+Timos Papagatsias

Tuesday, 9 August 2011

Trials, trials everywhere!

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Taking a look at what the large pharma companies are doing in terms of clinical trials that they have currently underway or planned to start in the near future one can get a feel of the current status of pharma and biotech R&D.


Looking a bit deeper at what is happening with vaccine- and gene therapy-related trials and who the major players are in these fields at the moment perhaps would allow for an estimate of where some really innovative and rsik-taking companies are being active. So, let's have a look at the graphs and tables below...
(All data is publicly available through clinicaltrials.gov; search parameters were "Open Studies | Industry", "Vaccine | Open Studies | Industry" and "Gene Therapy | Open Studies | Industry". Search results valid on 15th of July 2011.)
Novartis, Pfizer, Roche and GSK are the leaders in the number of open studies with each one of them having ~250 and above studies currently ongoing or planned to initiate soon. Altogether, the Top 10 companies account for approximately 16.5 % of the current/planned studies at the moment. 


But this only tells half the story, as you can see below...
Sanofi, #10 in terms of ongoing/planned studies (86), is recruiting ~940,000 volunteers into its studies (a large proportion of which involve vaccine candidates) and is followed by GSK who will be involving approximately 700,000 patients in its 248 trials. As you can see, GSK features in the Top 5 in terms of both number of studies and patients recruited. Pfizer and Novartis can be found further down the list with ~220,000 patients and ~110,000 patients to be recruited respectively.


So, no real surprises so far, with the "usual suspects" appearing at high positions in the lists and with GSK justifying its strong reputation amongst big Pharma. 


Time to look a bit more in detail on what is happening with studies involving vaccine and gene therapy candidates.


In terms of number of vaccine-related studies (see chart below), GSK tops the list with more than double the number of studies from its three followers, Pfizer, Novartis and Sanofi. Some interesting companies also appear on the list, such as Intercell, Bavarian Nordic, Crucell and Dendreon (going through some rough times at the moment).
Looking at the number of patients involved in vaccine-related studies, no real surprise there-Sanofi leads the pack with almost 900,000 patients. However, GSK is again in the picture, claiming a second place with almost 650,000 patients enrolled or planned to be enrolled in its vaccine studies. Pfizer is #3 in this list with only 90,000 patients in its studies.

So far, GSK has almost dominated the different lists, but the situation is somewhat different when we take a look at companies who are active in the Gene Therapy field. Names such as Oxford Biomedica, Sibiono Genetech, Genzyme, Introgen and Diamyd dominate the Top 10 list.
In terms of numbers of patients recruited in these studies, Sibiono is a clear winner, with 2,400 patients recruited in its 3 studies with its recombinant adenovirus p53 candidate. NovaRx, with its candidate for treatment of NSCLC Lucanix (which is in fact merging the concepts of Gene Therapy and Vaccine) is second in the list with ~500 patients enrolled in its single study.   
So here it is, a view of the current status of clinical trials and what the large (and small) pharma and biotech companies are doing at the moment. Obviously, I had to rely on the search engine within clinicaltrials.gov, so it is quite likely that a few trials have been omitted from these results, however, I do not believe that the results are significantly affected by this.


Overall, GSK is really strong and very active, both in terms of number of trials and numbers of patients enrolled. I believe that this is to be expected. GSK's strategy seems to be aligned with expansion in all therapeutic areas either through partnerships and collaborations but also through acquisitions. And the company now seems to be establishing itself as the dominant player in the vaccines field. Obviously, big names such Sanofi and Pfizer still maintain a strong presence; and let's not forget about Novartis, one of the most innovative biotech companies around.


Although some big names dominate the lists in terms of clinical trials as a whole and in terms of trials involving vaccine candidates, the situation is strikingly different when it comes to Gene Therapy trials. Smaller in size companies appear to be active in this field, something which should perhaps be expected due to the higher than average risks involved in development of gene therapy candidates and the higher versatility and focus that small companies exhibit. Sibiono is the clear leader at the moment, being the first company to market a Gene Therapy product (Gendicine, a recombinant adenovirus expressing the p53 gene for treatment of  head-and-neck cancer on top of radiotherapy). Oxford Biomedica appears on the list, with its Parkinson's treatment candidate, ProSavin.


