Category → Big Pharma
The ax is falling on more pharma R&D jobs. Earlier today, Derek Lowe brought word from readers that research jobs were being cut at Bristol-Myers Squibb. The company just confirmed that “fewer than 100″ positions were being eliminated in the U.S. Here’s the official word from BMS:
“Bristol-Myers Squibb is strategically evolving the company’s Research focus to ensure the delivery of a sustainable, innovative drug pipeline in areas of serious unmet medical need and potential commercial growth.
The Company is aligning and building internal capabilities to support the evolution of its Research focus. In doing so, certain research areas will be streamlined and there will be investment and growth in other areas. This strategic evolution has resulted in job eliminations in the short term to allow longer term investment. This initiative will result in a reduction in employee headcount of fewer than 100 people in an R&D organization of more than 7,000 employees. Impacted employees were notified on August 1, 2012 and transitions will take place within two weeks of this date.”
The company will not confirm whether they are, as Derek’s sources suggest, in the metabolic disease area or limited to New Jersey. If indeed they are all coming out of its N.J. labs, today’s announcement will add to challenging times for the state. As we wrote last month after Roche announced plans to shutter its Nutley site, costing some 1,000 jobs, the number of drug industry jobs in N.J. fell by 22.4% between 2007 to 2010, according to a report by Battelle and the Biotechnology Industry Organization.
When you think of reaction screening, what comes to mind? Most would say LC-MS, the pharma workhorse, which shows changes in molecular polarity, mass, and purity with a single injection. Some reactions provide conversion clues, like evolved light or heat. In rare cases, we can hook up an in-line NMR analysis – proton (1H) usually works best due to its high natural abundance (99.9%).
Please welcome a new screening technique: 13C NMR. How can that work, given the low, low natural abundance of ~1.1% Carbon-13?
Researchers at UT-Southwestern Medical Center have the answer: rig the system. Jamie Rogers and John MacMillan report in JACS ASAP 13C-labeled versions of several common drug fragments, which they use to screen new biocatalyzed reactions.
Biocatalysis = big business for the pharma world. The recent Codexis / Merck partnership for HCV drug boceprevir brought forth an enzyme capable of asymmetric amine oxidation. Directed evolution of an enzyme made sense here, since they knew their target structure, but what if we just want to see if microbes will alter our molecules?
Enter the labeled substrates: the researchers remark that they provide an “unbiased approach to biocatalysis discovery.” They’re not looking to
accelerate a certain reaction per se, but rather searching for any useful modifications using the 13C “detector” readout. One such labeled substrate, N-(13C)methylindole, shows proof-of-concept with their bacterial library, producing two different products (2-oxindole and 3-hydroxyindole) depending on the amount of oxygen dissolved in the broth. NMR autosamplers make reaction monitoring a snap, and in short order, the scientists show biotransformations of ten more indole substrates.
This paper scratches multiple itches for various chem disciplines. Tracking single peaks to test reactions feels spookily close to 31P monitoring of metal-ligand catalysis. Organickers, no strangers to medicinally-relevant indole natural products, now have another stir-and-forget oxidation method. Biochemists will no doubt wish to tinker with each bacterial strain to improve conversion or expand scope. The real question will be how easily we can incorporate 13C labels into aromatic rings and carbon chains, which would greatly increase the overall utility.
Janssen Research and Development, part of J&J, has asked the FDA to approve bedaquiline, a diarylquinoline to treat multi-drug resistant tuberculosis. If given the green light, bedaquiline would be the first drug with a new mechanism of action to be approved for tuberculosis in over four decades. Janssen points out that the pill would also be the first drug approved for multi-drug resistant TB.
If approved, Johnson & Johnson will score a Priority Review Voucher, an incentive created in 2007 to prompt more R&D in neglected disease. A PRV, given to a company that wins U.S. approval for a new drug for neglected disease, is a coupon good for shaving the review time for another new drug application. The value of that coupon depends on the drug its applied to—in theory, if a drug has lofty sales potential, gaining a few extra months (as we’ve written, it could shorten the FDA’s decision time by anywhere from four to 12 months) could translate into hundreds of millions of dollars.
To date, Novartis has been the only company to be granted a PRV, which it gained through the U.S. approval of the malaria drug Coartem. But that first test of the incentive had some questioning its value, as Novartis cashed in its PRV for a supplemental new drug application for Ilaris, an antibody for auto-inflammatory disorders that brought in just $48 million last year.
