New Antibody Data Indicate Tough Battle for RNAi Therapeutic PCSK9 Approach

The past week has been a busy one for the hypercholesterolemia field. New clinical data for PCSK9-targeting monoclonal antibodies from Amgen and Regeneron/Sanofi-Aventis were presented at the 2012 American College of Cardiology meeting, while ISIS/Sanofi-Aventis separately presented long-term efficacy, and especially safety data on the ApoB antisense compound mipomersen (aka KYNAMRO) for which marketing applications have now been submitted in Europe and the US. As hypercholesterolemia also represents a significant medical and commercial opportunity for RNAi Therapeutics due to the advances in knocking down genes in the liver, I will briefly summarize the new data and discuss some of the implications for RNAi approaches, including the phase I candidate ALN-PCS02 by Alnylam.

If there ever were doubts as to the commercial attractiveness of PCSK9 as a target for treating high cholesterol, last week dispelled them all. When it seems that all the thought leaders in the field, including famed cardiologist Steven Nissen, otherwise known for his ultra-critical views of certain medicines, and Wall Street (expected annual sales as a class of up to $20B thrown out) hail the data as proof that PCSK9 will be the final nail in the hypercholesterolemia coffin and thus throw their support behind the class, the commercial success of PCSK9-targeting therapeutics seems a foregone conclusion.

Although pretty much every large pharmaceutical company sports a PCSK9-targeting antibody, the excitement this time centered around the phase II data of Regeneron’s/Sanofi-Aventis’ REGN727 and phase I data of Amgen’s AMG145.

The REGN727 phase II 8-12 week multi-dose studies were conducted in close to 300 patients with elevated ‘bad’ LDL-cholesterol (LDLc) on statins. Depending on the amount and schedule of antibody administered, mean LDLc reductions (note: it is not entirely clear to me whether this refers to the LDLc reduction over time, or the peak LDLc reductions) of 40-73% were achieved. Interestingly, one press report said that ‘727 suffered from relatively short-lived activity such that subcutaneous administrations every 2 weeks would be required.

The phase I studies with ‘727, just published in NEJM (Stein et al.) indicated that the apparent rebound effect after 2 weeks may be due to the concomitant use of statins and that without statins, 50-55% persistent LDLc reductions can be achieved with close to 4-week dosing intervals. This is relevant for example for the statin-intolerant population. With statins, that type of persistent knockdown (more on the higher end of that range) would probably require every 2 week dosing.

AMG145 seemed to attract even more excitement than '727. In the 6 to 8-week phase I studies in around 100 patients taking statins, mean LDLc reductions of 63-75% were observed. These numbers indicate more potent, and likely more persistent LDLc lowering compared to REGN727, although without having seen the LDLc response curves over time, it is difficult to conclude that for sure.

Route of administration and dosing frequency are often cited as important competitive criteria for this class of drugs. In the case of ALN-PCS02 which is enabled by Tekmira’s SNALP technology, the current data indicate that a range of 40-55% persistent LDLc reductions with intravenous dosing every 4 weeks are conceivable. This, however, would require further improvements in potency over the 0.25mg/kg dose level which was the highest dose for which data was presented by Alnylam at their early January update. For this indication, it will also be important to wean the SNALP formulation off the transient immune suppression currently used. This would not only address criticisms that such immune suppressions carry risks, but it also would likely get rid of the observed PCSK9 rebound effect that was apparently linked to it and would thus contribute to prolonging the efficacy.

Of course, an important wildcard in the competition between MAbs and RNAi pertains to the safety of each drug candidate, especially when they are used long-term. The monoclonal antibodies seem to perform quite well in this regard in the short-term, albeit multi-dose studies. RNAi, however, has the theoretical advantage in that it does not involve the formation of antibody-PCSK9 complexes which could eventually have an impact on both long-term safety and efficacy/dosing frequency.

