Tekmira and Arrowhead Advance Cancer RNAi Therapeutics

This week, important developments for two of the most advanced cancer RNAi Therapeutic candidates were announced. Arrowhead reported that it has now completed enrolment of the phase I CALAA-01 study and is initiating a dose-optimizing phase Ib study, while Tekmira disclosed that it has received the green light from the FDA to go ahead with an additional phase I study of TKM-PLK1, this time using Hepatic Arterial Infusion to complement an ongoing effort involving intravenous administration. This study will be conducted in collaboration with the National Cancer Institute (NCI).

CALAA-01: Optimizing dosing schedule

CALAA-01 is a targeted cyclodextrin-based nanoparticle formulation (RONDEL) of unmodified siRNA against RRM2, a gene involved in DNA synthesis (more background on CALAA-01 here). Enrolment in the phase I clinical trial commenced 3 years ago. Interim data were presented last year in a Nature paper and the ASCO annual meeting. At that time, about 15 patients with various forms of advanced solid cancers had been treated. Encouraging qualitative biopsy results showed that at least some of the RNAi Therapeutic reached its physical target and was able to mediate RNAi target cleavage there.

Until then, no dose-limiting toxicities had been seen. The ASCO presentation, however, revealed that there were fairly widespread, albeit low-grade (g1-2) immune stimulations (‘flu-like symptoms’). The reason why immune stimulation with this candidate was fairly common is likely related to the fact that unmodified siRNAs were used. Judging from Arrowhead’s quarterly conference call this week, it seems as if the immune stimulation warranted a discontinuation of further dose escalation. The company stated, and I certainly agree, that it should use modified siRNAs in the future to mitigate this side effect.

Interestingly, what the company apparently found in the study is that in some patients the immune stimulation subsided following repeat-administration of the drug, as if they became desensitized to the immunostimulatory potential. It is therefore the goal of the newly announced phase Ib study to find dosing regimes that take advantage of this preliminary finding to achieve higher doses, e.g. by first giving a lower dose in order to desensitize before continuing with the predicted higher, hopefully efficacious dose. If this hypothesis can be confirmed, it would not only be positive for CALAA-01, but a valuable insight for the entire field of RNAi Therapeutics.

Having said that, in light of the clinical findings so far and reservations about the chosen gene target, I do not find CALAA-01 to be a compelling candidate. While I can agree with the phase Ib study, it is more because it will allow the company to gather further information about the RONDEL delivery system without much further delay as it continues its efforts to partner and monetize the delivery technology.

Situations like these highlight the risk of RNAi Therapeutics platform companies like Arrowhead/Calando and Benitec that refuse to have in-house R&D. In this case, in-house R&D could have already readied a modified RRM2 siRNA formulation, or even a formulation targeting a more exciting cancer gene target, without too much additional effort. Instead, more needs to be invested in a candidate that is difficult to partner already and may never make it into phase II, leaving Arrowhead to hope that their argument that the CALAA-01 studies are a way of de-risking the RONDEL delivery platform will convince potential partners and investors.

In my opinion, virtual drug development may be possible for one-in-a-kind therapeutic candidates, but is not compatible with building a platform.

Tekmira and NCI to Begin Hepatic Arterial Infusion (HAI) Study of PLK-1

The clinical development of TKM-PLK1 began earlier this year with a phase I dose escalation study using intravenous administration. Similar to ALN-VSP02, TKM-PLK1 is a SNALP-based formulation, but should be more widely applicable because its pharmacology was tailored so that it can also reach tumor tissues outside the liver. What makes TKM-PLK1 particularly exciting is that its gene target is probably the most potent one in the cancer field, having emerged many times as a top hit in genome- and kinome-wide RNAi screens for rapidly killing cancer cells without affecting normal cells.

The new phase I study of TKM-PLK1 that was announced this week will not only allow the company to more quickly gather important pharmacologic information on the drug, but should also be a viable alternative route of administering TKM-PLK1 for treating primary liver cancer and cancers with liver involvement by using Hepatic Artery Infusion to expose tumors to very high concentrations of the drug which would otherwise not be possible by simple intravenous administration.

Black box less black

One challenge in the development of novel cancer therapeutics is that it can take a long time before their true potential becomes clear. Biomarkers are therefore highly sought after, with RECIST tumor response criteria being a popular way of determining anti-tumor efficacy. Unfortunately, merely measuring immediate tumor responses is not always predictive of therapeutic success as sometimes you see such responses, but without concomitant increases in life expectancies (e.g. Avastin in advanced breast cancer, and many chemotherapeutic settings), and sometimes you don’t see them, yet you do get increases in life expectancies, an issue particularly relevant for targeted therapeutics (e.g. Provenge in prostate cancer).

