinical pipeline, it is TKM-HBV, Tekmira’s gene silencing candidate for the finite treatment of HBV infection, which stands out as the most important, if not existential asset to be watched in 2015.

After generation 1, 2, 3, and now even 4 SNALP LNP, and 10, 100, 1000x fold improvements in the potency and therapeutic window, the time has come to stop telling us that ‘next time will be better’ after yet another immunostimulatory setback.  In both cases (TKM-ApoB, TKM-EBOLAold), I was willing to take the bait as the company and Dr MacLachlan explained the basis for their continued confidence with scientific authority.  For TKM-EBOLA, the plausible explanation for the immunostimulation seen in the healthy volunteer study was particle heterogeneity following resuspension of the lyophilized liposomes (note: a lyophilized formulation was used in that case because Ebola may have to be used in areas with unreliable cold chains; other SNALP LNP products are provided as 'wet' formulations).

However, with the recent initiation of phase I studies of generations 3 and 4 formulation of TKM-HBV and the departure of Dr MacLachlan, the company seems comfortable with taking their last two shots at proving that SNALP LNPs can enable potent gene knockdown in the absence of transient immune suppression at comfortable safety margins and with profiles that are competitive with the emerging conjugate platforms in RNAi and RNaseH antisense.

Although a bit under the radar for the moment, the new studies with non-lyophilized 3^rd generation TKM-Ebola Guinea should be informative as to whether the lyophilization hypothesis holds water.  As these studies should likely be of shorter duration than the TKM-HBV phase I studies, the safety results from those studies should be a harbinger for the safety for at least TKM-HBVgen3, if not TKM-HBVgen4.  

The changes at the company will be welcome by some investors which might have grown tired of holding shares in a lab experiment.  On the other hand, they dampen my outlook for other liposomal delivery opportunities not only in RNAi for oncology (see today's ho-hum update on TKM-PLK1), but also in the sizzling hot fields of mRNA and CRISPR Therapeutics.

So good luck Ian and thanks for leaving the company in good order. Yours is also a great loss to the field of RNAi Therapeutics.  Hope you will come back to Nucleic Acid Therapeutics with renewed motivation.

Hello 2015

Lastly, a Happy New Year to all my readers.  2015 should be a year that will be marked by clinical RNA Therapeutics data of ever higher quality which will make it crystal clear that RNA Therapeutics has become the 3^rd major drug discovery engine of the pharmaceutical industry. 

First up: Regulus end of January/February 4mg/kg RG-101 in HCV.

Alnylam’s Second-Generation GalNAc Data Impress

Earlier this week at the American Society of Hematology meeting in San Francisco, Alnylam presented first multi-dose knockdown data in humans for its second-generation GalNAc-siRNA conjugate technology (ESC-GalNAc).  Accordingly, an almost 60% knockdown was seen in the first (and so far only) patient dosed at 0.045 mg microgram per kilogram ESC-GalNAc siRNA with the knockdown yet having to reach its nadir.  Moreover, further knockdown benefits are likely to accrue with dosing beyond 3 times weekly as was the case in this study.

At these low doses, no remarkable adverse events were reported, including injection site reactions or increases in liver enzymes which were seen with first-generation GalNAc-siRNAs in humans at much higher doses.

Though the data from this phase I study of ALN-AT3 in hemophilia patients is still early and there will be gene target-dependent differences in knockdown potency, they do support Alnylam’s claim that second generation GalNAc is indeed considerably, as much as 50x more potent than first-generation GalNAcs.  Only last week I had speculated that it may be more appropriate to estimate 2^nd gen GalNAc to be ‘only' 5x more potent than 1^st gen GalNAcs.

I was wrong.

In non-human primates, ALN-AT3 had an ED90 of 0.5mg/kg with weekly dosing.  Based on the phase I data thus far, I expect the corresponding ED90 dose in humans to be a ~ weekly 0.075mcg/kg 0.075mg/kg for a ~7-fold improvement in potency in humans versus non-human primates, a relative potency improvement that is not seen for first-generation GalNAcs.  Add to this the inherent 5x improved intra-species potency of second- versus first-gen GalNAc (Nair et al 2014), it is indeed possible that ESC-GalNAc enjoy an up to 50x improved potency advantage.

In other words, it should be possible to now achieve highly potent knockdown with a once-monthly dosing regime and sub-1 ml subcutaneous injection volumes. 

The value of this for the ALN-AT3 program, which harnesses a unique mechanism in an otherwise crowded hemophilia field which in general is moving towards less frequent dosing/infusion regimens and less immunogenic molecules, remains to be seen.  The slow enrolment pace of the phase I trial, ~5 hemophilia patients enrolled in 6 months, gives cause for commercial concern.     

