Promising New Frontiers for RNAi Therapy


In 2001 Elbashir and Tuschl (1) published they had managed to silence gene expression in mammalian cells using small interfering RNA (siRNA). This was the catalyst for an explosion of research using siRNA to demonstrate the effect of knocking out targets without the need to identify compounds capable of doing this job. Potentially highly specific, the opportunity to use these as therapeutics was rapidly explored. Ten years later the first clinical trials are coming through; impressively fast.

Probably the largest obstacle to therapeutic siRNA has been delivery, which often is either toxic, or not very effective – as any of us who have tried to transfect siRNA into primary cells will be able to appreciate. Advances in materials science are seemingly solving this problem encapsulating siRNA in nanoparticles, resulting in safe and effective delivery. CALAA-01 (Calando Pharmaceuticals) lead the way  being the first to deliver siRNA therapeutically demonstrating phase I efficacy and safety, as well as localisation to melanoma metastases.

One particular advantage of siRNA is that once delivery has been optimised, it is possible for several different siRNAs for different targets to be contained within on package. This could enable simultaneous delivery of different targets simultaneously effecting different aspects of the same disease, i.e. metastasis and well as tumour growth. By also hitting a known resistance pathway this duel delivery could enable the chemotherapy to be more effective.

A recently published article (2) has done just this, delivering two siRNAs in lipid nanoparticles (known as ALN-VSP) for both VEGF-A (vascular endothelial growth factor-A) and kinesin spindle protein (KSP) for the treatment of advanced solid tumours with liver metastases.  KSP is involved in cancer proliferation and VEGF-A in the growth of new blood vessels.

The study was phase I, dose escalation, on patients who had already been heavily pre-treated with chemotherapy and/or anti VEGF/VEGFR agents with the ALN-VSP administered as 15 minute IV every 2 weeks for 1 month.

The safety profile was very encouraging with ALN-VSP being generally well-tolerated with mainly low-grade fatigue, nausea and fever noted in 15-24% of patients. The lipid nanoparticle of ALN-VSP distributes primarily to the liver and spleen and the delivery was also excellent. Liver biopsies were performed on 12 patients before the first dose and then at 2 and 7 days post dose. qPCR identified VEGF siRNA present in all 12 patients and KSP siRNA present in 11 of the 12.

Of the patients treated, 7 had no disease progression (measured by computerized tomography [CT] scan) after the treatment cycles and continued onto an extension study. One patient in particular with endometrial cancer achieved a complete response after 20 months of treatment

This is clearly fantastic progress for ALN-VSP, and specifically for the handful of patients who were positively affected from participation in the trial. The results from this study also demonstrate the ability for safe delivery of multiple siRNA to specific sites tumour and this extends the promising start for these methods of siRNA delivery which may open up previously un-druggable targets.

 

1.           Elbashir SM, Harborth J, Lendeckel W, Yalcin a, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494–8, 2001.

2.           Tabernero J, Shapiro GI, Lorusso PM, Cervantes A, Schwartz GK, Weiss GJ, Paz-Ares L, Cho DC, Infante JR, Alsina M, Gounder MM, Falzone R, Harrop J, Seila White AC, Toudjarska I, Bumcrot D, Meyers RE, Hinkle G, Svrzikapa N, Hutabarat RM, Clausen V a, Cehelsky J, Nochur S V, Gamba-Vitalo C, Vaishnaw AK, Sah DWY, Gollob J a, Burris H a. First-in-Man Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement. Cancer discovery (January 28, 2013). doi: 10.1158/2159-8290.CD-12-0429.

 

 

 

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Amyloid in Alzheimer’s Disease – The End of the Beginning or the Beginning of the End?


In terms of drug discovery, there are four general ways of identifying new drugs: 1) there is serendipity, where a chance preclinical or clinical observation is translated into a novel therapeutic (with the initially cardiovascular Viagra being an example, the clinical utility of which you could quite literally hang your hat on); 2) Iteration, in which a new drug is an improvement upon an existing drug (e.g. reduced side effects or better pharmacokinetics); 3) repositioning, whereby a drug approved or initially evaluated for Indication A proves efficacious in Indication B and finally; 4) hypothesis-driven drug discovery, in which drugs are targeted towards a pathway or protein specifically implicated (e.g. genetically or pathologically) in a disease process. This latter process is the most rational and intellectually satisfying and forms the basis of the multiple amyloid-related approaches to treating Alzheimer’s disease since the amyloid core at the centre of the hallmark senile plaques  as well as the genetics of familial cases of AD all point the scientific finger of guilt towards the amyloid pathway.

As regards the amyloid hypothesis of Alzheimer’s Disease, it is now a few months ago that we discussed the big summer of data that lay ahead with Bapineuzumab and Solanezumab. Well, the data has now been chewed over and digested and as the year draws to a close, it is a good time to be reflective and assess where the field stands. So, in alphabetical, chronological and clarity of what-happens-next? order let us first consider Bapineuzumab. The data for the first Phase III study, Study 301, was disappointing but not surprising since the AD patients were the ApoE4-carrier subpopulation that the Phase II study suggested were less susceptible to the potential benefits. Hopes were therefore pinned on data from the ApoE4-noncarrier Study 302. However, these data were unambiguously negative (follow the links for data of Studies 301 and 302 presented at the September meeting of the European Federation of Neurological Societies) with the complete lack of ambiguity resulting in the termination of the two additional ex-US and incomplete studies (Studies 3000 and 3001). So, all-in-all, quite an emphatic end of story for i.v. Bapineuzumab.