Access to tumor biopsies is therefore very valuable in determining at an early stage whether your drug functions as expected on a molecular level and what tissue concentrations you need to achieve to trigger these responses. It is therefore an attraction of the new study that it will allow for biopsy collection. Through this, Tekmira should further learn more about which tumors types may be most suitable (e.g. primary/metastatic, genotype, pH).

Aside from the scientific value of the study, this study has the added benefit in that it could help validate Tekmira's platform technology for cancer in a controlled and timely manner, at a time when Alnylam evaluates Tekmira’s technology mainly for knocking down genes in ‘normal’ liver. Clinical data from both these approaches are expected in coming months and should serve as catalysts.

A treatment in its own right

Liver tumors almost exclusively derive their blood supply from the arterial circulation, whereas 75% of the blood flow in normal liver comes from the portal vein. Because of SNALP pharmacokinetics, this means that directly infusing TKM-PLK1 should have the benefit of increasing the drug exposure of liver tumors while at the same time greatly reducing potentially dose limiting exposures of the normal liver(***see correction and clarification below), the predicted dose-limiting organ for SNALP technology. This therefore should make it possible to achieve higher maximally tolerated doses, an important goal in most cancer drug developments.

It is for this reason that Hepatic Artery Infusion (HAI) has become an accepted and frequently used drug delivery modality in the treatment of unresectable liver tumors. Therefore, should the results suggest therapeutic efficacy in this setting, it could well pave the way towards studying HAI of TKM-PLK1 directly in phase III studies.

****Correction and clarification: I have received justified criticism of my statement that HAI would ‘greatly reduce potentially dose limiting exposures of the normal liver’.

The criticism was based on the notion that the normal liver in patients with liver tumors would still go on and be supplied by blood from the hepatic artery in addition to the blood supplied by the portal vein. Consequently, a good chunk of what you provide by HAI would also end up in the normal liver parenchyma. On the other hand, the critique was based on the assumption that the liver tumors would not compete for blood from the hepatic artery. My take on that is that this is probably a good assumption especially for smaller tumors, but in cases where liver tumors make up the bulk of the total liver mass, at least based on high-school physics (pressure and diameter of a tube determining the flow of liquids), there should be at least some quantitative shunting of hepatic arterial blood away from the normal liver.

Moreover, the criticism raised another factor determining whether direct HAI of SNALP will enhance SNALP uptake by cancer cells relative to intravenous infusion, namely whether the SNALP particles get taken up efficiently during the first pass of SNALP through the liver tumor. SNALP uptake is determined by various factors such as time, ionization behavior, active targeting, LDL-receptor status, so that’s probably a more complicated discussion.

Overall, the point is well taken, and while SNALP administration by HAI should have a positive effect on the ratio of drug concentration in Tumor relative to Normal Liver and therefore should increase the therapeutic index, I will have to partially retract my statement in that this is mainly due to optimized exposure of liver tumors during first pass and may vary significantly from tumor to tumor, and that another reason for choosing the hepatic artery vs portal vein may be just the relative surgical ease of accessing these structures.

CALAA-01 Results Indicate RNAi Therapeutics to Revolutionize Solid Cancer Treatment

In yet another important proof point that RNAi Therapeutics is slowly but surely morphing into a therapeutic reality, Calando just reported in the highly prestigious journal Nature an interim analysis of their phase I clinical study of CALAA-01 demonstrating an RNAi mechanism of action in solid cancer patients. The results are the most direct demonstration of RNAi in Man thus far, and, at least equally significant, show that the Enhanced Permeability and Retention (EPR) effect is indeed about to turn into the Achilles' Heel of solid cancers in the era of nanoparticle siRNA delivery.

Solid cancers are considered by many the most important near-term value driver for RNAi Therapeutics. The fact that Calando’s RONDEL nanoparticle delivery technology has now been shown to accumulate in solid cancer tissues is not only an important de-risking event for CALAA-01 itself, but it immediately suggest that RONDEL, and also quite likely other nanoparticle-siRNA delivery technologies, can facilitate the targeting of essentially any gene in solid cancers. It is this flexibility of the platform that makes RNAi Therapeutics ideally suited to satisfy the demands of a genetically such heterogeneous disease group as cancer.

