Alnylam GalNAc Improvements Incremental, but Likely Enough to Beat PCSK9 Antibodies

Over the last week, Alnylam presented pre-clinical data for their new development candidates for the treatment of hypercholesterolemia (ALN-PCSsc) and liver disease related to forms of alpha-1 antitrypsin deficiency (ALN-AAT).  These candidates are based on second-generation GalNAc-conjugate chemistry that the company is now dubbing ESC (Enhanced Stabilization Chemistry).  They involve the increased use of chemical nucleic acid modifications for stability with attendant improvements in knockdown potency and duration over first-generation GalNAc conjugates such as ALN-TTRsc.  ALN-TTRsc is the lead GalNAc candidate and currently in phase II development.

Borderline first-generation GalNAcs

In a phase I study of ALN-TTRsc, potent knockdowns were achieved with about:

-60% knockdown at 2.5mg/kg;

-80% knockdown at 5.0mg/kg (ED80), and

-90% knockdown at 10.0mg/kg.

At the risk of insulting medical geneticists for oversimplifying, assume that an RNAi technology that can safely achieve an 80% target gene knockdown provides for a solid platform.  In the case where a subcutaneous route of administration is desired and/or necessary, this should ideally also fit into a 1ml injection volume which in the case of GalNAc conjugates would correspond to a 2.5mg/kg dose.

There is some controversy around acceptable injection volumes and as often is the case, increased standards are applied to RNAi Therapeutics.  I say this because drugs and drug candidates such as expected mega-blockbuster PCSK9 antibody from Amgen, AMG-145, has been administered at 2ml volumes.  In fact, to achieve once-every-4-week dosing, 6ml (3x2ml) have been administered (see Giugliano et al. 2012).

In light of this, ALN-TTRsc has failed the 1ml test, but 80% are certainly possible with this first-generation GalNAc chemistry.  There is therefore room, and in some cases a competitive need (àcompetition with more potent delivery technologies such as Tekmira’s SNALP LNPs and Arrowhead’s single molecule DPCs) for improvements in GalNAc conjugation technology.    

Second-generation data could indicate progress

In agreement with this, Alnylam is now advertising the ESC second-generation GalNAc and has presented critical non-human primate data for their new development candidates ALN-PCSsc and ALN-AAT.  Non-human primate data are ‘critical’ because the RNAi knockdown observed in monkeys typically closely predicts what will be seen in humans based on the experiences with ALN-PCS (SNALP), ALN-TTR (SNALP), and ALN-TTRsc. 

In interpreting the newly presented data, it should be noted that in the case of ALN-TTRsc, an 80% knockdown was already observed at 2.5mg/kg (and 5mg/kg) in non-human primates, but that this shifted to 5mg/kg in humans.  Numerically a relatively small difference, in practical terms an important one.   

ALN-PCSsc achieved 80% PCSK9 target gene knockdowns at 2mg/kg in a weekly multi-dose study in non-human primates.  This resulted in a highly competitive 60% LDLc lowering in the absence of statins.  Similarly impressive in light of the monoclonal antibody competition was that 80% PCSK9 knockdown and 50-60% LDLc reductions were achieved and sustained for over 3 months (!) when a single dose of 10mg/kg (2x2ml) was given.  Compare this to 57% LDLc lowering with AMG145 in a once-every-4 week regimen in the MENDEL-2 phase III study of AMG145:

-ALN-PCSsc (RNAi): 50-60% LDLc reduction, 2x2ml subcutaneous, once-every-3-months

-AMG145 (monoclonal antibody): 57% LDLc reduction, 3x2ml subcutaneous, once-every-4-weeks (phase III MENDEL-2 monotherapy study)

(Yes, I do keep an eye on cash-rich, sub-$2B market cap The Medicines Company, Alnylam’s licensee for ALN-PCSsc for this reason).

Before I get carried away with all the advantages of the RNAi platform over monoclonal antibodies for even extracellular targets such as PCSK9, in terms of GalNAc improvements, these knockdown results are very much in line with what was seen for TTR in non-human primates. 

