From Blog: The Haystack
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 Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!
5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.
6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.
7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.
We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!
From Blog: The Haystack
Over the weekend Bristol-Myers Squibb and Pfizer announced that their blood-clot-preventing drug candidate, Eliquis (apixaban), bested the workhorse anticoagulant Coumadin (warfarin) in a large clinical trial. The results were announced at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine. This is the first time that one of the cadre of anticoagulants seeking to replace warfarin has been shown to be superior to warfarin at preventing dangerous blood clots that can lead to strokes while also having a lower rate of bleeding compared to warfarin.
In the 18,201 patient Phase III clinical trial, called ARISTOTLE, apixaban reduced the risk of stroke in patients with an abnormal heart rhythm called atrial fibrillation by 21 percent, major bleeding by 31 percent, and mortality by 11 percent.
More statistics are available in the announcement, the journal article, and in this Forbes report, which plucks out these illustrative numbers:
The investigators calculated that for every 1000 patients treated with apixaban instead of warfarin for 1.8 years
•stroke would be avoided in 6 patients,
•major bleeding would be avoided in 15 patients, and
•death would be avoided in 8 patients.
Analysts reacted positively to the data, with Leerink Swann analyst Seamus Fernandez raising his 2017 sales estimate for apixaban by $1.1 billion to $4.1 billion in a note to investors.
We’ve previously explained how apixaban works– briefly, it blocks Factor Xa, a protease enzyme near the end of the complex biochemical pathway that regulates blood clotting. Another Factor Xa inhibitor, rivaroxaban, has been approved in Europe but awaits FDA approval. Pradaxa (dabigatran), which blocks the enzyme thrombin, has been approved by FDA for reducing the risk of stroke associated with atrial fibrillation.
So what’s the secret of apixaban’s success? Continue reading →
From Blog: The Haystack
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 conditions.”
From Blog: The Haystack
In the last year we’ve covered many up-and-coming drugs for controlling the delicate balance between clotting and bleeding. But what happens when something—an injury or a major surgical procedure—overwhelms that system?
Controlling big bleeds is big business, from the battlefield to the operating room. This Monday, at the American Chemical Society’s Middle Atlantic Regional Meeting (MARM) in College Park, Maryland, I heard from Matthew Dowling, CEO of a startup looking to make its mark in that space. The company is called Remedium Technologies, and it’s developing chemically modified versions of a natural biopolymer to make improved materials for stanching blood flow.
Remedium is one of several companies getting on its feet with help from technology incubation programs the University of Maryland. Representatives from several of those companies, including Dowling, gave talks at a MARM symposium on the science of startups. Look here for the MARM session’s program- it includes other companies in the drug and vaccine space, including Azevan Pharmaceuticals (which C&EN wrote about in 2001 when it was called Serenix), Leukosight, and SD Nanosciences.
The biochemical pathway that regulates clotting can’t support severe injuries that lead to profuse bleeding, Dowling said Monday. While several treatments exist for this kind of severe injury, where sutures might not work to close a wound, they have drawbacks that Dowling thinks Remedium’s technology can address.
The company’s material of choice is chitosan, a biopolymer that can be scavenged from waste shells of shrimp or crabs. Chitosan wound dressings are already on the market, but they become saturated with blood and quit sticking to tissue after about 30 minutes, which can lead to more bleeding. As a bioengineering graduate student at Maryland, Dowling developed an alternative chitosan modified with hydrophobic groups that help it stick to tissues longer. This modified biomolecule is the basis of Remedium’s technology. The company likens the material to Velcro because it is the sum total of weak interactions between hydrophobic groups and tissue that help the material stick around, Dowling explains. Once the wound has had time to heal, the material can be gently peeled away. The chemical structure of Remedium’s hydrophobic groups is proprietary; Dowling used benzene n-octadecyl tails in graduate school.
