David Cavalla – Drug Repositioning Panel Talk Transcript

David Cavalla


So I’ve just got a few slides here, hoping to pick out a couple of points on Drug Repurposing.  The title emphasizes two points, obviously looking ahead but also trying to make use of a retrospective view.  So what I’m trying to convey in that title is the idea of seeing a little bit further than the science into the commercial arena into which the science will play, and I’d also be talking about the utilization of retrospective analysis of clinical trials as a way of validating the projects you want to look at.  So a couple of points which I hope maybe instructive for the audience.

Numedicus was founded three years ago based on quite a long number of years experience in drug repurposing field.  We worked in all kinds of therapeutic areas offering advice to big pharma companies, listed biotech companies, as well as smaller micro biotech companies.  A lot of what we do is confidential; however, there are two repurposing projects which have been taken through phase two, one of which came out the other end with a pretty close to phase 2b result and the other is currently running due to read out next year, and we’ve also had quite a lot of experience in prosecuting and granting or prosecuting to grant various method of use patents.

So what I want to get across here is what I see as the pinch points, the rate limiting steps or rate determining steps in successful drug repurposing.  I actually believe that there are plenty of opportunities placed on new uses for existing drugs; however, those opportunities are limited by number of breaches – most obviously commercialization issues, secondarily patentability and freedom-to-operate issues.  And in addition to those limitations, there are some key variables which will affect the quality of the projects that you want to undertake.  Obviously the quality of the new data connecting the existing drug and the new use, the availability of the old data on toxicology and so on, which helps you advance your projects rapidly into clinical trials, and then you need to think carefully about the regulatory pathway.

So the two areas I want to focus on in this tool are the commercialization issues, the quality of the new data, which is highlighted in italics.

The commercialization aspects, there are obviously a series of things which clearly impact on the commercialization of your project.  But the one factor which is most prominent and affects nearly all drug repurposing projects is the issue of differentiation, which I’m sure other speakers will have referred to yesterday, at least I hope they have, and that is essentially the issue of whether you’re able to control the opportunity of an existing drug, vis-à-vis generic competition, and that affects so many different projects that it’s not just the basic issue of an exact comparison of your drug with something that’s on the market in the generic form, there are all kinds of sort of gray areas which can drastically reduce the value of the project you’re trying to develop.  And so that’s shown as the central tree facing your route through to the sunlight in the back of the forest and on either side of them, you can see the safety and efficacy and the free to operate issues, and other obstacles which you need to circumnavigate.

One of the ways that you can get around the differentiation angle is by – or a couple of the ways – are by reformulating or by slightly changing the active ingredient, and you don’t have to do much to reformulate it or to change that active ingredient in order to end up with an entirely differentiated product.  The important point about this grant is that the risk associated with your projects can be dramatically reduced, and that’s obviously the advantage that you want to gain from drug repurposing to the strategy whilst at the same time gaining access to a huge value increment by a slight change in other formulation or active ingredient.

And a couple of examples of that which are highlighted in the paper that we published a couple years back are for instance the Paclitaxel stent, which is making use of the anti-inflammatory aspects of accumulated cells in the indication of restenosis and putting it together with – – it’s not quite a reformulation but it’s a drug device combination and that has been a hugely successful commercial product.  Another example, which is in the respiratory field is the use of glycopyrronium for the treatment of COPD, so this is an old anticholinergic compound based on muscarinic receptors, which was repurposed by Airicus* and then that taken over by Sosa* and then licensed on to Aventis, and that’s an example of the project which was not only discovered in the biotech field but was also on the basis of formulation patents licensed into a large pharmaceutical company, namely Novartis, and that project is now in late pre registration phases.

Now to switch a gear a bit and talk about the retrospective clinical trial analysis side of things.  This is obviously something that has historically been the feature of a number of drug repurposing projects, but I don’t think anybody has done this in a more proactive and systematic fashion.  Obviously the advantage of clinical trial data is that you’re dealing with humans and you don’t have to worry about translation from an animal situation, which might not that valid.  And it could not only give information on new indications, but it will also give indications on patient subgroups, and it’s worth emphasizing in that context that most new therapeutics only work in a small number,I’m sorry, a minority of patient responders.  That proportion can be as low as 25% in the oncology field, and that’s quite remarkable really.

Retrospective clinical trial analysis is obviously not the same as prospective.  It doesn’t generate regulatory standard data. You have a problem of confounding situations where by chance you can have things turning up to be statistically related when they aren’t really related in real life and you’re also restricted by what has been or can be measured. I’ll emphasize that by reference to some of the examples I’m showing on the next slides, and I also in these examples come back to the issue of commercialization, and I hope to do that.