The same applies for ALN-AAT where a single dose of 3mg/kg translated into a 60% knockdown which, based on TTR and PCSK9, will likely translate into a weekly multi-dose ED80 of 2.0-2.5mg/kg in non-human primates.

However, with the caveat of different half-lives for different target genes, the durability of the PCSK9 knockdown is quite impressive and more than what is typically seen with e.g. SNALP LNPs which have historically utilized minimally modified RNAi triggers.  Such triggers may be turned over more rapidly in liver cells.

Similarly, the RNAi trigger sequence in the TTR development candidate is an extraordinarily potent one with low single-digit picomolar EC50 potency in tissue culture.  It is therefore possible that equivalent animal potencies have now been achieved with less potent sequences meaning that the underlying delivery technology has improved.

It’s been fascinating to watch the various delivery platforms, and indeed RNaseH antisense, compete over the years and pushing each other to new heights.  In this context, I am anxiously waiting for Arrowhead’s presentation at next week’s TIDES meeting with the intriguing title:  “Next Generation Dynamic Polyconjugates for siRNA Delivery in vivo,”

Market commentary: I remain mostly on the sidelines.  Years ago, these scientific data would have made me jump head-first into the market with me buying all I could in the opening minutes.  These days, however, I view them as ensuring the long-term value of RNAi stocks, but fail to see how they will support share prices in the current, growth-to-value rotating trading environment for more than a trading week or so.  I am therefore speculating on a capitulation event before some of the important clinical data read-outs roll in.  

A First Clinical Step Towards Subcutaneously Administered RNAi Therapeutics

Today, Alnylam reported more detailed results from their phase I study of ALN-TTRsc for the treatment of the cardiomyopathy form of TTR amyloidosis (press release here, data presentation here).  As telegraphed by COO Barry Greene at the recent Morgan Stanley Healthcare Conference, 5mg/kg and more of the subcutaneously administered ALN-TTRsc were required to obtain a persistent knockdown of 80% (5mg/kg) and more (10mg/kg dose).  

As these doses fail the 2.5mg/kg challenge the company had set itself earlier, increased injection volumes and injection numbers are being evaluated.  A phase II trial with ALN-TTRsc is planned to start at the end of the year with a pivotal phase III study slated to start in 2014.

Small potency differences to monkey studies matter for ALN-TTRsc

As I had indicated earlier, the preclinical monkey studies with ALN-TTRsc (see slide 7) left open the possibility that with an 80% target knockdown, ALN-TTRsc can be sufficiently effective at 2.5mg/kg which corresponds to the magical injection volume of 1ml for safe and convenient subcutaneous administration.  However, the phase I human data are shifted by 1 dose cohort meaning that 5.0mg/kg were required for an approx. 80% sustained knockdown (see slide 11 where 2.5mg/kg clearly missed).

If you are confused about the press release prefers which talks about an 87.5% 'mean' (n=3) knockdown ‘at nadir’ for the 5.0mg/kg dose, it is more appropriate for this indication to refer to the average knockdown level over time which was more like 80-82% (slide 11).  

Nevertheless, oozing with optimism, Alnylam set itself an even higher bar for ALN-TTRsc for future studies with a sustained target knockdown of 90%.  Such a level of knockdown was only achieved in this study at the very high dose of 10mg/kg.  Indicative that 10mg/kg is not a desirable dose, the company amended its study to evaluate 7.5mg/kg given as two 1.5ml injections in addition to 5.0mg/kg and 7.5mg/kg every 2 weeks to determine whether less frequent dosing is feasible.

Personally, I believe 5.0mg/kg twice a week would be a more promising dosing schedule as with higher doses there should be diminishing returns due to receptor saturation.

Safety OK, but questions raised

The reported safety profile did not yield apparent nasty surprises.  This is obviously very good in a phase I study of a new chemistry.  However, it has also become obvious that injection site reactions could become an issue.  Unlike ISIS Pharmaceuticals which has declared such reactions to be a cosmetic problem in the past, injection site reactions have to be closely watched as they could indicate systemic immune issues.

Despite the small numbers, the injection site reactions appear to be dose-related with 3 out of 3 subjects at the 10mg/kg exhibiting them during the 5 weeks of the study.