Nanoparticle-siRNA delivery such as RONDEL is currently the most promising approach for treating solid cancers with RNAi Therapeutics. All of these rely on the particles being able to circulate sufficiently long in the blood stream and being small enough so that they can passively accumulate through EPR in the solid tumors as these lack an effective way of draining them through lymphatics. While the absolute amount of RONDEL particles that accumulated in the tumors remains to be determined, the Nature study clearly showed that a decent amount of them does accumulate there at ~0.6mg/kg.

While particle stability and ability to accumulate through EPR is a critical first step where we should also expect to see important differentiation between the technologies, once there, the nanoparticles then have to be taken up by the cancer cells and moreover mediate the cytoplasmic release of the RNAi trigger into the cytoplasm. Once again, RONDEL meets this challenge as it was possible to detect cleaved target mRNA characteristic of an RNAi mechanism of action. Although the so called RACE assay used for this analysis is not quantitative, in my experience, you have to get sufficiently robust RNAi to cleanly detect such products. Consistent with this notion, well over 50% target knockdown was detected for CALAA-01, although the limited number of samples (3) and the reliance on often only historical negative controls leaves open the question of the exact knockdown potency of CALAA-01.

It is in fact the pioneering work with RONDEL-siRNA delivery from which this pharmacokinetic model has been derived and that is now informing quite a bit our thinking of how to design siRNA-nanoparticles for solid cancer applications. For example, it was work on CALAA-01 that showed that the utility of the (transferrin) targeting ligand is in enhancing the cellular uptake of the nanoparticles, not so much in concentrating them in the tumors in the first place, and should be influential in the selection of targeting ligands being contemplated now for all types of delivery technologies, including SNALPs.


Summary of CALAA-01 results


CALAA-01 was also the first serious RNAi Therapeutics candidate for solid cancers that had entered the clinic in 2008. For a more thorough molecular background on this program, please refer to a previous entry (here) that was part of a 3-part collaborative series with Tobias Wolfram on the first RNAi Therapeutics solid cancer candidates. Briefly, CALAA-01 is a self-assembled nanoparticle system based on a cationic co-polymer containing cyclodextrin complexed with siRNA targeting RRM2, a gene involved in DNA replication, and that like most of the advanced nanoparticle-siRNA systems is stabilized through pegylation (some of these carry the transferrin targeting ligand). While Tobias and I had cautioned about a relative lack of preclinical in vivo characterization of CALAA-01, particularly not having directly demonstrated that CALAA-01 can knock down genes via RNAi in solid tumors following intravenous administration, it seems that the gamble of skipping some of the pre-clinical proof-of-concept has paid off for the investigators and Arrowhead Research (of which Calando is a subsidiary).

It was also a clever move that, amongst other tumor types, a number of melanoma patients were enrolled as such tumors can be easily accessed through biopsy and thus represent good material for molecular analysis of a clinical candidate. 3 of these volunteered to be biopsied. Despite the limited sample size, a number of conclusions can be drawn from the data: 1) RONDEL-siRNAs accumulated in the tumor tissues in a dose-dependent manner; 2) consistent with this, in the patient that received the highest dose, an RNAi mechanism of action was unambiguously confirmed by 5’ RACE; 3) this effect was long-lasting (>4 weeks) and accompanied by mRNA knockdown and disease stabilization; 4) RONDEL was safe and well tolerated in a study that involved repeat administrations and dose-limited toxicity has yet to be reached (right now at ~0.6mg/kg with dose escalation ongoing).

Clearly, these are highly encouraging results and call for the continuation of the phase I studies and further investigation of the modular RONDEL delivery platform. Importantly for shareholders, it should put Arrowhead in a better position to fulfill their stated goal of monetizing RONDEL either through licensing or outright sale. Part of the value would derive from the pioneering position of the RONDEL technology and from representing a complementary approach to lipid-based delivery which is currently dominating RNAi Therapeutics development programs.

Implications beyond CALAA-01 and RONDEL

Taking a step back, the CALAA-01 results add to the increasing amount of clinical data that first of all lay to rest concerns that there is a prohibitive fundamental (acute) toxicity issue for RNAi Therapeutics per se, and secondly provide evidence that therapeutic reality is within the reach of current systemic RNAi delivery technologies. They come on the heels of SNALP-ApoB results that showed preliminary signs of RNAi efficacy at a similar dose level while ongoing improvements in SNALP efficacy continue to widen its therapeutic index, and continuing dose escalations for both Alnylam’s VSP-02 and Silence Therapeutics’ Atu-027 solid cancer programs which can be interpreted as confirming the tolerability of some of the important delivery technologies in the space (SNALP and Atuplex).