The competition

While the improved potency is great for Alnylam, the gene knockdown competition is unlikely to yield the liver to Alnylam.  Highly potent knockdowns are possible with other platforms by Arrowhead, ISIS, Tekmira, and possibly Dicerna, too. Beyond route of administration [subQ for Alnylam GalNAc, ISIS (GalNAc-) ASOs, Arrowhead’s single molecule DPCs, and Dicerna GalNAc versus intravenous for Arrowhead’s 2-molecule DPCs and Tekmira’s SNALP LNPs], differentiation will come from safety/tolerability and dosing frequencies.

The next datapoints in this regard will come from the R&D Day by Dicerna early next week (Dicer-substrate GalNAcs) and the 4mg/kg phase I data from the immensely exciting anti-miR122 program by Regulus Therapeutics (employing GalNAc-antisense chemistry) in January 2015.

Tekmira with Multi-Trigger and Parallel Development Plans

As a veteran armchair RNAi Therapeutics strategist, I am frequently frustrated at the inflexibility of companies in the face of rapidly moving competitive and drug development environments.  The worst offenders are those with management and Boards that view their positions as entitlements and could not care less about the science and acknowledge the flaws of their technology.  

Often related to this, another common violation is a failure to cut your losses on an obviously failed development program at the cost of the platform, a strategy though that sometimes works if you can find a greater fool (the ~$700M acquisition of Prosensa by Biomarin yesterday falls into that category).  

Tekmira, too, has been at risk of suffering from such inflexibility in light of an industry-wide shift from nanoparticle-based to small conjugate-based delivery.  This does not mean that nanoparticle-based delivery will not have an important role to play in the future of RNA(i) Therapeutics, but that you have to realize your relative strengths in a highly competitive space.  In addition, Tekmira has been slow to realize the shifting regulatory and payor landscape making biomarker-focused orphan drug development in genetically defined patient populations highly attractive.

Having listened to the Tekmira Analyst Day last Friday, I was therefore quite pleased that not only is Tekmira catching up by beginning to realize that it is running a business and not a scientific think tank, it can even be considered to take on a strategic leadership role in at least two regards:

1)      the adoption of multi-payload candidates thereby addressing the i.v. nanoparticle versus single molecule subQ debate and leveraging key advantages of nanoparticle technology;

2)      running trials in parallel to quickly find out which delivery chemistry platform works best in humans.

1.       Multi-targeting: a key differentiator of nanoparticle-enabled RNA(i) Therapeutics

At the Analyst Day, Tekmira re-iterated that it will put a multivalent HBV formulation into the clinic that will contain three RNAi triggers.  In addition to ensuring that most patients thus become a match for the therapy, just as the two-trigger ARC520 by Arrowhead Research had been geared towards, Tekmira also wants multi-targeting to address viral resistance of the kind it observed in the woodchuck model of HBV.  

From that perspective, the intravenously administered TKM-HBV is preferable to single molecule approaches by Alnylam and ISIS Pharmaceuticals which are both administered subcutaneously.

Tekmira does not limit multivalent RNA Therapeutics to viral applications such as in their HBV and Ebola programs, it will also apply the concept outside that space such as in its hypertriglyceridemia program where it is considering dual-targeting formulations with ApoCIII, ANGPTL3, and DGAT2 as candidate targets.  

Equally or even more intriguing, in the Q&A session it was hinted that other therapeutic strategies that the company is considering may not merely involve multiple payloads of the same type, but even payloads from different categories such as an mRNA and an RNAi trigger.  Obviously, such combinations could open up entirely new therapeutic strategies (e.g. mRNA-RNAi combos for alpha-1 antitrypsin), or maximize potency (e.g. RNAi trigger-RNaseH ASO for HBV).

Scientifically, I see no reason why single molecule technologies such as GalNAc-siRNAs should not be amenable to certain (but not all, e.g. mRNA) multivalent approaches.  Culturally, however, multi-valency takes away from the single molecule simplicity that the pharmaceutical industry apparently loves, ideally in pill form.  From a regulatory point of view, it seems to be the case that nanoparticle-encapsulated RNAi products are seen as just one drug no matter how many RNAi triggers it contains, and it remains to be seen what the regulatory thinking would be when combining multiple single RNAi triggers (I can imagine Alnylam trying to combine their HBV mRNA-targeting GalNAc-siRNA with its PD-L1 GalNAc-siRNA).

In some ways, ARC520 (which is not a nanoparticle) strongly indicates that multi-targeting is not an insurmountable challenge for the non-nanoparticle approaches, so that regulatory advantage may not exist in the future. 