 

These observations are also relevant to the competitive DPC delivery technology by Arrowhead Research because both involve galactose conjugations.  In the case of the intravenous version of DPC, the galactose has been added to the endosomolytic peptide, while a cholesterol is added to the RNAi trigger administered separately. 

Initially, I had thought IP issues could have prompted Arrowhead to put the galactose on the ‘less precious’ peptides.  However, an alternative explanation could be that galactose conjugated to nucleic acid might be more prone to immune stimulations.  Due to the apparent dose-relatedness of the reactions, it will be important that future subQ candidates (both Alnylam's GalNAc and Arrowhead's subQ DPC which have galactose and the RNAi trigger on the same molecule) have therapeutic knockdown potencies at 2.5mg/kg and below.  

A very perplexing observation, albeit not discussed at all, is the fact that elevated immune cytokine levels were reported in the placebo cohort, but none in the ALN-TTRsc cohorts (see slide 15 of the presentation).  I really don’t know what to make of this. 

Summary

Despite some of the blemishes above, the results are a decent start for subcutaneously administered RNAi Therapeutics for liver-expressed gene expression.  In addition to the safety profile, this thus renders also the last argument for phosphorothioate-based RNaseH antisense technology in such indications obsolete, namely the ‘patient-friendly’ route of administration.  Patients with TTR amyloidosis and their relatives can now look forward to two attractive RNAi options, and I expect there to be continued RNAi improvements for this indication.

For those interested in Tekmira, the results are positive in the sense that they increase the value of ALN-TTR02 given the modest potency of ALN-TTRsc, and support SNALP to be the clinically validated gold standard in RNAi delivery.  For those interested in Arrowhead Research, the results are positive as they underline the value of more potent subQ RNAi delivery technologies and because they lower the safety risk around the galactose chemistry.

Alnylam Comments Suggest SubQ Tech Failed to Achieve Efficacy Goal

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

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

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

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

Alnylam’s GalNAcs As Cholesterol-siRNA 2.0

That Alnylam bets its future on GalNAc-siRNAs is remarkable and indicates that the company feels the technology is clinically viable.  Accordingly, the preclinical animal data leaves open the possibility that the required volume of an effective dose of ALN-TTRsc, the first GalNAc-based clinical candidate, can be administered in a volume of 1ml or less, the stated goal of the company (results to be presented at HFSA, Sep22-25).  

While I view ALN-TTRsc as a cliffhanger in terms of commercial viability, not just because of the volume issue but also in light of the likely more effective SNALP option in the form of ALN-TTR02, the potency of GalNAc-based ALN-AT3 for hemophilia looks quite adequate.

Alnylam’s claim that a simple ligand-siRNA conjugate was able to mediate gene silencing in vivo required a rethinking of RNAi delivery by many since similar efforts involving especially aptamer-siRNA conjugates have been ‘viewed with skepticism’ to put it nicely.

Did Alnylam mislead the competition?

If you are a student and your funding body just spent $3000 to send you to a conference to learn about your subject, you might be forgiven if you came away with the notion that simple siRNA-conjuates such as Alnylam’s GalNAc-siRNAs can be effective (see e.g. slide 16 of the presentation by John Maraganore at the OTS last year).  The trick apparently is that with a magic ligand-receptor pair such as GalNAc-ASGPR all you need is to conjugate an RNAi trigger chemically modified for stability.  

Of course, the imaginary student here is only collateral damage as the real target audience of a presentation by Alnylam is its investors, potential partners, and competition.

As such, it may not surprise that according to patent application US2012/0136042A1, a simple GalNAc-siRNA conjugate has no activity on its own.  

Instead, silencing activity critically depends on the molecule also having a cholesterol (=lipophilic group) attached to it.  Since Alnylam had worked on such cholesterol-siRNA conjugates before (Soutschek et al. 2004), what now appears to be the actual GalNAc-siRNA structure can be viewed as an evolution of the cholesterol-siRNA which showed knockdown activity only at doses of 50mg/kg and higher.