In retrospect, RNAi has picked a tough battle here. As a target that acts extracellularly, readily accessible from the blood, it seems an ideal target for monoclonal antibodies and thus falls outside the undruggable target space that currently still drives the interest of large pharmaceutical companies in RNAi Therapeutic development. On the other hand, the PCSK9 field is populated with antibody approaches, and should there be antibody-specific class adverse effects, RNAi could be the last one standing (note: the antisense candidates by ISIS and Santaris have already dropped out of the race, at least for now), something that one of the few Big Pharma/Biotech that has not yet invested in a PCSK9 candidate may value from a strategic point of view alone (RE partnering).

Meanwhile, the mipomersen extension study data presented this week suggest that the high drop-out rates and liver fat accumulations* (both possibly linked to some extent) at modest ~30% LDLc reductions make it a niche drug for the very small indication of homozygous familial hypercholesterolemia in the US and Europe, and possibly severe hypercholesterolemia in Europe. Although ISIS continues to claim that the liver fat accumulations normalize after reaching maximum median increases of +13% over baseline at week 52 (note: according to the mipo-related Visser et al. 2009 study, 5.6% absolute intrahepatic triglyceride contents are considered the upper-limit of normal), the absolute values would call for caution, especially when there are outliers in whom almost half the liver consists of fat. In the related conference call, ISIS further claimed that the apparent normalizations were not the result of the patients that discontinued mipomersen (possibly due to high liver fat contents). However, since ISIS has a history of erring on the side of optimism when it comes to mipomersen safety and tolerability, I’d like to see the liver fat-related sub-group analyses that take into account the discontinuations, dose reductions and interruptions.

The liver fat data may also mean that ApoB is unlikely to be a suitable stand-alone target for an RNAi Therapeutic, especially if even more pronounced ApoB knockdowns can be achieved than with mipomersen. Consequently, in order to exploit the therapeutic utility of ApoB as the critical protein of atherogenic lipoproteins, an ApoB-targeting RNAi Therapeutic should involve at least one other target gene which will also reduce liver fat content. It remains to be seen whether ApoC-III can be that target.

* Note: Despite the caution expressed in this article, I should add that there is general controversy about the relevance of simply elevated liver fat (NAFLD) in the absence of inflammation.

RNAi Therapeutics Financial Viability Looking Up Following String of Clinical Results

By: Dirk Haussecker

Note: A PDF version of this article is available at myfirstnameDOTmylastnameATgmailDOTcom

Abstract

Shortly after the 2006-8 period of exuberance during which access to capital was easy, the RNAi Therapeutics industry found itself in a financially difficult position. At the roots of this change were the eventual recognition of some poor science, clinical setbacks, and the tension arising from the more gradual progress of science and impatient markets. Clinical validation of RNAi-mediated gene knockdown following systemic delivery was seen as the only way out of this situation. This review summarizes how such critical validation was provided by a series of recent clinical results from the ALN-VSP02, Atu027, ALN-TTR01, and ALN-PCS02 development programs. These results are expected to reinvigorate investments in the technology.

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Background

In the spring of 2011, the RNAi Therapeutics industry had just gone through two financially very stressful years. A few large pharmaceutical companies (‘Big Pharma’), among them Roche and Pfizer, made high-profile exits from the space [1], pure-play RNAi Therapeutics companies were crashing, and optimism gave way to a sense that RNAi in humans may take much longer to achieve than once thought due to the delivery challenge and the risk of causing immune stimulations [2]. This negative view of the technology and its financial prospects came sudden. After all, it was only in 2006-8 that the medical importance of RNAi had been recognized with the Nobel Prize in Physiology or Medicine [3], and Merck and Roche alone accounted for almost $2B of investments in the technology.

