Aram Mangasarian explains the elegant mirror image technology of NOXXON Pharma for extracellular targets




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Video title: Aram Mangasarian explains the elegant mirror image technology of NOXXON Pharma for extracellular targets
Released on: May 11, 2012. © PharmaTelevision Ltd
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In this episode of PharmaTelevision News Review, filmed in Amsterdam at BioEurope Spring 2012, Fintan Walton talks to Aram Mangasarian, CBO of NOXXON Pharma AG.
Spiegelmers Platform technology: Advantages and uniqueness
Fintan Walton:
Hello and welcome to PharmaTelevision News Review. On this show I have Aram Mangasarian, who is the Chief Business Officer at a company called NOXXON which is based in Berlin, welcome.
Aram Mangasarian:
Thank you very much, it's a pleasure to be here.
Fintan Walton:
Very good. Aram, NOXXON as I said is a Berlin based company, it has its own special science, its own special scientific platform called Spiegelmers and we'll talk a little bit about those, it's also a company that's funded by some of the you know top venture capital firms as well so what I would like to do is explore a little bit about the history and why we should all bet on NOXXON , as a company.
Aram Mangasarian:
It's my pleasure to tell you about that. The company was founded actually quite a while ago back in 1997 as a fellow called Sven Klussmann, who is currently our Chief Scientific Officer and this came out of his graduate work at the University in Berlin, he decided to found a company based on the technology and Spiegelmers are essentially they are oligonucleotides but they use the mirror-image stereochemistry and that gives you a number of very interesting advantages over some of the other oligo based platforms, for example stability RNA is of course known to be unstable in the body due to the presence of nucleases, but when you take this mirror-image stereochemistry these nucleases don't see the molecule as RNA and thus you have excellent biological stability. One of the other interesting aspects of the technology is that for similar reasons it doesn't activate the immune system, so the Toll-like receptors which normally respond to the presence of RNA floating around again don't see our products as RNA and don't respond.
Mechanism of Spiegelmers platform
Fintan Walton:
Okay, so brings in a different angle a new angle into a therapeutic approach, so you've got the technologies as they say then you've got to find the right therapeutic use of that technology?
Aram Mangasarian:
Exactly.
Fintan Walton:
So tell us about what the indications you've gone for and why you went for those in particular?
Aram Mangasarian:
It was really, it was really target driven because we wanted strategically to avoid the issue of getting into a cell with an oligonucleotide we choose to go after extracellular targets. So the sweet spot if you will for NOXXON are small protein targets that are soluble, chemokines are an excellent example two of our products target chemokines, the first one MCP-1 also called CCL2 and which attracts monocytes and other immune cells to sites of inflammation in the body. Now we are developing that as a therapy against diabetic nephropathy , so there is macrophage influx in the kidney and diabetics and this correlates very well with kidney damage and this inevitable decline of kidney function towards end stage renal failure . And we are hoping to stop that process perhaps repair it, but at the very least just slow the decline.
Fintan Walton:
Right. So just for me to understand, I mean the idea of a mirror-image form of an oligonucleotide presumably that then interfaces with the proteins themselves is that right?
Aram Mangasarian:
It does indeed.
Fintan Walton:
So how does that mechanism work?
Aram Mangasarian:
Well so we use a process called SELEX and this was developed by a fellow named Larry Gold in Colorado and we have an exclusive license to use SELEX which is an evolutionary screening technology [PharmaDeals ID = 9595], we put 10 to the 15th molecules of RNA random which is a huge number and you select out those that bind and this process was really, really fine tuned over the years by various companies, we've now got a license to that exclusively to make mirror-image therapeutics. Now this is how we do that is very interesting, because we actually make a mirror-image of our target and we use natural RNA and so we then get a natural RNA that binds with completely useless target which is a mirror-image of a biological target, but the interesting thing then is we take the sequence of that RNA we synthesis it using the mirror-image oligos and we now have something that binds the natural target so it's a very elegant technology that works.
Fintan Walton:
And that works?
Aram Mangasarian:
And that works.