So I’ve got three slides on examples here. I think everyone’s aware of aspirin, one of the most commonly used drugs and one of the most well known drugs was revealed in December through a retrospective analysis of patients who’ve been diagnosed with colorectal cancer to have a low risk of that diagnosis when they had been treated with aspirin.  So an example of one of the most commonly used drugs set up against one of the most feared diseases.  Then there’s Tamoxifen, a estrogen receptor motivator used for the treatment of breast cancer.  Actually according to meta-analysis of retrospective trials, quite large meta-analysis involving tens of thousands of patients, can give rise to a 30-to-40% reduction in risk death from myocardial infarction, and that information has now been – – it is being used by a biotech company called Protexa to underpin a development program for the treatment of acute coronary syndrome or unstable angina.  Angiotensin II blockade is – – and there’s quite a lot of data actually on the – – this pathway being effective in fibrotic conditions.  There’s a relatively recent study that came out a couple years back on the reduced incidence of liver fibrosis in patients with Hepatitis C, so these are patients who are hypertensive treated with angiotensin blockers and they have a low risk of the – – perhaps the – – going on to the fibrotic condition. And lastly, statins have been shown to give rise to about a 30% reduction in the risk of hospitalization from epileptic conditions.  Now all of those examples cross a whole range of therapeutic indications, cardiovascular to CNS to cancer then fibrosis.

The next two slides will focus a little bit on some disease specific examples of clinical trials. The first one talks about cancer, and the reason why there are a bunch of clinical trial, retrospective clinical trial analysis focusing on cancer is obviously because the occurrence of cancer in a patient treated with a drug is normally a yellow card incident which is reported to the authorities, so it’s something that we picked up in for instance the general practice research database, which is one of the largest epidemiological databases in the world and it’s founded in the U.K.  Incidentally that analysis was the basis for the third example on this screen, the association between tricyclic antidepressants and the incidents of colorectal cancer and glioma. That study incidentally showed a dose related effect of these antidepressants specifically in those diseases – glioma and colorectal cancer and not statistically significantly in other cancers.  Raloxifene, the first example on that slide, was actually originally anticipated to be a development candidate for the treatment of Tamoxifen-resistant cancer. It failed in that indication and it was repurposed for the treatment of osteoporosis and it was only many years after it was marketed in that indication that people started to look again at breast cancer and it’s now been shown epidemiologically to be effective in breast cancer and that’s now been approved in that application.  Metformin‘s another interesting example known as an insulin sensitizer and first line treatment of diabetes.  It’s also of great interest in the treatment of breast cancer.

And the last slide, I’m going to focus on a specific pathway.  This is beta blockade.  So beta blockers were interestingly first approved for the treatment of super ventricular tachycardia.  They then went on to be used in hypertension, and again later in their life there have been all kinds of other indications for beta blockers, so there’s a large meta-analysis showing that Propranolol is associated with a 30-to-40% reduction in fractures, and that has been taken up by a West Coast company.  It’s name momentarily escapes me.  They tried to raise all the money for the development of Propranolol for the treatment osteoporosis, but they really were faced with a difficult commercialization proposition because beta blockers are so well known that there’s about 40 of them that it’s difficult – – that they had difficulty persuading investors that they would not face an obstacle from generic compounds in that class so they were unable to raise money.  The middle example is for the treatment of melanoma.  That’s something which has come out I think in the past couple years. And the last examples on this slide show ways in which different companies have tackled the commercialization problem to try to develop beta blocker compounds for the treatment of cachexia, so this association of beta blockade and cachexia came out of a retro-analysis of various heart failure trials in which cachexia accompanies congestive heart failure.  The first way in which it was avoided or attempted to be avoided was by combining beta blocker with an NSAID, and you’ve heard about that I think yesterday from Vicus who are developing the combination of Etodolac, and although whether or not NSAID actually induces a significant benefit in addition to the Propranolol, I’m not sure whether that’s been shown yet.  The other way in which the off label problem has been tackled is by identifying a particular beta blocker with a complex pharmacology that is referred to as a catabolic/anabolic transforming agent, so this is sort of beta blockade plus something else.  The exact nature of the compound hasn’t been publicly revealed, but that’s a project that’s currently in phase two.

So in conclusion, my view is that drug repurposing opportunities are pretty easy to identify but often hampered by commercialization issues.  Secondly that you can tackle the differentiation problem pretty effectively by only small changes in the active ingredient or formulation, and thirdly that retrospective clinical trials and epidemiological evidence is extremely valuable but still relatively untapped source of the opportunities.

So thank you very much.

Barry Bunin

Thank you, David.  So given your unique experience, you’re a biologist who’s been involved in management at big pharma and worked with small companies, in these areas that you mentioned, the differentiation and the challenge of commercialization, how do you see that evolving – irrespective of small companies, big companies, foundations, government agencies, how all these groups are going to get aligned and where do you see it going?

David Cavalla

Well I see there’s a huge opportunity for the publically funded bodies – who aren’t so exposed to the pressures of commercialization – to develop projects, but not just the government bodies but also charities and so on, that are interested in developing products specific to the disease of interest to them. There is a great opportunity for these types of organizations to take up some of these drug repurposing projects without some of the commercialization pressures that affect big pharma, and I think big pharma for very justifiable reasons needs to focus on the commercialization end point much more clearly than these more public-facing bodies.  So as they become more important, and I think they are becoming more important in terms of generating new products, the opportunity of drug repurposing projects to get air time and to become products is increased in my view.

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