The argument can be made that the RNAi Depression was catalyzed by the US Housing Crisis and the ensuing global financial turmoil towards the end of 2008. This triggered a retrenchment of capital from high-risk innovation, capital that failed to return to the RNAi space. The seeds, however, had already been planted during the RNAi Therapeutics hype phase. As often is the case in such periods, it attracted the attention of the notorious promotional biotech schemes which in turn were readily followed by the fast money crowd, all of which, of course, did not mix well with the more gradual pace of technological progress. The scientifically leading pure-play RNAi Therapeutics companies can be accused as well for having catered to the cravings of fast money by over-promising on timelines and pushing programs into the clinic which were not adequately mechanistically validated (e.g. clinical candidates based on the local administration of naked, sometimes entirely unmodified siRNAs to the eye and respiratory epithelium). Similarly, the scientific community and journals can be blamed for failing to better police the quality of the science that got published [4,5]. Consequently, considerable investments were made (and wasted) with little discernment to what was deserving science and what was not. When it was realized that only a very few of the claimed technical solutions had clinical potential, the equally erroneously conclusion was drawn that the technology as a whole had poor prospects instead of realizing that only a very few successful platform technologies can already create considerable value.

With investors tiring of ‘promising’ pre-clinical results and refusing to put more money into RNAi Therapeutics development unless clinical validation was seen, it was up to the science to prove itself in Man. If not, probably all of the significant pure-play RNAi Therapeutics companies, possibly with the exception of Alnylam, would find it impossible to raise capital on acceptable terms. Fortunately, despite the attendant contraction in the number of new development programs, some of the early capital meant that four candidates in particular had entered clinical development in time to be the industry’s chance at unambiguously validating RNAi in Man: ALN-VSP02, Atu027 ALN-TTR01, and ALN-PCS02. If this could be achieved, it was likely that capital would return to the space. If not, the added wait before such clinical validation could come would have been a great setback to the industry, a setback from which it might have been difficult to recover from financially.

ALN-VSP02 and Atu027: clinical safety of two leading delivery technologies

Together with CALAA-01 (sponsor: Arrowhead Research), Alnylam’s ALN-VSP02 and Atu027 by Silence Therapeutics were the three leading RNAi Therapeutics candidates in cancer, with enrolment starting in 2008-2009. Not only were these candidates important in their own right for their medical and commercial potential, they were supposed to clinically validate the three distinct systemic delivery platforms on which they were based: the cyclodextrin-containing polycation RONDEL technology (CALAA-01), the AtuPLEX lipoplex technology (Atu027), and SNALP liposomes (ALN-VSP02). In addition to cancer, together with hepatic applications the commercially most critical application of RNAi Therapeutics in the near to medium term, AtuPLEX has potential for endothelial cell-directed gene knockdown in general, and systemically administered SNALP also for liver and phagocytic cell-directed gene knockdown.

CALAA-01 enjoyed a year head-start and reported a first data update in a high-profile paper in April of 2010 [6]. Attracting the widespread interest was the fact that by taking tumor biopsies, the investigators were able to demonstrate, with the help of the 5’ RACE assay on tumor biopsies, that RNAi had occurred in target tissues. Moreover, evidence was provided that consistent with this functional finding, RONDEL nanoparticles could be detected in the biopsies. On the other hand, the data on the target knockdown was more ambiguous. Although the RNA analysis suggested measurable gene suppression, the protein analysis did not fully support that. The early promise was only short-lived, however, as a subsequent 2010 ASCO presentation (Abstract No: 3022) showed ample innate immune stimulations which forced the company to concede in late 2011 that at least another phase I trial was necessary in an effort to better manage them. In retrospect, it seems obvious that a major omission of the program was in leaving the RNAi trigger (targeting the M2 subunit of ribonucleotide reductase, RRM2) chemically unmodified, meaning that the risk of inducing such responses was quite high. In the absence of evidence for clinical efficacy and unexplained trial delays (it has taken ~3 ½ years to conclude enrolment), the CALAA-01 phase I results were thus unable to positively impact perceptions of RNAi Therapeutics.