Fintan Walton:
Every time?
Aram Mangasarian:
Every time.
Fintan Walton:
Amazing.
Aram Mangasarian:
That's fascinating.
Fintan Walton:
So with this technology with these mirror oligonucleotides can you adjust the affinity of those so you can alter the response?
Aram Mangasarian:
Indeed you can, so there is an initial selection and from that selection you generate multiple families of oligos with varying affinities and now actually what we've discovered is you can actually find two nodes in going with substitutions of basis and refine affinity still further and it's with that type of technique that we've actually have been able to drop the inhibitory constant the IC50 from high nanomolar down to sub nanomolar in some cases, so it's a very interesting and a little bit surprising finding.
Fintan Walton:
So, okay so what is the so you've a got a means by which you can act, you create is an antagonist effectively?
Aram Mangasarian:
Exactly.
Fintan Walton:
Now what is it that your antagonist does that other antagonist don't?
Aram Mangasarian:
So, I think there are many different platforms that will go bind compounds obviously the ones that are most known are antibodies go after ligands, we like many of the antibody therapeutics we target ligands you know VEGF is a good example of a ligand target, going after chemokines is a very interesting proposition because in some cases one chemokine will actually interact with multiple receptors. So the standard small molecular weak compounds that bind and antagonise a single receptor are not necessarily a good strategy if you want to neutralize all the effects of a given chemokine and that's actually the case with our second program which neutralizes SDF-1 which is a chemokine that is involved in trafficking of stem cells from the bone marrow to tumors, but also interestingly trafficking of tumor cells back to areas of high concentration of SDF-1, for example the bone marrow and one of the reasons you get bone metastasis and cancer. So neutralizing that gradient of chemokine in the body will have beneficial effects we hope in two directions, blocking the vascularization of tumor by preventing the endothelial progenitor cells from getting to the tumor and the other direction blocking metastasis of the tumor.
Programs and clinical trial stages
Fintan Walton:
Okay, so that brings us into the indications that you've selected is where we set out to define, so describe where those programs are in terms of your own clinical development, preclinical clinical development?
Aram Mangasarian:
Sure. So all three are finishing Phase I, one of them is actually now gone into Phase II, we will announce that actually in the coming weeks that's the oncology compound NOX-A12. So we've now started recruiting two Phase IIa trials one in Chronic Lymphocytic Leukemia , the other in multiple myeloma . Now the mechanism of action there is it's placed on top of the current standard of care therapy, because it's essentially if you will a chemosensitizer and in the case of solid tumors it blocks metastasis and invasiveness, so the multiple myeloma trial is on top of VELCADE Dexamethasone and the CLL trial is on top of Bendamustine and Rituximab.
Fintan Walton:
When you say on top of you mean that you are seeing that as a add-on?
Aram Mangasarian:
It's an add-on therapy.
Fintan Walton:
An add-on therapy?
Aram Mangasarian:
Yes, and so the goal there is to improve the response rate, and proof of our mission rate and also hopefully to keep the cancer and our mission for longer after the therapy.
Financing and partnerhip model
Fintan Walton:
Right, now doing drug development is an expensive game?
Aram Mangasarian:
It is indeed.
Fintan Walton:
You've got some nice investors all sitting there and peeling of their dollar notes or Euro notes whatever they put into your company, but in the end you need to have partners as well?
Aram Mangasarian:
Indeed.
Fintan Walton:
So where are you with those?
Aram Mangasarian:
So those discussions are ongoing. I think in the past so there was a long period 97 really to 2007 which was if you will a technology development period, I think the company was learning the ropes was understanding where it's technology could be used best, we've got into the sweet spot now of outside the cell, small proteins although we have a compound that binds as Sphingosine-1-phosphate as well, but these soluble smart proteins that work at a distance that form gradience seem to be really the ideal place to use our technology. We had a number of alliances we had alliances with Lilly [PharmaDeals ID = 30478], with Pfizer [PharmaDeals ID = 23818] for example, but I think in retrospect what we found was these companies of course all have their own internal platforms and the targets we got were the ones they couldn't make good inhibitors to with all of their existing technology, so they were willing to give it another shot and these were often not ideal for Spiegelmers. So 2007 there was a big refinancing led by TDM they brought in some French investors Sofinnova, Edmond de Rothschild. There was another round in 2010 which brought in NGN from New York, so between those two rounds which were essentially kind of a refocusing of the company on it's own products, getting those into the clinic advancing those we've raised 72 million Euros. So that will fund us through end of first quarter next year and I think that is within the time frame of getting some of the Phase II data from all three programs that are currently in the clinic.
