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Chemotalk NewsletterChemotalk Newsletter, Vol. 44: December 1, 2011 End of the year. Wow, that was fast. This month, I'm highlighting some of the "peripheral" news about treatment developments, as opposed to what you can get through TV and newspapers. Again, I'm emphasizing that many of these trials will never result in drugs we can use. But some will. Another point: Some of these studies get very technical. I like to see if I can figure that information out but you can skip it and still get the gist of the piece. To wit: VACCINE SHOWS PROMISE FOR BREAST CANCER PATIENTS WITH HER2 A biotechnology company focused on developing innovative, targeted oncology treatments that address major unmet medical needs to advance cancer care, announced that positive data from Phase 2 clinical trials of NeuVax was presented at the 26th Annual Meeting of the Society for the Immunotherapy of Cancer. The abstract entitled: "Vaccination with the HER2-derived E75 peptide vaccine in BREAST CANCER patients may confer greater benefit to patients with less aggressive disease," was presented by Alan K. Sears, MD et al. The Phase 2 trials evaluated the NeuVax (the HER2-derived E75 peptide) vaccine in breast cancer patients in the adjuvant setting. The results suggested that patients with less aggressive disease traits may derive greater clinical benefit from vaccination and have lower rates of breast cancer recurrence. These included vaccinated patients with node negative disease, lower levels of HER2 expression, lower grade tumors, hormone receptor positivity, or lower Adjuvant! Online scores. This analysis is part of the continued focus on the targeting of active cancer immunotherapies to patients with a lower bioburden of disease. This strategy is the cornerstone of the development strategy for NeuVax, and represents a potent pathway for the development of the next generation of cancer vaccines. A total of 187 patients were enrolled in the combined trials (vaccine=108, control=79). Patients enrolled in the trial were node positive or high-risk node negative breast cancer patients with any level of HER2 expression (IHC 1+, 2+, or 3+), and rendered disease-free after standard adjuvant therapies. With 60 months median follow-up, the vaccine group experienced a 10.6% recurrence rate compared to 20.3% in the control group (48% risk reduction, p=0.098). Recurrence rates for vaccine and control patients with different disease features (nodal status, HER2 expression, tumor grade, and hormone receptor status) were also analyzed. "The results show additional evidence that NeuVax may provide a meaningful clinical benefit in patients with less aggressive forms of breast cancer, and potentially keep them free of their disease, a clear unmet medical need," said Mark J. Ahn. "It is important to note that this study included an expanded population from the patients we are targeting for our Phase 3 trial. Even with this larger and more diverse group of patients, NeuVax continued to show almost a 50 percent improvement over the control group." NeuVax consists of the E75 peptide derived from human epidermal growth factor receptor 2 (HER2) combined with the immune adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF). Treatment with NeuVax stimulates cytotoxic (CD8+) T cells in a highly specific manner to target cells expressing any level of HER2. NeuVax is given as an intradermal injection once a month for six months, followed by a booster injection once every six months. Based on a successful Phase 2 trial, which achieved its primary endpoint of disease free survival (DFS), the Food and Drug Administration granted NeuVax a Special Protocol Assessment (SPA) for its Phase 3 PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment) study. The Phase 3 trial is expected to commence in the first half of 2012. According to the National Cancer Institute, over 200,000 women in the U.S. are diagnosed with breast cancer annually. Of these women, about 75% test positive for HER2 (IHC 1+, 2+ or 3+). Only 25% of all breast cancer patients, those with HER2 3+ disease, are eligible for Herceptin® (trastuzumab). NeuVax targets the remaining 50% of HER2-positive patients (HER2 1+ and 2+) who achieve remission with current standard of care, but have no available HER2-targeted adjuvant treatment options to maintain their disease-free status. * * * ŒSUICIDE SWITCH' MAY PAVE WAY FOR SAFER CANCER THERAPY By Robert Langreth Cell-transplant therapies that offer promise for fighting CANCER and other diseases also come with a risk: rogue cells that can turn deadly. Now researchers at Baylor College of Medicine in Houston report on a method that engineers a so-called suicide switch into transplanted cells that, when activated with a drug, rapidly kills off the ones that cause harm. The method, tested in children undergoing stem-cell transplants to treat LEUKEMIA, wiped out the cells that turn on the body of the patient, a complication called graft-versus-host disease. The scientists created the switch by adding a gene to transplanted cells that produces a protein causing cells to self-destruct. The switch remains dormant until doctors infuse a drug called AP1903 that activates the cell suicide. The method may ultimately apply to other therapies, including embryonic stem cells, that can cause complications such as tumors. ³The issue is that cells are complex living things and sometimes they do something we don¹t want,² said Michel Sadelain, an oncologist and cell therapy researcher at Memorial Sloan-Kettering Cancer Center in New York, who wrote an editorial accompanying the study. ³If you want to get rid of them, this study reports a very remarkable novel approach.