An important step forward in that direction was made with the 2011 ASCO presentations of the fully enrolled phase I study of ALN-VSP02 and a quite encouraging interim update for Atu027. The data suggested that Atu027, an endothelial cell-directed multilamellar cationic lipoplex containing an RNAi trigger against PKN3 [7], was surprisingly well tolerated as dose escalation had reached dosages at which gene knockdown efficacy could be expected based on the preclinical animal data. Dose escalation has been ongoing since and has exceeded predicted RNAi-functional doses- and still no dose-limiting toxicities or serious adverse events were claimed as of December 2011. The reason why this is somewhat unexpected is that the positively charged lipoplexes may have been considered prone to induce various innate immune responses [8], also because no immune suppressive regime was used in the trial. It is possible that the extensive 2’-O-methylation of the AtuRNAi-type trigger partly accounted for that. Activations of the alternative complement pathway, however, were noted, although these were claimed to be clinically not significant. Tumor responses by stringent RECIST criteria meanwhile remain to be demonstrated. Nevertheless, the overall safety profile and well-behaved pharmacokinetics have encouraged further investments in the AtuPLEX and related cationic lipoplex delivery platforms from Silence Therapeutics and can be considered a meaningful step forward for the field.

Of the three candidates, the most ambitious phase I study was that for ALN-VSP02, a SNALP formulation that includes two siRNAs, one against VEGF and KSP for anti-angiogenic and anti-proliferative mechanisms of action, respectively. Enrolling 41 patients with advanced solid cancer with liver involvement, this study included a battery of tests, including biopsies to test for target mRNA cleavage and siRNA tissue concentrations, the measurement of tumor blood perfusion as an indicator of anti-VEGF activity, and various other pharmacological parameters. The study succeeded in demonstrating that this SNALP formulation was fairly well tolerated in these advanced cancer patients at dosages of up to 1.0-1.25mg/kg (ASCO 2011 poster #3025). Among the dose-limiting toxicities were a liver failure with subsequent death at 0.7mg/kg, two cases of transient grade 3 thrombocytopenia at 1.25mg/kg, a grade 3 hypokalemia at 1.5mg/kg, and four grade 1-2 rigor/chills at 1.0mg/kg (one case) and 1.25mg/kg (three cases). The death at the 0.7mg/kg dose was deemed to be possibly related to study drug and occurred in a patient where the tumor burden in the liver was quite extensive. The enrolment criteria were subsequently adjusted to exclude similar patients with a greater than 50% tumor burden in the liver.

Based on the pre-clinical studies (AACR 2009 poster #B204), knockdown activity could have been expected at dosages of 1.0-1.25mg/kg. Consistent with this notion, the 5’ RACE for VEGF (but not KSP) RNAi cleavage performed on the biopsies revealed RNAi activity. In terms of functional activity, the Ktrans, a measure of tumor blood perfusion, declined by 40% or more in over half the patients that had received one or more doses and was consistent with anti-angiogenic activity of the drug. It has to be said though that the Ktrans response was not nearly dose related. Evidence for dose-responsiveness, however, was provided when categorizing patients according to RECIST criteria of tumor responses. Accordingly, only one in 13 patients treated with up to 0.4mg/kg had stable disease for two months or more. This compared to 12 of the 24 given higher doses. Moreover, there was a 70% partial tumor response in an endometrial cancer patient at 0.7mg/kg who stayed on study drug for months; at the 1.0mg/kg dose, the recommended dose for further studies, 7 of 11 achieved stable disease. Despite these preliminary signs of activity, there remain questions about the choice of the target genes, particularly the suitability of VEGF as an RNAi target and the absence of detectable KSP cleavage. Moreover, systemic SNALP delivery to even tumors in the liver is thought to require extended blood circulation times in order to harness the EPR effect, yet the half-life of siRNA in the blood was only in the 15-30 minute range. This is consistent with the relatively short C14-PEG lipid anchor in this formulation. Notwithstanding, the ALN-VSP02 study was a stringent test for the safety of SNALP delivery and added considerable clinical pharmacokinetic experience to this technology. Among the latter was the detection of amounts of siRNAs in normal liver which strongly indicated [9] that gene knockdown with SNALP was possible for liver-expressed genes.

