%u25BA AVAX and CTCA Collaborating for Cancer Therapies

VAX Technologies, Inc., a developer of therapeutic cancer vaccines located in Philadelphia, PA, and Cancer Treatment Centers of America, Inc. (CTCA), a network of cancer treatment hospitals and facilities, are collaborating for the benefit of both parties’ cancer therapeutic products. The agreement will advance AVAX’s OVax ovarian cancer vaccine by facilitating a study at CTCA’s centers. At the same time, AVAX will produce CTCA’s activated natural killer cell technology for the treatment of various cancers.

	The terms of the collaboration are for a three-year period, during which CTCA will provide AVAX with a funding of $1.15 billion for research and development. CTCA will fund the initial production of vaccines, and for AVAX’s clean room facility, where the company will produce its vaccines as well as CTCA’s natural killer cell preparations.

	AVAX plans to activate a phase I/II IND for the treatment of stage III and IV ovarian cancer patients who have relapsed after chemotherapy. The study will evaluate patients for safety and immunological responses. It will be based at CTCA’s hospital in Zion, IL, where CTCA expects to start treating patients this summer.

	The new O-Vax vaccine looks promising because it is based on the same technology as AVAX’s metastatic melanoma vaccine M-Vax, which has already been launched commercially in Switzerland and has the US FDA’s orphan drug designation. The technology, called haptenization, works by attaching a chemical hapten to tumor antigens, making it easier for the immune system to recognize the tumors. The safety and efficacy of M-Vax has been evaluated in more than 400 patients with stage III and IV melanoma, and the vaccine has been shown to increase five-year overall survival in patients with stage III melanoma. The newer O-Vax product has also seen good news recently—two phase I/II trials for the O-Vax product have provided  encouraging results showing that the vaccine may prove effective in chemotherapy-resistant ovarian cancer.

	“To win the fight against cancer, it is absolutely vital we do everything we can to make innovative new treatments like this available to patients as soon as possible,” said Edgar Staren, chief medical officer of CTCA. “It’s inconceivable that treatments like these that  give hope to patients are often lefton the laboratory bench, while cancer patients are told there is nothing more that can be done for them.”

                                                                                                                                                                                              —Prachi Petal-Predd

%u25BA Full Speed Ahead for GPC Biotech's Satraplatin

fter recently announcing positive results from a phase III registrational trial evaluating satraplatin against hormone refractory prostate cancer, biopharmaceutical company GPC Biotech AG has launched an expanded access program for the drug. The results of the trial showed that satraplatin significantly reduces the risk of disease progression in patients.

	GPC Biotech, which is headquartered in Frankfurt, Germany, is expecting overall survival data later this year, but the company is moving forward with marketing approval applications. It has already filed the New Drug Application for satraplatin with the US FDA and expects to file an application in the EU by the end of the second quarter.

	“Moving forward, we plan to work closely with the FDA regarding our application for marketing approval of satraplatin in the US,” said Bernd R. Seizinger, MD, PhD, chief  executive officer of GPC Biotech. “We also are continuing to aggressively build our marketing and sales organization in the US to prepare for a potential launch of satraplatin later this year.”

	The company announced the results of the Satraplatin and Prednisone Against Refractory Cancer (SPARC) trial at the American Society of Clinical Oncology Prostate Cancer Symposium in September 2006. The trial compared the effectiveness of  satraplatin plus prednisone and placebo plus prednisone in 950 patients with refractory cancer who have failed chemotherapy treatment. Final progression-free survival (PFS) results for the SPARC results were presented by Daniel Petrylak, MD, associate professor of medicine at Columbia University College of Physicians & Surgeons, director of the Genitourinary Oncology  Program at New York-Presbyterian Hospital/Columbia, and a principal investigator in the SPARC Study on February 24 at the American  Society of Clinical Oncology (ASCO) Prostate Cancer Symposium in Orlando, Florida. Two different designs of the study showed a relative risk reduction in disease progression of 40% and 33% respectively. These results were consistent irrespective of the chemotherapy that the patients had already received.

	According to Dr. Petrylak: “As there are currently no approved therapies for patients with hormone-refractory prostate cancer whose disease has already failed on one chemotherapy regimen, satraplatin has the potential to address a mounting area of unmet medical need. The data I am presenting show statistically significant results in progression-free survival in favor of those patients treated with satraplatin. These results are consistent no matter what the prior chemotherapy treatment, including Taxotere® [docetaxel, Sanofi-Aventis].”

	Under GPC Biotech’s newly launched expanded access program, patients whose first-line chemotherapy has failed will have access to satraplatin free of charge from clinicians’ offices. Unlike other platinum compounds, which need to be administered intravenously, satraplatin comes in the form of capsules that patients can take at home.

                                                                                                                      — Parts of this story were contributed by John D. Zoidis, MD

%u25BA Collaboration for New Oncology Compounds

ristol-Myers Squibb Company and Adnexus Therapeutics have announced a partnership to discover and develop Adnectin-based biological compounds for oncology-related targets. Waltham, MA-based Adnexus is the sole developer of Adnectins, a class of therapeutic proteins derived from human fibronectin that are designed and optimized using the company’s PROfusion protein design engine.

	Under the agreement terms, Adnexus will identify and deliver pre-clinical Adnectin candidates to Bristol-Myers Squibb, which will then focus on global development and commercialization. Adnexus will retain a limited co-promotion right to the first product that is approved in the US.

	Bristol-Myers Squibb will provide approximately $30 million over the next three years to Adnexus. These funds will consist of upfront and guaranteed research payments.

	In addition, Adnexus is eligible to receive regulatory milestone payments of up to $210 million per product, as well as royalties on product sales and sales-based milestone payments.

                                                                                                                                                                                           —Prachi Petal-Predd

%u25BA Graffinity and Amgen in Drug Discovery Ageement

raffinity Pharmaceuticals GmbH, a developer of fragment-based drug discovery technology headquartered in Heidelberg, Germany, announced a drug discovery research agreement with Amgen on February 25. As per the agreement, Graffinity will get technology access fees and success payments for generating small molecule hits against a broad range of drug targets. According to the company, it offers one of the largest fragment libraries commercially available today—about 20,000 fragments and 90,000 lead-like structures.