² The suicide switch is activated by a single dose of an otherwise inert drug. In four children with leukemia who started to develop graft-versus-host disease after getting transplanted immune system cells from bone marrow, one infusion of the drug killed more than 90 percent of the rogue cells in just 30 minutes, the researchers reported. It stopped the graft-versus- host disease. Control Mechanism With transplanted cells, ³you have to have a mechanism where you can control them,² Malcolm K. Brenner, a hematologist at Baylor College of Medicine, and senior author on the study, said. The new suicide switch ³is a much faster and more effective control mechanism than we have had up until now.² The suicide switch has worked in various types of stem cells in test-tube studies his team has conducted, Brenner said. Bone marrow transplant is a method used to treat leukemia and other types of cancer by wiping out diseased bone marrow cells with drugs and radiation and transplanting in new bone marrow cells from a donor. Partial Match Unlike conventional bone marrow transplants using matched donors, in this study the Baylor College of Medicine researchers were treating kids with leukemia using cells from donors that were only a partial match to the children receiving them, increasing the risk of side effects such as graft-versus-host disease. To mitigate the complication, the researchers added the suicide gene to T-cells, a type of immune system cell that was transplanted into the patients. Graft-versus-host disease is a well-known and potentially lethal complication of bone marrow transplants in which transplanted cells attack the patient¹s body. * * * MULTIPLE SCLEROSIS DRUG FAST-TRACKED BY FDA The drug Tovaxin® has been granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of patients with SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS (SPMS). The FDA's Fast Track program is designed to facilitate the development and expedite the review of drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. According to the FDA, products with a Fast Track designation often receive priority review, which may offer a significant benefit in that, historically, the review time of a priority product is almost half that of a standard review. Additionally, as per the FDA, Fast Track priority review products are more likely to be approved on the first review cycle than those without the designation. Fast Track also entitles the drug manufacturer to more frequent interactions and dialogue with the FDA, further benefiting the drug's development. ³Patients with progressive forms of multiple sclerosis (MS) are faced with no proven effective treatment options, so the Fast Track designation for Tovaxin is meaningful as it should enable Tovaxin to move more rapidly through the regulatory process, once it is proven to be efficacious,² commented Dr. Mark Freedman, M.D., FRCP, FAAN, Professor of Medicine at the University of Ottawa and Director of the Multiple Sclerosis Research Unit at the Ottawa Hospital. ³Novel therapies such as Tovaxin offer hope for patients with a diagnosis of progressive MS.² SPMS is characterized by a steady accrual of irreversible disability, despite, in some cases, reversible relapses, remissions, or clinical plateau. Tovaxin is derived from T-cells isolated from peripheral blood, expanded ex vivo, and reintroduced into the patients via subcutaneous injections. This process triggers a potent immune response against specific subsets of autoreactive T-cells known to attack myelin and, thereby, reduces the risk of relapse over time. * * * Is it possible that we owe some acceleration of attention to pancreatic cancer, to Steve Jobs? If so, he's still at work. Although it's unlikely that Jobs has any direct connection to projects in the works for a long time, it seems as though when celebrities are stricken, media focus shifts a little toward the type of cancer that brought them down. Hopefully, this will infuse more money into cancers that don't strike large numbers of people. COLLABORATION SUPPORTS EARLY DETECTION OF PANCREATIC CANCER Molecular diagnostics startup Abcodia is collaborating with Oxford Gene Technology to discover and validate biomarkers for early detection of PANCREATIC CANCER. Abcodia has a serum biobank including samples from people with pancreatic cancer from up to 7 years before diagnosis, and will use data mining to select sets of samples. Oxford Gene Technology will then screen these samples using its functional protein array platform and Genefficiency microRNA profiling array to identify biomarkers specific to pancreatic cancer. * * * SKIN CANCER DRUG GETS FDA PRIORITY REVIEW The Food and Drug Administration has accepted and filed a New Drug Application for vismodegib for the treatment of adults with ADVANCED BASAL CELL CARCINOMA (BCC) for whom surgery is considered inappropriate. The application has been granted Priority Review status and the FDA confirmed the action date is March 8, 2012. Vismodegib is an investigational, oral, targeted medicine designed to selectively inhibit signaling in the Hedgehog pathway, which is implicated in more than 90 percent of BCC cases. BCC is the most common type of skin cancer, which is generally considered curable by surgery. However, when it advances, BCC can