With such progress, urgency to invest in RNAi Therapeutics, particularly in enabling delivery technologies should return. As the transition into the clinic is fraught with uncertainties for new chemistries (safety, efficacy, and manufacturing scale-up), it is particularly the less than a handful of delivery technologies that have made it there for which a land-grab might erupt as is also indicated by the fact that Tekmira now counts 8 RNAi-related pharmaceutical collaborators (both early and advanced stage), mdRNA at least 3 such early-stage collaborators, and a rumor-driven rise in the shares of RXi Pharmaceuticals possibly due to their mysterious claims on ‘self-delivering’ siRNAs. With the publication of the results that are about to garner widespread attention, Arrowhead Research/Calando should, of course, also get a few enquiries for RONDEL as it resumes its search for partners. Considering the generally weak share prices of RNAi Therapeutics companies, all the ingredients seem to be in place to see related deal activities, with a significant portion of the value being driven by the solid cancer opportunity for RNAi Therapeutics.

Update May 29, 2010: More details about the study, including the safety profile was published recently in an abstract for the upcoming 2010 ASCO cancer conference:

Systemic delivery of siRNA via targeted nanoparticles in patients with cancer: Results from a first-in-class phase I clinical trial

Author(s): A. Ribas and colleagues

Background: Systemically delivered small interfering RNA (siRNA) would allow targeting oncogenic molecules beyond current approaches. We report on the first siRNA trial with a targeted nanoparticle delivery system. Methods: Open-label, dose- escalation trial in pts with solid refractory cancers receiving 4 i.v. infusions (30 min) on d 1, 3, 8, and 10 of 21-d cycles. CALAA-01 nanoparticles consisted of a cyclodextrin-based polymer, transferrin protein (hTf) targeting ligand, polyethylene glycol (PEG) for stability, and siRNA against ribonucleotide reductase M2 (RRM2). The 70 nm particles were designed to minimize renal clearance and allow tumor vasculature permeation with binding to tumor hTf receptors (TfR). Primary endpoints (safety, MTD determination) were based on the first cycle. Results: 15 pts accrued to 5 dose levels (3, 9, 18, 24, 30 mg/m²), median age 62 (range 53-85). Most common histologies: GI (4), melanoma (3). Dose escalation progressed with no DLTs. Most common treatment-related AEs: fatigue (47%), fever/chills (33%), allergic (33%), constipation (33%), nausea/vomiting (20%), all g1-2. 1 pt had g3 anemia and 2 pts had g2 thrombocytopenia, all shortly after CALAA-01 infusions with rapid recovery. 1 pt had possibly-related sinus bradycardia (g2). No objective tumor responses were seen; 1 pt at highest dose had stable metastatic melanoma for 4 mo, a change from prior course. Biopsies in 3 pts (melanoma) showed particles in tumors. At 30 mg/m² RRM2 knockdown (mRNA and protein) was seen with confirmation of mechanism by specific cleavage sequence (RACE-PCR). TfR was not downregulated in cancer cells.Conclusions: Systemic delivery of siRNA via targeted nanoparticles is safe and can induce specific, siRNA-mediated gene silencing. This approach could be expanded to any currently undruggable cancer therapy target.

Calando’s RONDEL RNAi Therapeutics Delivery Promising, but CALAA-01 Prematurely Entered into Clinic

[Part 1 of a 3-part collaborative series with Tobias Wolfram on the first notable attempts at RNAi Therapeutics for solid cancers that have entered the clinic]

When during the company's R&D day the CEO of Alnylam, John Maraganore, highlighted Calando’s cyclodextrin-based siRNA delivery technology (RONDEL) as one of the noteworthy non-SNALP systemic siRNA delivery technologies out there, it certainly piqued my interest. This is not least because any cash infusion and longer-term commitment by a partner like Alnylam would do wonders for the parent company of Calando, Arrowhead Research which is a conglomerate of early-stage, IP-focused business units and has just barely scraped by bankruptcy through a diet of cutbacks. While I always remembered the maturity of RONDEL, developed in the Mark Davis lab at Caltech, to be years behind SNALP, Tobias and I decided to to take a closer look at the development path of CALAA-01, the first clinical RONDEL delivery candidate and also investment focus of reorganized Arrowhead Research.