	Thousand Oaks, CA-based Amgen will gain access to Graffinity’s fragment-based drug discovery technology. The technology uses microarrays to screen for molecule fragments that bind to a variety of drug targets that are already available or about to be discovered by genomics, which would help in fighting many major human diseases, including cancer.

	The major focus of the collaboration is chemistry research and the identification of novel modes of action. The companies did not disclose the financial details of the transaction.

                                                                                                                                                                                             —Prachi Petal-Predd

%u25BA Roche Suspends Enrollment in CERA Phase II Oncology Trial

n February 23, Roche announced that it is temporarily suspending recruitment into its phase II dose-finding study (NH19960) with the investigational drug CERA (Continuous Erythropoiesis Receptor Activator) in anemic patients with advanced (stage IIIB or IV) non—small-cell lung cancer who are receiving chemotherapy. An independent drug safety monitoring board involved in the study recommended this course of action, which Roche’s drug safety committee endorsed, according to Roche.

	In this trial, enrolled patients were randomized  to receive CERA 6.3μg/kg, 9μg/kg, or 12μg/kg subcutaneously every 3 weeks, or darbepoetin alfa according to the approved local label (either 6.75 μg/kg subcutaneously every 3 weeks, or 2.25 μg/kg every week).

	Roche halted enrollment because of “a numerical imbalance in the number of deaths across the four arms of the study (three arms with CERA and one arm with darbepoetin alfa).” The investigators reported all deaths among study enrollees were unrelated to the study drugs.

	Roche representatives said in a written statement that there “appears to be no association of these events to excessive hemoglobin levels or the administered doses based on the current review of the data.” They said they have not observed similar types of imbalance in previously completed studies with CERA in cancer patients receiving chemotherapy.

	A review of patient data showed that there were imbalances in baseline disease characteristics—including extent of metastatic spread, presence of liver metastases, and incidence of chronic obstructive pulmonary disease&mdash;among enrollees in the different arms of the trial.

	To date, 153 patients have been enrolled and randomized. Patients who are already enrolled will continue with the study as planned. The safety data from the patients continuing in the study will be closely monitored by Roche working with the Drug Safety Monitoring Board. Roche is further investigating the potential causes for the imbalances in the study arms.

	The temporary suspension of recruitment and the decision to allow currently enrolled patients to complete the 12-week study period will permit an in-depth analysis of the data to determine potential confounding factors and potentially allow recruitment to be restarted.

	Roche has informed all investigators involved in the study of its decision and is working closely with them. The company has also informed health authorities in the countries where the study is taking place.

                                                                                                                                                                                              — John D. Zoidis, MD

Articles

Companies in the news:  1) AVAX and CTCA Collaborating for Cancer Therapies  2) Full Speed Ahead for GPC Biotech's Satraplatin 3) Bristol-Myers Squibb Company / Adnexus Therapeutics:     Collaboration  for New Oncology Compounds, and more

The Industry Insider: April 2007

	Bill To Solve Reimbursement Problems Introduced to House of Representatives

ew legislation that addresses solutions to problems with Medicare reimbursement for cancer care has been introduced in the House of Representatives. The legislation—known as the Community Cancer Care Preservation Act of 2007 (HR 1190)&mdash;is

	being cosponsored by Representatives Artur Davis (D-AL) and Jim Ramstad (R-MN).

	Representatives Davis and Ramstad, who both sit on the House Ways and Means Committee, have heard first-hand from practices about the problems with Medicare reimbursement for community cancer care. These members have visited community cancer clinics in their districts, have met with the leadership of the Community Oncology Alliance (COA), and have been very involved in understanding the issues. Mr. Ramstad sponsored legislation addressing this issue in the prior session of Congress.

	HR 1190 seeks to address the key problems with drug and services reimbursement, including:

	• Elimination of “prompt payment” discounts

	  sales price (ASP) so that ASP is not artifcially

	• Removal of the 6-month lag in ASP so

	  unfairly subsidizing the Medicare system

	  There were more than 100 price increases

	• Creation of payment codes for essential

	  components of quality cancer care that

	  Medicare does not currently reimburse;

	• Restoration of appropriate payment for

	  the first hour and subsequent hours of

	The use of ASP to determine reimbursement is not without controversy, however. According to the National Association of Chain Drug Stores, using ASP to determine pharmaceutical reimbursement under Medicare Part B, rather than Average Wholesale

	Price (AWP), will have a significant negative impact on pharmacies. This negative result will be further magnified and  multiplied if other public and private prescription drug programs such as a Medicare outpatient drug benefit, Medicaid, private pharmacy benefit managers (PBMs), insurance companies, the Department of Defense’s Tricare program, and the Federal Employees Health Benefit Program (FEHBP), use ASP rather than their current reimbursement system.

	The COA has worked with Representatives Davis and Ramstad and has expressed appreciation for their support for community

	cancer care. More details on the bill are expected in the near future.

                                                                                                                                                                                             — John D. Zoidis, MD

NCI Budget Cuts Affecting Cancer Research

he recent congressional decision on the 2007 budget for the National Cancer Institute (NCI) keeps the budget essentially the same as last year, which means a flat funding for more than two years in a row that is leading to cuts in key cancer research across the country.

	In February, Congress approved a continuing resolution that finalized the NCI’s budget at $4.79 billion. This is an increase of $46 million over the 2006 budget, which members of the cancer research community say is an insignificant increase. This is “essentially a cut because in a situation where you have a flat fund over a period of two to three years, inflation begins to take over and so effectively your spending power is less,” Deborah Kamin, senior director for cancer policy and clinical affairs at the American Society of Clinical Oncology (ASCO) told 

. “What the cancer research community has done in response is begin to pull back and tighten their belts to live within the budget constraint.”

	The effective budget cut is adversely impacting research at Cancer Cooperative Groups, a network of institutions and practices across the country that conduct cancer clinical trials funded by the NCI. According to ASCO, 95 new trials, comprising 60% of all new trials that were planned for this year, will not be started or will face significant cutbacks. In addition, Kamin said that the cancer cooperative groups have also been told to reduce patient accrual to their existing trials.

