Luc Dochez on why Prosensa’s exon skipping therapy is personalised medicine in its ultimate form for Duchenne’s




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Video title: Luc Dochez on why Prosensa’s exon skipping therapy is personalised medicine in its ultimate form for Duchenne’s
Released on: January 12, 2011. © PharmaTelevision Ltd
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In this episode of PharmaTelevision News Review, Fintan Walton talks to Luc Dochez, CBO and Senior VP BD, Prosensa.
Prosensa:Origin and Technology
Fintan Walton:
Hello and welcome to PharmaTelevision News Review here in Munich at BIO-Europe 2010. On this show I have Luc Dochez , who is the Chief Business Officer at a company called Prosensa, which is based in AL Leiden in The Netherlands, welcome to the show.
Luc Dochez:
Thank you.
Fintan Walton:
Luc Dochez , Prosensa is a company is a very specialist company has its own unique underlying technology that can be applied to specific types of diseases, can you tell us little bit about the underlying technology?
Luc Dochez:
Sure, we are focused on RNA modulations so it's a company using antisense oligonucleotides to work at the RNA level so it is not gene therapy it is genetic therapy, but we tried to correct something that went wrong at the DNA level at the RNA level to then have the positive effects that we want to have downstream at the protein level. One example of that is for example of exon skipping in which we apply duchenne muscular dystrophy which is our lead therapeutic indication and in the case of exon skipping apply skipping an exon we tried to convert them out-of-frame mutation into an in-frame mutation which then leads to a shorter but still functional protein.
Fintan Walton:
So this particular technology particularly lends itself to duchenne muscular dystrophy because of the nature of that particular disease?
Luc Dochez:
Exon skipping is one application of RNA modulation and exon skipping indeed is perfectly suited for duchenne muscular dystrophy , but also has potential other applications and other genetic diseases, but like I said we have developed this as far as possible today with the Duchene application indeed.
Fintan Walton:
So let's just see look at back at the origins of the company itself, so when was the company was originally incorporated?
Luc Dochez:
The company was founded in 2002 by three entrepreneurs who wanted to do something with RNA therapy you know but quite quickly got in contact with Professor Gert-Jan van Ommen who is a Professor in human genetics, a quite known Professor in human genetics at Leiden University Medical Center who was thinking about applications of exon skipping and that quickly became the lead focus of the company in as of 2002, 2003.
Fintan Walton:
And it is backed by venture capital?
Luc Dochez:
Ultimately yes, so the initial funding came from the entrepreneurs, but also lot from the patient advocacy group and the patient organization, so although the company was incorporated in 2002 the first series A financing only took place in 2007 when LSP (Life Sciences Partners) out of Holland and Abingworth out of the UK kind of started to really back the company with some serious venture capital.
Technology and application in Duchenne muscular dystrophy
Fintan Walton:
Right, so now let's just shift a little bit to the actual clinical program or the underlying technology and how is applied specifically to duchenne muscular dystrophy , so could you tell us what's the strategy has been in particular in selecting the various approaches that you can take to that because patients have this variance?
Luc Dochez:
Yes sure happy to do that. So first the little bit about duchene may be, duchenne muscular dystrophy is caused by the lack of a certain protein called the dystrophin protein which acts as kind of a shock absorber between muscle cells, so obviously if you don't have a shock absorber if you can't you know make it continuously it's leads to a deterioration of the muscle cell and obviously the muscles we use most can damage first, so this is these boys first end up in a wheel chair so they start having walking problems when they are five, six, seven-years old, when they are in their teens they end up in a wheel chair when they you know in their late teens they can't use their arms anymore and then whey they are in the 20s we need to get them to ventilation they start to have heart problems and ultimately you know life expectation is around and 20 so years old, so it's a very disabilitating and then very you know bad disease not only for the patients but also for the care takers as you see here, their health get kind of deteriorate over time into somebody who is still in a good state of mind, but can't use his muscles any more is a kind of trapped into his own body and has there a lot of limitations, so this lack of dystrophin is caused by a mutation in the dystrophin gene. The dystrophin gene is one of the largest gene in the is the single largest gene in the human body and has 79 exons, you can imagine that and sometimes in the process something goes wrong and if some of these exons are missing so the deletion of some of these exons leads to a out-of-frame which then leads to a non-production of dystrophin and that causes all the problems that I've just described.
Fintan Walton:
Right, so clearly then each patient can be different therefore the applications of your technology or the use of that therapeutic approach can vary from patient to patient?
