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Biotech Survival In A Bleak Economy: The Story Of Addex Pharmaceuticals - Life Science Leader

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9/19/12 4:30 PM

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Biotech Survival In A Bleak Economy: The Story Of Addex Pharmaceuticals

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By Wendy Meyeroff Considering how hard it is for people, let alone companies, to say “Hmmm. We may have made a mistake. Let’s try something else,” it’s refreshing to hear how a company not only did that, but is succeeding at it.

That’s the story behind Addex Pharmaceuticals, a biopharma firm based in Geneva, Switzerland. “We started out seeking ways to fight addiction [hence the company name],” says Vincent Mutel, Addex’s CEO, “but we realized that addiction is such a complex disease that to try and treat it strictly through pharmacological methods, although an appealing idea, was an oversimplification.”

So in 2003 (the company was founded in 2002), Addex reviewed its goals. That actually meant changing foci a few times, starting with moving away from addiction and exploring other options.

The Shift to Allosterics Current drugs are orthosterics. They bind to a specific area, known as the active site, and try to block it or activate it. Like flipping a light switch, they either turn the body’s receptors on or off, no matter how strong the need is for them at that active site. “The pharmaceutical industry has been developing drugs that follow one simple mechanism for many years — our body has mechanics that are blocked or activated. Then there are natural factors that block or activate those mechanisms. So the industry model was to mimic whatever the natural stimulus was doing — either activating that stimulus or blocking it,” Mutel says.

Allosterics, by contrast, find a different location to bind to, away from the active site. Perhaps of even more interest to the pharmacological world, allosteric modulators only do their work when they’re needed.

Mutel uses this analogy: “It’s like a dimmer switch, where you can control the signal when and if a light is turned on, versus a straight on/off light switch. In other words, the body remains in control of the on/off cycle, and allosteric modulators modify the intensity of the signal. Throughout the last 100 years of drug discovery, we’ve used drugs that strictly turn something on or off. And those drugs stay in the system, having the same impact 24/7, whether the need for them is peaked or not.

“However, our body’s natural systems don’t operate with simple on and off switches. Think of hormones and how they peak at certain times a day or month. Our allosteric modulators don’t bother the body when they aren’t needed; if there’s no signal they are silent. That’s a very big differentiation,” he says. Negative allosteric modulators (NAMs) reduce a signal (“dimming the lights”) and positive allosteric modulators (PAMs) increase a signal (“turning the lights up”).

From Addiction to Anxiety to Migraine Coming from addiction, Mutel says, “We were working in the central nervous system (CNS) area anyway,” so the company decided to look at trying to turn the lights up and down on receptors for glutamate, a neurotransmitter like serotonin and dopamine. While science has been able to develop dopaminergic and serotonergic drugs (the latter include the drugs for fighting depression known as SSRI, or selective serotonin reuptake inhibitors), it’s been much harder to modulate glutamate. Trying to target and control glutamate directly can cause too many neurological complications, including seizure and stroke.

Instead, scientists are looking to find ways to more specifically target the proteins called glutamate receptors, which sit on the neurons and transmit information once glutamate binds to them. Of the eight classes of glutamate receptors known as mGluR1, mGluR2, 3…etc., some are responsive to positive allosteric modulation (i.e. mGluR5 PAM) and some to negative ones. All eight receptors are now thought to play key roles in problems that include schizophrenia, depression, post-traumatic stress disorder, migraine, Parkinson’s disease, and anxiety. The latter is the area Addex moved into when it shifted its focus from addiction .

“A large body of clinical and animal data showed it might be interesting to look at the effectiveness of mGluR5 in the treatment of anxiety, so we decided to test anxiety in humans,” Mutel says.

