Merck Jumps into Antibody-Drug Conjugates With Ambrx Deal

Merck today has jumped into what has become one of the hottest areas in oncology, antibody-drug conjugates, through a deal with San Diego-based Ambrx. Merck will pay $15 million upfront and up to $288 million in milestones for access to Ambrx’s site-specific protein conjugation technology. Coincidentally, on the cover of today’s magazine, we take a look at the future of antibody-drug conjugate technology. Although people have been working on ADCs for three decades, interest in the approach has reached fever pitch after last year’s approval Seattle Genetics’ lymphoma drug Adcetris and the recent hubbub at ASCO over positive interim Phase III data for Genentech’s T-DM1. The idea behind ADCs is simple: use a targeted antibody to deliver a highly potent chemotherapeutic to a cancer cell, sparing healthy cells. But current ADC technology has limitations. This week’s cover story looks at efforts to improve upon each component—the antibody, the small molecule, and the “linker” that connects the two. Ambrx is focused on the antibody, using site specific protein conjugation technology to better control how many and where small molecules are placed on an antibody. Currently, companies manufacturing ADCs (most using technology from Seattle Genetics or ImmunoGen) wind up with a heterogenous product—each ADC has anywhere from zero to eight small molecules attached to the protein, but on average, 3.5 to four small molecule “payloads” linked. The placement of the payloads on the antibody also varies, leading to families of conjugates. As I explain in today’s story, even among the ADCs with four small molecules attached, some have all the cytotoxins clustered in one region, but they might be spread out on others. Ambrx incorporates a nonnatural amino acid into the antibody to allow precise placement of the drug payload. As I explain: Ambrx can insert p-acetyl-phenylalanine onto two sites of the antibody. The phenyl- alanine derivative has been modified to include a ketone that acts as a functional group for conjugation to the linker and small molecule. Although Ambrx can attach more than two chemistry “handles” to the antibody, its studies have shown that two small molecules make the most sense. “You really want to be mindful about preserving the native structures and function of the antibody, while trying to optimize therapeutic activity,” says Chief Technology Officer Ho Cho. “The more you stray away from that, the more risks there are in drug development.” The beauty of site-specific conjugation, researchers say, is that it allows them to me- thodically determine which ADC variety is the most active. “We can specifically attach whatever payload-linker combo we wish and do quantitative experiments to find out how it works,” Cho says. His team...

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Drug Candidate Structures Revealed At #ACSAnaheim
Mar27

Drug Candidate Structures Revealed At #ACSAnaheim

1PM Pacific: There’s one hour left before chemists will pack a ballroom in Anaheim to see potential new drugs’ structures unveiled for the first time. Watch this space for updates. 2:39PM Pacific: CEP-26401 This drug candidate now has a name: irdabisant company: Cephalon meant to treat: deficits in cognition and/or attention in diseases such as Alzheimer’s and schizophrenia mode of action: inverse agonist of histamine H3 receptor, which regulates several neurotransmitter pathways involved in cognition, attention, memory medicinal chemistry tidbits: Cephalon’s goal was to bring a high quality compound to the clinic to define the utility, if any, of H3 antagonists for these indications. The team studied compounds in this area that failed. Among the things they learned was that several adverse events could be tied to drug candidates’ lipophilicity. So the team prioritized lipophilicity and other such characteristics in its discovery workflow. status in the pipeline: completing Phase I in the beginning of April 2011, advancing to Phase II structure coming soon! UPDATED 3/29 with structure: 3:16PM Pacific: BMS-663068 company: Bristol-Myers Squibb meant to treat: HIV mode of action: inhibits HIV attachment to host cells by binding to the viral envelope gp120 protein and interfering with its attachment to host CD4 receptors medicinal chemistry tidbits: potency and getting the drug candidates to reach the bloodstream efficiently were key. Replacing a methoxy group on with heterocycles, such as triazoles, gave a big boost in potency. status in the pipeline: Completed Phase IIa clinical trials. Phase IIb studies are planned for later this year. 4:24PM Pacific:LX1031 company: Lexicon meant to treat: irritable bowel syndrome mode of action: blocks a subtype of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, in the gut. medicinal chemistry tidbits: Lexicon started their medchem program with an open mind. They could have made a molecule that was exquisitely selective for the subtype of tryptophan hydroxylase in the gut, they could avoid hitting the other subtype by making their molecule stay out of the brain, or both. They ultimately ended up using the latter strategy, making molecules slightly on the heavy side (above 500 or 550 molecular weight) and adding groups like a carboxylic acid, that tend to keep things out of the brain. status in the pipeline: Completed Phase IIa clinical trials. 5:30PM Pacific: MK-0893 company: Merck meant to treat: type 2 diabetes mode of action: blocks the receptor for the hormone glucagon. Glucagon is released by the pancreas in response to falling glucose levels. medicinal chemistry tidbits: Merck kept several chemical scaffolds in play during this research program. But the team’s big breakthrough was adding a methyl group to the benzylic position of a...