Nevertheless, my prediction is that multi-targeting will be mostly practiced in the nanoparticle and not the conjugate sector of RNAi Therapeutics and nanoparticle-based companies ought to consider multi-targeting almost a Must when there is direct conjugate delivery competition.

Although Tekmira is the most visible RNAi company for multi-targeting, it should be added that multi-targeting has been the motto for US-China-based Sirnaomics from the get-go in 2007.

2.       Testing Multiple Delivery Technologies in Parallel

The RNAi Therapeutics field is both blessed and plagued by the rapid progress in refining particular delivery platforms.  Tekmira has already arrived at the 4th generation of SNALP LNPs while Alnylam is now talking about GalNAcs with standard and enhanced chemistries.  With a multitude of preclinically validated alternatives, it is often difficult to determine which one should be prioritized for human development. 

This can lead to protracted development timelines when a first formulation yields unsatisfactory results in the clinic and the payload has to be re-formulated into a new delivery chemistry.  Especially in competitive environments this can be fatal.  And even if you were somewhat satisfied with the initial results, chances are that you left a lot of money on the table by not finding out about the performance of other formulations in humans.

Needless to say, having multiple candidates for a target is not a unique challenge in the pharmaceutical industry and if money were not an issue, we would see a lot more parallel development programs.  However, RNAi and related delivery is unique as the investment can be amortized across the platform.  

Moreover, in practical terms, RNAi offers a number of opportunities to directly and accurately measure target engagement and thereby assess the impact of changing the formulation.  This is one of the reasons why the early RNAi programs targeting genes in the liver involve targets which can be found in the blood.  For other modalities (e.g. microRNA inhibition in the RNA Therapeutics field), what you measure in your blood sample or other biopsies may differ significantly from what is actually going on in the body.

For these reasons, namely to speed up time-to-market in a competitive market and to inform which delivery formulations should be used with other LNP-enabled candidates, Tekmira announced that it is about to put two formulations of TKM-HBV in the clinic that will only differ in their delivery chemistry while using the identical (3) RNAi triggers.

Tekmira investors are not seeing double: the company is becoming a modern drug developer.

Dicerna Admits Defeat, Licenses LNP Tech from Tekmira

Show me the non-human primate data.  Robust evidence of gene knockdown in monkeys is a key requirement to gain confidence in a company’s liposomal delivery claims.  Dicerna has never done that and yet been able to pull off an IPO and make claims about clinical development timelines without actually being in possession of a realistic delivery technology.

In retrospect, it is not surprising that they eventually had to come hat in hand to the liposomal delivery powerhouse, aka Tekmira- after claiming that its liposomal delivery technology (EnCore) was superior to Tekmira’s…  After all, Dicerna is under pressure to get its first proper development candidate in the clinic for Primary Hyperoxaluria Type I (PH1), especially after Alnylam had publicly announcedtheir intention to go after PH1, too.

According to the agreement announced today, Dicerna will use Tekmira’s 3^rd generation LNP technology and manufacturing to get DCR-PH1 into the clinic sometime in 2015.  In return, Tekmira will get $2.5M upfront, $22M in potential development milestones and single-digit royalties- in other words, nothing to write home about other than the satisfaction that they were proven right scientifically.

You may interject that Dicerna already has a clinical program using EnCore technology, DCR-MYC for cancer.  Unfortunately, there are many ways to curing cancer in mice and I am yet to be convinced that they have been primarily the result of RNAi mechanism of action.

In summary, a moral victory for Tekmira, a deal that made sense for Dicerna and which could and should have happened a long time ago.  In a final twist of irony, Dicerna has given Tekmira a back-handed compliment in issuing another press release today where it announces that future development programs will be based on Dicerna’s conjugate delivery technology.

Now that makes actually sense for a Dicer-substrate-based company.  Expect Alnylam to increase its saber-rattling vis-a-vis Dicerna.

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Disclosure: Long Dicerna, no position in Tekmira

Co-delivering Antisense and RNAi for Cancer

The upcoming phase I top-line data for ISIS-STAT3Rx in liver cancer (HCC) to be presented at the upcoming EORTC-NCI-AACR triple meeting in Barcelona (Nov 18-21) will be an important test of the potential utility of RNAseH antisense oligonucleotides (ASOs) incorporating high-affinity chemistry in oncology.  

Based on the body language by ISIS Pharmaceuticals* and last week's $7.5M milestone payment from partner AstraZeneca for progress on ISIS-STAT3Rx (aka AZD9150) , I am tempted to speculate on more than just ‘encouraging’ results.  On the other hand, Regulus Therapeutics partner Sanofi at the Canton Nucleic Acid Forum (CNAF) also last week, noted the need for formulating antisense oligonucleotides to get their anti-miR21 oncology candidate into liver cancer tissue. It is likely that they will be using liposomes for that (--> Tekmira?).