Fintan Walton:
And also looking for new partners in that same process?
Aram Mangasarian:
Of course, so the diabetic nephropathy product has generated a fair amount of interest and we have a number of companies that have indicated as soon as the data's are blinded from the Phase Ib where we treated diabetics for one month they would very much like to see that. And we've also scheduled interim unblinded data review into the Phase II, so we'll actually get 25 patients out of the 75 reporting in September of this year, another 25 in November and the full 75 in January, February of next year. So we will know how things were going we will be able to show that with partners and hopefully generate the interest we need to see the partnership quite quickly.
Future business strategy and plans
Fintan Walton:
Okay, so going into the future business strategy, business model very typical of a biotech these days you got you're in a fortunate state of having a reasonable funding going into your company to take these products in the next important inflection point we call it, so traditional model just look for partners?
Aram Mangasarian:
Yes. I think, I mean we're reasonably conservative we think people want to see we understand in the indications like cancer , diabetic nephropathy people would like to see some efficacy data. We also understand that it's a new platform and in that sense people are reluctant to move before they see evidence of efficacy and safety and so you know we are not expecting people to jump at this before we can prove that type of data and then we are happy to move into partnerships and I think the idea there is keep some, some markets, some geographic or co-promotion rights somewhere to get some upside for the company and find a good partner that will help us develop it.
Fintan Walton:
Aram Mangasarian, thank you very much indeed for coming on the show.
Aram Mangasarian:
It's been my pleasure, thank you Fintan.
Fintan Walton:
Thank you.
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).
Aram Mangasarian
Chief Business Officer
At the time of recording this PTV interview Aram Mangasarian serves as Chief Business Officer at NOXXON Pharma AG. Aram Mangasarian brings over ten years experience in biotechnology and pharmaceutical business development to NOXXON . He holds a PhD in Biology from the University of California, San Diego and an MBA from INSEAD in France. Aram began his career at ExonHit Therapeutics (Euronext:ALEHT) in May 2000, eventually heading the business development function as Vice-President. He concluded a number of important agreements for ExonHit, in particular the strategic alliance with Allergan (NYSE:AGN). In October 2005 Aram joined Novexel as Vice-President Business Development. In this capacity he concluded the licensing agreement for North American rights to the NXL104 beta-lactamase inhibitor with Forest Laboratories (NYSE:FRX) in January 2008, which provided for a "75m upfront payment, "75m in pre-commercial mile-stones and double-digit royalties. Aram was also a member of the team that negotiated the acquisition of Novexel by AstraZeneca (NYSE:AZN) in March 2010 for up to $505m. Aram joined NOXXON in May 2010 as Chief Business Officer and Executive Committee member.
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.
NOXXON Pharma AG
NOXXON Pharma AG is a biopharmaceutical company pioneering the development of a new class of proprietary therapeutics called Spiegelmers, the chemically synthesized, non-immunogenic alternative to antibodies. NOXXON has a diversified portfolio of clinical stage Spiegelmer therapeutics: " anti-CCL2/MCP-1 Spiegelmers NOX-E36 for diabetic nephropathy " anti-CXCL12/SDF-1 Spiegelmers NOX-A12 for oncology " anti-hepcidin Spiegelmer NOX-H94 for anemia of chronic disease The Spiegelmer platform provides the Company with powerful and unique discovery capabilities, which have generated a number of additional leads under preclinical investigation. Located in Berlin, Germany, NOXXON is a well financed mature biotech company with a strong syndicate of international investors, approx. 60 employees and a highly experienced management team.