When Tobias first heard of the technology, it struck him as a very elegant, because simple, and modular method to formulate targeted nanoparticles. In fact, there are not many targeted nanoparticle siRNA delivery approaches where the components supposedly can be assembled by the pharmacist just before patient administration. RONDEL siRNA delivery consists of mixing together siRNA, a short cyclodextrin-containing polycation, and adamantane-coupled PEG stabilizers some of which carry a transferrin ligand, so as to create 60-80nm particles. These particles were rationally conceived to satisfy a range of pharmacologic and formulation considerations. Their suitability for solid cancer relies on the enhanced permeability and retention (EPR) effect of nanoparticles with reasonably long circulation times (here supposedly achieved by PEG stabilization), the ability of the particles to be taken up into cancer cells by transferrin receptor-mediated endocytosis and their subsequent release into the cytoplasm in a pH-dependent manner.

Unfortunately, what we soon came to realize was that while the concept is a very nice one indeed, the particles, particularly CALAA-01, remain to be better characterized both physically (shape, uniformity, storage and biological stability etc) and for their RNAi knockdown ability in vivo. For example, knockdown of RRM2, the target of CALAA-01, and subsequent tumor inhibition have not been demonstrated in a convincing in vivo system. Instead, knockdown efficiencies have largely been limited to in vitro studies. Moreover, these involved siRNAs that were selected with what today would be considered outdated methods and probably as a result were not very potent. The in vivo studies were essentially limited to pharmacological investigations, with the combination of in vitro efficacy and in vivo pharmacology forming the rationale for moving CALAA-01 into the clinic. Moreover, even when considering only the pharmacology, measures such as biodistributions and circulation times did not fit the model which may be explained by nanoparticle instability in vivo, something that really needs to be investigated further. Also, since the siRNAs were unmodified it strikes me as rather strange that no innate immune induction and only moderate adaptive immunity were reported.

What I found to be a valuable take-home message from those studies, although according to Tobias’ liking resting too much on indirect evidence, but not necessarily data obtained with the CALAA-01 clinical candidate, was that the utility of the targeting ligand appeared to be in increasing the cellular uptake of particles with little positive surface charge, less so in skewing the biodistribution towards the solid cancers per se. This could also be because the particles were cleared relatively rapidly from circulation, mostly into the kidney and bladder, which raises further questions about the purity and integrity of the particles. In this light, the mention of nanoparticle assembly by a pharmacist may also be interpreted a necessity due to storage problems of fully formulated particles. Nanoparticle assembly is notoriously sensitive to even slight changes in parameters such as temperature, speed of mixing etc so that it would be preferable for the physician to just administer the drug without the need for prior handling. It is therefore unfortunate that results from long-term storage and robustness of the formulation method were not presented. Nevertheless, an enhanced cellular uptake through the addition of a ligand could critically increase the therapeutic index of a cancer RNAi Therapeutic, and the modular nature of the RONDEL system should easily facilitate such additions.

Our assessment that CALAA-01 was probably entered into the clinic too early naturally rests on the publicly available data only. The publication dates of the relevant data, however, strongly suggest that they indeed represent the relevant data points and considering the financial situation of Calando, it would not appear that much were to be gained by holding back on positive data. This is by no means to belittle what otherwise is very rich science. Unfortunately, it is here that the tension between corporate demands for advancing a pipeline and the need to sufficiently advance the science is most evident and in the end risks harming both objectives. Optimistically, completion and evaluation of the CALAA-01 phase I trial will allow for valuable insights into the performance of RONDEL delivery in man for the benefit of any follow-up programs. Without any such strong data, it is questionable however whether the promise of RONDEL as a differentiated and flexible platform for RNAi Therapeutics delivery alone will be enough to make Arrowhead Research a good RNAi Therapeutics investment.

PS: To expand on the latter point, Tobias and I also discussed that, in general, it is easy to caution against entering RNAi Therapeutics candidates into the clinic early and dismiss such as a move of desperation. On the other hand, the case can be made that, when it comes to RNAi Therapeutics as a broadly applicable platform, clinically evaluating candidates which for example would not be expected to effect large knockdowns can be justified in that the data coming out of these studies may provide timely data invaluable for follow-up programs using very similar delivery approaches. Although investors will rightly fear the costs of a failed trial particularly for small biotech companies, such data may be valued more highly by a potential Big Pharma partner. This argument receives added weight in an environment like now where it is very difficult to raise capital from the public markets, and partnering is the primary means for small biotech to obtain capital at acceptable terms.

