Alzheimer’s Meds from Plants: Satori Digs up New Leads
Jul20

Alzheimer’s Meds from Plants: Satori Digs up New Leads

Earlier this week, Satori Pharmaceuticals reported from the 2011 Alzheimer’s Association International Conference two new promising lead molecules, SPI-1802 and SPI-1810. Both block gamma-secretase, one of several enzymes involved in snipping the lengthy amyloid precursor protein down to beta-amyloid, the peptide that makes up the plaques coating the Alzheimer’s brain. A slew of big pharma companies are pursuing compounds that inhibit the enzyme (see here for more on the subject). So, you ask: What’s so new about Satori’s approach? For starters, Satori is trying to be very specific about what their compounds target. The researchers claim their compounds promote selective degradation of a single type of brain plaque – Amyloid β-42, the plaque most commonly associated with the disease – without destroying other, shorter amyloid residues (Aβ-38 and -40) that may actually confer neural health benefits. A Satori patent from June 2010 shows the selective amyloid-destroying  abilities are due to six-ring structures isolated from flowering plants. Who says new drugs aren’t discovered from natural products anymore? The patent literature dug up by our gang suggests that Satori’s leads come from the earth; specifically that they are semisynthetic derivatives of compounds extracted from the roots of black cohosh (snakeroot). Native American and Chinese herbal medicine use preparations of this plant, usually brewed as root teas, to aid muscle cramps and pain associated with menstruation or menopause.  Just a casual glance at Satori’s lead structure evokes phytosterol hallmarks: cyclopropanation at C9-C10 (a precursor to B-ring expansion in compounds like cortistatin A, a sea sponge isolate), a highly oxygenated terpene end chain, and a glycosidic linkage off of carbon 1 (far left), coupled to a typical plant sugar such as arabinose or xylose. A major critique of early Alzheimer’s drugs was that it wasn’t clear they were actually binding to their intended enzyme targets, which could explain some of their disappointing clinical results. Indeed, Eli Lilly this week provided more data confirming semagacestat, its lead gamma-secretase inhibitor, actually worsened rather than ameliorated patients’ conditions. Interestingly, Satori’s lead molecules look nothing like most of the big pharma compounds: Semagacestat is a peptide-linked lactam, while Merck’s lead molecules are iminopyrimidones with heterocycles stapled on. It's still too early to tell if the major structural differences in these new lead compounds will overcome the issues associated with semagacestat. But Satori scientists have one selling point: their compounds do not interfere with Notch, a protein involved in a host of key cell–signaling processes, including helping to control cell differentiation, proliferation, and cell death. It also happens to be a substrate for gamma-secretase. The challenge of blocking gamma secretase without disrupting Notch has caused many drug companies to...

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Big Pharma Talks Emerging Markets Strategy
Jan14

Big Pharma Talks Emerging Markets Strategy

Last year’s JP Morgan Healthcare conference brought a flood of proclamations and projections about growth in emerging markets. Although the topic is now more of a given rather than a new arm of drug companies’ strategies, it seemed worth compiling some of the comments on emerging markets made at this year’s event. Of note? With many of the best assets in developing countries already snatched up and so much attention on what remains, prices are rising. Several big pharma CEOs underscored the need to grow at a profit, instead of just for the sake of growing. Time will tell if companies can heed their own advice. GlaxoSmithKline is very deliberately shifting resources away from the U.S. and into emerging markets. In just a few years, the number of sales reps in the U.S. is down to 5,000 from 9,000, while the number of reps in emerging markets has grown from about 8,500 to 13,000, said GSK’s chief strategy officer David Redfern. Of the 17 significant M&A deals undertaken by GSK since mid-2008, nine were in emerging markets. When asked whether that pace would continue, Redfern said the company no longer needed acquisitions to gain entry into those markets. And while bolt-on deals are still possible, he notes that “There’s no doubt prices are going up in emerging markets and we’ll maintain our discipline,” Redfern said. “In 2008 we did quite a few deals. We’ve walked away from a lot more deals last year.” Sanofi-Aventis is also bolstering its sales force in emerging markets at the expense of jobs in the U.S. and Europe. Chris Viehbacher said there has been a 40% reduction in pharmaceutical operations between 2009 and 2011, and a significant overhaul of its European operations is underway. Meanwhile, headcount in emerging markets is expected to increase by 40% in that same timeframe. As a result, “in 2011, we expect to sell more in emerging markets than we do in Europe or the U.S.” Merck said it had also “significantly reduced” the number of sales reps in developed markets. The company’s goal is to grow sales in emerging markets from 18% to 25% by 2013. “We’ve been frank to say that companies are ahead of us,” Merck’s CEO Ken Frazier said. However, he pointed out that it’s still an open field: the leading player in China only has about 3% of the market share. Frazier also stressed the importance of achieving profitable growth in those regions, a nod to the rising prices for assets. “We think value-creating partnerships are the right way to go, because that way our partners have a strong stake in the growth and success...