* I was surprised that at the CNAF in Guangzhou, China, Brett Monia from ISIS mentioned STAT3Rx and cancer right after gene silencing in the liver as the next interesting application for ASOs- that is ahead of even the exciting CNS opportunity.

The discrepancy in body language may be explained by just cultural differences (conservative, blasé Big Pharma versus risk-taking, enthusiastic biotech); it may also be a reflection of different requirements for effective tissue concentrations with RNaseH versus anti-microRNA modalities or different target requirements.  Whatever the reason, the Sanofi comments clearly support the notion that getting naked, even phosphorothioated oligonucleotides into cancer tissues is not as robust as with other tissues such as the liver and kidney.

I am therefore pleased that it is a Big Pharma, the last place where I had expected that from, that is connecting the dots and is considering delivery formulations, even the supposedly ‘toxic’ LNPs.  The concept is that the nanoparticle would facilitate a higher tumor concentration of the oligonucleotide, and once in the tumor interstitial space, cellular delivery may be facilitated via two routes.  Firstly, it may be traditional liposome-dependent cell uptake and cytosolic release.  Alternatively, those LNPs that get stuck in the interstitial space would spill the phosphorothioate oligo which may then diffuse further and get into the target cell by self-delivery. 

The same concept, of course, applies not only to phosphorothioate ASOs, but also to self-delivering RNAi triggers (+/- conjugation).

But why stop there? I propose that for cancer delivery, one should strongly consider and co-formulate RNAi triggers and ASOs into a shared nanoparticle.  They could target either the same gene, or they could target different genes thus taking into account the desire for a multi-pronged attack on cancer   (-> resistance).  In that scenario you would benefit from the superior gene silencing efficacy of RNAi triggers in those cells that they were able to reach, but then extent your reach with the help of the more agile, penetrative single-stranded antisense molecules. 

As such, PS-ASOs have an advantage in addressing intra-tumor heterogeneity of the EPR effect which is a well-recognized problem of nanoparticle delivery for cancer.

Another benefit of combining RNAi triggers with RNaseH ASOs is that you could achieve additive gene silencing activity when going after a shared target.  For example, if the RNaseH ASO and the RNAi trigger had both say a 70% knockdown activity on their own in the nucleus and cytoplasm, respectively, the combined activity would likely be ~90% which genetically could make a huge difference.

There is also a potency benefit, although more minor, when going after different targets because at least in RNAi, the best you can hope for when combining RNAi triggers against different targets is that they do not interfere/compete with each other.

With solid cancer data from both Tekmira (RNAi) and ISIS/AZ out over the coming weeks, we will soon get a sense of whether the field has moved forward in oncology and what the next steps ought to be.

Tekmira Presents Solid Pre-clinical Package for Upcoming HBV Clinical Candidate

Yesterday, Tekmira Pharmaceuticals presented the long-anticipated RNAi candidate for the treatment of HBV infection at the Annual Oligonucleotide Therapeutics Society conference (click here for the corresponding slide deck).  Accordingly, it was shown that TKM-HBV mediated solid knockdown of all HBV viral RNAs and proteins.  This included data in the challenging (and costly) mouse model carrying humanized livers (comprised of a mixture of mouse and human liver cells) competent of supporting the full HBV viral life-cycle.

In these mouse models, repeat doses of 0.3mg/kg resulted in ~90% reductions of both the critical HBV surface antigen (HBsAg) and viral DNA.  This may be an underestimate of the true potency of TKM-HBV as suggested by data targeting the human apoB gene in this model.  These suggested (although not proved) that it is much more difficult to achieve potent knockdowns of genes expressed in the human liver cells as compared to genes expressed in the neighbouring mouse cells of the same liver: around 10x the amount of RNAi trigger was required to achieve comparable knockdowns for the human ApoB gene relative to the mouse ApoB gene.

Based on these results, I expect an approx. ~85% knockdown of HBsAg in single-dose studies at doses that I conservatively expect to be very well tolerated (~0.2mg/kg).  As indicated by the recent clinical results with ALN-TTR02 and chimpanzee studies by Alnylam/Merck, both of which involved Tekmira's SNALP LNP delivery technology, these knockdown numbers are likely to improve with more prolonged repeat administration.

In case that Tekmira is able to safely dose escalate to higher dosages, say 0.5mg/kg, significantly more potent knockdowns can be expected.  One ought to, however, keep in mind that such higher doses are not necessarily supported by the clinical history of SNALP LNP which indicates that innate immune stimulations could become an issue around 0.3mg/kg. On the other hand, the otherwise conservative Tekmira management has been surprisingly optimistic as to 3rd gen SNALP LNP-enabled TKM-HBV being devoid of innate immunostimulatory activity.