One company not mentioned in this list, but worth having a look at, is Scancell, a UK-based company with its pioneering ImmunoBody technology which has applications both in the treatment of cancer and in infectious diseases.


It will be interesting to repeat this analysis in one or two years' time, when R&D restructuring and process optimization by the major pharma companies will have taken place and when, hopefully, more funds will have been available for development of innovative treatments.
However, I would predict that more medium sized players will be featuring in these lists, either on their own, but more likely in partnership with one (or more) of the big pharma companies, who will be looking to bring "innovation" into their pipelines.









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Monday, 25 April 2011

"Next generation vaccines" from Etubics Corporation

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Etubics Corporation is experimenting with developing new generation adenoviral-based vectors that can be used in vaccination protocols and other gene delivery approaches. The company's proprietary Adenovirus Vector Vaccine Platform (AVVP) technology can be used to construct gene delivery vectors that can be incorporated in vaccination protocols that require repeat administrations; according to the company's website, this is due to the extensive genetic deletions of the adenoviral genome which reduce vector-associated immunity issues. Etubics also claims that its adenoviral vector system can induce both antibody and cell-mediated immune responses, even in the presence of pre-existing adenovirus immunity. For those more interested in finding out some more about Etubics' AVVP, a recently published patent contains some more information.


An interesting point of discussion regarding Etubics investability is the fact that the potential for success for the AVVP technology still remains to be demonstrated through conclusive late stage clinical trials. The company has advanced various vaccine candidates (breast cancer, HIV amongst others) to preclinical stage but it has yet to conduct a large scale trial that will demonstrate successful application of its technology (according to the company's pipeline information webpage, a Phase III programme in colon cancer is due to start in 2013).


Currently, the company operates with grants and contracts from the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Health (NIH). Additionally, extra investment has originated from private investors and company employees/owners. Etubics claims that it has brought its technology from "bench to bedside" with a total cost under $5 million (although a more realistic representation of the true costs incurred so far can be found in the company's factsheet, which sates that approximately $20 million have been spent on developing the AVVP technology).


It will be interesting to see how Etubics fares in the adenovirus-based vector field in the next 3-5 years, when its products will have progressed further along the clinical pipeline. A direct competitor to the company is Crucell (recently acquired by J&J), with its proprietary PER.C6 technology and its AdVac system that utilises rare serotype adenoviral vectors, thus avoiding or minimising issues of pre-existing immunity (but not necessarily avoiding issues with repeat administrations). In comparison, Etubics' vector system is based on serotype 5 adenoviruses, one of the most common strains.


We anticipate that positive clinical results will generate strong interest around Etubics and its AVVP technology both from private investors as well as large biotech/pharma companies that could use this technology to complement/strengthen their pipeline portfolio. The results from a Phase I trial with the company's carcinoembryonic antigen (CEA) vaccine candidate, due to come out in the second half of 2011, should hopefully provide an indication of the technology's future potential.
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Monday, 21 February 2011

It all started with EpiMatrix...

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Applying computational approaches to immunogen selection and modification has set new standards in vaccine design. Consider codon optimization, a method which allowed scientists to circumvent codon usage bias in order to achieve high levels of difficult-to-express proteins outside their native hosts. Codon optimization has helped immensely in the development of HIV prototype vaccines where viral genes (gag, env, pol etc.) were expressed in the absence of the Rev-RRE system.