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Lilly Diabetes Setbacks Mount
Oct21

Lilly Diabetes Setbacks Mount

Lilly’s diabetes pipeline is taking its lumps this week, a situation that has all but quashed any notions of earnings growth in coming years. The first setback came on Tuesday, when FDA issued a complete response letter for Bydureon, a long-acting form of the diabetes treatment Byetta. Lilly and its partner Amylin won’t be able to submit a response to the CRL until late 2011, significantly pushing back the much-needed new revenue stream. Now, along with today’s third-quarter earnings report, Lilly said teplizumab, an anti-CD3 antibody, had failed Phase III trials in Type 1 diabetes. Although expectations for the treatment were modest, the latest disappointment doesn’t do much for confidence in the company’s pipeline. Further, the setbacks of Bydureon and teplizumab are not the only challenges to the company’s diabetes portfolio. Last month, in a move that was not entirely surprising, Lilly and Transition Therapeutics dropped development of TT-223, a gastrin analogue that failed to meet its goals in a small study testing the drug in combination with a Lilly GLP-1 analogue in Type 2 diabetes. Meanwhile, news this week that Pfizer was paying $200 million for Biocon’s biosimilar insulin program caused some to worry that Lilly’s generous slice of the insulin market was at risk. On a call with analysts this morning, Enrique Conterno, president of Lilly Diabetes, tried to quell investor concerns. Bangalore, India-based Biocon “basically sells when it comes to insulin about 1% of what Eli Lilly sells today,” he noted. Conterno acknowledged that Pfizer could put some heft into the Indian biotech’s commercial infrastructure, but suggested that innovation around delivery devices would differentiate players in diabetes. “Clearly this is something we will watch, but we feel very confident in our ability to be effective with our insulin portfolio,” he added. But Lilly’s pipeline woes are not limited to diabetes. In August, the company experienced a major blow when it ended development of semagacestat after the compound worsened cognition in people with Alzheimer’s disease. Semagacestat, a gamma secretase inhibitor, had been viewed as a leading contender to be the next big Alzheimer’s drug on the market. As it stands, Lilly’s profits through 2014 will be driven by what is in its pipeline and efforts to rein in costs. Last fall, the company said it would eliminate 5,500 jobs, and for those keeping track of industry-wide layoffs, today said it was only about halfway through that process and has no immediate plans to expand the cuts. The company is staring down a wave of patent expiries on key products, and with the recent pipeline setbacks, earnings growth is “moving into sharply negative territory from 2012-2015,” Bernstein Research...

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Are Lilly & Covance Trend Setters?
Jul01

Are Lilly & Covance Trend Setters?