DPCs by Arrowhead Research Take another Step

The 10-20 fold gains in potency with the addition of the GalNAc ligand shows how comparatively inefficient ApoE/LDL-based uptake systems are for liver-directed RNAi delivery.  The reason why SNALP is still more effective than GalNAc-siRNA is because cholesterol-siRNAs do an even poorer job when it comes to the next rate-limiting step in delivery: endosomal release.

With Arrowhead’s Dynamic Polyconjugates (DPCs) for liver-directed knockdown, you combine the best of both worlds: effective attachment to hepatocytes via multivalent GalNAc-ASGPR interactions and effective endosomal release through endosomolytic polymers/peptides.  

In fact, because of the potent chemistries used for the latter step, the endosomolytic agent has to be masked which initially made me a bit wary about the safety of DPCs (note: clinical safety data for ARC520 are about to be released, probably in October, and the preclinical safety performance looks good so far). 

According to Arrowhead’s research, this combination allows for more than 500-fold potency gains compared to cholesterol-siRNAs (Wong et al. 2012).  

Because the ratio of siRNA to endosomal-release peptide has to be held constant in the clinical studies of ARC520 which is based on the 2-molecule DPC version, you will not see these improvements in potency translated into clinical practice.  This is not all that critical anyway since ARC520 is administered intravenously and cholesterol-siRNAs should not be toxic even at elevated dosages.  Still, while I’m excited about ARC520 for all the stated reasons (see the HBV Knockdown Blog), for the sake of Arrowhead’s platform, I really would like to see the elegant single-molecule DPCs enter development.  This should not take much longer given the advanced data presented at OTS 2012.

But hey, maybe they have already advanced into development, but they are just being referred to as 'GalNAc-siRNA'.

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

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

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

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

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

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

RNAi Therapeutics Ebola Candidate Achieves Critical Milestone

Yesterday at the TIDES meeting, Tekmira reported new efficacy data for its Ebola RNAi Therapeutics development program.  The non-human primate data suggest that the main remaining hurdle before regulatory approval for this biodefense agent (on which any government stockpiling contract would hinge), safety in healthy human volunteer studies, is now more realistic than ever.     

Is second time's the charm?

In 2010, Tekmira and collaborators from the Geisbert lab and the US Army reported in The Lancet of a breakthrough in the post-exposure treatment of Ebola infection.  In the gold-standard rhesus monkey model for Ebola infection, their were able to demonstrate that SNALP-RNAi could effectively rescue Ebola-infected animals from near-certain death. 

The efficacy, however, depended on doses of 2.0mg/kg is likely too high a SNALP dose to be considered safe.  Based on the SNALP human clinical trial experience to date, first dose-limiting toxicities are observed at 1.0mg/kg (note: SNALP potencies are very comparable between humans and monkeys).  Moreover, at doses higher than 0.5mg/kg, sporadic signs of immune stimulations (flu-like symptoms) can be observed.  These caused Alnylam and Tekmira to adopt precautionary transient immune suppressions with corticosteroids in some of their other SNALP-based clinical studies.   

It therefore became important to take advantage of the improvements in SNALP potencies and develop more potent Ebola SNALP-RNAi candidates.  Fortunately, Tekmira was able to get the blessing from the US Department of Defense for this, and announced in April that it would receive up to ~$7M in additional funding on top of the up to $34M initially agreed upon in order to bring such a candidate to the end of phase I clinical studies. 

Importantly, since Ebola efficacy trials cannot be conducted in humans, the regulatory approval of TKM-Ebola will be according to the Animal Rule.  The Animal Rule states that for indications where human efficacy trials are not possible due to ethical considerations, it is sufficient to show efficacy in accepted animal models and then establish drug safety at corresponding doses in healthy human volunteer studies.  

With the new formulation, 12 out of 12 monkeys treated with the magic dose of 0.5mg/kg RNAi stayed alive in a post-exposure treatment setting, compared to only 1 out of 6 treated with placebo.  This means that should the human volunteer trials show good safety at the same 0.5mg/kg dose level, Tekmira will stand a good chance at gaining regulatory approval under the Animal Rule.  Of note, the first Ebola trial were likely conducted in the absence of corticosteroid pre-treatment and it is very likely, also in light of Alnylam's recent announcement of tapering off corticosteroids in the ALN-TTR02 trial, that the future TKM-EBOLA studies will also be conducted without them.

