New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. The cancer research conference season kicked off in earnest in 2013 with the American Society of Clinical Oncology (ASCO)’s Gastrointestinal Symposium, held in San Francisco in late January. Some of the most anticipated data to be presented at ASCO GI was for drugs that treat pancreatic cancer, with three drugs—Celgene’s Abraxane, AB Science’s masitinib, and Sanofi’s S1, generating the most interest. With this post, we’ll take a closer look at the most advanced of the three agents, Abraxane, which generated encouraging results in a Phase III study. Later this week, we’ll tackle masitinib and S1. Abraxane is a nanoparticle albumin-bound form of the breast cancer drug paclitaxel, and is designed to improve the activity of the active ingredient. Abraxane is already approved in the US for advanced breast and lung cancers, and recently showed signs of activity in metastatic melanoma. At ASCO GI, Daniel Von Hoff, director of the Translational Genomics Research Institute, presented data from a randomized phase III study called MPACT that compared the effects of Lilly’s Gemzar, the current standard of care, to a once weekly combination of Gemzar and Abraxane in patients with metastatic adenocarcinoma of the pancreas. With 861 patients, this was a large global study that sought to determine whether the combination would outdo the regulatory standard of care. A note on the trial design: Although this study uses Gemzar as the standard of care, in practice, many leading oncologists prescribe FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for advanced pancreatic patients. But because FOLFIRINOX is generic, and is not formally approved by FDA for advanced pancreatic cancer, Phase III studies tend to match new drug candidates up against Gemzar. As Hedy Kindler, director of gastrointestinal oncology at the University of Chicago, explained, FOLFIRINOX is widely used because the regimen has “the higher response rate, and that has the longer median survival.” However, FOLFIRINOX also has unpleasant side effects, and in private practice settings, oncologists prefer to use less toxic combinations based on Gemzar—namely, Gemzar alone, GemOx (with oxaliplatin), or GemErlotinib (with Tarceva, an EGFR TKI). To provide context, FOLFIRINOX typically has an improved survival of approximately 11 months, while gemcitabine or gemcitabine plus erlotinib elicit a 6-7 month improvement in median overall survival (MOS).  Erlotinib added 12 days of extra survival over gemcitabine alone, but unfortunately we have no way of selecting those advanced pancreatic patients most likely to respond to EGFR therapy. Celgene is exploring the combination of Abraxane and Gemzar based on preclinical work that suggests Abraxane can knock out the...

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Epizyme & Celgene to Develop Epigenetics-Based Cancer Drugs

Cambridge, Mass.-based Epizyme has scored $90 million upfront as part of a broad cancer drug development pact with Celgene. The deal adds to a spate of lucrative pacts to find compounds to modulate epigenetic targets, or enzymes that control gene expression without altering the underlying DNA. As we wrote in last week’s cover story, DNA carries the instructions for assembling all of life’s essential building blocks, but epigenetics dictates how and when that DNA is put to work. Recently, companies have made significant process in understanding the complex biology behind epigenetic processes, while also figuring out how to design compounds that can potently block epigenetic enzymes. With the science and business rationale for pursuing epigenetic targets dovetailing, big pharma and big biotech alike are forging deep ties with the handful of companies with expertise in the field. Under the three-year deal announced today, Celgene has the right to opt-in to the ex-U.S. rights for any unencumbered histone methyl transferase program at Epizyme. Eisai currently has the rights to Epizyme’s EZH2 inhibitor, while GlaxoSmithKline has a deep collaboration with Epizyme against undisclosed targets that would be excluded from today’s pact with Celgene. Epizyme says the partnership makes sense because Celgene shares “our vision in oncology and epigenetics,” says Epizyme’s president and CEO Robert J. Gould. “That’s been a fundamental bedrock of our partnering strategy–to partner with people who share our enthusiasm for this space.” Indeed, Celgene has long played in the epigenetics space, boasting two of the four currently marketed drugs that act on epigenetic targets. However, Celgene’s drugs, Istadax and Vidaza, hit first-generation epigenetic targets. Epizyme’s activities, meanwhile, center on one of the next waves of epigenetic targets: a family of enzymes called histone methyltransferases (HMTs). Of the 96 members of that family, Epizyme has identified roughly 20 HMTs for which there is a clear link to a specific form of cancer, Gould says.  To date, the company has two compounds—the EZH2 inhibitor partnered with Eisai, and a DOT1L inhibitor—in preclinical studies. (Check out last week’s cover story on epigenetics for more on how Epizyme went about discovering those two compounds.) Celgene is kicking off the pact by opting into the inhibitor of DOT1L, an HMT that is implicated in mixed lineage leukemia, a rare subtype of the blood cancer that the Leukemia and Lymphoma Society says affects about 1,500 new patients in the U.S. each year. With each program thereafter that Celgene buys into, Epizyme could score up to $160 million in milestone payments. The cash influx, coupled with the U.S. rights to the programs, “positions us nicely to maintain our independence, but also control our own future as a...