So, readers, any thoughts on how J&J might cash in its PRV if granted?
Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation.
However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months.
At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them?
An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic.
One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone.
Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Continue reading →
The American Society of Clinical Oncology (ASCO) meeting, held in Chicago earlier this month, brought some fascinating presentations on progress in two very tough to treat cancer types, lung cancer and advanced melanoma. This week, we’ll take a look at some of the data that emerged out of ASCO on small molecules that could overcome the limitations of existing therapies.
Treatment for lung cancer and melanoma has commonalities. Small molecule kinase inhibitors targeting a particular aberration driving the tumor have been approved for both types of cancer. But in each case, tumors eventually develop resistance to those kinase inhibitors, usually after about 6 to 9 months of treatment. Researchers are now trying to pinpoint the mechanism that tumor cells use to overcome the activity of kinase inhibitors, and then design new compounds or combinations of drugs that can improve patient outcomes.
Today we’ll focus on advances in non-small cell lung cancer (NSCLC). ASCO brought data from several new agents—most notably, Boehringer Ingelheim’s afatinib, AstraZeneca’s selumetinib, and Novartis’ LDK378—as well as new combinations of existing drugs.
First, some background on the current treatment paradigm in NSCLC: To date, scientists have identified several key protein receptors—EGFR, KRAS, and ALK—as drivers of the disease. Patients with a mutation in EGFR can take Genentech’s Tarceva (erlotinib) or AstraZeneca’s Iressa (gefitinib), but only after undergoing four cycles of chemotherapy. Although Tarceva was approved based on its ability to shrink tumors, it only prolongs survival in NSCLC patients by one month (12 months Tarceva vs. 11 months for placebo). Meanwhile, people who have the anaplastic lymphoma kinase (ALK-ELM4) translocation, can receive Pfizer’s Xalkori (crizotinib), which was approved in the U.S. in 2011.
Unfortunately, people with the KRAS mutation, which is considered mutually exclusive with EGFR, do not benefit from either additional chemotherapy or EGFR inhibitors. New therapies are desperately needed, since prognosis tends to be rather poor.
At ASCO this year, clinicians reported new data that answered some key questions about how best to treat people with these particular mutations: Continue reading →
The evolution of the model for academic-pharma collaboration has been a topic of much discussion as more companies try to tap into university talent for early-stage research (recent examples of collaborations can be found here and here). Industry observers question whether anything tangible will come out of the efforts (see here for a recent critique), believing the divergent missions and cultural differences of each organization inevitably sidelines these pacts.
Pfizer is making one of the more aggressive pushes through its Centers for Therapeutic Innovation. Under the CTI model, Pfizer has set up labs in research hotbeds like Boston and San Francisco, where, through partnerships with various academic institutions, its scientists work side-by-side with university scientists to discover new biologics-based drugs. This week at BIO, I sat down with Tony Coyle, CTI’s chief scientific officer, to talk about CTI’s progress. A more in-depth look at the CTI model will come in the pages of the magazine, but in the meantime, I wanted to share some facts and figures that came out of our chat:
Number of CTIs formed: Four (San Francisco, San Diego, New York, Boston)
Number of academic centers involved: 20
Number of Pfizer scientists across each of its dedicated labs: roughly 100 (Coyle says about 75% were hired from the outside, coming from biotech, academia, with a few from big pharma)
Number of proposals reviewed in the last year: 400
Percentage of proposals overlapping with internal Pfizer efforts: <5%
Number of proposals funded so far: 23
Number of therapeutic areas being studied: 4 (rare diseases, inflammation, cardiovascular disease, and oncology)
Facts and figures aside, Pfizer is trying to move as quickly as possible given the learning curve of teaming with academia. Coyle said he’s promised his bosses that by the third year of the effort, at least four drugs will be in human studies across multiple therapeutic areas. “We’re well on our way to identifying a number of candidates, and I have no doubt that in the next 18 months, we’ll be in our first patient studies,” he added.
Those numbers could change in 2013, when Pfizer potentially expands its CTI outside the U.S. “Ex-U.S is still our ambition,” Coyle says. “2012 has been a period of ‘lets build the group, get the programs and start executing on the pipeline.’ For 2013, we will be and are looking at opportunities ex-U.S., and have had some pretty good discussions to date externally.”
