Category → Infectious Diseases
Guest blogger SeeArrOh comments on the limited chemical weapons available to treat E.coli and its Gram-negative brethren. SeeArrOh is a Ph.D. chemist working in industry.
Yesterday’s post at In the Pipeline asking what kind of translational research should be done garnered some remarks about the importance of developing antibiotics for Gram-negative bacteria. It’s a timely appeal, because this May an especially virulent strain of the Gram-negative microbe E. coli
These outbreaks are not uncommon, as bacteria constantly evolve and adapt. So, when a superbug strikes, why don’t we have anything better to fight it with? Continue reading →
Merck is going bare knuckles in the marketing battle for Hepatitis C patients. Just days after receiving FDA approval to market its protease inhibitor boceprevir, now known as Victrelis, it revealed Roche has signed on to co-promote the drug alongside its pegylated interferon drug Pegasys, a cornerstone of HCV treatment.
Competition in the HCV arena is expected to be fierce, as Vertex Pharmaceuticals is expected to get the FDA nod to market its own protease inhibitor for HCV telaprevir, to be marketed as Incivek, no later than Monday. Both the Merck and Vertex drugs will need to be taken in combination with the current standard of care, pegylated interferon and ribavirin.
Although the two drugs have never gone head to head in the clinic, telaprevir is widely considered to have a better dosing regimen and a slight safety and efficacy edge over Victrelis. As such, analysts have believed that Merck’s main advantage in the HCV market would be its ability to promote Victrelis alongside its own pegylated interferon PegIntron. Now, it will also have Roche’s sales force out there hawking Victrelis with Pegasys, as well.
No financials for the deal were announced, so its hard to say at this point how much Merck is giving up in its quest for a bigger piece of the HCV market. It’s also important to note that this is a non-exclusive pact, so time will tell whether Roche and Vertex establish a similar alliance.
The deal also allows Merck and Roche to “explore new combinations of investigational and marketed medicines.” As readers will recall, the ultimate goal is to eliminate the need for interferon and ribavirin, which have harsh side effects, and treat HCV using only a cocktail of pills. Roche and Merck each have promising small molecules against HCV in their pipelines: Merck has vaniprevir, an NS3/4a protease inhibitor in Phase II trials, while Roche has the polymerase inhibitor RG7128, the protease inhibitor RG7227, and the earlier-phase polymerase inhibitor RG7432.
Read here for past coverage of the race to get new HCV drugs to market.
Last week, Lisa wrote a story about India-based Cadila Pharmaceuticals becoming a partial investor in a proposed drug manufacturing site in Rwanda. This guest post from C&EN reporter Linda Wang explains another partnership in that vein.
Cameroonian billionaire entrepreneur Celestin Tawamba is hoping that the enormous success he’s had in building a pasta empire in central and sub-Saharan Africa can be replicated in his latest endeavor—to establish a state-of-the-art generic drug production facility in his native Cameroon.
In April 2010, Tawamba, who is widely known as “the pasta king,” launched Pharmaceutical Industrial Company (Cinpharm S.A.), in Douala, Cameroon. With financial backing from foreign investors such as Cipla, India’s largest pharmaceutical company, cinPharm has started blister packing and distributing generic drugs, including paracetamol, ibuprofen, metronidazole, amoxicillin, and cotrimoxazole. Continue reading →
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:
How some laid-off pharma chemists migrate to new careers
How academic programs are adapting
And the views from the ground in New England and California, two hotbeds of pharma/biotech (hint- it ain’t pretty).
For more jobs insight, join the discussions happening with Chemjobber and Leigh aka Electron Pusher, and check out their chemistry jobs blog roundtable, which just wrapped today.
In May, Belgian scientists reported early results on the path to a new type of antiviral- one that blocks an interaction between HIV integrase, which helps the virus integrate its DNA into that of a human host cell, and a human protein that is critical for this process as well. In contrast, the FDA-approved drug raltegravir interferes with the integrase protein itself. The Belgian scientists’ report, which you can read here, does not include tests on humans or animals, but it suggests that the approach of blocking this interaction, rather than going straight for the integrase itself, might be a viable option for AIDS drug development.