ALN-TTR01 and ALN-PCS02: most impressive demonstrations of RNAi in Man

Despite the largely acceptable safety and promising pharmacokinetic data from the Atu027 and ALN-VSP02 studies, the field still lacked black-and-white evidence for target gene knockdown following systemic delivery. The SNALP-enabled TKM-ApoB by Tekmira in early 2010 was close to providing such evidence. Unfortunately, concomitant with the achievement of slight ~20% ApoB reductions, moderate immune stimulations were observed at 0.6mg/kg in the dose escalation trial, causing the company to terminate the trial (http://clinicaltrials.gov/ct2/show/NCT00927459?). The burden thus fell onto ALN-TTR01, another SNALP-enabled RNAi Therapeutics targeting the liver-expressed transthyretin gene. Mutations of this genes frequently cause familial amyloidotic polyneuropathies and cardiomyopathies which shorten the lives of ca. 50,000 patients worldwide.

This time implementing transient immune suppression (corticosteroids and H1/H2 histamine receptor blockade) as a precautionary measure, the trial began enrolling patients in June 2010 in Europe. A little more than a year thereafter, Alnylam presented almost full trial data at the November 2011 FAP conference in Kumamoto, Japan. It came as a great relief that at the highest, 1.0mg/kg dose the 5 patients exhibited a mean reduction of serum TTR of 41% following a single intravenous infusion. One patient exhibited a text-book 81% RNAi-type TTR reduction at nadir (week 1), with pronounced knockdown persisting out to 4 weeks (50%). Without ifs or buts, this was clear demonstration of effective RNAi in Man. Equally important, except for mild-to-moderate infusion reactions which were readily managed by simply slowing the rate of infusion, no meaningful adverse events were reported. As that trial is currently being wrapped up with more patient data expected for the 1.0mg/kg dose cohort, the sponsor Alnylam is aiming to further enhance the competitive profile of its TTR candidate and has filed a CTA for clinical trials with a new, ALN-PCS02-type SNALP formulation for which equivalent gene knockdown can be expected at 10-fold or more reduced dosages (patent application WO 2010/144740 A1). The goal here is to achieve a more potent knockdown with a higher margin of safety and a once every month or two dosing frequency.

The RNAi clinical dataflow culminated in early January 2012 with Alnylam announcing dose escalation data for the phase I study of ALN-PCS02 for the treatment of hypercholesterolemia. As predicted, equivalent knockdown to ALN-TTR01 were obtained at much reduced dosages with this improved ‘MC3-type’ SNALP formulation from Tekmira: ~60% mean peak reductions in serum PCSK9 for the 0.15mg/kg and 0.25mg/kg dose cohorts. As PCSK9 antagonizes ‘bad’ LDL cholesterol removal from circulation [10], its inhibition was accompanied by ~35% reductions in LDL cholesterol. Due to the favorable safety profile (rashes were noted, but these were likely related to route of administration as they also occurred in the placebo cohort), dose escalation is expected to proceed. At the higher dosages, more robust, less variable knockdown can be expected for both PCSK9 and LDL-cholesterol. This would put it in a favorable competitive position vis-à-vis the PCSK9 monoclonal antibody competition (e.g. REGN727/SAR236553).

The most significant limitation of the ALN-PCS02 study turned out to be the use of transient immune suppression. These caused short-lived (+65%) spikes and (-25%) depressions of PCSK9 and LDL-cholesterol, respectively. While transient immune suppression should be acceptable for many of the initial indications of high unmet medical need for which SNALP-based therapeutics are largely being developed at the moment, especially if once every month or two dosing can be achieved, they can not only complicate the analysis of studies such as ALN-PCS02, but would also restrict the eligible patient population for a condition such as hypercholesterolemia. Introduced as a precautionary measure following the TKM-ApoB experience, the question is whether it is possible to do entirely without it as SNALP potency has improved [11], lipid-specific toxicities been minimized, and more predictable innate immune stimulation assays been introduced as presented by Tekmira at a Drug Information Association (DIA) meeting on March 23, 2010, in Bethesda, MD.

