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Chemotalk NewsletterChemotalk Newsletter, Vol. 49: May 1, 2012 Spring is here - well, actually Southern California is spring-challenged, so this is pretty close to what the rest of you call "summer". Here's an important update on a drug affected by shortage problems: JOHNSON & JOHNSON TAKES NEW STEPS TO MANAGE DOXIL SUPPLY DURING SHORTAGE Johnson & Johnson said it would update a rationing program for the CANCER drug Doxil to maximize the remaining supply and provide additional treatment cycles to patients already enrolled in the allocation program. A shortage of Doxil, which treats ovarian and other cancers, emerged last year after J&J's contract manufacturer, Boehringer Ingelheim GmbH's Ben Venue Laboratories unit, experienced production problems. Ben Venue halted production at its Ohio plant in November to address regulatory concerns about contamination; it expects to resume production in late 2012. No new Doxil has been manufactured, but J&J still has some unused supply to provide to patients under an allocation program created last year to manage the shortage. Some 3,300 patients are in the program. J&J will ask doctors to reconfirm their current allocation for each patient by April 23. If J&J doesn't receive a patient's allocation confirmation or new-supply order by the April 23 deadline, the patient will be removed from the allocation program. "We want to be sure that physicians reconfirm they continue to need their allocation," said Lisa Vaga, spokeswoman for J&J's Janssen unit, which markets Doxil. In addition, doctors now have the option to re-enroll patients already in the program, regardless of whether they have completed their prior allocation or continue to receive therapy. Doctors who determine a patient is receiving a clinical benefit from Doxil may request up to seven cycles of the drug to continue therapy. All requests will continue to be fulfilled on a first-come, first-served basis. When J&J created the allocation program last year, it allotted up to seven cycles per patient on a first-come, first-served basis. J&J stopped accepting new enrollments after Ben Venue suspended production. Hundreds of patients were once on a waiting list but J&J said in January it had enough supply to provide to all remaining patients on the list. The company has been able to periodically identify additional supplies of Doxil for various reasons, including some patients having used less Doxil than the amount originally allotted. It is unclear how far the remaining supply will go because J&J doesn't know how much will be requested by doctors or used by patients, Vaga said. In February, the U.S. Food & Drug Administration allowed the temporary importation of Sun Pharma's LipoDox as an alternative to Doxil. J&J continues to try to restore a reliable Doxil supply, including by switching to another manufacturer. * * * Nanotechnology is beginning to emerge as a source of hope for improved cancer treatment. The next two pieces explain... WILL NANOTECH OUTPACE BIOTECH? By Damian Garde Nanotechnology's applications in drug formulation and delivery are well-established, but what about in consumer products? That's where the industry is headed, and that's why it'll eventually eclipse biotech in size and profitability, according to Liquidia Technologies CEO Neal Fowler. Speaking at last week's Nanotech Commercialization Conference in North Carolina, Fowler said his company's proprietary nanoparticle manufacturing tech has applications far beyond medicine. Fowler said a huge market is waiting for nanotech companies; it's just a matter of harnessing the field's potential into practical uses. "Our challenge going forward is, our opportunity will be, how to pace those events to get the technology (going) faster and faster," said Fowler. "(We) had to go through three or four years of understanding what we have on our hands. (We're) now figuring out how to unleash it." Charles Hamner, chairman of the nonprofit research outfit Hamner Institutes for Health Sciences, said new applications for nanotech are in their infancy. However, with some goading and incentivizing from the government, the field can move from the innovation stage to the growth stage. Then there's nothing to stop nanotechnology from outpacing biotechnology, Hamner said. Liquidia's bread and butter is in next-gen vaccine formulation, and the company got $10 million in backing from the Bill & Melinda Gates Foundation to fund that work. Fowler said the company remains focused on vaccine development, but the possibilities are endless with its nanotech