+Timos Papagatsias

Sunday 26 June 2011

"Profecting" vaccines for HIV?

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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) 
Total 43.75
25-May-11Phase 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 RevenueNPV of Cash FlowRisk-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 evidentAdditionally, 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. 

Total number of HIV-infected individuals33,000,000*
HIV infections growth rate8.997%*
Peak market penetration (years) 3
Revenue per unit ($)150
Revenue Years12
Number of Subjects Phase I60
Number of Subjects Phase II600
Number of Subjects Phase III5,000
* 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.