cause disfiguring and debilitating effects and in some patients can ultimately be life-threatening. Currently, there are no effective treatment options for advanced BCC. About Basal Cell Carcinoma and the Hedgehog Pathway According to the American Cancer Society, BCC accounts for approximately 80 percent of all diagnosed skin cancers. The disease is generally considered curable if the cancer is restricted to a small area of the skin. However, if the disease is left untreated or recurs after surgery, it becomes locally advanced, and the cancer may invade further into surrounding tissues such as sensory organs (ears, nose and eyes), bones or other tissues. In a small proportion of patients (estimated at less than one percent of those affected), BCC can metastasize, spreading to other parts of the body. The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and becomes less active in adults. In addition to BCC, mutations in the pathway that reactivate Hedgehog signaling are seen in several types of cancer. * * * SMALLPOX VACCINE EXTENDS LIFE IN CANCER TRIAL A genetically engineered smallpox vaccine reduced the risk of death for patients with ADVANCED LIVER CANCER by nearly 60 percent in a mid-stage study, prompting the launch of a later-stage trial. Scientists at institutions including the University of California, San Diego, and privately held biotech company Jennerex Inc presented Phase 2 trial data showing that patients given high doses of the altered vaccine, known as JX-594, lived for a median of 13.8 months compared with 6.7 months for patients treated with one-tenth of that dose. The small 30-patient study found that 66 percent of the high-dose patients were alive after one year, compared with 23 percent of the low-dose group. Temporary flu-like symptoms were the main side effect seen in the trial, which was presented in San Francisco at a meeting of the American Association for the Study of Liver Diseases. Scientists have been intrigued for decades with the idea of using viruses to alert the immune system to seek and destroy cancerous cells. That interest has taken off in recent years as advances in genetic engineering allow them to customize viruses that target tumors. "Viruses are inherently cancer selective and tumor cells are inherently susceptible to viral attack," said Dr. David Kirn, chief medical officer at Jennerex. "We enhance selectivity by further attenuating and weakening the virus in normal tissue." He said the first patient has been enrolled in a Phase 2b study comparing JX-594 with standard care in 120 liver cancer patients who have stopped responding to Nexavar, also known as sorafenib. Patients in the trial will first be given an intravenous infusion of JX-594, followed by direct injections into the tumor. Dr. Kirn said the trial will also allow for more continuous dosing than in earlier studies. Jennerex plans to launch next year a Phase 3 head-to-head trial comparing JX-594 with Nexavar and is conducting earlier-stage trials in other types of cancer. Other forays into using engineered viruses include biotech giant Amgen Inc's deal in January to pay up to $1 billion for BioVex and its cancer drug development platform based on the herpes simplex virus. Amgen said last month that it had completed enrollment in a Phase 3 trial of the therapy in MELANOMA patients. * * * Who says there's not much progress in cancer research?!: ORPHAN DRUG APPROVED FOR TREATMENT OF RARE FORM OF LEUKEMIA EUSA Pharma, a transatlantic specialty pharmaceutical company focused on oncology, oncology supportive care and critical care, announced that the US Food and Drug Administration has approved its orphan drug Erwinaze (asparaginase Erwinia chrysanthemi) for the treatment of ACUTE LYMPHOBLASTIC LEUKEMIA in patients with hypersensitivity to E. coli-derived asparaginase. The drug will be available to patients throughout the United States immediately. ALL is the most common form of childhood cancer, with approximately 2,900 patients under the age of 20 diagnosed in the USA each year. It is also one of the most curable forms of cancer, with remission rates in treated children of over 95% and 75 - 85% surviving at least five years without recurrence of leukemia. Treatment involves a number of stages and drugs, and typically includes asparaginase as an essential component of current protocols. The new drug, Erwinaze, is indicated as an integral part of a multi-agent regimen for the treatment of ALL patients who develop hypersensitivity to current products derived from E. coli, and is therefore the first and only approved treatment option available for patients with hypersensitivity to standard-of-care treatment with pegaspargase. An estimated 15 - 20% of ALL patients develop hypersensitivity to E. coli-derived asparaginase, representing approximately 450 - 600 children in the United States each year. The approval of the new drug is an important advance because it is the only treatment option that can enable at-risk patients to continue and complete their full course of therapy," said Stephen E Sallan MD, Chief of Staff, Dana-Farber Cancer Institute and Professor of Pediatrics, Harvard Medical School. ERWINAZE is an asparaginase enzyme that depletes the level of asparagine in the bloodstream. Asparagine is essential for cell growth, and its removal from the blood inhibits the growth of cells associated with acute lymphoblastic leukemia. Asparaginase products are derived from bacteria, and approximately 15 - 20% of patients develop hypersensitivity