AAV making a splash (?)

Looking at Sanofi's early stage pipeline I noticed a couple of Gene Therapy products (coming through from Genzyme's pipeline) in Phase I development:

• AAV2-sFLT01 for Age-related Macular Degeneration (AMD, more about this disease here) 
• AAV2-hAADC2 (human Aromatic L-Amino Acid Decarboxylase-2) for Parkinson's disease

As can be seen by the names of the candidates, they both make use of adeno-associated virus serotype 2 (AAV2) gene delivery technology. Doing some research around how Genzyme got hold of this tech, I stumbled across Avigen Inc.; Genzyme appears to have licensed the AAV technology from Avigen in 2005 and has been developing products based on it since then. 

A quick search for "AAV" or "adeno-associated virus" on clinicaltrials.gov returns 9 ongoing Phase I and Phase II studies (with about another 50 or so studies that have previously been completed/terminated). It is interesting to note at this point, that it is mainly AAV2 or AAV1 serotypes that are being used in these studies, despite development of other AAV serotypes (from serotype 3 all the way up to serotype 11 as well as some of their hybrid versions such as AAV-2/5). This is not entirely surprising, given the experience that researchers have working with these vectors. A nice recent review on AAV-based gene therapy can be found here.

The main problems with this gene delivery approach revolve mainly around safety (avoiding unwanted effects due to virus integration in the host genome), identifying the vector serotype with the appropriate tropism for the target tissue/organ and quite importantly, being able to achieve production of large high grade GMP amounts of viral vector.

So, I would be interested to see how Sanofi's trials develop and how the FDA will look upon this approach. Looking at some other interesting news around AAV-based therapeutics, AMT's Glybera failed to get approval by the EMA earlier this year, although it had shown some promising results (more info about Glybera, the AAV1-based delivery of lipoprotein lipase can be found here). Glybera would have been the first gene therapy product to be marketed in Europe, however now the program is suspended and AMT is facing tough financial problems. 

In conclusion, it is pretty early days for an AAV-based therapeutic to hit the market although a few companies are working in the field. I would keep an eye out for news coming from Ceregene though as they have a strong advisory board (including R.J. Samulski) and that could translate into some interesting tech and positive clinical outcomes.

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Trials, trials everywhere!

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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"Profecting" vaccines for HIV?

Profectus Biosciences develops novel vaccine approaches, primarily focussing on HIV and HCV. Formed in 2003, as a spinout of the Institute of Human Virology (IHV) at the University of Maryland, Profectus includes amongst its founders well-known names in the field of virology research: Dr Robert Gallo, Dr William Blattner and Dr Robert Redfield; the same group are also members of the company's scientific advisory board. 


In 2008, Profectus has in-licensed Wyeth's HIV, HCV HepB and HSV vaccine programs which allowed it access to Wyeth's proprietary DNA and vectored vaccine technologies. According to the company's website, focus is placed on therapeutic vaccination and on development of immunotherapeutics. 


The therapeutic vaccination protocols are based on "prime-boosting" approaches. Profectus uses modified plasmid DNA (pDNA) vectors for priming the immune system against HIV antigens and then "boosts" the generated responses through vaccination with a Vesicular Stomatitis Vector (VSV). The priming process is enhanced by the simultaneous expression of interleukin-12 (from a different co-administered plasmid) and the use of electroporation for delivery of the pDNA. The company has already completed a set of experiments in non-human primates, demonstrating strong immunogenicity and safety. 


Some more information on Profectus' exciting and pioneering technology of "transition-state vaccines" and genetic adjuvants being developed by the company can be found here. The "transition-state vaccine" approach (a quite promising approach, however, still in its infancy) basically aims on targeting key antigenic regions and their structural conformations presented to the immune system only for small amounts of time during an infection process; characteristic example is the interaction of HIV's gp120 with the CD4 receptor. In terms of adjuvant systems in development, Profectus is combining the enzymatically-active region of cholera toxin (CTA1) with a number of cytokines. Although the use of adjuvants in vaccine products is widely considered to be necessary for augmenting vaccine efficacy, extremely stringent FDA regulations have resulted in no adjuvanted vaccines being approved for almost 80 years (apart from vaccines containing alum), other than the recent approval of GSK's Cervarix in 2009.