Since 0.5mg/kg is right on the border, however, there still remains an element of risk before victory can be declared on the safety front.  It is therefore good to hear that 4 out of 6 monkeys stayed alive at the 0.2mg/kg dose. This should provide a good safety cushion despite the aggressive daily treatments that will be required in this demanding setting.

Critical human safety data, ideally from repeat-dosing studies, should be forthcoming in 2014 as Tekmira has guided that it will commence clinical studies with the new candidate by the end of 2013.

Update 16/5/2013: One issue on the efficacy side of the equation that I forgot to mention in the original post is that the DoD might ask the company to test TKM-EBOLA with longer delays after the infection in monkeys.

SNALP Shows Good Potency with Subcutaneous Dosing

Also at the TIDES meeting, Tekmira presented efficacy data for SNALP when given via the subcutaneous route of administration.  To wit, SNALP has largely been administered intravenously which may not be suitable for a number of indications, especially the lower risk, chronic diseases.  Pfizer once famously criticized the state of RNAi delivery as being limited to intravenous options.

Comments like these (which are very relevant for partnering purposes) and trends in the industry to adopt subQ dosing, most notably Arrowhead’s DPCs and Alnylam’s GalNAc-conjugates, probably motivated Tekmira to explore this route of administration with SNALP further.

 

Based on an early ApoB patent application, Tekmira had clearly had some familiarity with subQ, and I had always wondered why the company did not pursue this further.  It could be that the more potent SNALP chemistries now allow for much more potent and robust subQ RNAi gene knockdown.

The new data show a very impressive 96% knockdown of transthyretin (TTR) with a single subQ administration of 1.0mg/kg SNALP in rodents.  This compares to a much more modest ~55% knockdown with ALN-TTRsc at 1.0mg/kg given on 5 consecutive days, the subQ GalNAc-siRNA candidate by Alnylam which just entered clinical development for the FAC form of transthyretin amyloidosis.

Of course, we need to learn more about the safety of subQ SNALP to know whether it really is a clinically viable strategy and superior to the competition.  GalNAc-siRNAs in particular look quite benign, albeit not very potent.  However, since peak plasma concentrations seem limiting for SNALP in terms of safety (infusion reactions can be managed by slowing the infusion), subQ, due to its slower systemic release might actually turn out to be safer, not just more convenient.  On the other hand, my impression is that subQ SNALP could cause the type of ‘nuisance side effect’ that is frequently seen with phosphorothioate antisense.

The GalNAc comparison is obvious since Alnylam developings both a SNALP- and a GalNAc-based TTR RNAi Therapeutics in parallel.  In terms of competition for potential partnering, however, the DPCs by Arrowhead Research would be the more appropriate and challenging comparison.  I look forward to watching the race unfold as healthy competition is propelling the RNAi Therapeutics field into a highly competitive industry.

What to Expect from RNAi Therapeutics in 2013

2012 was the most exciting year in the ~12-year history of RNAi Therapeutics- both from a scientific and financial perspective.  Left for dead by most, unambiguous gene knockdown results in Man have allowed the technology to regain much-needed respectability.  With the start of 2013, the industry is looking to build on these successes with additional clinical trial results, interesting new therapeutic candidates and product-specific and platform-related deals, particularly in the area of delivery.  With appetite for innovation increasing in a low interest rate economy and with the orphan drug tsunami, 2013 could be a quite rewarding year for the discerning investor.

Clinical results to look out for

Clinical results in 2013 that will continue to shape perceptions of the technology include phase II study results for ALN-TTR02 in TTR-FAP by Alnylam, phase I results from its GalNAc conjugate version ALN-TTRsc, and phase I results from a number of other programs, foremost from oncology drug candidate TKM-PLK1 by Tekmira, ALN-AT3 for hemophilia by Alnylam, and finally RXI-109 for dermal scarring by RXi Pharmaceuticals.  