GSK said today that it had finalized plans to sell its Medicines Research R&D center in Verona, Italy, to contract research organization Aptuit. Normally a change of ownership causes fear in the hearts of employees, but in this case, all 500 workers in Verona will be transferred to GSK. They can do that because GSK is hiring Aptuit to perform R&D services at the site. This kind of arrangement sounds awfully familiar. Readers may recall that in 2008, Eli Lilly sold its Greenfield, Ind., operations to drug development firm Covance. A good chunk of the Lilly staff came with the deal, as did a nice, fat, ten-year R&D contract worth some $1.6 billion. Covance is conducting toxicology testing and providing some other R&D functions for Lilly, and more recently signed a three-year pact to conduct analytical testing of Lilly’s bioproducts. So why farm out what you previously owned? Lilly has said its Covance collaboration is about risk sharing and cost savings. The big pharma company thinks it can save tens of millions of dollars each year by putting the ball in Covance’s hands. Meanwhile, the goal is to reduce the amount of time it takes to choose a lead candidate and advance it through proof-of-concept studies in humans. If rumors are true, Sanofi-Aventis will be the next to adopt this type of arrangement. Dow Jones reported this week that Sanofi would sell its Porcheville, France, and Alnwick, U.K., sites, along with 300 or so employees, to Covance. I’m going to go out on a limb and guess that the deal will also include an R&D contract. In the press release, GSK’s R&D head Moncef Slaoui said the Aptuit deal “a modern option for drug discovery expertise to remain as part of the science research community in Italy.” Clealry, GSK had its hands tied by the Italian labor union, and couldn’t just shut down the site or compromise jobs in its sale. But I’m wondering how much money it will save by putting the work in other hands—well, the same hands under a new employer. How much of an impact can this strategy...

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Forest licenses TransTech’s glucokinase activators
Jun08

Forest licenses TransTech’s glucokinase activators

Interest in glucokinase activators, a class of diabetes compounds with a rocky past, appears to be reviving. Forest Laboratories agreed today to pay $50 million upfront and up to $1.1 billion in milestones for access to TransTech Pharma’s glucokinase activator program. The deal includes the rights to TTP399, which is poised to start Phase II trials, and several other compounds in pre-clinical and Phase I studies. TransTech’s glucokinase activator (GKA) program was developed during a six-year research pact with Novo Nordisk. The Danish firm licensed the program back to TransTech in 2007, when it decided to divest its small molecule drug discovery programs. So what makes glucokinase an interesting diabetes target? A few words on GKAs from our earlier coverage: Glucokinase belongs to a family of enzymes called hexokinases, which catalyze the phosphorylation of glucose to glucose-6-phosphate, a critical first step in metabolizing sugar. Hexokinases are generally marked by their ubiquity—several serve housekeeping functions and are thus found in nearly every tissue in the body—and their tight bond to glucose. But glucokinase is something of a black sheep among hexokinase kin. It is found in relatively fewer tissues, and its affinity for glucose is delicate. In the pancreas it is believed to "sense" just the right concentration of glucose in β cells to signal the release of insulin. And in the liver glucokinase initiates the first step of glucose metabolism, kicking into action after a meal and later sensing when the body is in a fasting state and needs to store glucose. Back when we wrote about GKAs in 2008, several of the companies publicly working on this target talked up the dual roles of glucokinase in the liver and pancreas. While newer diabetes drugs like Merck’s Januvia and Amylin’s Byetta only affect the pancreas, GKAs were expected to have an effect on both organs, improving their control over blood glucose. TransTech, however, is touting the fact that its GKA compounds are “liver selective.” The biggest safety concern with GKAs in development has been hypoglycemia, or low blood sugar. TransTech says that “by activating glucokinase selectively in the liver but not in the pancreas, it may increase glucose utilization and lower blood glucose levels without inducing excessive insulin secretion thus reducing the risk of hypoglycemia.” Interest in glucokinase as a target has waxed and waned. Roche was actively pursuing GKAs not long ago, but a perusal of their public pipeline, which includes multiple diabetes programs,  shows no mention of the target. And a quick look at clinicaltrials.gov shows that Lilly suspended work on its program—licensed from OSI Pharmaceuticals for $25 million upfront in 2007--pending further toxicology testing. Still, late...

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