The company has two products in development- a modified chitosan “sponge” and a spray-on blood clotting foam. Neither of those products is yet available for purchase. In College Park, Dowling showed a video demonstrating how the modified chitosan makes blood congeal quickly, and how the effect can be reversed by applying alpha-cyclodextrin. In a second video, the sponge is tested on a bleeding pig that’s had a major blood vessel cut open. This presentation is similar to what Dowling gave Monday.
Dowling has been running Remedium full-time since he obtained his doctorate from Maryland in 2010—the company was founded while he was still in graduate school, and several classmates are also in the company’s management. The company has an exclusive license for the chitosan technology from the university, and has four patents pending. It has also won several business competitions, including Oak Ridge National Laboratory’s (ORNL) 2010 Global Venture Challenge. Dowling says the university’s technology incubation resources are what made it possible for him to start a company while still in grad school, from providing office space in a building just off campus, to regular meetings with staffers knowledgeable about navigating the regulatory and funding process.
From Blog: The Haystack
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 story goes something like this: Genzyme had a tumultuous year, as it struggled to correct the manufacturing issues that created product shortages and eventually led to a consent decree with FDA. In walked Sanofi, who offered—in a friendly way—to buy the company for $18.5 billion. Genzyme refused to consider what it viewed as a lowball offer. Weeks passed, they remained far apart on price with no signs of anyone budging, until Sanofi finally went hostile. Genzyme suggested it would be open to an option-based deal, which would provide more money later on if its multiple sclerosis drug candidate alemtuzumab reached certain milestones. Sanofi stuck to its $18.5 billion guns and is now trying to extend the time period to convince shareholders to consider its offer.
4. Final Stretch in HCV Race
This year, the industry finally got a peek at late-stage data for what are likely be the first drugs approved for Hepatitis C in more than two decades. Based on Phase III data, analysts think Vertex’s telaprevir will have an edge over Merck’s boceprevir once the drugs hit the market. Meanwhile, the next generation of HCV drugs had a bumpier year, with several setbacks in the clinic. Still, the flood of development in HCV has everyone hoping that eventually people with HCV can take a cocktail of pills, rather than the current harsh combination of interferon and ribavirin.
5. Pharma Covets Rare Diseases
Historically, research in rare diseases has been relegated to the labs of small biotechs and universities. But in 2010, big pharma firms suddenly noticed that if taken in aggregate, a pretty sizable chunk of the public—on the order of 6%–suffer from rare diseases. They also noticed that when there’s a clear genetic culprit, drug discovery is a bit more straightforward. Further, rare disease can sometimes be a gateway to approval in larger indications, making them all the more appealing. With that, Pfizer and GlaxoSmithKline both launched rare diseases units and made a series of acquisitions and licensing deals (Pfizer/FoldRx, GSK/Amicus, GSK/Isis, etc) to accelerate their move into the space. Meanwhile, Sanofi is trying to jump in with both feet through its proposed acquisition of Genzyme.
6. MS Pill Approved
Novartis gained approval in September for Gilenya, the first treatment for multiple sclerosis that is a pill rather than an injection. In even better news for people with MS, there more pills are rounding the corner towards FDA approval: Sanofi’s teriflunomide, Teva’s laquinimod, and Biogen’s BG-12. All of these drugs come with safety caveats, but the idea of new treatment options after years depending on interferons has gotten everyone in the MS field pretty excited.
7. Antibody-Drug Conjugates Prove Their Mettle
The concept of linking a powerful chemo drug to a targeted antibody, thereby creating something of a heat-seeking missile to blast tumor cells, isn’t new. But antibody-drug conjugate technology has finally matured to a point where it seems to be, well, working. Seattle Genetics presented very positive results from mid-stage studies of SGN-35 in two kinds of lymphoma. And ImmunoGen provided clear data showing its drug T-DM1 could significantly minimize side effects while taking down breast cancer.
