Tweaking A Workhorse Anesthetic
Aug22

Tweaking A Workhorse Anesthetic

In this week’s issue of C&EN, I’ve written about the search for new anesthetic drugs, as well as the accompanying quest for a better understanding of how anesthetics work. Anesthesia is safer than it’s ever been because highly trained physicians and nurses can manage its complications. The drive to improve anesthetics is nowhere near as strong as it is for other drug classes such as oncology drugs, as Imperial College biophysicist Nick Franks told me. But that doesn’t mean the drugs in use are perfect. Take propofol, or 2,6-diisopropylphenol, which is marketed as Diprivan by AstraZeneca. It’s arguably the most commonly used injectable anesthetic for surgeries in developed nations. It even has a nickname around the operating room, “milk of amnesia”, because of its effects on memory, and because of the milky appearance the sparingly water soluble compound takes on in the oil-water emulsion needed to deliver it to the bloodstream. But propofol has side effects. Several firms have made adjustments to propofol or its formulation in order to address the limitations, and they’re finding out whether those chemical tweaks translate into benefits for patients. For example, researchers at PharmacoFore, a privately-held biopharmaceutical company in San Carlos, Calif., reasoned that small changes to propofol’s structure might cut down on the pain experienced when propofol is injected. Anesthesiologists often use a topical numbing agent such as lidocaine to alleviate this pain. Work from other researchers suggested that the low concentration of propofol in the aqueous phase of the oil-water emulsion acts directly on a receptor on the inside of blood vessel walls to cause pain, says Thomas E. Jenkins, PharmacoFore’s chief scientific officer. “Short and sweet, our strategy was to make propofol more lipophilic,” in order to further reduce the concentration of the drug in the aqueous phase, the portion thought to be responsible for the pain, Jenkins says. PharmacoFore’s chemists also tried to leverage the concept that a single stereoisomer of a molecule can have pharmacological properties different from those of a mixture of stereoisomers. They investigated specific stereoisomers of 2,6-di-sec-butylphenol, which is more hydrophobic than propofol. The racemic version of this compound was similar enough to propofol that it hadn’t escaped chemists’ notice in the past- its anesthetic properties were evaluated in the 1980’s by the company that developed propofol itself (J. Med. Chem., DOI: 10.1021/jm00186a013). PharmacoFore evaluated a specific stereoisomer, (R, R)-2,6-di-sec-butylphenol (PF0713), in a phase I clinical study. In that study, PF0713 rapidly induced general anesthesia without injection pain and with minimal drop in blood pressure (blood pressure lowering is another known side effect of propofol). In addition, data from a preclinical study in rats combined...

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Orexigen Partners With Takeda for Potential Obesity Drug Contrave
Sep02

Orexigen Partners With Takeda for Potential Obesity Drug Contrave

This morning Orexigen Therapeutics became the second of the three leaders in the obesity drug race to partner with a larger company. They've successfully courted Takeda, which now gets exclusive marketing rights to obesity drug Contrave in the U.S., Canada, and Mexico, if the drug gets regulatory approval. Orexigen's shares soared on the news, first released in the pre-dawn hours this morning. In the deal, Orexigen gets $50 million upfront from Takeda and could nab up to $1 billion more, depending on whether Contrave meets certain regulatory and sales milestones. Further details about the agreement are available on an Orexigen press release. Contrave refresher: Contrave is a combination of two drugs already on the market: naltrexone, which is typically used to manage alcohol or opioid dependence, and the antidepressant bupropion. Orexigen’s developed a sustained-release formulation of those active ingredients. This is thought to alleviate the nausea that cropped up in clinical trials, but also could come in handy in terms of real-world prescriptions if the drug is approved. People might want to save money by taking the generic versions of Contrave’s two components but it isn’t clear how that would work for them. In July we covered the first partnership deal in the obesity drug race, that of Eisai and Arena Pharmaceuticals, which is developing the obesity drug candidate lorcaserin. It's worth stepping back to compare and contrast the deals. At a glance, much looks the same. U.S.-based biotech company developing a potential obesity medication partners with a company based out of Japan. Biotech gets $50 mil upfront, with a tantalizing promise of more if certain milestones are met. But Arena's press release about the Eisai deal contains a few more specifics about pricing. I don't see comparable language in the Orexigen release. From Arena's release: Under the terms of the agreement, Arena will receive an upfront payment of $50 million from Eisai and, upon regulatory approval and the delivery of product supply for launch, up to an additional $90 million in milestone payments. Arena will sell lorcaserin to Eisai for a purchase price starting at 31.5% of Eisai's annual net product sales, and the purchase price will increase on a tiered basis to as high as 36.5% on the portion of annual net product sales exceeding $750 million. Arena is also eligible to receive $1.16 billion in one-time purchase price adjustment payments based on annual sales levels of lorcaserin and up to an additional $70 million in regulatory and development milestone payments. John Carroll of FierceBiotech noticed something's been missing from the obesity drug deals: U.S. companies. Noticeably absent from the deal-making are the U.S. pharma companies, several...

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Eisai Will Sell Arena’s Obesity Drug Lorcaserin, Pending FDA Approval
Jul01

Eisai Will Sell Arena’s Obesity Drug Lorcaserin, Pending FDA Approval

Arena Pharmaceuticals has landed a partner for marketing its weight loss drug, lorcaserin- Japan's Eisai. This makes Arena the first of the three big contenders in the obesity drug race to nab a partner. In the deal, announced in the wee hours of this morning, Arena gets $50 million upfront from Eisai, and stands to make more in milestone payments upon delivering the product for launch time, if lorcaserin gets approved by the FDA. Still more additional payments, which could total up to $1.16 billion, will be tiered based on how well lorcaserin sells. Eisai gets exclusive U.S. rights to market the drug. Arena's stock jumped this morning on the news. You can get the specifics on the deal from Arena's press release. OK. You know it's news when the company provides snazzy photos with the press release. Arena said last month it planned to go it alone with lorcaserin if it couldn't find a partner. But at the time, Leerink Swann analyst Steve Y. Yoo said in a report to investors that "the best source of funding, in our view, would be an upfront payment by a partner for lorcaserin." Well, now Arena's got that cash. What does it mean for the obesity drug race as a whole? Around the interwebs a few folks are wondering whether the terms of the deal still signal some caution on the part of Eisai. My two cents are that in the obesity area, safety may reassure potential partners more than efficacy does. As we wrote back in 2009, lorcaserin disappointed investors as early Phase III trial results came to light, because the compound met some but not all of FDA's numerical weight-loss benchmarks. But lorcaserin's safety profile is very good. Perhaps it's because Arena had the most to prove. Lorcaserin targets the same serotonin receptor as fenfluramine, an ingredient in the infamous Fen-Phen obesity drug combo. Fenfluramine was associated with heart valve damage and a fatal lung disorder- it was pulled from the market in 1997. But lorcaserin is different from fenfluramine- it is more selective for one specific subtype of serotonin receptor and avoids the one that's found in the heart. Arena has had to pay special attention to safety throughout lorcaserin's development and they haven't run into heart valve trouble. Given the history of failures in the weight-loss drug field (Fen-Phen, rimonabant, etc), and given that a weight loss drug will be taken by many people who are otherwise healthy and may not even be clinically obese, it could be that safety will turn out to be...

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