Comparison with Arrowhead's ARC520

The results support the notion that Tekmira's HBV candidate will be more potent than Arrowhead's competing HBV candidate, ARC520.  However, there are many uncertainties in making such a prediction, most importantly the dose levels found to be safe and well tolerated in the clinical studies.  To wit, ARC520 is still dose-escalating and so far has exhibited a very good safety profile meaning that 90% (1log)-type knockdowns are well within reach, especially with repeat dosing.

Beyond potency, it should be noted that TKM-HBV comprises of 3 different RNAi triggers, both to cover the vast majority of viral sequence variation and to minimize the potential of breeding drug resistance.  To my surprise, such resistance mutations were observed in a woodchuck model that Tekmira conducted together with HBV powerhouse Bristol Myers Squibbs.

Oh, BMS? You can bet that should RNAi Therapeutics be able to meaningfully increase HBV cure rates from the low bar set by current standard of care (~15% with ill-tolerated immune stimulants), not only will BMS, but also the likes of Gilead be very interested to swoop in to pick up one or both of these compounds and/or companies.

An IND filing for TKM-HBV is on track for year-end 2014 with first drug administrations in early 2015.

Disclosure: I am long both TKMR and ARWR.

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.

Arrowhead’s HBV Candidate Requires Further Dose Escalation

Today, we learned about some hard HBsAg knockdown numbers from the phase IIa Hong Kong study of ARC520 in chronically infected HBV patients.  The data relate to the first 2 cohorts in this ongoing dose escalation trial.  Accordingly, the mean HBsAg knockdown at nadir for the starting dose of 1mg/kg was 39% within a range of 22-57% (n=6) while it was 51% within a range of 46-59% for the 2mg/kg cohort (n=6).

ARC520 was given as a single dose to patients already stably on polymerase inhibitor entecavir.

It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was only 12%, this is likely the result of the apparent high variability at the lower dose level with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi mechanism is starting to be solidly engaged with the expectation of a steepening dose response going forward.

While clearly missing the company’s own guidance of a 1 log reduction at 2mg/kg, the good safety profile-no SAEs at all in the study with all AEs rated to be unrelated to ARC520- in addition to the steepening dose-response curve following 2mg/kg means that ARC520 is far from being out of the HBV knockdown race.  Still, the stock market over-reacted, punishing ARWR stock with a percent decrease that matched the reported knockdowns.

Although even I ended up willing myself into believing that a 70-80% knockdown was possible following a single ARC520 dose of 2mg/kg, revisiting the chimp study which involved 2 doses of ARC520 (first one at 2mg/kg then one at 3mg/kg), it should be noted that at the time the 3mg/kg dose was administered, the HBsAg levels had only declined by 50%...about the same as achieved in the phase IIa study.  It is thus possible that Arrowhead gave the 2^nd dose just as HBsAg levels were about to go up again, consistent with the already rebounding levels of HBV DNA and HBeAg in that study.

As a result, my expectations for the single 3mg/kg dose are now 70-75% based on the ~75-80% peak HBsAg knockdown in the chimp study following the 2mg/kg and 3mg/kg doses.  This also means that in order to reach that 1log knockdown goal the company had set for itself, 4mg/kg will most likely be needed.  Importantly, in the concurrent phase I dose-escalating study in healthy volunteers, this quite large amount of drug seemed to be well tolerated and the company is awaiting approval to adopt this dose in the Hong Kong study.

This projection is not much off the 90% knockdown achieved in the ARC-AAT program at 3mg/kg in non-human primates.  The improvement of this 2^nd DPC-based candidate about to enter the clinic is possibly explained by progress in the potency of 2-molecule DPC delivery technology.  I add this as today many were confused about what the interim phase IIa results meant for the platform and the value of the company.

Overall, as long as 4mg/kg is an acceptable dose from a tox point-of-view, ARC520 is still in the game to be first-in-class in HBV knockdown.  It would have been much worse if say a 70% knockdown had been reported, but worrisome safety signals emerged.  On the other hand, the continued need for a dose escalation would seem to delay Arrowhead’s broad-based phase IIb study plans, meaning that the competition, in particular Tekmira's TKM-HBV is coming closer.

At a market cap of ~$400M, the market has almost fully discounted the potential of ARC520 given the $150M+ in cash as well as the IND-ready, first-in-class ARC-AAT for which we can expect solid knockdowns in the clinic.  Interestingly, data for this candidate were selected for an oral presentation at AASLD while the ARC520 data will be in less prestigious poster form. Finally, should the single-molecule DPC which got me excited about the Arrowhead RNAi platform in the first place finally reach the clinic, it would necessitate an upward revision of the value of the company.