	Needless to say, the cancer research community is expressing concern, and ASCO is calling for at least a 7% increase in the NIH budget to keep pace with inflation. The society is also taking a lead in speaking with the cancer community and making legislators aware of the full impact of the NCI budget cuts on cancer research, Kamin said. “[We are] finding out which trials are not going to happen, how many, what’s the real impact, and share that information with congress so they understand the full impact of even flat lining the budget.”

                                                                                                                                                                                             — 

Senate Panel Weights Pros and Cons of Generic Biologics for Cancer

n mid-March, the US Senate weighed arguments concerning the pros and cons of generic biologic drugs for cancer and other diseases. Legislation that would give the FDA legal authority to approve alternative versions of biologic drugs after patents expire is being considered by the Senate Health, Education, Labor and Pensions Committee. The core issue is the cost savings with generics versus the documented safety of brand biologics. Also at issue is whether generic versions of biologics can undergo an abbreviated approval process without first conducting clinical trials.

	More than 20 years ago, congress gave the FDA power to clear generic versions of conventional drugs, but did not address  costly medicines derived from living cells, such as Amgen’s Epogen®/Aranesp® and Johnson & Johnson’s Procrit®—all proprietary formulations of epoetin alfa.

	According to Jay Siegel, head of research for Johnson & Johnson’s biotechnology business, “You just can’t take a molecule that you don’t know what it is and market it to the people. It’s too risky.” Senators Hillary Clinton (D-NY) and Charles Schumer (D-NY)—sponsors of the bill&mdash;said their plan allows the FDA to decide how much testing is needed on a case-by-case basis. A similar measure has been introduced in the US House of Representatives by California Democrat Henry Waxman.

	Employers and insurers consider clearing a path for generic biologics as a means of reducing escalating health care costs. According to Sid Banwart, vice president for human services at Caterpillar, Inc., “This is our single the trend is simply not sustainable.”

	Supporters believe Congress should act soon on this issue. “This is an area that if we don’t address, everything else we do in healthcare is not going to be sufficient because we can’t keep up,” remarked Clinton.

	Republicans advocate a more cautions approach. “Any time we start legislating on complex scientific issues and don’t know all the facts, we risk endangering lives,” explained Senator Mike Enzi (R-WY), the committee’s ranking member.

                                                                                                                                                                                               — John D. Zoidis, MD

n February, two new bills were introduced in Congress with the goal of protecting quality cancer care. On February 15, Reps. Lois Capps (D-CA) and Tom Davis (R-VA) reintroduced the Comprehensive Cancer Care Improvement Act of 2007. The legislation aims to give physicians the resources they need to provide patients with quality cancer care. The bill would establish a new Medicare service for cancer planning from diagnosis through treatment to survivorship. It also includes provisions for the improvement of symptom management and palliative care. The proposed legislation is supported by the National Coalition for Cancer Survivorship, members of the patient advocacy community, and the American Society of Clinical Oncology.

	Reps. Carolyn McCarthy (D-NY), Gene Green (D-TX) and Joseph Pitts (R-PA) introduced another cancer care-related bill on February 28. The Access to Medicare Imaging Act of 2007 would delay additional cuts for Medicare imaging over the next two years. It would require the Centers for Medicare and Medicaid Services to stop additional cuts that went into effect at the start of 2007. Moreover, the proposed legislation calls for the Government Accountability Office to evaluate the impact of the cuts on patient access to care and quality services. The bill has 38 co-sponsors in the House and is expected to be introduced in the Senate soon.

CDC Panel Chair Says No to HPV Vaccine Mandate

on Abramson, the chair of the Centers for Disease Control and Prevention’s (CDC) advisory committee on immunization practices, said in late February that lawmakers should not make the human papillomavirus (HPV) vaccine mandatory. The CDC advisory committee had recommended that girls ages 11 and 12 receive the vaccine soon after the US Food and Drug Administration (FDA) approved Merck’s HPV vaccine Gardasil® for sale and marketing in July 2006.

	Merck’s Gardasil and GlaxoSmithKline’s Cervarix™ were shown in clinical trials to be effective against two strains of the sexually transmitted HPV that together lead to about 70% of cervical cancer cases. More than 20 states and Washington, DC are considering making the vaccine a requirement for girls and women. The issue has raised protests from many opposing fronts: parents who say the vaccine requirement would interfere with control over their children, groups that oppose legislative  vaccination requirements, and conservative religious groups that say it would encourage premarital sex. The cost of the vaccine—taken in a series of shots at $120 each&mdash;has also sparked criticism, although about 45% of children would be eligible for free vaccines under the federal Vaccinations for Children program, and a few states are considering offering the vaccine at no

	Abramson said that he opposes requiring the vaccine because HPV is not a contagious disease and he is not sure that states can afford to inoculate all students. He also said that he and other panel members told Merck not to lobby lawmakers to require the vaccine for school attendance. “The vaccines out there now are for very communicable diseases,” Abramson said. “A child in school is not at an increased risk for HPV like he is measles.”

	Merck, who had begun to lobby state legislatures last year, suspended its lobbying efforts early in February under pressure from parents, public health officials and patient advocacy groups.

This month's Fed Focus highlights such topics as Medicare reimbursement for cancer care and NCI budget cuts that affect cancer research.

Politics & Policy: April 2007

GSK’s Tykerb® Approved for Advanced Breast Cancer

Drug is Poised to Reposition the Company as a Major Player in the Oncology Business

resh offthe heels of winning US FDA approval on March 13 for their advanced breast cancer drug lapatinib (Tykerb®), GlaxoSmithKline (GSK) is concentrating on the start of a large-scale international phase III trial of lapatinib for the treatment of squamous cell carcinoma of the head and neck (SCCHN) based on results from a phase I study of lapatinib in SCCHN. The announcement came February 26 at the International Meeting on Innovative Approaches in Head & Neck Oncology in Barcelona, Spain, where GSK presented the results from its phase I study.