platform, including diagnostics, solar panels, building materials and consumer products. "The world is full of particles," he pointed out. * * * COMPANY TOUTS POSITIVE RESULTS FOR CANCER-FIGHTING NANOPARTICLES By Damian Garde While CHEMOTHERAPY is often effective in treating cancer, its taxing drug regimens can lead to debilitating side effects. But new research from Bind Biosciences may point to a way to deliver high concentrations of chemotherapeutic drugs directly to tumors, while avoiding many of the pitfalls of traditional treatment. Bind, a known-to-be innovator in the field, is using its nanoparticle drug delivery platform Accurin to deliver docetaxel with Bind-014. The Accurin particles are filled with tumor-killing docetaxel and coated with proteins that seek out cancer cells. Loads of the particles are injected into patients every three weeks, tracking down tumors and delivering the drug payload. Bind published some early results from a still-in-progress Phase I trial last week in Science Translational Medicine, finding that 6 of the study's 17 participants with advanced or metastatic cancers experienced slowed tumor growth or even shrinkage, with one patient's cancer almost disappearing. `While the research is still in very early stages, scientists are excited about the implications of delivering chemotherapeutic drugs directly to tumors. Researchers discovered that this method leads to 10 times the concentrated drug activity in tumors than through normal treatment. "If you try to get that concentration in a conventional form, you will kill the patient," said Omid Farokhzad, one of the study's authors and a co-founder of Bind, as quoted by the AFP. Over the past decade or so, scientists have struggled to use nanoparticles to treat cancer, and Bind's early results could provide a way to maximize chemotherapy's effect while minimizing its toxic dangers. "The emerging Bind-014 clinical data showing signals of efficacy even at relatively low doses validates the potential for the revolutionary impact of nanomedicines and is a paradigm shift for the treatment of cancer," said researcher Philip Kantoff, as quoted by Scientific American. And another, similar progress report: 'CHEMO BOMB' NANOTECHNOLOGY EFFECTIVE IN HALTING TUMORS By Damian Garde Researchers at Case Western Reserve University have developed a novel way of getting CHEMOTHERAPEUTIC drugs into cqncer cells: stringing together chains of nanoparticles loaded with drugs, and then detonating them once they've penetrated a tumor. The method works like this: The scientists take magnetic, iron-oxide nanoparticles and alter the surfaces so they bind together in a chain, and then fill them with cancer-fighting doxorubicin. In a trial, the researchers injected the nanochains into mice with highly aggressive TRIPLE-NEGATIVE BREAST CANCER. After waiting a day for the chains to embed themselves within the tumors, the scientists placed a solenoid wire coil next to the mice, creating a radiofrequency field that vibrated and detonated the nanoparticles, dispersing the drug into the heart of the tumor. And the results were positive. When compared with cancerous rats receiving normal doses of doxorubicin, those treated with the nanochains experienced half the tumor growth and a higher rate of cancer cell death. In those rats who received two doses of the nano treatment, tumor growth was reduced to one-tenth that of those treated traditionally. The twice treated rats also survived for 31 more days than the traditionally treated ones. "Other nanotechnology has been used to get a drug inside a tumor, but once the drug gets in the door, it stays by the door, missing most of the building," said Professor Efstathios Karathanasis, leader of Case's research team. "We used a different kind of nanotechnology to smuggle the drug inside the tumor and to explode the bomb, releasing the drug in its free form to spread throughout the entire tumor." While much more study and additional trials are certainly in store, the researchers note their method wasn't just more effective than traditional chemo, but it was also safer. The nanochains contain only about 5% to 10% of the doxorubicin used in standard chemo, reducing the chances of toxic drugs harming healthy cells. The results of the experiment were published in the journal ACS Nano. * * * While the following piece is hopeful, it's also scary. Diagnostics in combination with drugs pose a double danger. Are doctors going to trust the diagnostics exclusively? What if, as is bound to be the case, the diagnostic tool - in this case, an "imaging agent" - eliminates someone