Instead, the company showed its flexibility once again. “The results of studies showing where in the brain the receptor for anxiety was expressed led us to believe it would work in migraines,” Mutel says. Not only would it work in migraines, but it might lead Addex to an interesting shift in migraine therapy: from treatment to prevention. “The current therapy for acute migraine, a class of drugs called triptans, work as a vasoconstrictors, constricting the inflamed blood vessels, to reduce the migraine crisis. Those drugs can’t be used to prevent migraine because they treat inflammation, which is a symptom that appears at the end of the migraine process,” Mutel says.

http://www.lifescienceleader.com/magazine/past-issues3/item/3318-biot…urvival-in-a-bleak-economy-the-story-of-addex-pharmaceuticals?list=n

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Biotech Survival In A Bleak Economy: The Story Of Addex Pharmaceuticals - Life Science Leader

9/19/12 4:30 PM

That was the initial benefit of Addex’s drug (currently labeled ADX10059). It could reduce migraine pain 2 hours after delivery. But because ADX10059 works via a neural mechanism, not on blood vessels, Addex and leading researchers advising the company think it could also work to stop the beginning of the migraine process, thereby acting as a prophylaxis. “The migraine preventative market isn’t being served. It’s a very empty market with a large medical need for prevention,” Mutel says, and thus a huge potential market. So the company is shifting the drug’s focus to that arena.

More Outside-the-Box Thinking One of Addex’s newest accomplishments (in 2008) is the development of a modified release formulation of ADX10059, known as ADX10059 MR. Why is a modified release formulation of certain drugs important? “Normally when you develop a drug you have to come to a formulation — tablets, capsules, whatever. We went to the Phase IIA trial on ADX10059 with the pure compound — as a powder in capsules — something that’s normally not done,” Mutel says.

The result was the original formula entered extremely quickly into the blood. In fact, Mutel says, it was entering the blood too fast and producing a number of abnormal responses that are known to be common for drugs that enter the brain rapidly. “So we worked on a slow-release formulation to control these problems, and, indeed, the modified release formulation was devoid of the fastrelease side effects,” he says. That was an important factor in allowing Addex to move forward with Phase IIB trials which, he says, “We are in today for both migraine prevention and gastroesophageal reflux disease [GERD].”

The GERD endeavor is another example of the company’s ability to see opportunities that others might miss. “There were a couple of papers, including an animal report, that indicated the glutamate receptor we were targeting with a PAM [positive allosteric modulator] for migraine therapy might also have a benefit regarding GERD. It seemed it might be something interesting to look at, but that’s all it was, something interesting,” Mutel says. Nevertheless the company proceeded and took it into Phase II research on GERD as well as migraines.

Other new disease areas in which Addex is expanding its allosteric modulation discovery include inflammation (e.g. arthritis) and metabolic disorders (e.g. diabetes and obesity). The company already has disclosed that it has found orally available PAM of a key receptor implicated in diabetes, called GLP-1 receptor (GLP-1R). Eventually Addex expects that its GLP-1R PAM will be available as pills that will cost a fraction of an injectable drug and potentially will work better due to their allosteric mechanism. Indeed, Mutel says, allosteric modulators could one day replace many injectable drugs with cheaper orally available alternatives that may also offer better safety and efficacy.

Rethinking The Business Model Its library of allosteric compounds and its ability to shift in its thinking have helped Addex work through some extremely tough economic times. “When we started in 2002, it was the back of the biotech bubble and already a hard time to raise money,” Mutel says. He thinks one thing that helped the company move forward was that “many of us came from pharma and had knowledge of allosteric modulation and were prepared, in our own mindset, to explore its possibilities. That was key in enabling us to convince first ourselves, and subsequently our investors, that this was a viable investigative road to take.”

Mutel believes another advantage of having big pharma experience was that the company founders, including himself, “had a strong business experience prior to embarking on this adventure.” That experience led to a key decision before the company truly launched. “In 2002 I went to visit people in the pharmaceutical industry — our future customers — and asked, ‘What do you think about this kind of work? Would you be willing to follow this road?’” The answer was overwhelmingly positive, indicating that whatever Addex developed using the new allosteric focus was likely to find a place. By contrast, he says, the defeat of many biotechs has been their focus on the product first. “When I was on the other side, people would come to me for funding saying, ‘We have this,’ and I’d be saying ‘Yes, so what?’ We’d tell them to come back in phase II when they had a human result, which of course is when you have taken the most risk, something that small biotechs need to avoid.