	The new phase III study of lapatinib, whose results are expected in 2008, will test the drug’s effectiveness in high-risk head and neck cancer patients who have had surgery and are being treated with chemotherapy and radiotherapy. The principle objective of the study is to assess the length of time without disease symptoms.

	GSK plans to enroll 680 patients in the US and the EU who are suffering from stages II, III and IVa of head and neck cancer and have undergone surgery. Within four to seven weeks after surgery, patients will receive either 1,500 mg of lapatinib or placebo tables once a day with radiotherapy and cisplatin for seven weeks. After this, the participants will continue with lapatinib or placebos for one year. The dosage is based on results of the phase I dose-escalation  study that GSK presented in Barcelona. In that study, 1,500 mg of lapatinib combined with oncedaily chemoradiation was found to be an optimal dose for 31 head and neck cancer patients—89% of the patients had a tumor response.

	The drug has already showed encouraging results in the treatment of metastatic HER2-positive breast cancer in women who have received prior therapy, leading to the FDA approval on March 13. The results of a phase III trial, published in late December 2006 in the 

, showed that the combination of lapatinib with capecitabine (Xeloda®, Roche)  was more effective than capecitabine alone in the treatment of HER2-positive advanced breast cancer. Specifically, in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab (Herceptin®, Genentech)—based therapy, lapatinib delayed the progression of breast cancer for nearly twice as long as did treatment with capecitabine alone. Prior to the published results, in September 2006, GSK had submitted marketing approval applications for lapatinib in combination with capecitabine for breast cancer treatment in the US, EU and Switzerland.

	Tykerb should enjoy several advantages over competitors, including its dual tyrosine kinase activity, oral formulation, convenient administration schedule, and favorable toxicity profile. Now approved, Tykerb represents a significant addition to GSK’s  oncology portfolio. The company noted that the drug — which will be available by the beginning of April at a cost of $2,900 a month – is the first targeted, once-daily oral compound approved for this patient population in the country, and analysts estimate Tykerb will bring in $258 million for GSK in the US by 2010 and $1.1 billion by 2015. Before Tykerb, the company marketed only three major cancer products, and overall sales have suffered following patent expirations on key products in other disease areas.

	“Having already shown such promise as a breast cancer treatment, we are very excited to continue investigating lapatinib in SCCHN,” said Paolo Paoletti, MD, senior vice president of the Oncology Medicine Development Center at GSK. “Lapatinib may represent a new treatment approach to difficult-to-treat tumor types, such as head and neck cancer, offering hope to patients in need of a further treatment option.”

	In addition to Tykerb, GSK has high hopes for pazopanib (a tyrosine kinase inhibitor and angiogenesis inhibitor), HuMax-CD20 (ofatumumab; a fully human, high-affinity antibody targeted at the CD20 molecule in the cell membrane of B-cells), and two supportive care products—casopitant (a neurokinin 1 [NK1] receptor antagonist) and eltrombopag (small-molecule  thrombopoietin receptor agonist). All could be approved between 2007 and 2010.

	GSK also has a therapeutic vaccine for lung cancer that is expected to begin final phase III trials this year, as well as several earlier-stage products. In a phase II, randomized, placebo-controlled trial, patients had tumors expressing a tumor-specific antigen known as MAGE-A3, which is present in approximately 35% to 50% of early non—small cell lung cancers. The researchers studied 182 patients who received either GSK’s new MAGE-A3 vaccine or placebo. Tolerance was excellent.

	“We have five drugs that could be approved in the next few years,” Paoletti said. “It’s unprecedented. The approval of Tykerb is just the beginning for us.”

With FDA approval for their advanced breast cancer drug Tykerbï¿½, GlaxoSmithKline is poised to reposition itself as a major player in the oncology business.

GSK%u2019s Tykerbï¿½ Approved for Advanced Breast Cancer

CDC Adopts Advisory Panel's HPV Vaccine Recommendation

he Centers for Disease Control and Prevention (CDC) has adopted the recommendations of its advisory committee on immunization practices (ACIP) for girls and women ages 11 through 26 years to routinely receive the human papillomavirus vaccine Gardasil. The ACIP vaccination guidelines were published in the CDC’s 

, which finalizes the advisory committee’s recommendations. The guidelines are available to physicians.

	Clinical trials have shown that Merck’s Gardasil is effective against HPV strains 16 and 18, which lead to about 70% of cervical cancer cases. In July 2006, the US Food and Drug Administration approved the vaccine for sale and marketing to girls and women ages 9 to 26 years. Later that month, the CDC’s advisory committee voted unanimously to recommend Gardasil for girls aged 11 and 12. The guidelines allow for girls as young as nine to receive the vaccine, and they also say that females aged 13 to 26 get vaccinated if they have not already done so or have not completed the full series.

	Even with the CDC’s recommendations, there is expected to be some resistance at the state level (see below in the State Focus).

Changes in Medicare Coverage of ESAs for Cancer-Related Anemia

ollowing the US Food and Drug Administration’s advisory on erythropoetic stimulating agents (ESAs), the Centers for Medicare and Medicaid Services (CMS) has issued an instruction to local Medicare carriers that would prohibit Medicare coverage of the agents—darbepoetin alfa and epoetin alfa&mdash;when used for the treatment of cancer-related anemia, according to the American Society of Clinical Oncology (ASCO). However, ESAs that are used to treat anemia resulting from chemotherapy would not be affected by this policy change.

	The CMS has not yet made public its instructions to local Medicare carriers. “ASCO was contacted by physicians who had  conversations with their Medicare carrier medical directors regarding the CMS directive,” Jenny Heumann, assistant director of public affairs at ASCO, told 

. “ASCO spoke with CMS about the directive; however, the publication details regarding the directive were not disclosed.”

	On March 9, the FDA issued a public health advisory and outlined new safety information for ESAs, including updated product labeling. The advisory was based on four new studies in cancer patients, which have found a higher chance of death or life-threatening side effects such as blood clots, strokes and heart attacks with the use of ESAs. The studies were analyzing off-label drug dosage, a patient population for which the agents are not approved, or a new unapproved ESA. But because all ESAs work in the same manner, the FDA believes that the concerns apply to the entire class of drugs and is now re-evaluating the safeuse of the class.