who could actually be helped by the drug? This drug company appears to be trying to save money, as well as lives. Maybe a good thing. Except for the fact that they now have two items on the market, instead of one. The drug company wins, no matter how it turns out for the patient. MERCK SNAGS RIGHTS TO ENDOCYTE'S OARIAN CANCER DRUG IN $1B DEAL Merck has scooped up worldwide rights to Endocyte's late-stage OVARIAN CANCER drug in a billion-dollar deal, paying $120 million upfront and committing up to $880 million in milestones. And West Lafayette, IN-based Endocyte will also get co-promotion rights and a split of U.S. profits while earning double-digit royalties in the rest of the world. Investors liked the sound of big round numbers, bidding up Endocyte shares by 111% once the news hit. Merck says the drug--Vintafolide, or EC145--matches the profile of what it's looking for in a cancer drug, highlighting Endocyte's development of a companion diagnostic to identify patients most likely to respond to the treatment. And Endocyte says it's only months away from filing for U.S. approval. The treatment has been given orphan drug status in Europe. Endocyte's strategy is to use an imaging agent, EC20, to identify patients whose tumors express folate receptors. Those patients who test positive are treated with EC145, which combines a chemotherapy with a conjugate that includes vitamin folate, targeting specific cancer cells. That approach has produced positive results in mid-stage studies, with folate receptor-positive patients achieving a median 5.5 month PFS rate compared to a control arm's 1.5 months. "Vintafolide is a promising and innovative late-stage cancer drug candidate. In addition to pursuing the lead indication of platinum-resistant ovarian cancer, Merck plans to further evaluate its potential for treatment of multiple other cancer types," said Peter S. Kim, executive vice president and president at Merck Research Laboratories. "This agreement underscores our strategy of building a portfolio of oncology therapeutics that employ a companion diagnostic to facilitate selection of those patients most likely to respond to treatment." * * * MAYO TEAM SPIES NEW CLASS OF BREAST CANCER MUTATION BREAST CANCER is among the more studied cancers. So it is particularly noteworthy when scientists discover something new, such as a novel class of molecular mutation in various forms of the disease. Mayo Clinic researchers and others have done just that in discovering what are known as fusion transcripts, or mutated forms of RNA, for various breast cancer subtypes. Details are published in the journal Cancer Research. The researchers explain that fusion transcripts are more typical in LEUKEMIA, LYMPHOMA or other blood cancers. Finding them in breast cancer tumors matters, they say, because it potentially moves cancer diagnosis and treatment beyond the three typically acknowledged kinds of breast tumors: estrogen receptor (ER)-positive, HER2-positive and triple negative. More studies are needed, the scientists say, but the potential value of the finding runs the gamut of possibilities as far as producing a more personalized breast cancer treatment. Fusion transcripts appear, they say, when chromosomes break apart and recombine--something typical for cancer cells. Senior investigator Edith Perez, deputy director of the Mayo Clinic Comprehensive Cancer Center in Florida, said in a statement that the discovery is the first step toward finding gene biomarkers that could predict how a specific breast cancer tumor will respond to a given treatment. Adds E. Aubrey Thompson, professor of biology at the center: "Fusion transcripts have the power to produce proteins that are relevant to tumor development, growth and sensitivity to treatment, so we may have a brand new set of genomic changes that may help us understand, and treat, breast cancer in a new way." * * * DRUG IMPROVES DISABILITY SCORES IN MULTIPLE SCLEROSIS PATIENTS Sanofi, France¹s largest drugmaker, said its experimental medicine Lemtrada led to an improvement in disability scores in patients with MULTIPLE SCLEROSIS compared to an older treatment. Lemtrada, also known as alemtuzumab, slowed the progression of disability versus Merck¹s Rebif in a late-stage trial, and scores improved in some patients who were given Lemtrada in the two-year study, suggesting a reversal of disability. At two years, 29 percent of patients treated with Lemtrada had experienced a six-month reduction in disability, compared with 13 percent of those treated with Rebif, which presented full data from the trial at the 2012 American Academy of Neurology meeting. The disability data ³is big news,² Michael Panzara, Genzyme¹s therapeutic area head for multiple sclerosis, immune diseases and neurology, said in a telephone interview. ³Alemtuzumab versus Rebif improves function; that¹s unique.