8. Pharma Forges Further into Academia
With nearly every pharma firm paring back internal research, the focus on external partnerships has never been greater. Broad deals with universities are becoming more common, and Pfizer has arguably gone the furthest to evolve the model for working with academic partners. In May, Pfizer announced a pact with Washington University under which the academic scientists will look for new uses for Pfizer drug candidates. As part of the deal, they gain unprecedented access to detailed information on Pfizer’s compound library. And last month, Pfizer unveiled the Center of Therapeutic Innovation, a network of academic partnerships intended to bridge the “valley of death,” between early discovery work and clinical trials. The first partner is University of California, San Francisco, which scores $85 million in funding over five years, and the network will eventually be comprised of seven or eight partners, worldwide. Most notable is that Pfizer is planting a lab with a few dozen researchers adjacent to the UCSF campus to facilitate the scientific exchange.
9. Finally, New Blood Thinners
This year saw the FDA approval of a viable alternative to coumadin (aka warfarin), a 50-plus-year-old workhorse blood thinner that interacts with many foods and herbal supplements.
Boehringer’s Pradaxa (dabigatran) got a unanimous thumbs-up from an FDA panel for preventing stroke in patients with a common abnormal heart rhythm called atrial fibrillation. FDA approved the drug in October. The next new warfarin alternative to be approved could be Xarelto (rivaroxaban), which has had favorable results in recent Phase III clinical trials, as David Kroll over at Terra Sig explained. Both Xarelto and Pradaxa had already been approved for short term use outside the US.
Rivaroxaban and dabigatran work at different stages of the biochemical cascade that leads to clotting, as we illustrated here. Another drug candidate in the warfarin-alternative pipeline is BMS’s and Pfizer’s apixaban. Check out coverage of apixaban trials here and at Terra Sig. And in a separate blood-thinner class, FDA today rejected Brilinta, a possible competitor to mega-blockbuster Plavix.
10. Alzheimer’s Progress & Setbacks
Alzheimer’s disease has been a tough nut to crack, and news in 2010 has done little to dispel this reputation. This year Medivation’s Dimebon, which started life as a Russian antihistamine and showed some promise against Alzheimer’s, tanked in its first late-stage clinical trial. Later in the year, Eli Lilly halted development of semagacestat after the compound actually worsened cognition in Alzheimer’s patients. Semagacestat targeted the enzyme gamma-secretase, and the New York Times and other outlets reported the news as shaking confidence into a major hypothesis about what causes Alzheimer’s and how to treat it– the amyloid hypothesis.
But not everyone agreed with that assertion. Take Nobel Laureate Paul Greengard, who told C&EN this year (subscription link) that semagacestat’s troubles may have been due to the drug’s incomplete selectivity for gamma-secretase.
This year Greengard’s team discovered a potential way to sidestep the selectivity issue, by targeting a protein that switches on gamma-secretase and steers it away from activities that can lead to side effects. Greengard thinks the amyloid hypothesis is very much alive. But the final word on the amyloid hypothesis will come from trial results in next year and beyond, for drugs such as BMS-708163, Bristol Myers Squibb’s gamma-secretase inhibitor.
11. Avandia (Barely) Hangs On
Avandia was once the top selling diabetes medication in the world, but in 2010 long-running rumblings about the drug’s cardiovascular risks reached fever pitch. By the fall, Avandia was withdrawn from the European Union market and heavily restricted in the US.
Avandia (rosiglitazone) helps diabetics control their blood sugar levels by making cells more responsive to insulin. Widespread scrutiny of Avandia dates back to 2007, when a study led by Vioxx-whistleblower and Cleveland Clinic cardiologist Steve Nissen suggested Avandia increased the risk of heart attacks. In February 2010, a leaked government report that recommended Avandia be pulled from the market made headlines. In July, an FDA advisory panel voted on what to do about Avandia, and the results were a mixed bag, with most panel members voting either to pull the drug entirely or add severe restrictions. In the end, FDA sided with the “restrict” panelists- Avandia is still on the market, but it can only be prescribed to patients who can’t control their blood sugar with a first-line medication.