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First Time Drug Disclosures at #ACSAnaheim

Medicinal chemists, it’s that time of year once again. Time for the ACS National Meeting, and the accompanying symposium where drug companies reveal the structures of drug candidates in clinical trials for the first time. I’ll be on the ground in Anaheim and will be posting from that session (which lasts from 2PM-5PM Pacific Sunday the 27th) and others. Here is the Anaheim Division of Medicinal Chemistry program (pdf). And here is the list of disclosures: Discovery and characterization of CEP-26401: A potent, selective histamine H3 receptor inverse agonist: R. Hudkins, Cephalon Discovery of BMS-663068, an HIV attachment inhibitor for the treatment of HIV-1: J. Kadow, Bristol-Myers Squibb Discovery and development of LX1031, a novel serotonin synthesis inhibitor for the treatment of irritable bowel syndrome: A. Main, Lexicon Discovery of MK-0893: A glucagon receptor antagonist for the treatment of type II diabetes: E. Parmee, Merck Discovery of ELND006: A selective γ-secretase inhibitor: G. Probst,...

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Haystack 2010 Year-In-Review

This Friday, we’re looking back at 2010’s big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed. 1. Provenge Approved In April, Dendreon’s Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines. 2. Obesity Field Slims The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen’s drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet. Orexigen’s Contrave and Vivus’s Qnexa are both combinations of already-approved drugs, whereas Arena’s Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight. But FDA’s panels didn’t always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus’ Qnexa. The fact that FDA’s panel voted favorably for Orexigen’s Contrave, a drug that’s thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott’s Meridia, a diet drug with cardiovascular risks, from the market in October. The dust still hasn’t fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency’s formal decision on Contrave. And if you’re interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News. 3. Sanofi & Genzyme: The Neverending Story Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The...

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Platensimycin On My Mind

Yesterday we posted a Latest News item that heralds a potential new class of antibiotics. This is a topic near and dear to my heart, because I worked on the total synthesis of a potential new antibiotic in graduate school. Of course, my time in grad school also taught me not to trumpet ‘potential new antibiotics’ as the next big wonder drugs, because the molecules in question almost always have yet to be tested in people, a process that seldom goes perfectly smoothly. There was a slightly different twist to this story that made me think it deserved attention: it seems to be nudging researchers and saying, “Don’t get so caught up in the hoopla of fancy genomics technology that you ignore old antibiotic targets that still need exploring.” In the study, researchers at GlaxoSmithKline, in collaboration with the Wellcome Trust’s Seeding Drug Discovery Initiative and the U.S. Defense Threat Reduction Agency, found a small molecule that blocks DNA gyrase, or type IIA topoisomerase, in an entirely new way. The molecule was effective against a panel of drug resistant bacteria and revealed new nuances of the gyrase mechanism to boot. Since the news story discussed revisiting old antibiotic targets, I thought I’d spend some time reminding Haystack readers of a search for a new one. Over the last few years, C&EN has extensively covered the story of platensimycin, a promising antibacterial with an exciting target, first isolated from a South African soil sample. Here’s an abbreviated platensimycin timeline: May 2006: Merck researchers report the structure of platensimycin and describe its intriguing activity- it blocks FabF, an enzyme involved in fatty acid synthesis, one that has never before been targeted by antibiotics used in the clinic. October 2006: K.C. Nicolaou group at Scripps Research Institute reports the first total synthesis of racemic platensimycin, setting the stage for making analogs for exploring its bioactivity. April 2008: Lisa Jarvis’s C&EN cover story counts platensimycin among the natural product antibiotics in development. March 2009: Microbiologists report that pathogens can scavenge lipids from their mammalian hosts, suggesting that platensimycin’s target (part of the lipid synthesis pathway) may not be a viable target for an antibiotic, after all. August 2010: I contacted Merck to ask about the current status of platensimycin. Here is what Dr. Sheo Singh, Merck Research Labs Director of Medicinal Chemistry, who led the discovery team on platensimycin in 2006, had to say: “As part of the merger integration of Merck and Schering-Plough, platensimycin is being evaluated and prioritized along with all the other compounds in the early stage...

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