	The FDA’s warning issuance prompted the CMS to announce that it was reviewing all Medicare policies related to the  administration of ESAs. “We pay close attention to FDA black box warnings because the safety of our Medicare beneficiaries is paramount,” Leslie Norwalk, CMS acting administrator, said in that statement. “We will carefully examine the effect of these labeling changes on Medicare’s policies and we encourage treating physicians to review the warnings and to take them into account when prescribing ESAs for their patients.”

 went to press, not all Medicare Part B carriers had announced or implemented a change in their Medicare coverage policy, according to ASCO. By March 13, five Medicare Part B contractors that cover 24 states  announced policy changes for one or both drugs and one carrier had plans for a meeting to discuss policy changes.

hode Island’s health insurance commissioner Christopher Koller has unveiled new low-premium health plans to encourage small businesses to offer health coverage to workers. The plans will include coverage for physician visits, hospitalization, preventive services, and prescription drugs. One type of plan that the insurers will offer also carries good news for those seeking cancer screening.

	The plans will be offered by Blue Cross & Blue Shield of Rhode Island and United-Healthcare of New England. The two insurers will offer two types of plans, a basic plan and an advantage plan, both with the same premium payments. Advantage plan members will have lower deductibles, copayments and out-of-pocket expenses, but they will be required to participate in a wellness program—smoking cessation, weight loss or disease management&mdash;if necessary. The plans will cover annual physicals, mammograms and prostate cancer screenings without applying the deductible.

	Last year, the state passed a law stating that insurers must offer the plans to businesses with 50 or fewer employees beginning October 1. The law requires that the plans have premiums that are no higher than 10 percent of the average annual wages in the state; premiums have been higher in the past. Individual coverage premiums will average $322 a month for the Blue Cross plans, while the United Healthcare plans’ premiums will average $309 per month. These premiums are about 18%

	lower than similar plans that are currently available.

%u25BA THE HPV DEBATE HEATS UP AT THE STATE LEVEL

Virginia Governor: Drop Written Opt-Out Requirement in HPV Vaccine Bill

he Virginia General Assembly has voted in favor of Virginia Governor Tim Kaine’s amendment to a bill requiring sixth-grade girls to receive a human papillomavirus (HPV) vaccine that would make it unnecessary for parents to submit a letter to opt out of the vaccine requirement. Under the amendment, which Kaine proposed in late March, parents can verbally opt out of the vaccine requirement for their daughters.

	In his statement, Kaine had said that the purpose of the amendment is to “clarify that a girl’s parent or guardian has complete discretion to decide whether their child should be vaccinated.”

	The VA General Assembly approved the bill for the HPV vaccine in February, and earlier in March, Kaine had said that he would sign the legislation. The bill requires parents to be given information about the HPV vaccine, after which they were required to hand in a letter to their daughter’s school if they wanted to opt out. The amendment will make it easier for parents to state their choice.

	“While I believe that this vaccine shows great promise for preventing cancer, I believe that the decision to administer this vaccine should be made by parents,” Kaine said.

Georgia Bill Proposes Funding Roadblock for HPV Vaccine

eorgia member of Congress Rep. Phil Gingrey introduced a bill that would prohibit states from using federal funds to make the HPV vaccination mandatory for school-age children. The proposed legislation would not prohibit states from passing legislation to make the HPV vaccine mandatory. Rather, it aims to restrain states’ ability to use federal Medicaid or education funds to ensure that children from low-income families receive the vaccine.

	Since the FDA approved Gardasil, at least 23 states and Washington, D.C., have taken some kind of action on making the HPV vaccination mandatory for school-age girls. Texas legislators were the first in the US to require girls entering sixth grade to get vaccinated against HPV, while legislators in New Mexico and Virginia have approved similar bills.

	Rep. Gingrey, an obstetrician and gynecologist, is taking a different stand, saying that the vaccination should not be enforced by states, but should be taken voluntarily, because HPV is not a communicable disease like measles. “Whether or not girls get vaccinated against HPV is a decision for parents and physicians, not state governments," he told 

. His opinion reflects that of Jon Abramson, chairman of the Centers for Disease Control and Prevention’s advisory committee

	that issued the recommendation for school-age girls to take the vaccine.

	Rep. Gingrey plans to attach the bill as an amendment to the 2008 spending bill for the US Department of Health and Human Services. This increases the chances of the bill passing Congress because many appropriations bills include several legislative proposals that are hard for lawmakers to notice or block. By contrast, the chances of the bill passing as a stand-alone legislation would be slim.

	It is common for states to use federal money to help children receive vaccinations. Recently, the governor of Virginia has requested $4 million in state tax money to provide the vaccine to children from low-income families.

Texas Governor's Mandate of HPV Vaccine Does Not Carry Weight of Law, Says State AG

n a meeting with two Texas lawmakers, Texas Attorney General Greg Abbott said that Governor Rick Perry’s executive order mandating girls entering the sixth grade receive a HPV vaccine does not carry the weight of law, according to state Sen. Jane Nelson. A report in the 

 states Nelson as saying that she and Rep. Jim Keffer met with Abbott after they had requested the attorney general to issue an informal opinion on Perry’s order.

	In a joint statement, Sen. Nelson and Rep. Keffer said that “the attorney general met with both of us, and he answered  questions we had regarding the executive order. It appears that [the executive order] is, in effect, an advisory order and does not carry the weight of law.” It also appeared, they added, that the Health and Human Services commissioner is not required to follow Attorney General Perry’s executive order.

	Attorney General Perry’s office has said that Abbott did not meet with it to express his opinion. Meanwhile, Perry’s office is facing a lawsuit filed in a Travis County, Texas court by the parents of three Texas girls, challenging the governor’s authority to issue an executive order mandating the HPV vaccine for girls and women between ages nine and 21. Parents are allowed to opt out of the requirement.

overnor Bill Richardson said that he will veto a bill that would mandate the HPV vaccine for girls entering sixth grade. Last month, Richardson had said that he would sign the bill. The governor said that he changed his mind about the bill after physicians and patients voice their concerns. his concern is that there is insufficient time to educate parents, schools and health care providers about HPV and the vaccine. He signed a related bill that requires health insurance policies to cover HPV vaccinations for girls between the ages of nine and 14.