² Among patients treated with Lemtrada, 65 percent didn¹t experience relapses at two years, compared with 47 percent for those who were given Rebif in the 840-patient study, dubbed CARE-MS II, said Sanofi. The data shows Lemtrada ³becomes a very real treatment option at all stages of the disease,² Panzara said. ³It sets it apart in terms of efficacy from anything else out there.² In spite of its effectiveness, analysts such as Vincent Meunier of Exane BNP Paribas have said Lemtrada may be too toxic to become a blockbuster. ³The drug¹s sales potential will depend on its safety profile,² Pierre Corby, an analyst at Aurel BGC in Paris, said in an interview, before the data was published. Sanofi didn¹t provide additional information on Lemtrada¹s safety risks. It reiterated that 16 percent of patients developed an autoimmune thyroid-related side effect during the trial. That compares with 5 percent for Rebif. It also said 0.9 percent of patients suffered from immune thrombocytopenia, a reduction of platelets in blood cells. These cases were detected early and treated with conventional therapies. Lemtrada¹s safety profile ³is well-characterized,² Panzara said. ³Because it¹s known, it can be managed and we anticipate it will be managed in the marketplace based on what we¹ve learned.² The most common adverse events associated with alemtuzumab, the chemical name for Lemtrada, were reactions linked to infusion of the drug, such as headaches, rashes, fever, nausea, itching and fatigue. Full data from the CARE-MS II trial is likely to ³reinforce the high efficacy/high adverse event profile of Lemtrada,² Ravi Mehrotra and other analysts at Credit Suisse Group AG wrote in a note to clients. Sanofi is seeking ways to determine which patients are more susceptible to suffering from thyroid side effects, Panzara said. ³It¹s a very active area of research right now,² he said. ³We¹re looking for various predictors for thyroid, for any of the other adverse events also. We will not have any of that sorted out in time for our planned submission² but ³the more we can characterize that predictive risk, the greater potential² for Lemtrada, Panzara said. Sanofi is ³on track² to file for U.S. and European approval of Lemtrada in relapsing multiple sclerosis this quarter, Panzara said, declining to give more details. Genzyme is developing Lemtrada together with Bayer AG. (BAYN) * * * Finally, something to think about: THE BIGGEST R&D SPENDERS IN BIG PHARMA By John Carroll Over the past few years, there's been no end of discussion about the need to find more efficient ways to discover and develop new drugs. Giants like GlaxoSmithKline, Sanofi and Pfizer have been retooling pipelines and demanding better results from investigators. New analysis, meanwhile, has pointed to the persistent megablockbuster cost of drug development at most companies, as consultants and analysts pondered the effects of a long drought in the approval process. Last year, pharma did better on the development front, seeing a modest increase in new drug approvals, which helped inspire talk of a turnaround. But long after all the economizing and efficiency reviews have been launched, R&D expenses continue to go up. This past year, the top 10 collectively registered expenses of a bit more than $70 billion, up slightly over the year before, according to the figures we collected. Pfizer has yet to deliver on the bulk of the $1.5 billion in cost cuts that it has promised--though that is still in the works. And faced with paltry results from R&D, AstraZeneca is ordering some deep cuts. So the trend to ever-higher annual expenses may yet be challenged by the Big 10. But for every big cost-cutting effort, you'll see more examples of big companies holding the line or spending slightly more. Companies like Novartis, Eli Lilly and Merck show no sign of backing down on R&D budgets--though this year at least two of those companies are going to face growing demands to either put up impressive pivotal data or start changing strategies. Drug research remains one of the ultimate long shots in the tech industry. Finding a rational balance between what's spent and what's produced will continue to be one of the biggest challenges the industry faces. * * * Until next month ... * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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