Clearly, researchers still have a lot to learn about how the drugs in Avandia’s class work. But we enjoyed reading Derek Lowe’s self-characterized rant about just how much effort has been put in so far. Among several other drugs in Avandia’s class, Rezulin (troglitazone) was pulled from the market many years ago because of adverse effects on the liver, but Actos (pioglitazone) remains on the market and appears to be safe.
12. Executive Musical Chairs
The year after a trio of mega-mergers and at a time when patent losses are piling up, drug companies shook up their management. The most notable changes came at Pfizer: First, the company abandoned its two-headed approach to R&D leadership and picked Michael Dolsten, former head of R&D at Wyeth, to lead research. Martin Mackay, Pfizer’s head of R&D, meanwhile jumped ship to lead R&D at AstraZeneca. Then, in a move that took everyone by surprise, Pfizer’s CEO Jeff Kindler suddenly stepped down and Ian Reade took over. At, Merck, president Kenneth Frazier will take over as CEO in January; Richard T. Clark will stay on as chairman of Merck’s board. And just this week, Sanofi-Aventis saidformer NIH director Elias Zerhouni would replace Marc Cluzel as head of R&D, while Merck KGaA appointed Stefan Oschmann as head of pharmaceuticals. Oschmann comes on from Merck & Co., where he was president of emerging markets.
In the biotech world, the most notable shift came in June, when George Scangos moved over from leading Exelixis totake the top job at Biogen Idec.
13. RNAi Rollercoaster
The year has been a tumultuous one for RNAi technology. Leaders in siRNA technology are experiencing growing pains as they try to turn promising science into commercialized products. Alnylam, arguably the best-known and biggest player in the RNAi arena, laid off 25% of its staff after Novartis decided not to extend its pact with Alnylam. Things only got worse when Roche announced it was exiting RNAi research, a move that hit its development partners Alnylam and Tekmira. Roche seemed to be primarily worried about delivery, an issue that is holding the field back from putting more RNAi-based therapeutics into the clinic.
But it’s not all bad news: the year brought a spate of big-ticket deals for companies developing other kinds of RNAi technology. GSK signed on to use Isis Pharmaceuticals’ antisense technology, which uses single-stranded rather than double-stranded oligonucleotides. And Sanofi entered into a pact with Regulus, the microRNA joint venture between Isis and Alnylam, worth $740 million. Further, Isis and Genzyme made some progress with mipomersen, the cholesterol drug developed using Isis’ antisense technology.
14. Revival of Interest in Cancer Metabolism
In cancer research, the old was new again in 2010, with a flurry of publications about depriving cancer cells of their energy source by taking advantage of quirks in their metabolism. That idea has been around since the 1920′s- when German biochemist Otto Warburg noticed differences in how cancer cells and normal cells deal with glucose. This year, Celgene handed over $130 million upfront for access to any cancer drugs that come out of Massachusetts biotech Agios Pharmaceuticals’ labs. One target in Agios’s crosshairs is an enzyme involved in glucose metabolism- pyruvate kinase M2. In addition to the Celgene/Agios deal, we noted that AstraZeneca and Cancer Research UK are in a three-year pact related to cancer metabolism, and the technology behind GlaxoSmithKline’s much-talked-about $720 million purchase of Sirtris has to do with depriving cells of energy.
15. More Job Cuts
Not to end this list on a sour note, but it wouldn’t be complete without acknowledging the ongoing narrative of layoffs and retooling at drug companies. This year brought brutal cuts at AstraZeneca, GSK, Bristol-Myers Squibb, and Abbott, along with the widespread and ongoing layoffs at Pfizer and Merck. Several features in C&EN looked at the impact the cuts are having on chemists:
From Blog: The Haystack
What you’re looking at is an overview of the complex biochemical pathway behind blood clotting, and a smattering of the drugs researchers are developing to control clotting for preventing strokes and more.