Conclusion

The clinical results not only provided the long-awaited clinical validation and are a boost of confidence for the entire RNAi Therapeutics industry, but they directly de-risk two of the most important systemic delivery technologies: SNALP and AtuPLEX. The results with SNALP in particular set the stage for a forceful expansion of this delivery platform with already 5-6 candidates in active clinical development: ALN-VSP02, ALN-TTR01+02, TKM-PLK1, TKM-EBOLA, and ALN-PCS02. More still are expected to enter the clinic over the next two years. The following months should also add to the SNALP clinical experience in the form of results from the fully enrolled and dose-escalated ALN-TTR01 and ALN-PCS02 trials, an update on Tekmira’s cancer therapeutic candidate TKM-PLK1, and safety data from the TKM-EBOLA volunteer study. Since the ASCO 2011 presentation, Atu027 has attracted commercial interest in the form of various technology evaluations of AtuPLEX and related delivery technologies from Silence Therapeutics (partners: InteRNA Technologies, Mirna Therapeutics, an undisclosed Japanese ‘Top Ten’ global pharmaceutical company, and miRagen).

The space, however, awaits confidence expressed in the form of a more major financial commitment by a larger pharmaceutical company. This might break the gridlock caused by Roche’s decision to stop in-house RNAi Therapeutics development, a decision so powerful that it essentially caused all capital to retrench to the sidelines or leave RNAi Therapeutics entirely. What should not be lost is that the current situation also represents an attractive technical risk-financial reward opportunity for those companies that dare rely on their own scientific instincts rather than follow the herd. This includes mid-sized pharmaceutical companies and those in the newly emerged and emerging economies which are playing an increasingly important role in RNAi Therapeutics. As access to capital normalizes, platforms in addition to SNALP and AtuPLEX will likely emerge and help further expand the therapeutic reach of RNAi Therapeutics.

Abbreviations

5’ RACE: 5’ rapid amplification of cDNA ends; Ktrans: volume transfer coefficient; RECIST: Response Evaluation Criteria of Solid Tumors; RONDEL: RNAi/Oligonucleotide Nanoparticle Delivery; siRNA: small interfering RNA; SNALP: stable nucleic acid lipid particle.

References

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3. Zamore PD: RNA interference: big applause for silencing in Stockholm. Cell 2006, 127: 1083-1086.
4. Tolentino MJ, Brucker AJ, Fosnot J, Ying GS, Wu IH, Malik, Wan S, Reich SJ: Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina 2004, 24: 132-138.
5. Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E, Ostroff GR, Czech MP: Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 2009, 458: 1180-1184.
6. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A: Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010, 464: 1067-1070.
7. Aleku M, Schulz P, Keil O, Santel A, Schaeper U, Dieckhoff B, Janke O, Erdruschat J, Durieux B, Roeder N, Löffler K, Lange C, Fechtner M, Möpert K, Fisch G, Dames S, Arnold W, Jochims K, Giese K, Wiedenmann B, Scholz A, Kaufmann J: Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res 2008, 68: 9788-9798.
8. Yew NS, Scheule RK: Toxicity of Cationic Lipid-DNA Complexes. Adv Genet 2005, 53PA: 189-214.
9. Landesman Y, Syrzikapa N, Cognetta A 3^rd, Zhang X, Bettencourt BR, Kuchimanchi S, Dufault K, Shaikkh S, Gioia M, Akinc A, Hutabarat R, Meyers R: In vivo quantification of formulated and chemically modified small interfering RNA by heating-in-Triton quantitative reverse transcription polymerase chain reaction (HIT qRT-PCR). Silence 2010, 1: 16.
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ALN-PCS02 Results Provide Glimpse of First RNAi Therapeutics Blockbuster