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Celgene & Avila Forge Permanent Ties

Today brought a spate of M&A activity in the biotech space, with Amgen unveiling a $1.2 billion bid for Micromet, and Celgene agreeing to pay up to $925 million for Avila Therapeutics. Both deals brought the acquirer a drug in development to treat blood cancers, while also adding a platform technology to their research engines. Being all about the chemistry, The Haystack is particularly interested in the Celgene/Avila deal, which involves covalent drug development technology. Celgene is paying $350 million upfront, with the promise of up to $195 million more if Avila’s lead covalent drug candidate, AVL-292, reaches the market. Pushing other covalent drugs through the pipeline could garner Avila shareholders another $380 million. So what is a covalent drug, anyway? As C&EN’s Lila Guterman described last fall, covalent drugs form a permanent link with their target. By comparison, most conventional drugs are designed to reversibly bind to their targets—in other words, they can stick and “un-stick” to a protein. The beauty of a covalent drug is that its specificity and potency means it can be given in low doses. As Guterman explains, patients only be given enough of the drug for molecule to reach each target protein molecule, and then another dose only when the body has generated more of that target protein. The low dose means less potential for drug-drug interactions and off-target effects. Indeed, for years, scientists avoided developing covalent drugs out of fear that serious toxicity will arise if a covalent drug happens to permanently stick itself to the wrong protein. Check out Guterman’s piece for a cautionary toxicity tale from none other than “Rule-of-Five” inventor (and former Pfizer researcher) Christopher Lipinski. The current generation of covalent drugs, however, is designed to assuage those fears through their highly selective and weakly reactive nature. Avila isn’t the only one banking on better molecular design leading to successful drugs: Zafgen’s obesity drug candidate ZGN433 also covalently binds to its target, an approach that—if it works—could enable it to sidestep the side effect issues that have plagued the obesity drug space. So are these covalent drugs worth the price tag? Avila’s pipeline is relatively young, meaning there isn’t a lot of data to go on: AVL-292 is in Phase I studies in lymphomas; a compound targeting mutant EGFR is also in Phase I trials; meanwhile, two Hepatitis C drug candidates in preclinical studies. The company has also made public preclinical date on its PI3Kα-selective inhibitor (the same target as Intellikine’s INK1117, one of the drivers behind Takeda’s $190 million acquisition of...

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Celgene Goes After Cancer’s Achilles’ Heel

The drug industry seems to be coming back around to the idea that cancer has an Achilles’ heel. In the latest deal related to cancer metabolism, Celgene is handing over $130 million upfront for access to oncology drugs coming out of Agios Pharmaceuticals‘ labs. Under the pact, Celgene, for a period of time, can opt-in on any drug candidate generated by Agios’ cell metabolism technology. Celgene can also put up extra cash to extend the opt-in period on a candidate. Agios is focused on depriving cancer cells of their energy source by using small molecules to control critical metabolic enzymes. Those targets include isocitrate dehydrogenase (IDH1), shown to play a role in cancer formation, and pyruvate kinase M2 (PKM2), an enzyme involved in glucose metabolism. Carmen weighed in on their research in a piece on cancer metabolism back in February: Agios researchers are looking at several metabolic enzyme targets. For example, they have found a surprising effect for brain-cancer-associated mutations in the enzyme isocitrate dehydrogenase 1. Rather than halting the enzyme’s dehydrogenase activity, the mutations cause it to catalyze a reduction, the researchers find (Nature 2009, 462, 739). The product of that reduction, a metabolite called 2-hydroxyglutarate, is over 100 times more abundant in tumors with the cancer-associated mutation. So the compound could be a useful marker in tests of a patient’s blood, urine, or cerebrospinal fluid to determine whether their tumor has the mutation. It could even be an indicator of whether certain experimental cancer drugs are working, says Joshua D. Rabinowitz, a coauthor of the work and consultant for Agios who studies metabolism at Princeton University. The idea of targeting cancer metabolism isn’t new. As Carmen’s article notes, German biochemist Otto Heinrich Warburg first noticed a metabolic quirk in cancer cells—they break down glucose via an oxygen-free metabolic pathway, regardless of whether oxygen is available—in the 1920s. There has been a revival of interest in the idea as researchers begin to understand the limitations of targeted therapies, molecules that often block a single protein kinase and, while effective in treating cancer for awhile, eventually stop working as resistance develops. In an editorial in the New York Times last August, James D. Watson, the granddaddy of DNA, advocated revisiting the concept of commonalities in cancer cells, specifically, how they metabolize glucose. Now, interest is moving out of academic labs and into drug firms. In addition to the Celgene/Agios deal, AstraZeneca and Cancer Research UK are in a three-year research pact related to cancer metabolism. And the technology behind GSK’s questionable $720 million of Sirtris Pharmaceuticals is centered on depriving cells of energy. Will any of this research pan...

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