Over at Terra Sigillata, David Kroll has two back-to-back posts about some of these drugs that are worth reading.
In the first post, Kroll discusses news out of the American Heart Association’s annual meeting: Rivaroxaban (Xarelto), a blood clot preventing drug from Bayer and J&J, has been shown to be about as efficacious as the established medication warfarin (coumadin) and better with regard to spontanous bleeding complications. He also dishes on some of the fascinating historical context behind the drugs.
In the second, he brings attention to Pfizer and BMS’s announcement that they are halting a trial of apixaban, their investigational blood clot preventing medication. Eight other apixaban trials are ongoing. We covered some apixaban news last June, when a different apixaban clinical trial was stopped early because an independent analysis concluded that the drug candidate was more effective than aspirin at reducing strokes and blood clots in patients with a common abnormal heart rhythm.
As we’ve written in C&EN, many factors will determine whether patients at risk of strokes or other dangerous blood clots will end up taking warfarin or will take one of the new drugs. Boehringer-Ingelheim’s Pradaxa (dabigatran), which acts at a different target from apixaban and rivaroxaban, is already approved by FDA. Rivaroxaban and Pradaxa are already approved in a number of other countries for short-term use. Each drug is slightly different, from how many times a day it must be taken, to how much of it is cleared via the kidneys (a potential issue for patients on dialysis or other kidney conditions), and much more. And of course, a big question is what the difference in cost is going to be- warfarin pills are cheap but the quality of life costs- incessant testing and diet monitoring- can be steep.
From Blog: The Haystack
Let’s say your blood thinner got a unanimous thumbs-up from an FDA panel. And now, in anticipation of the drug’s possible approval, you’d like to raise awareness about atrial fibrillation, one of the conditions your drug candidate will treat. Why not send out some well-respected cardiologists or researchers to spread the word to the people? Not sexy enough, you say? OK, then, how about a soap opera star?
Yes, this internal monologue may sound implausible, but it pretty much describes the latest news on the blood thinner Pradaxa’s front. Boehringer-Ingelheim, the maker of Pradaxa, has announced it is sponsoring a press conference in Rockefeller Center this Thursday, and the featured speaker is none other than longtime “All My Children” star Susan Lucci. Her husband, Helmut Huber (love that name!) has atrial fibrillation, an abnormal heart rhythm that increases the risk of stroke, so the two of them will be on hand to tell their story while the company trots out a study about atrial fibrillation and stroke.
Here’s how atrial fibrillation can lead to stroke. The heart muscles in the atria normally coordinate their contraction to pump blood efficiently. But if you have atrial fibrillation, those muscles flutter around in an uncoordinated fashion instead. That leads to less efficient pumping, and what can happen is that blood will pool around in the atria. If that blood clots, and the clots end up traveling to the brain, then bam- you get a stroke. So using a blood thinner, which prevents clots, might reduce that stroke risk.
I wish I could be on hand to see this event for myself. But I guess I’ll have to do with seeing Lucci on YouTube instead. Below is a video of Lucci finally winning a Lead Actress Emmy Award. She was snubbed at the Emmys 18 times before finally winning in 1999. I suppose we’ll see whether Lucci’s track record at marketing blood thinners turns out to be better than her track record at awards ceremonies. And thanks to Cardiobrief for pointing me to this event. I agree with Cardiobrief’s assessment- if Pradaxa is approved it’s a guarantee that it will be more expensive than warfarin (coumadin), the drug that it would be replacing. So Boehringer needs to convince folks Pradaxa is worth plunking down the extra cash.