Washington, D.C. City Council Approves HPV Bill

he City Council has voted 7 - 3 to preliminarily approve a bill that would require girls entering the sixth grade to receive an HPV vaccine. The council adopted an amendment to the bill that would provide a parent education program. Council Member Marion Barry had proposed the amendment. Washington, D.C. Mayor Adrian Fenty has already given the measure an inital endorsement. Even though the measure will face a second and final vote in the upcoming weeks, the preliminary vote indicates that the bill will most likely pass, according to a report in 

This month's Fed Focus highlights the CDC's HPV vaccine recommendations as well as changes in Medicare coverage of ESAs for cancer-related anemia. Our reports from 

Politics & Policy: May 2007

laxoSmithKline’s (GSK) experimental cervical cancer vaccine Cervarix has proven 100% effective in preventing precancerous lesions due to cancer-causing human papillomavirus (HPV) strains 16 and 18 for up to five and a half years. The results, based on an extended follow-up trial and presented at the American Association for Cancer Research, demonstrate the longest duration of protection seen in any cervical cancer vaccine trial until now, according to GSK.

	The results could be a turning point in UK-based GSK’s race to get Cervarix to patients and it should now be a matter of time before the company will face its American competitor Merck in the market. Merck’s Gardasil is the first cervical cancer vaccine marketed internationally since the FDA approved it in June 2006. GSK, on the other hand, applied for FDA approval on March 30 and is expecting approval in Europe in the first half of 2007.

	HPV infection is the most common sexually transmitted infection in the US Some HPV strains cause genital warts, which do not pose a major health risk, but others can cause cervical lesions that can turn cancerous. Strains 16 and 18 are known to cause 70 percent of all cervical cancer cases.

	The study proved that Cervarix prevents precancerous lesions and showed that the vaccine induced a strong immune response in nearly 100% of women in the study, which was maintained over 5.5 years for both virus types 16 and 18. The vaccine also showed 68% efficacy against all precancerous lesions, regardless of the type of cancer-causing virus detected.

	Gardasil, in comparison, has proved effective for five years, and Merck says that it also prevent genital warts and other dangerous HPV strains. Because Gardasil has been in clinical trials longer, Merck has been able to show a greater reduction in precancerous lesions, a condition that the FDA is thought to consider required for approval, according to 

	Merck has the advantage of being first to market, and most market analysts foresee Merck’s sales leading GSK’s. But others say that Merck’s head start will not bring the company a huge advantage over GSK because the market is large enough for two big players. Indeed, analysts predict that the cervical cancer vaccine market could be worth more than $3 billion by 2008, according to 

. In just half a year of marketing and approval in 54 countries, Merck has showed sales of $235 million in 2006 for Gardasil, according to the Motley Fool.

	Max Herrmann, an ING analyst, has predicted that Cervarix will gain 40% of the market for cervical cancer vaccines and generate sales of $2.2 billion by 2011, according to Reuters London. Herrmann expects Cervarix to win European approval in the second half of 2007 and US approval in the first quarter of 2008, the Reuters report says.

	Glaxo’s positive results for Cervarix are based on an extended follow-up analysis of women who had participated in an initial efficacy study for the vaccine. Of the 1,113 women who took part in that initial study, this extended follow-up study looked at endpoints for 776 women for a period of up to 67 months. The women, between 15 and 25 years of age, were randomized to receive three doses of either Cervarix or placebo. Glaxo is now funding a head-to-head comparison to prove that Cervarix is more powerful than Gardasil.

	In spite of the tremendous market potential and the vaccine’s health benefits, GSK will face the same hurdles that Merck is facing now. One is fierce social backlash from conservative groups and vaccine skeptics for marketing a vaccine against a sexually transmitted disease. The other is a hesitance to adopt the vaccine because of its high cost. At $360 for a three-shot regimen, Gardasil is considered an expensive vaccine; and while GSK has not specified the cost for Cervarix, it is planning to match Merck’s price. The vaccine’s price tag will put a strain on the already tight budgets of federal and state programs that provide vaccines for little or no cost to children of low-income families. On the private side, most insurers cover Gardasil, but some have limited their reimbursements and administrative expenses.

How the Cervical Cancer Vaccines Match Up

GlaxoSmithKline%u2019s experimental cervical cancer vaccine Cervarix has proven 100% effective in preventing precancerous lesions due to cancer-causing human papillomavirus (HPV) strains 16 and 18 for up to five and a half years.

GSK%u2019s Cervical Cancer Vaccine Closer to Entering Market

	Two studies have shown a link between hormone replacement therapy (HRT) and women’s cancers. One study, an extended analysis of data from the National Cancer Institute’s cancer registries, reinforces a strong association between the use of HRT and increased breast cancer incidence. Researchers at The University of Texas M.D. Anderson Cancer Center in Houston, TX, reported these resultsin the 

. Another study, funded by Cancer Research UK and published online in 

, shows that women whotake HRT are more likely to be diagnosed with ovarian cancer and to die of the disease.

	The M.D. Anderson researchers studied breast cancer rates from 2002 to 2004 using the NCI’s Surveillance, Epidemiology and End Results registries. They found that breast cancer incidence dropped by 6.7% in 2003 and stayed at the same level in 2004. The investigators speculate that thesharp decrease in the use of postmenopausal HRT, which followed the results of the Women’s Health Initiative in mid-2002, correlates with the fall in new breast cancer diagnoses through 2003. The decrease was mainly found in women older than 50, and was seen mostly in estrogen receptor-positive cancer. ER-positive cancers fell by 14.7% , while there was a 1.7% decrease in ER-negative cancers.

	The researchers looked at several other factors that could be responsible for the decrease in breast cancer. They looked for flaws in the data itself, changes in reproductive factors, changes in mammogram screening rates, changes in environmental exposures, changes in diet, and change sin the use of HRT. Only the use of HRT changed substantially, with 47 million prescriptionsin 2002 but about half as many in 2003.