Disclosure: Long ARWR.  I sold most of my holdings at $11 and change given the underwhelming results and increasingly negative market reaction, but got back in below $6 when I considered the sell-off to be a gross over-reaction and imminent 3mg/kg data having the potential to surprise the market to the upside from now much lowered expectations.  Add to this ARC-AAT, the platform...

Developing Aerosolized TKM-EBOLA as Airborne Transmission of Ebola Likely

Knowing how a virus is spread, also from a cell biology point-of-view, is critical to curtailing its spread and devising effective treatment strategies.   

According to the World Health Organization (WHO), the first symptoms of an Ebola infection are ‘the sudden onset of fever fatigue, muscle pain, headache and sore throat’ (emphasis mine). Then also consider the following:

1)      Ebola once killed a number of monkeys are apparently spreading through the ventilation system in Reston, VA; 

2)      A nurse became infected in a reference hospital for infectious diseases in Spain despite the protective clothing she was wearing and her limited contacts with the infected patients she was looking after (taking temperatures twice);

3)      A single pregnant woman in Liberia infected atleast 10 people helping her as she came down with Ebola;

4)      Ebola virus can infect numerous cell types in the body (frequently cited are the liver, endothelial cells, and phagocytic cells) and is found in high amounts inthe respiratory tract in infected pigs with the virus spreading readily to cohabiting pigs in the colony;

If you still believe in the narrative, even propagated byotherwise fairly reliable sources such as the CDC, that Ebola is only transmitted by direct contact with body fluids, then you should start considering airborne transmission as a main route the infection is spread.

After all, since when are cough droplets not a bodily fluid?

If airborne is indeed an important route of transmission, this would not only raise concerns that just like in avian flu, a few mutations in the virus adapting it to better latch on to the human respiratory tract could further catalyze the spread of the virus, but would also mean that treating it at the respiratory stage could both prevent the virus from fully entering the body as well as limit its spread from person-to-person.

Enter TKM-EBOLA

An RNAi viral knockdown approach in the respiratory epithelium should obviously be able to achieve that goal.  All that would be required is to take the same RNAi triggers now part of the intravenous TKM-EBOLA formulation and incorporate it in something amenable for respiratory delivery.

Back in 2011, Tekmira revealed that it was developing aerosolized liposomal nanoparticles (LNPs) to deliver RNAi triggers to the respiratory epithelium.  A key challenge was to find formulations that not only could successfully transfect respiratory epithelial cells, but also withstand the shear forces involved in nebulizing them.  Initial structural and tissue culture RNAi knockdown results showed that this can be achieved.

The development was seemingly halted at the rodent preclinical stage as the company had to save financial resources as it was fighting off Alnylam in a trade secret case.  After coming out on top of the litigation in November 2012, the company was then able to once again expand the development of its LNP-based nucleic acid delivery technology, in addition to churning out clinical development candidates (e.g. the important HBV candidate to be revealed next week).

 

Given that the company established a separate biodefense unit headed by the ‘LNP-brain’ of the company, now Chief-Technology-Officer Ian MacLachlan, I would not be surprised if LNP nebulization was part of that effort with the next goal of showing efficacy in monkeys.

Such reformulation of TKM-EBOLA is just another example of the versatility of RNA Therapeutics, just as is the ability to rapidly adjust and optimize the medicine as the virus evolves (note: this is e.g. not possible with antibodies).  It also adds to the importance of scaling up the supply of the RNAi trigger now should airborne be recognized as a major route of transmission.  

Long-term, such developments would obviously benefit the development of LNP-delivered RNA Therapeutics for the lung epithelium in general, including mRNA delivery (e.g. for Cystic Fibrosis) and a universal RNAi agent against flu.   

Ebola Emergency Tests Oligo Manufacturing Readiness

With officials scrambling to put in place measures to contain the further spread of Ebola, it is highly likely that RNAi Therapeutic TKM-EBOLA will be on their shopping list.  This, however, requires the ability to manufacture the oligonucleotide-based medicine in quantities sufficient to treat at least 10 thousand or so either infected or potentially infected persons.  In the absence of commercial Oligonucleotide Therapeutics success stories this could prove to be a challenge, although in this case, I believe it's doable.