Luc Dochez:
Absolutely, I think this is personalized medicine and almost it's purist form or in its ultimate form indeed, so because of depending on the lesion and the exon that the patient miss we kind of skip an exon to kind of correct the reading frame into consolidated into an in-frame mutation, so obviously you need to many, many exon skippers as we call them to treat all the patients. Obviously and luckily enough there is some clustering around it and so you have bigger groups of patients that can be held by the same exon skipper and this is you know our lead product which is called PRO051 or now GSK968 thanks to a partnering deal that we did last year with GlaxoSmithKline, [PharmaDeals ID = 3399] it's targeting about 13% of all possible duchene boys so there is there are some hot spots there so you have some bigger indicate or bigger serve populations than others.
Challenges in clinical development program
Fintan Walton:
So tell us about the actual clinical development program and there must be challenges to try and get a product which is quite novel into the clinical, tell us how you overcome those challenges and where are you know in your clinical development program?
Luc Dochez:
Now absolutely we did a lot of work first you know preclinically in vivo with the patients cells and you know certainly in collaboration with the Leiden University Medical Center where this research actually originated already in 2000 [PharmaDeals ID = 35148] so after a long period in 2007 we were ready to move into the clinical and we did a safety study, one can understand and this cannot be done in healthy volunteers we directly have to go into patients so it took a little bit of convincing to the regulatory authorities into the ethical committees, but all of all you know that went pretty fast. We did it actually in two steps, first step was an intramuscular injection so injected directly into the muscle of the boys, four boys and then after a month we took a small muscle biopsy to see if we could restore dystropin if you could see dystropin in that biopsy and that was positive obviously otherwise we wouldn't talking about this at this stage which was a big breakthrough and that led to the financing by the venture capitalist Abingworth and LSP . Next challenge obviously was to move into a systemic delivery as that has been a big challenge for antisense oligonucleotides in the past, and so we did a subcutaneous injection in 12 boys five weekly injections in a dose escalating manner and then we took biopsies at the end of that period so a couple of weeks after the last injection we took again muscle biopsies, so the injection was in the abdominal reach and the muscle biopsies we were taking at a tibialis anterior so it required to you know distant location and you know we saw a very nice data coming out of that study so we saw those response and we saw dystropin expression in all 12 boys that we have treated with the drug, so systemic delivery of an antisense oligonucleotide could do the job for us was kind of the key message there which led to a lot of interest from investors, but also from big pharma companies and other companies that are interested in these orphan drugs.
Fintan Walton:
To deliver something systemically or particular in RNA to systemically what sort of formulations you have to come up with formulations presumably or how did you do that?
Luc Dochez:
No this is I think the one time I can say that you know we were lucky, quote on quote lucky with the disease because of the duchene disease muscle cells are more leaky, because of the lack of dystropin you know they can damage and they get bigger oppose the normal cells and that apparently leads to a better up take of large molecules such as antisense oligonucleotide, so here there was a fit of the disease with the therapy that we have developed, so it's no special formulation and it's obviously something that is only specifically applicable to duchene, but once more approved that exon skipping is something with antisense oligonucleotide is something that was quote on quote made for duchene.
Collaboration with GlaxoSmithKline
Fintan Walton:
Right, so clearly then this attracted as you've said the interest of both venture capitalist but also of major pharmaceutical companies that lead to your collaboration and partnership with GlaxoSmithKline tell us about that particular collaboration and what's left for you guys to take forward yourselves?
Luc Dochez:
Yes absolutely so, the deal is a combination of a license and an option deal, so Glaxo took a license on the lead compound and it's now responsible for further development and commercialization, it is being said we still play an active role you know with more in the back of the cars that of you know driving the car which is good because we can leverage our knowledge that we have about the duchene space and about antisense oligonucleotides to Glaxo we can tap into their development expertise which we can then learn from further development of other exons that we have retained for ourself, the option components means that they have options on three additional exon skippers, but this being said there is still many other exon skippers that are left for ourselves that we will try to bring to patient ourselves and that is the actually the ambition of the company to build a fully integrated specialty biopharma company and like and following the business model of the BioMarin's and the Genzyme's that have proven that this is possible, but with that deal we try to kind of combine together to I would say diminish or to minimize the first development risk of the share that with an experienced partner and still we can keep a little bit of the upside that is out there and the potential that is out there for ourselves.
Fintan Walton:
Right, so with that with GSK taking the clinical development program forward where are they now and what's the next important piece of research that's going to take place?
Luc Dochez:
Yes also as you can imagine that I have to follow a little bit GlaxoSmithKline's policies about communicating about the further development, so what is public we are in the mid stuff or we have started the Phase IIb and they have started to get it with us the Phase IIb dose-ranging an optimization study which is a placebo-controlled study results so additional clinical work going on and a fully randomized pivotal study is about to start. So and these you know these different studies will all lead to interesting data point, because there is not it's not as same as developing a traditional pharma product in the orphan space there is a large unmet medical need there is nothing so, if for example the Phase IIb data would be very positive you know we can always consider how to move this forward at that stage, but these are the programs that are running.