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 tests biophysical stability, pharmacokinetics, and efficacy to understand how much of the drug can be given before toxicity kicks in.
The ADCs in the current clinical pipeline are all to combat cancer, but Ambrx believes its site-specific conjugation technology will open the door to using ADCs in other therapeutic areas. As Cho told me, the heterogeneous nature of current ADCs has limited their use. “What we’re excited about is taking this into non-oncology indications,” Cho says. “We’ve started to generate some interesting pre-clinical data sets…This is where Ambrx really thinks the field is moving.”
It’s worth noting is that Ambrx was founded by Scripps Research Institute’s Peter Schultz, who Merck recently appointed head of Calibr, a San Diego-based non-profit funded by the big pharma firm that will act as a vehicle for academic scientists to turn their ideas into drug candidates. For more on Calibr, click here.
“Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.”
Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Continue reading →
Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease.
Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.”
Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.”
Petsko shared some not-yet-published work with TEDMED’s audience. Continue reading →
You know you’re at an interesting conference when the director of the NIH starts off his presentation with a guitar duet, and shares a session with Cookie Monster.
But the organizers of TEDMED made a very deliberate decision in opening this year’s conference with Francis Collins. This is the first year that the gathering of medical luminaries, artists, and design gurus (TED stands for Technology, Entertainment, Design) is taking place in Washington, DC, after moving from San Diego. It marks a philosophical shift for the organization, from TEDMED as idea incubator to TEDMED as inserting itself into the national conversation on health and medicine. What better way to do that then bringing in the head of the biggest biomedical funding agency?
Collins wants to compress the time it takes to get a drug development pipeline, and make the pipeline less leaky. This isn’t news to folks around the pharma blogosphere, including here at the Haystack, Ash at Curious Wavefunction and Derek Lowe, who’ve followed last year’s announcement of NIH’s venture for drug discovery, the National Center for Advancing Translational Sciences.
Folks have expressed some concerns about the concept, and its emphasis on the promise of gene-based drug discovery. But, as Derek noted, the fact of the matter is that everyone in drug discovery wants the things Collins wants, so there’s a measure of goodwill for the venture too.
Collins spent his time on the TEDMED stage emphasizing two things: drug repurposing and developing high-tech cellular solutions to supplement and replace often-imperfect animal models.
On the tech side, Collins showcased the Harvard-based Wyss Institute’s lung-on-a-chip, which combines tissue engineering and electronics to mimic the interface between the lung’s air sacs and capillaries (Science, DOI: 10.1126/science.1188302). He said that technologies like this suggest viable alternatives to animal testing are possible.
When New Scientist reported on the lung-on-a-chip in 2010, researchers praised it as a step in the right direction, but cautioned that immortalized cell lines, such as those on the chip, don’t neccesarily behave like primary cells from patients. Collins also noted that it might be possible to use such devices with patients’ own cells someday.
On the repurposing side, Collins cited an article on the topic in Nature Reviews Drug Discovery (DOI: 10.1038/nrd3473), and alluded to lonafarnib (SCH 66336), a farnesyltransferase inhibitor that was originally designed to be part of cancer-treatment cocktails. It didn’t pan out as a cancer drug, Collins said, but now clinical trials are underway to test whether the drug is effective at countering a rare mutation that causes Hutchinson-Guilford progeria, an ailment that leads to rapid aging in children. Collins shared the stage with 15-year-old Sam, a progeria patient.
To bridge the massive gap between ideas and applications in medicine “we need resources, we need new kinds of partnerships, and we need talent,” he told the audience.
In a conversation with reporters after his talk, Collins provided another repurposing story published last month– bexarotene, a retinoid X receptor agonist intended for lymphoma that was just shown to clear amyloid-beta and reverse cognitive deficits in a mouse model of Alzheimer’s (Science, DOI: 10.1126/science.1217697)
At that chat, I asked Collins how the repurposing effort and his call for talent squares with massive layoffs in industry and flat or declining funding.
“It would help if we had a strong foundation of support,” Collins said. He said his agency’s purchasing power has decreased 20% over the last 8 years.
Another reporter asked what was the main obstacle to getting repurposing become habit. “IP,” Collins said. He told reporters that a model intellectual property sharing agreement with pharmaceutical companies has been drafted. Asked if companies had signed on to it, Collins said “we’re working on it.”