Achieving efficient expression of a vaccine agent in the target tissue/cell, however, does not always guarantee the desired immunogenic effect; and this is where companies like EpiVax can be very useful. Using the tools and technologies available by the company, one can identify putative T cell epitopes (EpiMatrix), MHC Class II epitope clusters (ClustiMer), human(or other species)-like peptides (BlastiMer), de-immunize a protein sequence (thereby creating alternative candidates with altered immunogenic profiles) (OptiMatrix-in combination with their DeFT service) and finally identify conserved epitopes (Conservatrix) in multiple sequences of highly mutating pathogens, such as HIV. The company has also recently introduced VaccineCAD, which is a vaccine-design algorithm that assists in alignment of selected immunogenic epitopes in a vaccine construct, avoiding (or at least reducing) the formation of "nonsense" epitopes, usually appearing at junctions between consecutive epitopes. If you want to check out the web versions of all of EpiVax's tools, head over to the iVAX website.

EpiVax looks a promising company with services that are already finding their way in multiple stages of vaccine design. In addition, we are convinced that its DeFT service can have a significant impact in the field of Gene Therapy, where de-immunization of transgenes is of paramount importance. The company has received several awards from the NIH and it is now making good strides in establishing itself as an one-stop-shop for immunoinformatics. For some more information, here is an article by EpiVax's Founder, CEO and CSO, Dr Annie De Groot.
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Wednesday, 26 January 2011

Inovio Pharmaceuticals

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Inovio Pharmaceuticals specializes in creating vaccines with superior characteristics in terms of immunogenicity and T cell responses.

At the heart of the company's development pipeline lies its proprietary 
SynCon™ DNA Vaccine Platform technology which is described on the company's website as: 
"More technically speaking, SynCon™ DNA vaccine antigens are designed by aligning numerous primary sequences and choosing DNA-based triplets for the most common amino acid at each site. These antigens are further optimized for codon usage, improved mRNA stability, and enhanced leader sequences for ribosome loading. The DNA inserts are therefore optimized at the genetic level to give them high expression capability in human cells."

I am not so sure how much this differs from other codon-optimization approaches (see Geneart for example) but, coupled with Inovio's electroporation technology, makes the company a strong competitor in the field of genetic vaccines.

Inovio's list of Partners includes Merck and Co., the HIV Vaccine Trials Network (HVTN) and the National Institute of Allergy and Infectious Diseases amongst others (see here for more information).

The company has recently announced a $24.3 million registered offering, with the proceeds going towards further development of its DNA vaccine candidate against cervical dysplasias and cancers, as well as towards funding of other preclinical and clinical studies (the full announcement from the company can be found here).

We believe that DNA vaccines constitute one of the most important developments in the last 10 or so years, in the vaccine field. Technically speaking, a DNA vaccine consists of a DNA sequence coding for the desired immunogen, combined with an appropriate delivery method (most commonly used nowadays an intramuscular injection or a transdermal delivery approach) and preferably complemented with an immunomodulating adjuvant agent. Inovio Pharmaceuticals seems to be ticking all the boxes, or at least has made good progress towards developing truly novel DNA vaccines, with a gene optimization algorithm that allows for ehanced transcription/translation of its products and with an efficient delivery method in the form of electroporation. 

It is quite interesting to see vaccine companies such as Inovio Pharmaceuticals, making use of electroporation for the delivery of their vaccines; DNA vaccines, especially the very first ones that were based on early generation plasmid backbones, are inherently difficult to deliver to the target site and achieve long-lasting expression or even a strong immune response to begin with. Electroporation seems to solve the delivery problem and in certain cases can also have an adjuvant effect through associated cell death and local site inflammation following vaccine delivery. Of course the debate over usefulness and the best delivery method between viral vectors and approaches such as electroporation still holds on, but for the time being, and until we start seeing these approaches reaching late stage clinical trials and the market, one should choose the most appropriate method depending on their needs. 

In the meantime, Inovio Pharmaceuticals looks to be well positioned for a strong "push" forward. The company is currently running clinical trials in the cancer (cervical, breast, lung and others) and infectious diseases (HIV and influenza) fields. More information on positive results from its Phase I HIV vaccine trial can be found here.




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