From Blog: The Haystack
Warfarin prevents formation of blood clots and can reduce ongoing clots. Doctors prescribe it to prevent painful leg clots in patients getting hip or knee replacements, to prevent stroke in patients with an abnormal heart rhythm called atrial fibrillation, and more. We recently wrote about how warfarin is a dirt cheap and effective medication, but it interacts with a plethora of foods, herbal supplements, and other drugs.
Pradaxa is already approved in several countries outside the U.S. for short-term use, preventing leg clots in patients getting hip or knee replacements. The drug blocks thrombin, a protease enzyme that sits near the end of the complex biochemical pathway known as the coagulation cascade. Just about all of the drugs being developed to replace warfarin, at least the ones toward the end of the pipeline, target either thrombin or Factor Xa, the protein immediately before thrombin in the pathway.
FDA’s cardiovascular and renal drugs advisory committee voted 9-0 in favor of approving Pradaxa for preventing stroke in patients with atrial fibrillation. (Boehringer-Ingelheim press release) This will be a longer-term stint on Pradaxa than post-hip or knee surgery patients typically experience. So the most important part of the panel’s discussion, to me, was their assessment of the drug’s effects on the liver. That’s because in 2006, another thrombin blocker called ximelagatran, developed by AstraZeneca, was pulled from the market because of liver toxicity. When you dig into the briefing documents that FDA provided to the panel, you find this blurb on page 103:
Based on these data, the risk of severe drug induced liver injury from dabigatran appears to be low. Because the perceived risk is low and frequent liver monitoring may not prevent serious cases from occurring (even if an association did exist), regular monitoring of liver tests is not recommended.
So it seems that ximelagatran’s liver issues may not be a class-wide problem. Still to be determined is what doses of the drug might be approved- read this post by Pharmalot for an assessment of why doses matter. FDA is expected to make its call on Pradaxa by Oct. 19. And in related clot-stopping news: at a November conference, Bayer and Johnson & Johnson will release data on their blood thinner, rivaroxaban (Xarelto), in atrial fibrillation patients. Xarelto is a Factor Xa inhibitor that, like Pradaxa, is approved in other countries for short-term use.
Thanks to Shelley Wood of heartwire at theheart.org for live-tweeting this panel.
From Blog: The Haystack
C&EN’s cover story this week is about finding replacements for the blood thinner warfarin, something that hasn’t happened in the more than fifty years since the drug went on the market.
Warfarin prevents blood clots from forming and reduces active clots as well. When it works, it’s great for preventing strokes. As a bonus, it’s a dirt cheap pill, costing on the order of a couple of cents a day. But the trouble is that warfarin doesn’t always work well. It is extremely unpredictable in the body. Foods and other drugs affect its activity, as do certain genetic traits.
The last thing you want to do is to take too much or too little warfarin. Too much warfarin could lead to uncontrolled bleeding, something that can be deadly in a place like the brain. And of course too little warfarin won’t be effective at preventing clots. So patients on warfarin must constantly monitor how well their blood is clotting, so their doctor can get their dose just right.
The fact that it’s easy to overdose on warfarin is a pain for doctors and patients. But it comes in pretty handy in warfarin’s other, perhaps less well-known application: rat poison. It seems that messing with rodents’ blood clotting pathways is a very efficient way to off them. My cursory research indicates that we’ve got many rodenticide options, and warfarin isn’t the most common one. I couldn’t find warfarin at three different D.C. hardware stores. But it’s still available online.
YOUR KEYWORD FOR THIS BLOG IS: COMING
As an aside: medical websites seem to use the name “coumadin”, but the rat poison boxes read “warfarin”. I’d love to know the history behind this name divergence. It could be another instance of name-changing to assuage patient fears. I can certainly understand how a patient would find it disconcerting to see a giant box of their blood thinner in the pest control aisle at Home Depot. Think of how a nuclear magnetic resonance spectrometer uses essentially the same technology as a magnetic resonance imaging instrument. But the name you see used in the health field drops the “nuclear”.
From Blog: The Haystack
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. Continue reading →