Seattle Genetics’ Brentuximab Validates ADC Approach

After years of plugging away at antibody-drug conjugates, Seattle Genetics has finally secured significant validation for its technology. This morning, Seattle-based biotech announced impressive results from a pivotal trial of brentuximab vedotin, an anti-CD30 antibody linked to an auristatin, a small molecule that blocks the formation of microtubules. Brentuximab, also known as SGN-35, shrank or got rid of tumors in 75% of Hodgkin’s lymphoma patients who had failed to respond to other treatments. Further, that response to SGN-35 lasted for over six months in many of those patients. In this patient population, medical experts had felt that anything more than a 30% response rate would have been solid, Needham & Co. analyst Mark Monane said in a note to investors. The results “underscore the importance of targeting CD30 in the treatment of Hodgkin’s lymphoma and provide strong validation for our proprietary antibody-drug conjugate technology,” Seattle Genetics’ CEO Clay Seagall said in a conference call this morning. With today’s data, Seattle Genetics appears to be succeeding in an area that has proven challenging for many. In theory, designing an antibody-drug conjugate (ADC) is straightforward: tether a powerful chemotherapeutic to a cell-specific antibody that can deliver it directly to tumors. And voila, the therapeutic window is opened on chemo drugs that are excellent cancer killers but too toxic to healthy cells. But developing an ADC has turned out to be tougher than anticipated. The biggest hurdle for scientists has been finding the right link between the antibody and the small molecule–the link after all enables scientists to control where and when that toxic payload is released. Most companies have used pH as the trigger for release, an approach that has proven to be too promiscuous; if the ADC wanders into the wrong environment with the right pH, the cytotoxic drug would get released, damaging healthy cells. Wyeth’s Mylotarg, the first and only ADC to be approved, was taken off the market this summer after it was found to cause more deaths than chemotherapy alone. Most view the unstable linker as the culprit behind Mylotarg’s safety issues. Based on today’s positive data, Seattle Genetics seems to have overcome that challenge. For SGN-35, the biotech uses a linker that is snipped by cathepsin C, an enzyme found inside cells that is turned on an off based on pH. Even if some cathepsin C is in the bloodstream, the cytotoxic molecule won’t be released because the pH is too low. Seattle Genetics and Millennium expect to file for U.S. regulatory approval for SGN-35 in the first half of 2011. FDA granted the drug fast-track status in Hodgkins’ lymphoma, meaning U.S. approval could come in...

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China, Heparin, And Heterogeneity
Jul22

China, Heparin, And Heterogeneity

Back in 2007 and 2008, tainted heparin from China was responsible for the deaths of over 80 people in the U.S. If you had some sort of warm and fuzzy reassurance that authorities were looking into the matter, a new congressional probe should quash that feeling pretty quickly. Today the Wall Street Journal reported that the probe, by two congressmen from Texas, has found that China never looked into the heparin scandal at all. This is despite repeated warnings from FDA, as C&EN wrote last year. The probe comes ahead of FDA Commissioner Margaret Hamburg’s first trip to China in her new official capacity. The congressmen, Reps. Joe Barton and Michael Burgess, urged the commissioner to bring the issue up during her trip. According to the WSJ, a spokeswoman for China’s State Food and Drug Administration said the results of the probe were “not true.” It’s a shame this scandal had to happen at all- all because heparin, a drug so many people rely on, is easier to harvest from a pig intestine than it is to make in the lab. As a refresher, heparin is a blood thinner, and chemically speaking, it’s a variably sulfated glycosaminoglycan polysaccharide composed of alternating D-glucosamine and uronic acid residues. Now, the blood thinner term is sort of a misnomer- heparin doesn’t actually thin the blood. What it really does is inhibit coagulation- prevent blood clots from forming or reduce clots actively present. Heparin does this by binding to a protein called antithrombin III, ultimately affecting the proteases thrombin and Factor Xa, which both play important roles in blood clot formation. You can read some of C&EN’s heparin coverage here and here. We’ve known that heparin affects blood clotting since 1916, but the stuff’s been extraordinarily tough to replace. Today there exist many different heparin-type products. Garden-variety unfractionated heparin is used in certain surgeries and in kidney-dialysis patients. Fractionated heparins like the low-molecular-weight heparin Lovenox are used to prevent and treat dangerous blood clots in the leg veins of patients on bedrest or who are having a hip or knee replacement. And there are synthetic pentasaccharides like fondaparinux, essentially made from the business end of heparin, which affect only Factor Xa. All of these products have the same inconvenience- they all must be given via injection. And outside the fondaparinux-type drugs, it’s not easy to manufacture them from scratch in a lab because the structures are so unwieldy and heterogenous. There are a slew of drugs in the pipeline that target Factor Xa or thrombin directly, that are straightforward molecular entities, and that drugmakers would love to see replace heparins and their coagulation...

