News Reports: June 2007

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â–º Supplemental Drug Application Submitted for Postoperative Nausea and Vomiting MGI Pharma and Helsinn announce submission for Aloxi® injection for use in postoperative nausea and vomiting

MGI Pharma Inc., a biopharmaceutical company focused in oncology and acute care, and its partner Helsinn Healthcare SA, a privately owned Swiss pharmaceutical group, have announced that a supplemental New Drug Application (sNDA) for Aloxi® (palo¬nosetron hydrochloride) Injection for the prevention of postoperative nausea and vomiting has been submitted to the U.S. Food and Drug Administration (FDA).

Aloxi is a selective serotonin subtype 3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor. 5-HT3 receptors are located on the nerve terminals of the vagus nerve in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferent nerves to initiate the vomiting reflex. Currently, Aloxi is indicated for: (1) the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy; and (2) the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

According to Lonnie Moulder, President and Chief Executive Officer of MGI Pharma, “Postoperative nausea and vomiting affects approximately one-third of patients who undergo surgery, and can lead to increased health care costs resulting from delayed discharge from hospitals or ambulatory surgical centers, and hospital re-admissions. Studies have demonstrated an ongoing need for effective long-term agents that can improve the control of both nausea and vomiting post-surgery. The unique pharmacodynamic profile and extended duration of activity of Aloxi may prevent postoperative nausea and vomiting for up to three days with a single dose. We believe this submission is an important step in maximizing the potential of Aloxi.”

The sNDA submission is based on favorable results from two multicenter, randomized, placebo-controlled, Phase III trials conducted to evaluate the safety and efficacy of three doses of Aloxi. In these trials, a total of 1,219 patients undergoing elective outpatient abdominal or gynecological laparoscopic surgery (Study PALO-04-06) or elective inpatient gynecological or breast surgery (Study PALO-04-07) were randomized to receive one of three single intravenous doses of Aloxi or placebo prior to administration of anesthesia. Both clinical trials successfully met the primary efficacy endpoint of complete response, defined as no emesis or use of rescue medication, for the 24-hour time period following surgery, for the selected dose of 0.075 mg. In addition, both trials achieved the secondary endpoints of complete response for the 48- and 72-hour postoperative time periods.

Postoperative nausea and vomiting occurs commonly and affects more than one-third of patients undergoing ambulatory and in-patient surgical procedures. In the United States approximately 30 million doses of 5-HT3 receptor antagonists are used annually for the management of postoperative nausea and vomiting. The primary factors that can increase the risk for postoperative nausea and vomiting include female gender, non-smoking status, prior history of postoperative nausea and vomiting or motion sickness, length of surgery, and use of volatile anesthetics and opioids. If not prevented, postoperative nausea and vomiting may result in delayed discharge, hospital re-admission, and increased healthcare costs.

— John D. Zoidis, MD

â–º Medicare Proposes Limits on Coverage for Erythropoiesis-Stimulating DrugsMedicare has proposed limiting coverage for the erythropoiesis-stimulating agents Epogen® (epoetin alfa, Amgen), Aranesp® (darbepoetin alfa, Amgen), and Procrit® (epoetin alfa, Johnson & Johnson)—drugs that accounted for more than $10 billion in sales last year—amid renewed concerns over safety, including thrombosis, cardiovascular events, tumor progression, and reduced survival. The erythropoiesis-stimulating drugs have been under scrutiny in recent months after studies showed mixed results when used in cancer patients not receiving chemotherapy.

The Centers for Medicare and Medicaid Services (CMS) said in a statement that the drugs were “not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the erythropoiesis-stimulating agents on their underlying disease, or because the underlying disease increases their risk of adverse effects related to erythropoiesis-stimulating agent use.”

“We pay close attention to U.S. Food and Drug Administration (FDA) black-box warnings because the safety of our Medicare beneficiaries is paramount,” stated CMS Acting Administrator Leslie Norwalk. “We have carefully examined the evidence surrounding these labeling changes and have issued this proposed decision to protect our beneficiaries.”

Medicare spends more on the anemia medications, which are taken by more than 1 million people each year, than on any other drug. The agency started its review after the FDA added a “black-box warning” to the drugs in March, advising doctors to prescribe them at their lowest possible doses and only to approved patients.

The FDA approved the drugs more than a decade ago for the treatment of anemia caused by chemotherapy in an array of cancer patients and for patients with kidney failure. However, physicians have prescribed the drugs for a wide variety of other patients, including those not on chemotherapy, and in greater dosages than those recommended by the FDA. In its proposal to limit coverage, Medicare said it would no longer pay for cancer patients’ use of the drugs if their anemia wasn’t related to chemotherapy or if the drugs were prescribed to prevent chemotherapy-related anemia.

CMS said it would accept public com¬ments until June 13 before making a final decision on the coverage proposal, which is posted at www.cms.hhs.gov/mcd/view-draftdecisionmemo.asp?id=203.

The possibility of Medicare cuts for the anemia drugs is a potential watershed event, possibly opening the door to significant downstream private-payer pressure. The ramifications on earnings for Amgen and Johnson & Johnson are even more likely. If the cuts are actually made, it is hoped that appropriate use of the erythropoiesis-stimulating agents in the cancer setting would not be diminished.