RNAi Therapeutics: A Spoilt Market, or Waiting for Clinical Progress?

The market reaction to Alnylam’s deal with Takeda was, well, a bit disappointing. Although the argument can be made that next to the Sirna acquisition by Merck this has been the most favorable deal for the RNAi Therapeutics field yet, shares of Alnylam not only did not advance, but even declined on the news. Can the muted reaction be explained by a market spoilt by Alnylam’s RNAi mega-deals and that has come to expect an even larger cash component, or has Alnylam’s hinting at more deals given the shorts plenty of time to prepare for such an event by aggressively shorting the stock on the news as the considerable volume may have suggested? Possible. However, here I would like to consider the third possibility that for Alnylam’s stock to move to new highs, the market would like to see the deal making being complemented by scientific and clinical progress.

Actually, these platform licensing agreements are evidence for just that as the therapeutic areas covered by the non-exclusive license, namely metabolic disease and cancer, clearly indicate that the deal was driven by the maturation of liposomal RNAi delivery technology. Moreover, an important component of the Alnylam-Takeda relationship will be the exchange of RNAi delivery capabilities, suggesting that Takeda had also made progress in this area.

However, the bears would argue that what Alnylam, and the wider field, needs is further demonstrating progress with their development programs. Of course, we had the phase II ALN-RSV01 proof-of-concept data which was a great relief for everybody and should strengthen Alnylam’s position at the deal table if not on a PPS basis, but we should also remember that Alnylam had previously guided that it would advance one or two SNALP-related programs into the clinic in 2007. This has not happened and I can understand that some may have well been disappointed by that. Paradoxically, rather than reflecting science that has stalled, the delay can be explained at least partly by ongoing progress in SNALP RNAi delivery and it may not be wise to commit to a development candidate when improvements in both safety and efficacy can be made so readily as supported by recent conference presentations and publications.

Having followed biotechs for a while now, one major question I ask myself before investing in a biotech company is whether programs have been rushed into the clinic well before they have been properly validated pre-clinically. That often happens with small biotechs with acute fund-raising needs or when existing investors would like to exit and an IND is the goal, not final approval by the FDA. How otherwise could one explain e.g. Nucleonics’ decision to advance a plasmid-based, DNA-directed shRNA program for Hepatitis B into phase I when all the in vivo data consisted of some co-transfection studies (= glorified in vitro data) and when current non-viral plasmid delivery methods are unlikely to achieve the transfection rates sufficient for curing such a viral infection through direct gene knockdown. Next to Nucleonics, other early RNAi pipeline candidates, while somewhat more promising scientifically, may also serve the role of flag-waving programs demonstrating to investors that RNAi is not just a fascinating science, but also of clinical relevance.

Much has been learnt since the first candidates entered the clinic in 2004 and, like for SNALP RNAi in particular, it makes a lot of sense, also economically, to take advantage of the steep learning curve in general to increase the odds of late-stage pipeline success at the cost of slight early delays. Meanwhile, the irresistible expansion of RNAi into in vivo applications and the increasing number of RNAi-related conferences (another one, Beyond Genome, is just about to take place a little bit North of where I live) demonstrate that the field is vibrant and the science is making rapid progress.

If that weren’t enough, the coming months should bring more than enough RNAi clinical results to contemplate. Calando just reported this past week initial results from their phase I studies on CALAA-01, an unmodified siRNA in a targeted nanoparticle formulation for the treatment of solid tumours. According to their press release, the first patient has now completed a course of 4 intravenous doses over two weeks without any show-stopping adverse events. As this is the first clinical experience of systemically administered siRNAs, unmodified at that, it therefore also marks an important and reassuring milestone for the synthetic siRNA field in general. It is easy to envision scenarios how an adverse event could have had disastrous repercussions for RNAi Therapeutics. Well done, Calando!

Then there are the SNALP RNAi programs that, once entered, could yield relatively soon clear in vivo efficacy data on systemically administered RNAi Therapeutics. Finally, Benitec’s HIV program is another program that deserves some attention as quantitative patient data may emerge relatively soon; for example, an expansion of T-cells derived from the stem cells transduced with the lentiviral vector encoding for a triple-RNA antiviral relative to unmodified cells would be very promising.