to modern products derived from Escherichia coli, preventing their continued treatment. This drug, produced by Erwinia chrysanthemi, is immunologically distinct from other therapies and is suitable for patients with hypersensitivity to E. coli-derived treatments. * * * Good news ... Plus an interesting look at how two companies make research-driven decisions. BRAIN CANCER VACCINE EXTENDS LIFE By Maureen Martino Celldex Therapeutics, a drug developer, has unveiled overall survival data from a 65-person Phase II trial of the company's brain cancer vaccine rindopepimut. In the single-arm trial, the Needham, MA-based company said subjects who received the therapeutic vaccine had a median overall survival of 24.6 months from diagnosis; historical data on patients with the same eligibility of those in the trial had a median survival of just 15.2 months. Rindopepimut targets the epidermal growth factor receptor variant III (EGFRvIII). The vaccine was given to newly-diagnosed EGFRvIII-expressing patients whose cancer had been surgically removed. Three months after diagnosis and after standard chemo treatments, the patients were given the vaccine along with temozolomide therapy, which is a standard treatment for glioblastoma. Two year overall survival rates in the rindopepimut group were 52%, compared with 6% for the matched EGFRvIII positive cohort. The company noted the survival data were consistent with two previous smaller studies with rindopepimut. Celldex's stock price was hit hard in August after sluggish sales of Dendreon's prostate cancer vaccine Provenge dragged the entire cancer vaccine sector down. In 2010, Pfizer pulled out of a pact to develop rindopepimut, saying the programs was no longer a "strategic priority." "The consistency of data from three separate studies, including a large multicenter trial, is very encouraging and clearly supports our plan to advance clinical development of rindopepimut with ACT IV, a pivotal, randomized, blinded international Phase III study," said Celldex CMO Thomas Davis. Before the end of the year, Celldex will kick off a Phase III trial of rindopepimut as a frontline treatment for GLIOBLASTOMA, and a second trial for recurrent glioblastoma in combination with Avastin. The data were presented at the 16th Annual Meeting of The Society for Neuro-Oncology. * * * STUDY: TARGET VACCINES FOR DEADLY CANCERS CANCER vaccine developers are targeting cancers based on how many annual cases of those cancers occur, rather than the number of deaths they cause. That's according to research conducted at the University of Michigan, which finds that companies could have a greater impact on patient outcomes if they focused on targeting cancers with high mortality rates, rather than common cancers. "If a cancer is more commonly diagnosed in the United States, it is significantly more likely to have therapeutic vaccines in clinical trials," noted U-M's Dr. Matthew Davis in a release. "Focusing on annual incidence is a very common approach by drug companies in developing new therapies." There are currently 230 therapeutic vaccine trials in the works for 13 types of cancer, the researchers found. Vaccines for MELANOMA (40), BREAST (34), LUNG (30), PROSTATE (22), and BRAIN (20) cancer are the most common in development. But lung, pancreas, colon, breast and liver and bile duct cancers have the highest mortality rate, leading to an estimated 303,000 deaths annually. However, just 90 cancer vaccines are in development for these five diseases. "The lack of a connection between therapeutic cancer vaccine development and cancer deaths means that vaccine development in this arena today may not best serve the needs of cancer patients tomorrow," Davis said. "As a primary care doctor, I would like to see innovations with therapeutic vaccines that target cancers where our current therapies are less effective than average." * * * Finally, this story ran online on a biotech site. Makes you wanna smile (an' throw up both your hands) .. 10 PROMISING LATE-STAGE CANCER DRUGS By Ryan McBride For the CANCER drug research enthusiast, this report might read in places like a special oncology edition of a gun magazine. Indeed, there are plenty of weapons against cancer to read about here. Several of the drugs listed here represent the advancement of relatively new methods of attacking cancer, including "armed antibodies" and cancer-killing viruses. In addition, decades of basic research into the molecular drivers of cancer growth are bearing fruit for drug developers. Not only are these companies making progress in clinical trials, they have landed buyout deals and lucrative partnerships. It's also clear that relatively small companies like Aveo Pharmaceuticals and Curis are making inroads along side the big boys like Pfizer and Roche. There are 10 late-stage drugs listed in this report, but this editor hesitates to call them the "Top 10" only because there are so many variables to consider to rank them in such a way objectively. Yet these 10 drugs have certainly been generating news and, in most cases, lots of interest among investors and the medical community. All of the drugs have reached pivotal trials for at least one type of cancer. Here's the list in alphabetical order by each drug's most commonly used moniker, whether that is its alphanumeric code name or generic name.
1. Carfilzomib - multiple myeloma
See you in 2012! * * * 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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