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Safety Data On Vivus’s Qnexa Doesn’t Cut It For FDA Panel-UPDATED

You have to feel for the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee this week. They’d just finished the Avandia slog, but there was no rest for the weary. No, instead, they got to sink their teeth into the first of the potential new obesity drugs, Vivus’ Qnexa. In a vote that signals safety is king in the obesity drug realm, Qnexa got a thumbs down from the panel this afternoon. The panel was split, with 7 members recommending that FDA should approve the drug and 9 recommending against approval. The panel’s take home message was that a lack of safety data led to their decision. Several journalists live-blogged the panel session. Here are the two play-by-plays I followed: Lisa LaMotta, Minyanville Adam Feuerstein, TheStreet This decision comes after what seemed like an optimistic week for Vivus. On Tuesday, when FDA released its briefing documents about Qnexa, media reports on the data suggested that even though the agency’s review focused on safety, it didn’t look like safety would be a dealbreaker. In a note to investors, Leerink Swann analyst Steve Yoo wrote, “Overall, we believe the language in the FDA briefing documents to be fairly benign, but the FDA is requesting a pregancy category X label that would include contraindication in pregnant women and a warning/ precaution for females of childbearing potential.” At today’s panel, as expected, nobody really dwelled on Qnexa’s efficacy. But Vivus faced a lot of questions about safety, especially about the effects of Qnexa during a pregnancy. During clinical trials, 13 women on Qnexa gave birth, and none of the babies had birth defects. Because Qnexa is likely to be an appealing option for women of reproductive age if it’s approved, panelists were concerned that more data are needed to make sure Qnexa is safe during pregnancy. That’s because one of the components of Qnexa is topiramate, an epilepsy drug that is known to carry a risk of birth defects. What complicates things is that the dose of topiramate in Qnexa is lower than the dose used for treating epilepsy. It’s also lower than the doses used in studies that suggested topiramate carries a risk of birth defects. The panel also discussed the other four safety concerns mentioned in the briefing documents: cardiovascular risks psychiatric events cognitive events metabolic acidosis But at the end of the day, panelists who voted ‘no’ felt like more long-term safety data was in order. From Feuerstein’s liveblog: one of the “no” votes says obesity is a chronic disease, so tell me what happens to patients as they stay on the medication for years. The deadline for FDA to make...

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Merck’s Kamarck Talks Biosimilars

Reuters has a report out today on the potential market for biosimilars, or generic versions of biologic drugs. The players will be few, and the challenges many, the report suggested. “Access to the nascent market for so-called biosimilars, worth an estimated $10 billion (6.6 billion pounds) by 2015, will be limited to a close circle of specialist companies with the means to invest heavily and to fend off a legal onslaught, analysts said.” Coincidentally, I sat down earlier this week with Michael Kamarck, the new head of the company’s biosimilars arm Merck Bioventures. Kamarck, who previously headed up biologics manufacturing at Wyeth, had a strikingly similar perspective on the market. He also expects few players based on a high barrier to entry. Biosimilars players will need to have technology capabilities (see Genzyme’s woes for the challenges of manufacturing biologic products), the financial mettle to conduct large clinical trials, the ability to navigate a still fuzzy regulatory pathway, and the right commercial strategy once a biosimilar is approved. When asked about drug pricing, Kamarck noted that in markets with a limited number of players, prices tend to stabilize after an initial drop. The biosimilars approved in Europe generally cost about 70% of the innovator’s price, and he expects the U.S. market will shake out in a similar way. “We think that’s a good model and provides a fair return and a large advantage for patients,” he said. Why so little of a discount? As the Reuters article explains, the “development, production and marketing of a copycat version of biological drugs already cost about 50 times the amount needed to launch a generic copy of conventional chemical drugs.” However, biosimilars players could have an advantage of more cost-effective manufacturing. When asked whether he was worried about innovators simply lowering their price or selling their own biosimilars, a strategy Amgen seems prepared to pursue, Kamarck pointed to the significant improvements in yields of the mammalian cell culture lines used to make many top-selling biologics. The innovator, on the other hand, has to go through FDA to make changes to their manufacturing process. “It might well be that coming into the game now, you can make manufacturing improvements to the processes that the innovator is stuck with,” he adds. Merck has two biosimilars, both acquired last year from Insmed, in the clinic: MK-4214 and MK-6302, generic versions of Amgen’s Neupogen and Neulasta, respectively. The company plans to  have five biosimilars in late development n 2012, though isn’t identifying which innovator medicines they will be copying. Development of MK-2578, a similar version of Amgen’s Aranesp, was abandoned earlier this year due to regulatory and...