Manufacturing, an advantage of TKM-EBOLA over PMOs and antibodies

When the US Department of Defense selected TKM-EBOLA as its preferred Ebola development project a few years ago, manufacturing, and not just efficacy and safety should have been part of the equation.  The reason is that e.g. currently about 0.3mg/kg*70kg/day*7 days= i.e. approx. 140mg of TKM-EBOLA RNA oligonucleotide is required per treatment course.  Since its simple chemistry (a couple of spiked-in standardd 2’-O-methyls in an otherwise unmodified RNA) makes it one of the cheapest RNA oligonucleotides conceivable, let’s ballpark its manufacturing cost at $300 per treatment course at some of the largest possible manufacturing scales possible today (kilograms).  Note that the cost of the lipids in TKM-EBOLA is negligible compared to the oligo component.

1.4kg oligo and $3 million for 10,000 treatment courses.

Taking into account that these are the pure manufacturing costs when protocols have been established, and other monies will have to be spent when starting from sequence design---let’s say conservatively $5 million. I believe given the gravity of the current situation, this is a number we can live with (1/200 of investment in the response).

If you do the same Gedankenspiel for Sarepta’s Ebola therapeutic morpholino antisense candidate, you have to multiply the $3M number first by a factor of 30 for the much larger amount of oligonucleotide required and then by another factor of 6 or so for the greatly increased costs of making morpholinos over standard RNAà $500M+.  A non-starter not just for the increased costs, but also because the manufacturing capacities for that amount of oligonucleotides are not readily available today, let alone for the morpholino chemistry where Sarepta has experienced significant delays in obtaining sufficient oligo supplies for a relatively small (~100 patients on drug at 30mg/kg/week for 48 weeks) phase III program in an orphan diseases indication (DMD).

When we move to Tekmira’s antibody competition, in particular ZMapp, the situation is not all that different from Sarepta’s with the slight advantage that ZMapp could somewhat tap into the established know-how of monoclonal antibody production.  But in the end, we’d be talking about years of process development and scale-up compared to a few months TKM-EBOLA.

Wake-up call for oligonucleotide manufacturing

Although TKM-EBOLA should be within current oligonucleotide manufacturing capacities, the Ebola situation should get oligonucleotide manufacturers wondering whether they are ready for the upcoming surge in Oligonucleotide Therapeutics approvals and sales.  Following years of disappointment about the lack of big manufacturing requests, CMOs have been loath to build the plants that can churn out hundreds of kilos or even tons of oligonucleotides.

Consequently, I attribute the decisions of first ISIS and Sanofi/Genzyme, then Alnylam (for GalNAc conjugates), and more recently also Sarepta, to shift oligonucleotide manufacturing in-house, to this lack of outside manufacturing capacity.  While having manufacturing in-house may sound attractive for a number of reasons, spreading manufacturing risk across multiple vendors is an accepted risk reduction strategy in this and other industries. 

I am therefore hopeful that the ongoing Ebola outbreak will end up increasing oligonucleotide therapeutics manufacturing capacities to rule out a situation that manufacturing constraints could limit commercialization of agents like ISIS-ApoCIIIRx or the HBV agents with potentially very large patient populations. 

A Defining Month for Tekmira

As if Ebola has not showered Tekmira with enough attention, Tekmira will be front and center in the RNA Therapeutics industry in October.  It will be clinical results from two other drug candidates utilizing Tekmira’s RNAi delivery technology (TKM-PLK1 and ALN-TTR02) and pre-clinical data for TKM-HBV that will define Tekmira's trajectory as a 'normal' biotech company.  'Normal' as I have little idea how Ebola will change all this.

Accordingly, depending on the dataflow, Tekmira could finally be transformed into an established biotech company.  If there are serious disappointments, Tekmira risks being delegated to being 'the Ebola company'.

Event 1 (October 10-11): Do GI-NET patients respond to TKM-PLK1?

The first upcoming data event is the phase IIa update for TKM-PLK1 in gastrointestinal neuroendocrine tumor (GI-NET) and adrenocortical carcinoma (ACC) patients.  This one can be considered a bonus event for Tekmira as barely anybody has been paying attention to the potential of this first-generation SNALP-based product candidate.

 

Results from a  multi-dose escalating phase I study suggested a dose-dependent benefit with patients receiving 0.6mg/kg or more having an increased likelihood of showing ‘clinical benefit’ (stable disease or partial response) than those receiving less of the drug.  In particular, almost all (5/6) GI-NET and ACC patients in that trial with otherwise enrolled across a wide range of cancer types exhibited at least stable disease, with a partial response by RECIST and a 19.3% reduction in tumor size.

One aspect that I found particularly encouraging in these results was that TKM-PLK1 which involves a long-circulating form of SNALP achieved ‘several fold’ increased target tumor concentrations compared to an earlier, short-circulating SNALP product (ALN-VSP02 from Alnylam).   Unfortunately, the precise differences were not disclosed.

