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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Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points: 1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring. 2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work. 3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis. 4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the...

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Macrocycle Milestone for Ironwood Pharma
Aug17

Macrocycle Milestone for Ironwood Pharma

Ironwood Pharmaceuticals and Forest Laboratories last week announced submission of an NDA for linaclotide, a peptide macrocycle for treatment of irritable bowel syndrome (IBS). This is the first new drug application for Ironwood, a 13-year old Cambridge, MA company, and it could validate other companies’ strategies for large-ring drugs (covered recently by Carmen Drahl in C&EN). There’s an enormous potential market for this drug; by Ironwood’s count, a combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these conditions. So, how does linaclotide help IBS sufferers, um . . . go? This 14-amino acid peptide ring, taken orally, arrives at the intestinal lumen, where, according to Ironwood patent literature, it docks with a receptor enzyme called guanylate cyclase C (GC-C). The extracellular domain (part that sticks out of the cell membrane), upon binding, initiates the intracellular domain (inside the cell) to begin production of guanosine-3’, 5’-cyclic monophosphate (cGMP), a signaling molecule that induces changes in the intestinal wall. In short, cGMP prompts the intestinal surface to release chloride and bicarbonate ions into the intestinal tract, which decreases sodium uptake and increases fluid secretion (Note: interestingly, this is similar to the body’s response upon E.coli infection; a bacterial toxin called ST-peptide causes traveller’s diarrhea). In Ironwood’s own words, these physiological changes “accelerate intestinal transit,” which helps to move solid waste and decrease overall pain by acting on local nerve responses. Update (3:20PM, 8/17/11) – Changed “nearly 45 million people in the US alone suffer from IBS, yet few drugs are approved for this condition” to “combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these...

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Amgen Discusses Biosimilars Strategy

Yesterday, Amgen held its first business strategy meeting since the fall 2008, and mixed in with much talk of its bone-loss treatment denosumab was a discussion of its strategy around biosimilars. The company gave its view of the impact of generic versions of its biologic drugs in Europe and the U.S., as well as the opportunity for its own growth in the space. Several core drugs in the Amgen portfolio will be under pressure from biosimilars after 2015, but management downplayed the impact the competition would have on its business. Because of their complexity, biosimilars aren’t subject to the same “patent cliff” small molecules face when their patent expires, Amgen’s CEO Kevin Sharer said. And although the company expects biosimilars to exist in the U.S., and for prices to be impacted, “we do not expect revenues to go away overnight,” he added. Although U.S. regulatory authorities have yet to sort out a pathway for approving biosimilars, generic entrants have already made their way into European markets. Biosimilars have taken over about 6% of the market for Amgen’s anemia treatment Aranesp, and pricing has been “pretty disciplined” after their first few months on the market, noted Amgen’s president and chief operating officer Robert A. Bradway. European market share for biosimilar competitors to Amgen’s filgrastim franchise, which includes the multi-million dollar seller Neulasta, has also stayed steady at around 6%. At the same time, Sharer cautioned that things will not play out identically to the U.S. and Europe. Further, he reminded the audience that “there is no such place as Europe—that’s some figment of a travel agent’s imagination.” The experience across countries has not been uniform, and generic erosion has occurred much faster in some countries than others. Still, looking back to Amgen’s expectations for the impact of biosimilars had been far bleaker than what has occurred so far in Europe. “Frankly, if we’d beeen sitting here inside an Amgen meeting five years ago…we’d have anticipated a different outcome” regarding biosimilars, Sharer added. Amgen’s chief also pointed out that because Amgen has such broad experience in developing and manufacturing large molecules, there could be a significant upside as the company starts to compete in the biosimilars arena. The business won’t immediately skyrocket after 2015, “but in the several years after that, it has multi-billion dollar potential for us,” he said. The company has created a small biosimilars unit, and Sharer says that in talking with partners it appears that establishing a presence in the arena “will not require much investment on our...

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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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Is Pfizer After Biocon’s Insulin Portfolio?

The Economic Times is reporting that Pfizer is interested in buying the U.S. and European rights to Bangalore-based Biocon’s insulin franchise in a deal that would include a $200 million upfront payment. Rumors that Pfizer would buy Biocon’s oral insulin product emerged in August, but the specifics on a possible pricetag have caused shares of the Indian company to rise over 8%. Biocon’s diabetes pill is in Phase III trials in India and Phase I studies in the U.S. The potential for an oral insulin product is vast, but so is the risk—getting the right balance in insulin administration is a tricky business. (Click here for my colleague Ann Thayer’s take on efforts to make inhaled or oral insulin products.) One has to wonder how much money Pfizer would be willing to pay for another alternative insulin after the colossal failure of the inhaled insulin Exubera. Low demand for the treatment prompted Pfizer to pull it from the market a year after its approval, costing the company some $5 billion after licensing fees, R&D costs, and write-offs. To be fair, an insulin pill has been the holy grail for diabetes researchers for some time. It would be less onerous than daily injections and more discrete than the unwieldy to downright ridiculous inhaled insulin instruments. Some background on Biocon’s technology: Biocon’s oral insulin program came from its 2006 acquisition of Nobex, a N.C.-based biotech that developed a way to make a pill form of biologics, which normally need to be given as an injection or IV infusion. Nobex used what it called “PegAlkylation” technology, which links a polyethylene glycol chain (those same PEGs used to improve the delivery of interferons and other large molecules) and an alkyl to a biologic like a protein or peptide. The design creates a molecule with a water-soluble and fat-soluble end that can travel through the myriad environments inside our bodies. Nobex claimed its oral insulin drug effectively reproduces the “first-phase spike,” or the large hit of insulin the pancreas puts out after a meal, a challenge for injectable and inhaled forms of insulin. Pfizer wouldn’t be the first big pharma to invest in an insulin pill. GlaxoSmithKline licensed an earlier version of Nobex’s oral insulin drug, but gave back the rights in late 2003. Nobex abandoned worked on that molecule in favor of a newer and better one, which Biocon licensed in 2004, prior to its acquisition of Nobex. Oral insulin aside, its worth noting that today’s ET story says the $200 million is for Biocon’s insulin portfolio, whereas earlier stories focused on Pfizer’s interest in the oral insulin program. European regulatory authorities recently gave the...

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