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Reuters Nails Pharma Jobs Frustration But Misses On Biologics, Small Molecules

This AM, Reuters released a special report about the state of drug R&D. Overall, I enjoyed reading the piece. Though there isn’t a whole lot in there that C&EN’s readers who work in the area won’t already know, I think the article does a great job of capturing how scientists- and young scientists in particular- feel about their job situation. The folks quoted in the article are feeling more than a little frustrated. That said, there were a couple of statements in this article that were unfair, misleading, or downright pessimistic. In the section on biotech, we have this generalization: Biotech’s “large molecule” protein drugs, made using genetic engineering, have proven superior at fighting complex diseases like cancer to many conventional “small molecule” chemical drugs. That argument is a little hard to swallow. You might say that the side effects from a protein drug are more benign than those of traditional chemotherapies like 5-fluorouracil. And Herceptin, a biologic drug, has made a big difference for women with a specific type of cancer. But what about Gleevec? If you have cancer driven by a certain genetic mutation, Gleevec works-and it’s a small molecule. Look closely at Herceptin or Avastin-a biologic cancer drug the Reuters article mentions in its next paragraph- and you’ll notice that for treating some cancers they must be taken with small molecules– carboplatin, paclitaxel, or something else. Both parts of the treatment- the small molecule and the protein- are necessary for the treatment to work its best. Maybe cancer isn’t the best example- after all, every cancer is a different challenge. What about other diseases? In the past, we’d written about how biologic drugs are the best we’ve got for multiple sclerosis. Humira, a biologic treatment for rheumatoid arthritis, is another success story that the Reuters article mentions. But what about HIV? There are an awful lot of small molecules on this list of approved HIV drugs, and when used correctly, they keep the disease at bay for years. Yes, there’s some wiggle room in the Reuters statement because of the use of the word “many”. Maybe it’s the organic chemist in me speaking, but I get pretty miffed when I hear pessimistic statements about small molecules. A smaller nitpick but a nitpick nonetheless- the article seems to use the words “biotech” and “biologic” interchangeably, which might confuse someone who isn’t familiar with the area. By 2014, the world’s two top-selling prescription drugs won’t be tablets sold in blister packs but needle-based biotech treatments — Avastin for cancer, sold by Roche, and Humira for rheumatoid arthritis, from Abbott Laboratories — according to consensus forecasts compiled by Thomson...

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Drug Candidates to Watch (or not)

Thompson Reuters has come out with a review of what it considers the most promising drug candidates in clinical trials. Although definitions of “promising” may differ (projected sales? impact on patients? innovative approach?) the research firm thinks that cancer drugs and therapeutics that address small patient populations–so called “orphan” indications–are particularly interesting. We’ll leave you to take a look at the Phase III and launched drug lists yourselves, and instead peruse the research firm’s choices for the most intriguing treatments in early-stage studies. Without further ado, here’s what they’re keeping an eye on from the Phase II category: 1. ALKS-33: an alcohol addiction treatment from Alkermes 2. Recombinant PEG-interferon lambda-1: Hepatitis C treatment being co-developed by ZymoGenetics and Bristol-Myers Squibb. 3. PHA-848125: small molecule for the treatment of thymic cancer by Nerviano Medical Sciences 4. PCI-27483: a small molecule for the treatment of pancreatic cancer by Pharmacyclics 5. SBI-087: an antibody treatment for rheumatoid arthritis that Pfizer inherited from Wyeth, which in turn had licensed from Trubion Pharmaceuticals Some thoughts on their Phase II list. First, unsurprisingly, two out of the five picks are oncology drugs. Second, chemistry isn’t dead: three out of the five candidates are small molecules. Last, both of the biologics are quasi-next-generation versions of existing drugs. BMS and Zymogenics’ pegylated lambda-interferon is an alternative to pegylated alpha-interferon (see our coverage of the alternative interferon space here), while SBI-087 is going after CD-20, the same target as Biogen Idec and Genentech’s Rituxan. I’m perplexed at how one winnows out what the most promising Phase I candidates are, but of note is that there’s only one small molecule and one cancer drug candidate on this list. Here’s what Thompson Reuters is giving a shout out to from the earlier reaches of the pipeline: 1. Ad4-H5-Vtn: an avian flu virus vaccine by PaxVax 2. Adoptive T-cell therapy: an HIV treatment by Adaptimmune 3. BI-505: antibody to treat multiple myeloma by BioInvent 4. CHF-5074: a small molecule to treat Alzheimer’s disease by Chiesi 5. sFLT-01: gene therapy for wet age-related macular degeneration by Genzyme and Applied Genetic Technologies I will quibble with the choice of Chiesi’s Alzheimer’s drug, which combines a flurbiprofen analog (an anti-inflammatory agent) and a gamma-secretase inhibitor. Several big pharma firms have been working for years on molecules to block gamma-secretase, an enzyme that enables the formation of beta-amyloid, the main component of the plaque gumming up the brains of Alzheimer’s patients. Many of those compounds are already in late-stage trials, including one by Bristol-Myers Squibb that is exquisitely selective and potent. I’d be more impressed if Chiesi had a compound that blocks beta-secretase (the other...

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