Fintan Walton:
Okay, with the other potential therapies that can be used for duchene for the other group of patients that have not been covered by the GSK agreement presumably you are taking those forward yourselves at the moment?
Luc Dochez:
Yes we are and we are trying to you know do as much as possible and as much as a company our size can handle, but yes we try to move everything in parallel as swiftly as possible because there is a enormous patient pool as you can imagine as being said we have to be careful, we have to manage expectations as well because although first data have looked very promising there is still a long you know way to go.
Fintan Walton:
Sure, the application of this RNA based therapy to other diseases could you describe where that potential can be?
Luc Dochez:
Yes we have, we're working on another way to modulate RNA and that is to you know remove what they call toxic RNA and that is something that is applicable in the trinucleotide repeat disorders such as huntington and myotonic dystrophy and these are the two other indications we have within our priority list to try to develop or we have good initial but still very early and then preclinical results and we will also try to advance those, but the first priority remains duchene for us.
Future plans
Fintan Walton:
Okay, so where does that leave us when you look into the future for your company for Prosensa, where what can we expect? What are your own expectations for the company going forward in the next say three to four-years?
Luc Dochez:
Yes, I think the most important of all and actually the biggest wish we all have is that we are successful in developing something for the duchene boys you know making a change in their lives would be something which you know would makes us all very proud and very happy, so I think as I said that remains the biggest priority with that I think we will you know be successful in further developing as a standalone company that can have its place and the orphan space and that can make a difference to patients.
Fintan Walton:
Luc Dochez, thank you very much indeed for coming on the show.
Luc Dochez:
Thank you very much.
Fintan Walton
Dr Fintan Walton is the Founder and CEO of PharmaVentures . After completing his doctoral research on the genetics of cell proliferation at the University of Michigan(US)and Trinity College (Dublin, Ireland), Dr Walton gained broad commercial experience in biotechnology in management positions at Bass and Celltech plc (1982-1992).
Luc Dochez
Chief Business Officer
Luc Dochez , Chief Business Officer and Senior Vice-President Business Development joined Prosensa in November 2008 and is responsible for all business and corporate development activities at the company. He has over 10 years experience in the biotech industry and was directly involved in multiple financing rounds and partnering deals with various biotech companies. Before joining Prosensa, he was a consultant within Arthur D. Little's biotechnology practice, Director of Business Development at Methexis Genomics NV, VP Business Development at TiGenix Inc. and President of TiGenix Inc. Luc Dochez holds a PharmD degree from the University of Leuven (Belgium), a postgraduate degree in Business Economics from the same university and an MBA from Vlerick Management School.
PharmaVentures
PharmaVentures is a corporate finance and transactions advisory firm that has served hundreds of clients worldwide in relation to their strategic deal making in the pharmaceutical, life science and healthcare sectors. Our key offerings include: Transactions / deal negotiations; Product / technology valuations; Deal term advice; Due diligence & expert reports; Strategy formulation; Alliance management; and Expert opinion for litigation/arbitration cases. PharmaVentures provides the global expertise to ensure our clients generate the highest possible return on investment from all their deal making activities. We have experience of all therapeutic areas and can offer advice on both product and technology commercialisation.
Prosensa
Prosensa is a biopharmaceutical company focused on the discovery, development and commercialization of RNA modulating therapeutics. The company targets genetic disorders with a large unmet medical need, with a primary focus on neuromuscular and neurodegenerative disorders such as duchenne muscular dystrophy (DMD), Myotonic Dystrophy(DM1), Huntington's Disease (HD) and Spinal Muscular Atrophy (SMA). The company has developed a portfolio of clinical and pre-clinical RNA-based drug candidates. Prosensa's current clinical portfolio is focused on the treatment of duchenne muscular dystrophy . Its lead product, PRO051-GSK2402968, aims at restoring dystrophin expression and improving muscle condition and function in a relatively large subpopulation of Duchene patients and has successfully completed a Phase I/II study. Preparations are ongoing to start enrolling patients in a Phase III study in 2010. PRO044, the company's second product candidate, addresses another subpopulation of Duchenepatients and has entered clinical trials in the last quarter of 2009. Prosensa was founded in 2002 and is located in Leiden, The Netherlands. The company works closely together with Leiden University Medical Center (LUMC) and is supported by a consortium of leading biotech investors, including Abingworth, Life Sciences Partners, GIMV, AGF and MedSciences Capital. In October 2009, Prosensa entered into a strategic alliance with GlaxoSmithKline (GSK) to accelerate and broaden the development of its DMD product candidates.