For ALN-TTR02, it will be important to confirm the impressive knockdown results from the phase I study, but over longer periods of time and with still acceptable safety.  ALN-TTRsc will be an important proof-of-concept for the subcutaneous delivery of RNAi Therapeutics and should provide a good idea of what to expect for ALN-AT3 which is based on the same GalNAc siRNA conjugate technology.  The success or lack thereof of Alnylam’s GalNAc technology will also affect the perception of Arrowhead’s DPC technology as either a competing or necessary subQ alternative to GalNAcs.

Tekmira’s TKM-PLK1 has not gotten much credit so far.  This, however, could change with the presentation of the full phase I results, possibly at this year’s ASCO.  I consider PLK1 as the single most attractive target for cancer RNAi and I am bullish that the molecular analyses will show molecular, if not clinical efficacy at this early stage.  And while TKM-PLK1 could overcome the safety-efficacy hurdle for some indications, the importance of PLK1 as a target demands that Tekmira will continuously work on improved follow-on versions.

Finally, RXi’s second phase into RNAi for skin applications.  I also consider dermal scarring as an interesting differentiated, because cosmeceutical RNAi product opportunity.  

Cool pipeline additions

As detailed in my last blog entry, there are two exciting infectious disease drug candidates for which clinical development will ramp up in 2013: Arrowhead’s ARC520 aiming to achieve for HBV what has recently been achieved in HCV (dramatically increased cure rates and less suffering from the side effects of interferons), and Calimmune’s ddRNAi-based HIV drug candidate aiming to keep the virus out of immune cells.

It looks like we will have to wait for clinical efficacy results from these programs for a while (2014-2015), either due to the nature of the cell competition approach involved in the HIV program or because of the use of healthy volunteers.  I believe the latter is what Arrowhead has guided for ARC520, but from an investor perspective this would be highly unforunate as this would delay the demonstration of gene knockdown with the DPC platform.  And from a medical perspective, I am struggling to see what the value or necessity of a volunteer trial would be.  

Deals and Big Pharma

In addition to clinical trial results, RNAi Therapeutics investors will be getting up each morning to check the internet for whether a deal has been announced.  Alnylam’s ALN-PCSK9 is the most imminent partnering candidate and will be an indicator of the mere differentiation value of RNAi Therapeutics.  While clinically more advanced monoclonal antibody-based programs for the industry’s most desired target, PCSK9, exist, should monoclonal antibody stumble as a class, RNAi Therapeutics and ALN-PCS could suddenly have the market for itself.  Considering the multi-billion $$$ potential of PCSK9, a gamble worth taking for a Big Pharma in my opinion.

Similarly to ALN-PCS in the hypercholesterolemia market, the size and complexity of the clinical program that would be required to turn ARC520 into a major HBV drug well exceeds Arrowhead capacities, and this could mean that we will see an early licensing deal around that asset, too.  While proof-of-concept clinical knockdown data would greatly increase the partnering value of ARC520, from a financial perspective (--> di-lu-tion!) early partnering may be prudent if no alternative non-dilutive capital alternative presented itself.

As delivery is gating for all of the above RNAi Therapeutics product opportunities, delivery naturally should be the subject of a few more platform-type relationships.  Tekmira’s SNALP technology for addressing diseases of the liver, lung, and cancer tops the list for a meaningful partnership (>$10M upfront), and also Arrowhead’s DPCs for liver-targeted gene knockdown ought to see some interest.  

Delivery-related deals should also reveal which Big Pharma company is still committed to the RNAi Therapeutics platform.  For the efforts at Takeda, Merck, and Novartis (the three most significant ones in terms of investment to-date), it could be a make-or-break year.  I cannot imagine that these groups are allowed to exist in their current forms for much longer before they get anything into the clinic.  For this, they probably need to swallow their own pride and accept that expert outside help is necessary for their delivery needs (rather than attempting home-brew versions).  Given the recent clinical and late preclinical results for SNALPs and DPCs, chances that they will finally do something have certainly increased.

A Happy New Year everybody.

Genzyme Taps RNAi Therapeutics for TTR Amyloidosis

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

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

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

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

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

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