Addex Dishes About J&J Deal
May11

Addex Dishes About J&J Deal

Merck wasn't the only company holding an R&D Day today- Swiss pharmaceutical firm Addex Pharmaceuticals also held a briefing for investors and journalists. (I didn't get to go to Geneva, but I did watch the webcast and downloaded the presentations here.) Addex has dedicated its entire pipeline to allosteric modulators- drug candidates that work at protein sites other than the ones where the body's chemicals typically bind. Last fall we wrote about Addex's strategy and its potential usefulness in tackling G-protein coupled receptors (GPCRs), one of the biggest (if not the biggest) classes of drug targets. Today Addex updated attendees on a few different drug candidates. But the biggest news was that it disclosed the terms of its schizophrenia drug partnership with Ortho-McNeil-Janssen Pharmaceuticals, a unit of Johnson & Johnson. According to the terms of the deal, Addex could get as much as 112 million euros subject to successful completion of development and regulatory milestones. In addition, Addex is eligible for low double-digit royalties on sales of the possible schizophrenia drug it discovered, subject to regulatory approval and successful commercial launch. Addex's stock jumped up 8.75% on the news, to 13.05 Swiss francs (about $11.75) In the deal, Ortho gets to fund and perform preclinical and clinical development for Addex's potential schizophrenia drug, known as ADX71149. The molecule dials up the activity of a GPCR that responds to glutamate, called mGluR2. The dialing-up part is what's thought to be important. It's the whole point of taking an allosteric approach. Instead of just turning a receptor on or off, you adjust its activity to acceptable levels. The philosophy at Addex is that this more subtle approach will restore more normal glutamate signaling in schizophrenia patients, with fewer of the kinds of side effects that result from an all-or-nothing, on-or-off approach. Of course all that remains to be seen for ADX71149. Phase II clinical trials (which can give an indication of therapeutic potential) for the molecule are slated to start later this year. This nuanced approach to disease was clearly attractive to J&J, but it's also one that many, including Addex, have stumbled over. Last December, Addex had a big disappointment when they had to stop development of their lead drug candidate, ADX10059, because of safety concerns. The molecule was in clinical trials for migraine and heartburn associated with gastroesophageal reflux disease. But a safety monitoring turned up signs of liver abnormalities in people receiving...

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Untangling Tau & Alzheimer’s
Apr08

Untangling Tau & Alzheimer’s

While researching the ins and outs of beta-amyloid and Alzheimer’s, we of course wanted to know what other targets pharma companies had up their sleeves. The most obvious next big target is tau, the other hallmark pathology in the brains of people with Alzheimer’s. As we wrote, most of big pharma’s eggs are in the beta-amyloid basket, with nearly every drug in the Alzhiemer’s pipeline looking to block the production of or somehow clear the peptide. But in addition to beta-amyloid filled plaques, the brains of people with Alzheimer’s are marked by “tangles,” or clumps of an abnormal form of the protein tau. The beauty of tau as a drug candidate is that “it doesn’t rise and fall with the amyloid hypothesis,” Charles Albright, group director of neuroscience biology at Bristol-Myers Squibb, told us. In other words, because overproduction of tau hasn’t been definitively linked to overproduction of beta-amyloid (though some researchers do believe the link exists), it could still be a viable target if none of the beta-amyloid blockers in the clinic prove effective. And studies in animal models suggest that dampening tau production could improve the outcome for Alzheimer’s patients. “Certainly some of the experimental data suggests if you’re a demented plaque and tangled mouse and your tau level is knocked down, your behavior improves,” said Sam Gandy, associate director of the Mount Sinai Alzheimer's Disease Research Center. Further, he noted that scientists have shown that at least some neurons die by a tangle-dependent process. But when it comes to drug discovery, there are some key differences between beta-amyloid and tau. Beta-amyloid is a small peptide, whereas tau is a protein of about 50 kilodaltons. And despite clues, no one is really sure about a role for beta-amyloid outside of plaque-building, while tau is a rather ubiquitous protein that clearly binds to and stabilizes microtubules. The bottom line for tau, is it is “very interesting, and very challenging,” Mene Pangalos said just weeks before leaving his job as Pfizer’s CSO in Neuroscience to head research at AstraZeneca. One problem has been that the most obvious targets for tau are kinases that block the phosphorylation of tau. But it can be difficult to find selective kinase inhibitors without a lot of unpleasant side effects. “That’s where its been a struggle,” Pangalos added. “It’s more challenging, but in a way, the target is common to more dementing processes than is amyloid, so it is important to keep hammering away at it,” Mount Sinai’s Gandy said. Most companies involved in Alzheimer’s are indeed hammering away at it. David Michelson, vice president of clinical neuroscience and ophthalmology at Merck, believes that...

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Harnessing the Alzheimer’s Pipeline
Apr05

Harnessing the Alzheimer’s Pipeline

In today’s issue, we have a package about drugs in development to treat Alzheimer’s disease. The main piece looks at the different kinds of drug candidates targeting beta-amyloid, the peptide responsible for the plaques coating the brains of people with Alzheimer’s. Despite a slew of molecules in the later stages of development, there are still questions about whether blocking beta-amyloid accumulation makes the most sense. As the article says: “If the trials are successful—and the amyloid hypothesis is proven true—doctors will have a slew of new drugs that could slow the progression of the disease. If the trials fail, scientists will be forced back to the drawing board to develop new hypotheses and drug targets.” The second piece is a case study of the complicated chemistry campaign involved in developing Merck’s most advanced BACE inhibitor. BACE is an enzyme used to cut down a larger peptide into beta-amyloid, and it has proven to be a tricky target. The last piece asks whether Dimebon, the drug candidate being developed by Medivation and Pfizer, has any legs left in it after it performed miserably in a Phase III trial. The companies say the jury is still out, while most neurologists have less kind words for the drug. Overall, the stories try to harness the pipeline for a market in which big pharma is anxious to have a presence. In its pipeline review at the beginning of the year, Pfizer touted the 10 compounds in development for Alzheimer’s, making it the second only to oncology in terms of therapeutic focus. Bristol-Myers Squibb devoted a good portion of its R&D day last month talking about BMS-708163, its gamma-secretase inhibitor expected to head into Phase III trials later this year. And the number of basic patent filings for Alzheimer’s drugs has jumped from 652 in 2000, to 1995 last year, according to Chemical Abstract Services. Why all the interest? The market is vast and patients are greatly underserved. The two Alzheimer’s drugs currently on the market, Pfizer’s Aricept and Forest Laboratories’ Namenda, are at best mildly effective at temporarily easing the symptoms of the disease. Last year, Pfizer sold $432 million worth of Aricept, while Namenda sales totaled $949 million. With 5.3 Americans suffering from Alzheimer’s, imagine the potential for a drug that actually slowed the disease down. Now factor in the potential for that number of afflicted to quadruple by 2020, and the market for an Alzheimer’s drug starts to look pretty huge. Add in the likelihood that for a drug to have the most effect, it’ll probably need to be given before dementia sets in and for the rest of a person’s...

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