Where things become really interesting is the immunotherapeutics approach that Profectus has chosen to follow. In short the company is developing NF-κB inhibitors, and more specifically, inhibitors of p65 (one of the components of the NF-κB heterodimer). As the company states on its website, inhibition of NF-κB will result in suppression of the immune activation caused by certain viral infections, which will in turn lead to a better prognosis and slower disease progression. In my opinion, this is quite a risky strategy and has to be coupled with a targeted delivery approach. NF-κB is involved in the majority of cellular pathways and shutting those pathways down could simply cause more problems rather than solve them. However, targeted delivery of such inhibitors could well be extremely useful, especially in certain forms of cancers (solid tumours) where NF-κB inhibition-induced apoptosis would slow down tumour growth. Additionally, in cells infected by viral pathogens, shutting down NF-κB would result in apoptosis, decreased virus production and spread, and would additionally generate a good source of antigen for generation of antiviral immune responses.


Since its incorporation, Profectus Biosciences has received a substantial amount of money in terms of grants and private investments (approximately $44 million; a breakdown of this funding  is shown on the table below).

Date	Funds received ($M)
01-Feb-05	Incorporation
30-Mar-06	3
15-Jun-07	3
19-Jun-07	0.3
19-Jul-07	0.2
08-Dec-08	21.6
22-Jul-09	5
04-Oct-10	4.4
06-Oct-10	6.25
Total	43.75
25-May-11	Phase I start

You can find some more information on the Phase I trial by Profectus here. Briefly, the company is testing the effect of IL-12 on the immunogenicity of their HIV vaccine candidate, MAG pDNA. The vaccine will be delivered via electroporation and the trial will recruit 60 individuals. As this is developed as a therapeutic vaccine, subjects enrolled in the trial will be HIV-infected with CD4 counts of greater or equal to 500 cells/μl of blood and will remain on antiretroviral therapy throughout the study duration. The study duration is anticipated to be 36 weeks, which puts a publication of results likely to take place in Q2 2012.


Profectus appears to be a strong investment proposal, however, a more informed opinion could be formed towards the middle of next year, with Phase I results available, and that period could constitute a possible investment entry point. Strong Phase I results will lead to increased interest from potential biotech/pharma partners, something that will push the company's value upwards; nevertheless, the risk associated with HIV vaccine development is still high.


Below you can find a graphic depicting estimated rNPV for Profectus Biosciences and its HIV-vaccine candidate (data to 2031). Calculations are based on a heavily modified version of BioGenetic Ventures' previously published model.

PV of Revenue	NPV of Cash Flow	Risk-Adjusted NPV
$ 710,247,523	$ 160,799,596	$ 20,216,720

The following table highlights some of the key assumptions used to "feed" the model. A very modest estimate has been used for the price of a potentially successful HIV vaccine; HIV infections growth rate should also be viewed with caution, as the increased use of ARVs will slow down the epidemic spread over the next 10 years-in fact signs of reduction are already evident. Additionally, the incorporation of ARVs into HIV vaccine clinical trials (which makes it more difficult for a vaccine candidate to show efficacy) has not been calculated in this model, as not enough data is currently available. 

Parameter	Estimate
Total number of HIV-infected individuals	33,000,000*
HIV infections growth rate	8.997%*
Peak market penetration (years)	3
Revenue per unit ($)	150≠
Revenue Years	12
Number of Subjects Phase I	60
Number of Subjects Phase II	600
Number of Subjects Phase III	5,000
* UNAIDS Report 2010	≠ Very modest estimate

Profectus is an interesting company with a significant potential for profit generation, should its technology and vaccination approaches show promising results in the clinic. Competition from other HIV vaccine development companies is expected to be fierce but Profectus is definitely a company to watch closely.

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