The factor that makes me most optimistic about a positive update (--> multiple tumor responses) at the upcoming 7^th Annual NET Conference in Nashville is that there is evidence that SNALP LNP delivery should work particularly well in the GI-NET and ACC settings.  Not only did GI-NET and ACC patients seem to perform well in the phase I study, there have historically been apparent biological effects of other nanoparticulate cancer RNAi Therapeutics in neuroendocrine tumor patients, including cases of extended stable disease with Atu027 by Silence Therapeutics.  

Moreover, the adrenal cortex, and possibly other endocrine structures, seems to be a preferred target organ (next to liver) for SNALP LNP delivery.

What makes me less excited about this program is that TKM-PLK1 is based on fairly old SNALP LNP delivery technology, and wouldn’t it be nice to see the potent PLK1 RNAi trigger being utilized in the latest delivery formulation.

Event 2 (October 13): Does ALN-TTR02 show a therapeutic benefit in TTR amyloidosis?

At the upcoming American Neurological Association’s 2014 Annual Meeting, Alnylam will present first data from its high-profile ALN-TTR02 product candidate that will look not just at target gene knockdown (expected to be in the 80% range), but also whether this translates into an apparent therapeutic benefit.

ALN-TTR02 is an RNAi Therapeutic for the treatment of the FAP form of TTR amyloidosis and uses Tekmira’s delivery technology.  As a result, Tekmira stands to financially benefit from it in the form of development milestone payments and royalties (in the low to mid single-digit percent of revenues) which may reach ~$50-100M annually for this $500M market cap company if analyst projections as to the FAP market prove correct.

The data to be presented comes from the open-label extension (OLE) of the relatively short phase II study.  In this OLE study, Alnylam will look every 6 months how patients are doing according to the mNIS+7 functional score which will then be compared to data gathered from a Natural History study of the disease. 

It is expected that 20 patients that had been rolled over from the phase II study will now have reached the first 6 month time-point.  The phase II study was too short (2 doses spaced apart 3-4 weeks) to reasonably expect an obvious therapeutic benefit from the knockdown of the disease-causing transthyretin gene.

It is important to remember that a failure to see a therapeutic improvement after 6 months with ALN-TTR02 does not necessarily reflect badly on SNALP LNP delivery technology as long as the knockdown remains in the 80% range and is well tolerated.  In that scenario, target risk and an insufficient period of knockdown may be responsible instead and this is where each RNAi Therapeutic has its unique development risk.

My prognosis is that first divergences from the Natural History will be seen if the preclinical experiences and those from other amyloidotic diseases such as AA amyoloidosis are any guide (~50% knockdown and beyond should lead to a benefit).  From a Tekmira technology point-of-view, I will pay close attention as to the safety and tolerability of longer-term dosing, which so far looks quite good.

  

                Event 3 (October 15): Coming out for TKM-HBV

Possibly the dataset with the most impact on Tekmira is the revelation of the company’s RNAi candidate for HBV infection.  Based on data revealed earlier this year by Alnylam which showed a SNALP LNP-based RNAi compound to have multi-log viral knockdown and 2 log HBsAg knockdown in the challenging chimpanzee model with moderate amounts of drug, TKM-HBV is set to become most-potent and therefore hopefully best-in-class among the knockdown approaches by Arrowhead Research (ARC520, first-mover), ISIS/GSK, and Alnylam.

To facilitate cross-comparisons, Tekmira may wish to directly compare its candidate with Arrowhead’s ARC520 for which the structural identity is known.

One aspect that I will be paying particular attention to is whether the data support dosing without transient immune suppression.  This is because I am concerned that such a regimen, especially if it involved steroid use, would not be acceptable in the HBV setting. As you may remember, the company attempted to get away without immune suppression with TKM-EBOLA in a trial in healthy volunteers, but at moderate-to-high dose levels immune stimulations were seen prompting the FDA to put that program on Clinical Hold for the volunteer population. 

Having said that, TKM-Ebola is now being used in much more fragile patients actually infected with Ebola, and anecdotally even the most stringent dosing regimens such as 7x daily appear to be tolerated here, presumably without pre-medication.

As per the last quarterly conference call, Tekmira management seemed confident that TKM-HBV would not require pre-medication.  Since such immune stimulation is thought to be highly sequence-dependent, I do not fully understand their confidence, but maybe a little bit of immune stimulation is not that bad in the Ebola setting after all.

An IND for TKM-HBV is planned by the end of the year with first dosing starting in early 2015.

Buckle up for an exciting month with Tekmira, and if all that weren’t enough, it unfortunately looks like we are still in the early innings with Ebola as being ahead of the curve is a concept foreign to the governing authorities.

Disclosure: long Tekmira.