If the experts at Roche and other Big Pharma companies got you convinced that RNAi Therapeutics was about to disappear from the scene by pulling the plug on the technology…think again. Alnylam this morning reported tantalizing insights into the safety and efficacy of ALN-PCS02, a SNALP-formulated RNAi Therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. Given that PCSK9 is viewed as potentially the next biggest thing in cardiovascular drug development after statins have come off patent, and considering the results so far from the monoclonal antibody and antisense competition, this RNAi Therapeutic has the potential to become the field’s first blockbuster. As we know, a field does not need too many blockbusters to become more widely accepted, and it is acceptance, not so much lack of scientific progress, which has been lacking over the last 2-3 years. Together with the ALN-TTR01 results reported in November, I expect these results to dramatically change perceptions about RNAi Therapeutics in the pharmaceutical industry. And if I had to write the script, Alnylam will announce a share offering tomorrow or Friday afternoon in order to go hostile on Tekmira to remove the uncertainties arising from their use of Tekmira’s SNALP technology which critically enabled these results and on which most of Alnylam's $400M market cap depends on.

ALN-PCS02 Phase I Data

This trial was a simple single-dose escalation trial in subjects with slightly elevated levels of bad LDL cholesterol. Dosing in the 5 dose cohorts commenced at 0.015mg/kg and went up to 0.250mg/kg with each cohort consisting of 3 subjects receiving an intravenous infusion of ALN-PCS02 and 1 receiving placebo. As could have been expected with this particular rationally designed '2nd gen' SNALP formulation, robust target protein knockdown was observed at the highest dose tested with a mean 60% reduction in plasma PCSK9 levels presumably 3-5 days after administration. In line with PCSK9 genetics, this type of knockdown entailed a mean 39% reduction in bad LDL cholesterol. Importantly, and again consistent with the wealth of non-human primate data, this knockdown was sustained for days and weeks. Given that ALN-PCS02 apparently was well tolerated, with the only noted adverse event being a rash that was likely to be related to the mode of administration and not the drug itself, Alnylam now plans further dose escalation to a) increase knockdown potency, but b) also extend the duration of PCSK9/LDLc suppression. This is particularly desirable in light of the competitive situation.

The PCSK9 Competition

Needless to say, having now two examples in short order where RNAi Therapeutics unambiguously hit their targets, proof-of-concept of technical success can be claimed and one can now focus on the medical and commercial potential of these therapies. In this regard, the competition in the PCSK9 space is fierce. Big Pharma and Big Biotech have fielded their A-teams to develop monoclonal antibodies against PCSK9. Since much of the LDL-related effect is due to PCSK9 in the serum, this target is a particularly amenable to MAb technology.

Sanofi-Aventis/Regeneron are most advanced with REGN727 which is in the middle of a number of phase II studies. Amgen also reported recently phase I results with their PCSK9 MAb. Studies with both compounds have shown more potent LDLc reductions of around 65% compared to the 39% with ALN-PCS02 so far. This, of course, is a good reason for Alnylam to go ahead with its plans and continue dose escalation. However, once you achieve the type of 60-70% reductions in LDLc, the next major focus becomes safety, and so far the RNAi Therapeutic looks quite competitive in that regard.

As discussed in October, the PCSK9 antisense compounds by Santaris and ISIS have fallen a bit behind due to probably both safety (Santaris) and efficacy (ISIS) issues, although I expect ISIS to reciprocate tomorrow by presenting TTR knockdowns at their Investor Day tomorrow that are more pronounced than Alnylam’s first attempt with ALN-TTR01.