	The study does not suggest that decreasing HRT use would lower breast cancer incidence, the researchers caution. As a result, women should not stop their use of HRT, Peter Ravdin, MD, PhD, professor in the Biostatistics department at M.D. Anderson who led thestudy told 

. Dr. Ravdin tells his patients that they should use the drug at the lowest dose and for theshortest time period to control hot flashes and other menopausal symptoms. “I think that current guidelines are reasonable,” said Dr. Ravdin. “Basically these guidelines say that, for difficulties with menopause, women may benefit from HRT but that there are risks associated with use and that to minimize these risks women should not take HRT uncritically for long periods.”

	Further, the researchers said that their study cannot answer three key questions: whether stopping the use of HRT leads to a permanent or a temporary decline in breast cancer incidence; if this effect is seen with all types of HRT; and how much of a contributing role other factors may have played in the decline. “This is just another small piece of the puzzle to help women gauge the risks and benefits of using HRT,” Dr. Ravdinsaid.

 paper, which shows a link between HRT and ovarian cancer, is based on results from the Million Women study, a UK national study of women’s health, involving around one million women aged 50 and over. The results show that there is one extra case of ovarian cancer in every 2,500 women who take HRT, and that there will be one additional death from ovarian cancer for every 3,300 women who take HRT. The researchers at Oxford University’s epidemiology unit who conducted the study estimated that use of HRT since 1991 has led to an additional 1,300 cases and 1,000 deaths from ovarian cancer.

Two separate studies show the relationship between hormone replacement therapy and women's cancers.

HRT Linked with Breast and Ovarian Cancers

Study Examines Impact of Sedentary Work On Prostate Cancer Risk

According to a new study from the University of California, Los Angeles’s (UCLA’s) Jonsson Comprehensive Cancer Center, the health hazards of a desk job may go beyond loss of fitness and carpal-tunnel syndrome. Findings presented by the researchers, published in a recent issue of 

, suggest that men with desk jobs may be more likely to develop prostate cancer than those who are physically active each day at work.

Investigators examined the medical and job histories of more than 2,100 men at a nuclear and rocket engine testing facility in California’s San Fernando Valley. According to the data compiled by the study team, men who got little exercise at work, such as managers, analysts, and engineers, were more likely to have prostate cancer than people like masons, welders, and janitors who engaged in active physical labor.

The study compared 362 men who were diagnosed with prostate cancer from January 1988 and December 1999 with 1,805 men of similar ages and backgrounds who were cancer free. All worked at Rocketdyne Propulsion & Power, which Boeing Co. sold to United Technologies Corp. in 2005 for $700 million. The facility, located north of Los Angeles, has been used to test rockets since 1948. Employees were exposed to radiation and other chemicals that may boost their risk of prostate cancer, the researchers said.

The case-control study nested within a larger cohort of more than 10,000 male subjects who worked at the nuclear and rocket-engine testing site from the 1950s to the early 1990s. The cases of prostate cancer were diagnosed between January 1988 and December 1999. Researchers obtained cancer incidence data for the workers from the California Cancer Registry and seven other cancer registries in neighboring states where workers may have moved after retirement.

Data from Rocketdyne company records was used to construct a job exposure matrix that ranked job descriptions by the amount of physical activity required and any harmful exposures the workers might have experienced.

Physical activity was separated into jobs with low, moderate and high amounts of exertion. Men with low-activity jobs were typically managers, supervisors, analysts, administrators, and senior engineers. Those with moderately active jobs included senior mechanics and technicians, inspectors, and engineers. Masons and bricklayers, metal fitters, welders, packers, painters, tool and die makers, truck drivers, lift operators, and janitors were considered highly active.

The study found that the men who developed prostate cancer were less likely to have held the more physically active jobs. In addition to the association made by researchers between prostate cancer risk and the performance of physically inactive work, study findings also indicated that men who got cancer had more contact with and exposure to chemicals such as hydrazine, benzene, trichloroethylene, and polycyclic aromatic hydrocarbons. They also were more often black and more likely to have a family history of the disease and get tested regularly.

The findings support previous studies, which have asserted that regular physical exertion is needed to keep prostate cancer at bay. It remains unclear as to exactly how exercise combats the disease, the most common cancer in men, though some experts hypothesize that activity influences hormone levels to reduce the risk.

“The message from this study for today is that if you’re more active, you may be able to prevent this cancer from happening,’’ said Beate Ritz, MD, PhD, senior author of the paper and an Associate Professor of Epidemiology at the UCLA School of Public Health. “If you have a desk job, do something physically active to counterbalance it,” advised Dr. Ritz.

According to researchers, a strength of the study was that personnel records, job description manuals, industrial hygiene reviews, and interviews with retired workers were employed to develop the job exposure matrix, avoiding problems with subject recall and interviewer bias. Researchers were also able to obtain cancer incidence data and did not have to rely on mortality data. Prostate cancer is largely non-fatal, so mortality rates would not have been good data to analyze, Dr. Ritz said.

The study was limited in that researchers were not able to account for other potential factors that might affect prostate cancer risk, such as recreational physical activity and diet, said Anusha Krishnadasan, PhD, epidemiologist at Olive View—UCLA Education and Research Institute and first author of the study.

“All we can say for sure is that aerospace workers that were highly active on a regular basis for many years while working at Rocketdyne were at a decreased risk of prostate cancer,” summed up Dr. Krishnadasan.

Designer Gene Functions Differently in Different People

Researchers at Harvard Medical School, Boston, have discovered that, depending on a given person’s genetic make-up, a gene known as STAT3 can play completely different roles in glioblastoma. Investigators nicknamed STAT3 the “Jekyll and Hyde” gene because of the wide-ranging way it acts.

According to previous research, STAT3 is an oncogene—a gene whose normal functions are disrupted and, as a result, helps promote tumor development&mdash;in several types of glioblastoma. In such cases, blocking STAT3 would be a way of fighting these tumors.