In June, two independent teams determined what an antibody with unusually potent and broad activity against HIV strains looks like. The teams hoped this information could give a boost to the search for an AIDS vaccine. These results, which you can read here and here, are preliminary and nothing has been tested in animals or people yet. But because an AIDS vaccine would have to generate a stronger immune response to the virus than the body is capable of on its own, any clues as to how to make that immune response stronger (say, with a really powerful antibody) are welcome to scientists.
In July, researchers at the International AIDS Conference in Vienna reported that a microbiocidal gel containing 1% tenofovir (brand name Viread), an antiretroviral drug, helped lower the risk of contracting HIV and genital herpes. Unlike the more preliminary work I mentioned earlier, this study was done in human patients.
Also in July, Gilead Sciences announced it would close its research site in Durham, NC by the end of this year. Gilead first acquired the site when it bought Triangle Pharmaceuticals in 2003. Triangle scientists’ drug discovery efforts had led to Gilead’s AIDS drug Emtriva, which won regulatory approval months after Gilead acquired the business. NC-based news outlet the News-Observer had extra details on company history when the news broke:
Triangle was one of the Triangle’s most promising young drug companies. It was formed in 1995 by a group of former Burroughs Wellcome executives led by the late David Barry, who was a co-inventor of the first major AIDS drug, AZT. Tragedy struck the company in 2002 when Barry died of a heart attack at age 58.
And finally, at August’s American Chemical Society National Meeting in Boston, David S. Teager, a chemist with the Clinton Health Access Initiative, explained how his team reworked the multi-step recipe for tenofovir to cut costs- from $210 for a year’s supply of drug for one patient down to $87.
This is only a smattering of the news from AIDS research in 2010. But here’s hoping for more progress in 2011.
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 pipeline.”
Tetraphase Pharmaceuticals is starting the summer flush with cash after a Series C financing round yielded $45 million. Excel Venture Management led the round.
We last checked in with Tetraphase in January, when the company was making the rounds at the JPMorgan Healthcare conference to tout its novel antibiotics platform. Tetraphase was spun out of the labs of Andrew G. Myers, chair of the chemistry department at Harvard University. Myers came up with a fully synthetic route to tetracycline derivatives that significantly expanded the diversity of the compounds. In the past, the semisynthetic routes to make tetracycline limited chemists to making tweaks to the C-7 and C-9 positions on the molecule.
Tetraphase’s technology, on the other hand, enables modifications at any position on the molecule. Indeed, their scientists have already made over 2,000 compounds, Joyce A. Sutcliffe, the company’s senior vice president of biology told me.
So what does diversity mean in terms of antibiotic activity? Sutcliffe provided the example of Paratek Pharmaceuticals’ PTK0796, a broad spectrum antibiotic that Novartis licensed in October in a deal worth up to $485 million. A modification at the C-9 position of tetracycline endowed PTK0796 with the ability to be given both intravenously and orally—desirable properties when you want to transition a patient from the hospital to home. “It just shows that even small changes make different properties in terms of pharmacokinetics, efficacy, and spectrum,” Sutcliffe said.
Now imagine being able to make tweaks at virtually any position on the molecule. Not only can they enable a drug to be taken orally and by IV, but can also improve the activity of the antibiotic. For example, some modifications have proven important to getting around the tetracycline reflux mechanisms, basically the two major pathways bacteria have evolved to pump drugs out of the cell before they can work their magic.
Tetraphase will use its sudden influx of cash to push several drugs into Phase I and Phase II clinical trials. TP-434 is a broad spectrum IV antibiotic poised to start Phase II studies this year. Two IV/oral antibiotics, TP-2758 for urinary tract infections and TP-834 for community-acquired bacterial pneumonia, will also be advanced.