[Update 5Jan12: ISIS reported 44% mean TTR reductions at 200mg per week, very similar to ALN-TTR01 at 1mg/kg; and 81% reductions at 400mg per week, a dose that I consider too high for tolerability and commercialization; ISIS also disclosed that the BMS-partnered PCSK9 candidate was dropped citing a slow partner and regulatory concerns about PCSK9 as a drug target].

Overall, we can now conclude that the ALN-TTR01 results were no fluke (I never expected that to be the case anyway) and that in theory all targets in the liver are fair game now for RNAi Therapeutics. Moreover, the data show that the preclinical data with SNALPs translate very well into humans, removing a considerable uncertainty and opening up the prospect of further improvements in SNALP delivery based on what Tekmira and Alnylam have presented over the last few months.

A biotech company does not need many these PCSK9-type products to rise into the ranks of Big Biotech. While there is still a long clinical way to go, I believe that sometimes you are allowed to cheat and look at hard preclinical data, and in doing so I believe that today we may have seen the first glimpse of an RNAi Therapeutics blockbuster. I’m wondering how the Roches and Pfizers will be feeling over the coming months and years as the field of RNAi Therapeutics matures at this rate. It is also an opportunity for new entrants to build strong positions in the space with relatively small investments (still). Am I a bit vindictive today? Yes, definitely.

RNAi Therapeutics Investors Hoping for a Merry Christmas

I’ve just come back from working at the Starbucks across my street which strongly reminded me that Christmas was just around the corner. Christmas this year in RNAi Therapeutics is synonymous with data releases by Alnylam from its transthyretin amyloidosis (ALN-TTR01; data presentation November 20-22 in Japan) and hypercholesterolemia (ALN-PCS02; release of top-line results by year-end) phase I clinical trials. These have the potential to demonstrate, for the first time, direct and physiologically meaningful target gene knockdown following systemic RNAi delivery, and thereby have the potential to turn around still negative RNAi Therapeutics sentiments and depressed valuations.

Some of the anticipation can already be felt in the form of appreciating share prices of Alnylam and Silence Therapeutics, together with Tekmira the companies most directly exposed to the current RNAi Therapeutics dataflow, and the financial analyst-investment community which have turned noticeably bullish on Alnylam. Only Tekmira, the inventor of SNALP technology that powers ALN-TTR01, ALN-PCS02 and 5 other candidates in or close to clinical development, has not participated in the rally by failing to find investors willing to defend its stock after taking on well-connected Alnylam.

In assessing the data, a primary focus will be on whether dose escalation was able to proceedeup to the highest planned doses (1.0mg/kg for ALN-TTR01 and 0.25mg/kg for ALN-PCS02) and whether, despite the small number of patients at the high dose levels, there are clear signs for target gene knockdown. 50% target gene knockdown in both cases would be reasonable goals, and probably also necessary ones to have the desired impact. In the case of ALN-PCS02 there should also be at least a 30% reduction in ‘bad’ LDL-cholesterol, the intended pharmacologic outcome of a PCSK9-targeting agent. In terms of safety, the absence of grade 3 adverse events or worse would be highly welcome, of course, as we would be the absence of consistent and clinically meaningful innate immune activations.

Santaris’ anti-miR122 HCV Drug Continues to Impress

MicroRNA Therapeutics seems to have found its poster child already with Santaris’ miR122 LNA antagonist for the treatment of HCV. In an oral presentation at The Liver Meeting which is just wrapping up in San Francisco, the company reported robust dose-dependent anti-HCV activity in a phase IIa study, with close to a 3-log mean reduction of HCV RNA from baseline and viral load below detection in 4 of 9 patients at the highest dose of miravirsen (7mg/kg). The corresponding abstract marking a milestone in microRNA Therapeutics by reporting first clinical activity of an microRNA Therapeutic was released in early October (click here for commentary). There is no doubt that this drug candidate works as expected/hoped for, and unless the future of HCV treatment is in all-oral combos, anti-miR122 with its uniquely differentiated mechanism of action looks like a valuable addition to the fast-moving field of HCV care.