At Addex, we don’t put ideas into development unless we know there’s a potential buyer for the product at the end.” In the case of biotech, the initial “buyer” is more often big pharma than patients, he notes — and that means building strong partnerships within the pharmaceutical industry.

Successful Partnerships With Big Pharma The first successful partnership Addex had was with Ortho-McNeil-Janssen, a J&J company, in 2004. “We had a molecule, mGluR2 PAM, that we, and others, thought would work for schizophrenia.

Schizophrenia is a very difficult indication for biotech to target. You have to invest a lot of money, the preclinical and clinical trials require specialized expertise, and the probability of success is very low. We had the crude drug, but weren’t interested in taking the risk of developing it, because of the expense,” Mutel says. J&J was interested, however, and so Addex agreed to the partnership.

J&J committed about $4.25 million up front, plus approximately $6 million in research funding and the rights to undisclosed monies later on. The research collaboration ended successfully in 2007, with J&J taking ADX71149, an mGluR2 PAM, into development to fight schizophrenia and anxiety.

If the chance of success was so low, though, why did J&J agree? Mutel has three words: “Innovation, innovation, innovation. For now, the pharmaceutical industry’s products are still treating people the same as we did in 1960; what we’re doing is very innovative. That’s why we can get interest early on, we don’t have to put the money into the clinical testing, and our contract lets us keep royalties,” he says.

Similarly, 2008 brought two partnerships with Merck. The first was a deal comparable to the one with J&J: For an up-front fee ($3 million) plus nearly $200 million in discovery milestones and royalties, Addex is collaborating with Merck to identify mGluR4 PAM, targeting Parkinson’s disease. The second deal is already even more lucrative. At a competitive auction, Merck purchased the rights to ADX63365, an mGluR5 PAM, for $22 million up front and almost $700 million in milestones and royalties.

Addex now has a project in midstage clinical testing for GERD and migraine, the most advanced in its pipeline, and continues to look for partners for this and several preclinical programs. What makes someone the right partner for Addex? “They have strengths/expertise we don’t have. You need people who’ve been working in a field for 15 or 20 years, but who are willing to be creative,” Mutel says. “With these new molecules you don’t know what to expect; people have to be willing to look at a problem with new eyes. That’s not easy to find. And,” he adds, “they have to have lots of money to fully explore and develop these products into safe drugs that will benefit patients as soon as possible.” The company found all these attributes with both J&J and Merck.

Being Cautious Addex grew a lot in 2008, but now it’s proceeding cautiously. “We raised a lot of capital during our IPO, so in 2007 all we had to do was think about growth. We almost doubled the company; we were 77 people, and now we’re 135,” Mutel says. Still, Addex is watching other companies gaining ground in the field of allosteric modulators. “Novartis has published results on a molecule they have that has efficacy on Parkinson’s disease in humans. It has the same mechanism of action as another of our drugs, called ADX48621. So we’re planning to move ADX48621 into clinical testing for Parkinson’s disease, and we’ll see what happens,” Mutel says. Several other big companies have indicated their interest in this field, although specific products have yet to be disclosed, he adds.

http://www.lifescienceleader.com/magazine/past-issues3/item/3318-biot…urvival-in-a-bleak-economy-the-story-of-addex-pharmaceuticals?list=n

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Biotech Survival In A Bleak Economy: The Story Of Addex Pharmaceuticals - Life Science Leader

9/19/12 4:30 PM

While Addex now has the largest disclosed pipeline of allosteric modulators and a library of over 70,000 allosteric modulators, it’s being cautious in its growth. “In 2008, we realized we had to become very prudent and stopped hiring. We’re not considering laying off people because we have lots of resources, but we are conserving cash,” he adds. The company feels it’s well-funded through to early 2012, which is assuming there’s no other major income during that time. Besides, Mutel points out, they’re not planning to continue only as a small solo company. “We already have two of the biggest pharmaceutical companies in the world as partners, and we are always interested in finding others who share our vision,” he says.

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