However, in this new study presented by a Harvard Medical School team and published in a recent on-line edition of 

, findings indicated that STAT3 is actually a tumor-suppressor gene in other types of glioblastoma, meaning that the gene keeps renegade cancer cells in check.

“In other words,” wrote Azad Bonni, PhD, MD, Associate Professor of Pathology, Harvard Medical School, in a prepared media statement, “the same gene in the same cancer can play a completely different role from one person to the next, depending on genetic nuances between individuals.”

“This discovery,” continued Dr. Bonni, “lays the foundation for a more tailored therapeutic intervention. And that’s really important. You can’t just go blindly treating people by inhibiting STAT3." Dr. Bonni, a neurologist and neuroscientist by training, decided to investigate the genetic etiology of glioblastoma by studying whether certain regulatory genes that control the generation of astrocytes during normal development also play a role in these tumors. Nearly all brain cancers occur in a class of brain cells called astrocytes (or in the neural stem cells that generate astrocytes) which function as support cells, involved with functions such as providing nutrients to nerve tissue and repairing scars.

Dr. Bonni explained, “The logic here is simple: since disease is often the breakdown of a normal biological process, the more we understand how cells get it right, the more we understand what can go wrong. And since STAT3 is a key gene that turns neural stem cells into astrocytes during normal development, what is its role in glioblastoma?”

Dr. Bonni and colleagues, in collaboration with investigators in the laboratory of Ronald DePinho at the Dana-Farber Cancer Institute, Boston, began by genetically manipulating mouse astrocytes, then placing them into a second group of mice whose immune systems had been compromised. The findings surprised them.

Taking advantage of previously published data, the researchers looked closely at how two genes, EGFR and PTEN—whose mutated forms are associated with glioblastoma&mdash;affect the function of STAT3 in astrocytes. Dr. Bonni’s group found when EGFR is mutated, STAT3 is an oncogene; with a PTEN mutation, STAT3 is a tumor suppressor.

“EGFR, in its normal state, is a transmembrane receptor, usually performing its functions at the cell surface,” explained Dr. Bonni, “However, when it’s mutated, we find it in the cell’s nucleus interacting with STAT3—and turning it into an oncogene. STAT3 itself is not mutated or damaged. It’s the process of regulating STAT3 that gets damaged.”

“With PTEN, it’s a completely different story,” reported Dr. Bonni, “PTEN is itself a tumor suppressor gene. When PTEN becomes disabled in astrocytes, these potential tumors still have STAT3 standing in their way. This is because STAT3 acts as a tumor suppressor normally in astrocytes. However, as more PTEN becomes disabled, a cascade of molecular events is set in motion with the express purpose of inhibiting STAT3 function and thus turning the tide in the cells toward tumor formation.”

The researchers confirmed these findings in human glioblastoma tumors as well.

“The belief that STAT3 can only be an oncogene has been a pretty entrenched dogma in the field,” says Dr. Bonni, “so we performed many, many experiments to make sure this was correct. It took some very persistent investigators in my lab to get the job done. As a result, we’re convinced of our data.”

While glioblastoma tends to be uncommon, STAT3 has also been implicated in prostate and breast cancers, so these results may translate to other types of tumors as well.

Glioblastoma tends to strike people in the prime of life and is almost always fatal. There are limited treatment options, which have changed little over decades. The finding may help improve treatment of people with the deadly disease.

New Haven, Connecticut—based Yale School of Medicine researchers have announced the development of a blood test that they claim is refined enough to detect early-stage ovarian cancer at a 99% accuracy rate.

The new platform uses six protein biomarkers instead of four, building on the results of the same Yale research team’s effors in 2005 by increasing the specificity of the test from its previous accuracy level of 95% to its currrent reliability factor of 99.4%, reported leading investigator and study author Gil Mor, MD, PhD, Associate Professor of Obstetrics, Gynecology and Reproductive Sciences.

“This is the most sensitive and specific test currently available,” Dr. Mor said in a statement. “Previous tests recognized 15% to 20% of new tumors. Proteins from the tumors were the only biomarkers used to test for ovarian cancer. That is okay when you have big masses of tumors, but it is not applicable in very early phases of the tumor. Testing the proteins produced by the body in response to the presence of the tumor as well as the proteins the tumors produce, helped us to create a unique picture that can detect early ovarian cancer.”

Evidence of the test’s efficacy was established by a phase II clinical trial led by Dr. Mor which included 500 patients—350 healthy controls and 150 patients with ovarian cancer. Dr. Mor and colleagues validated the previous research, which showed 95% effectiveness, and used a new platform called multiplex technology to simplify the test into one single reaction using very small amounts of serum from the blood. The new platform uses six protein biomarkers. The team looked for the presence of those specific proteins and quantified the concentration of those proteins in the blood.

The Early Detection Research Network (EDRN) of the National Cancer Institute (NCI) Bethesda, Maryland, independently evaluated the results of the test.

The findings were published in a recent issue of the journal 

Dr. Mor said that epithelial ovarian cancer is the leading cause of gynecologic cancer deaths in the United States, and is three times more lethal than breast cancer, but is often not diagnosed until its advanced stages.

“The ability to recognize almost 100% of new tumors will have a major impact on the high death rates of this cancer,” said Dr. Mor. “We hope this test will become the standard of care for women having routine examinations.”

Dr. Mor and colleagues have begun a phase III evaluation in a multicenter clinical trial. In collaboration with EDRN/NCI and Laboratories Corporation of America (LabCorp), they are testing close to 2,000 patients.

The Academy delivers the latest news on biotech
and oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing the envelope of knowledge and discovery. In this issue: 
Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Harvard Medical School, Boston; Dana-Farber Cancer Institute, Boston; Yale School of Medicine, New Haven; and Robert Wood Johnson Medical School,Piscataway, NJ.

By Prachi Patel-Predd

Articles

The Industry Insider: April 2007

Politics & Policy: April 2007

GSK%u2019s Tykerbï¿½ Approved for Advanced Breast Cancer

Politics & Policy: May 2007

GSK%u2019s Cervical Cancer Vaccine Closer to Entering Market

HRT Linked with Breast and Ovarian Cancers

The Academy: June 16, 2010