The story for Eli Lilly’s Solaneuzumab is, however, not quite so clear cut. To recap, the EXPEDITION1  and EXPEDITION2 were pivotal Phase III studies. The EXPEDITION1 study missed its primary end-point but showed a significant effect on a secondary end-point, namely cognition in mild AD. This secondary end-point was then used as the primary end-point in the EXPEDITION2 study, but there were no significant effects of Solanezumab. However, combining data from these 2 studies – one of which showed efficacy, the other one not – showed a significant effect in mild but not more advanced moderate AD patients. This is entirely consistent with the way the field has been moving, namely that amyloid-related treatments need to be as early in the disease process as possible. There was a brief flirtation with the prospect that because of the large unmet need regulators may find a way to approving Solanezumab based on the existing data. However, subsequent to discussions with the FDA, Eli Lilly accept that approval would require a new Phase III study in mild AD patients, although their press release does note that “It is possible that different courses of action could be taken in different jurisdictions.”. Given their recent run of bad luck with neuroscience Phase III compounds (the γ-secretase inhibitor Semagacestat in 2010 and then this year the mGlu2/3 agonist pomaglumetad methionil and Solanezumab), one can only admire the depth of the company’s neuroscience financial trouser pocket and their obvious commitment to the area.

If the Solaneuzumab data tells us that treating earlier is the way to go, then the ultimate extension of this approach is a prevention trial. Such a trial, which commences in the spring of 2013 and is being organised by the Banner Alzheimer’s Institute in Phoenix, is being conducted as part of the 5-year, $100 million Alzheimer’s Prevention Initiative and will focus on a family in Columbia with genetic mutation associated with on onset of Alzheimer’s disease in their late 40s. Subjects with the mutation will receive Crenezumab, an anti-amyloid antibody developed by Roche/Genentech and licensed from the Swiss company AC Immune. An additional “branch study” will also take place in the US and will include an additional 150 US mutation carriers. A second prevention trial is also due to start in early 2013 and will be conducted by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN TU) and will evaluate the effects of three different drugs on subjects (160 carriers and 80 non-carriers) with AD-causing mutations.  These three drugs were selected from the more than a dozen drugs proposed by the 10 pharmaceutical companies that comprise the DIAN Pharma Consortium and include the anti-amyloid antibodies Solanezumab and Gantenerumab, a Roche antibody currently in a Phase III trial for very early, presymptomatic (prodromal) AD known exotically as SCarlet RoAD, with a third drug, the Lilly BACE inhibitor currently in Phase II, also being selected for potential inclusion.

So, there remains life in the amyloid hypothesis. But what about other approaches? Well, as we mentioned at the top of this article, drug repositioning (or drug repurposing) is an attractive potential alternative since it is a route accessible to research councils and academic centres (i.e., it lacks the huge development costs of novel therapies). Recently, a number of drugs currently in clinical use for other indications have been shown to have an effect on amyloid metabolism or the associated neuroinflammatory response in animal models, including, for instance, the anticancer (cutaneous T-cell lymphoma) drug Bexarotene, the antiepileptic drug Levetiracetam and the blood pressure drug Prazosin. Nevertheless, the extrapolation between effects in animal models and human is a large and tenuous one with, for example, Rosiglitazone producing marked effects in transgenic mice but there were no signs of efficacy in two  Phase III studies. So, despite claims that “Drug giants give up on Alzheimer’s cure” (The Independent, 19th September, 2012) it would appear that there still remains a major commitment to the development of new therapeutics for Alzheimer’s Disease and that recent developments in the field represent the end of the beginning rather than the beginning of the end.

Cancer Drug Targets: The March of the Lemmings


Whilst at a joint meeting with the ICR Computational Biology and Chemogenomics Team, and the Blundell Bioinformatics Group at Cambridge, this article in Forbes by Bruce Booth was brought to my attention.

This article discussed the current oncology portfolios being developed by major Pharma.  Their analysis illustrates that over 20% of current clinical oncology projects are focused on just 8 targets, each of which has at least 24 projects in clinical development, and further projects in pre-clinical development.

Bruce points out several advantages to this approach, for instance that by developing smarter follow-on molecules, some of the liabilities of the earlier molecules may be diminished possibly improving patient outcomes.  Also drugs based on different chemotypes may lead to differential responses and exhibit different toxicity profiles.  However, he concludes that this focus on a limited range of targets is a waste of resources. Although pursuing established targets may reduce the biological and chemical risk during the early stages of drug development,  “ the differentiation risks skyrocket” – at later stages of development. In particular he highlights that the downstream drugs may fail at a later, more costly stage.

Whilst agreeing that theses are all excellent targets, he suggests that resource should be more focused on the preclinical stages of drug discovery, identifying and validating new cancer targets, rather than chasing incremental improvements in drugs against existing ones.

 

Frances