— John D. Zoidis, MD

â–º Femara Reducses Risk of Early Breast Cancer Relapse in Postmenopausal Women Study shows a reduction in the risk of cancer spreading to the lungs, the brain, or the bones

A new analysis of the aromatase inhibitor Femara® (letrozole) shows that the drug reduces the risk of early breast cancer spreading to distant parts of the body such as the lungs, the brain, or the bones in postmenopausal women. Such distant metastases make it extremely likely that a patient will succumb to the disease.

Femara, made by Switzerland-based Novartis, is the only aromatase inhibitor to be approved in the U.S. for adjuvant therapy, extended adjuvant therapy, and advanced breast cancer.

Annals of Oncology

The new analysis reveals that after two years of post-surgical therapy, postmenopausal women with hormone-sensitive early breast cancer who are treated with Femara experienced 30% fewer early breast cancer recurrences at distant sites compared to women who were treated with tamoxifen. They study was published in the May issue of .

In the retrospective analysis, researchers at independent cancer research centers around the world looked at data from more than 7,700 women who were treated in the BIG 1-98 trial. The trial was conducted by the International Breast Cancer Study Group to do a head-to-head comparison of Femara and tamoxifen, and was supported by Novartis. The researchers found that at a median follow-up of two years, approximately three-quarters of early cancer recurrences occurred at distant sites such as bones of vital organs. However, they found that there were 30% fewer distant metastases in the Femara group as compared to the tamoxifen group. Femara also showed a significant reduction in the recurrence risk at the same breast, the other breast, and the lymph nodes.

The results showed that patients with the highest risk of early recurrence had tumors larger than five centimeters, four or more positive nodes, positive estrogen receptor status but negative progesterone status, grade three tumors, and invasive disease. Notably, women with node positive disease, who are considered to be at a higher risk of recurrence, maintained a lower risk of relapse when treated with upfront Femara than with tamoxifen.

“These results provide the tip of the iceberg and for the bigger picture,” said Hugh O’Dowd, Business Unit Director at Novartis Oncology UK. “Physicians will be eagerly awaiting the results of the BIG 1-98 sequencing arms, which hope to indicate the optimal strategy for using Femara post surgery and are due to be ready for 2008.”

— Prachi Patel-Predd

â–º Researchers Develop Pancreatic Cancer Risk Model

Will help physicians with early screening decisions

Inherited genes lead to about 10% of aggressive and highly fatal cases of pancreatic cancer. But with a new software model, people with a family history of pancreatic cancer have a way to accurately predict their chance of inheriting a gene for the disease and their lifetime risk of developing the disease. The model, developed by researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, MD, is designed to help genetic counselors and physicians decide who would benefit most from early screening.

Oncology & Biotech News

Pancreatic cancer strikes more than 37,000 people in the U.S. every year, and it kills about the same number. The disease is often not detected before it has metastasized and the prognosis is dismal, with the five-year survival rate at less than 5%. “Therefore, the only way to fight this disease is through early detection, and individuals at high-risk due to their family history represent a group that will benefit from early detection,” Alison Klein, PhD, assistant professor at Johns Hopkins who led the new model’s development told .

The risk calculator tool, called PancPRO, is very similar to the ones Johns Hopkins researchers have developed to predict familial breast and colon cancer risk, which should make it easy for physicians familiar with those models to use the new one, Dr. Klein said. “It is quite easy to compute risk,” she said. “A physician would need to obtain information on the current age or age at death and pancreatic cancer status for each relative of the patient being counseled. This information is then entered into user-friendly software.” The software evaluates a percentage probability score that a person carries a pancreatic cancer gene and also calculates an individual’s risk of developing the disease in his or her lifetime. Researchers have not yet identified specific genes that cause pancreatic cancer, but they can estimate high disease risk based on clusters of family members who have a history of the disease.

Dr. Klein and her colleagues tested the software by feeding in family history data given by more than 6,000 individuals in 961 families who were in the Hopkins pancreatic cancer registry. The researchers divided the registrants into groups representing the number of pancreatic cancer patients in each family. Then they compared their model’s predictions with actual disease occurrences in the families up to 100 years later. They found that PancPRO accurately estimates risk 75% of the time. By contrast, current methods for calculating the disease risk are accurate 61% of the time.

PancPRO is available on the web at http://www8.utsouthwestern.edu/utsw/cda/dept47829/files/65844.html.

— Prachi Patel-Predd

â–º Beyond BCG: New Bladder Cancer Treatments Offer Hope of Tailored, More Effective Therapies Identifying the expression of certain proteins by bladder tumors may point the way to more targeted therapies beyond the traditional “gold standard” of care

Leading cancer centers such as Memorial Sloan-Kettering in New York are participating in a number of investigational trials with the goal of creating more “tailored” bladder cancer treatments, from identifying high-risk patients by certain genetic markers in tumors to combining chemotherapy drugs that are already successful in treating other types of cancers.

The traditional course of treatment of superficial bladder cancer (tumors which have not invaded the muscle surrounding the bladder) has been surgical removal and periodic monitoring. Patients deemed to be at higher risk of recurrence are also often given Bacillus Calmette-Guerin (BCG) therapy following tumor removal. BCG, inactivated tuberculosis bacteria, is introduced directly into the bladder to produce an inflammatory response which hinders the reurn of tumors in many, but not all, bladder cancer patients.

Newer, genetically-based courses of treatment currently being investigated include identifying those patients most at risk for recurrence by the presence of a certain protein, p53, which monitors DNA changes in cells. Higher p53 levels can indicate the presence of a more aggressive form of bladder cancer and warrant early removal of the bladder. Another genetically based therapy being investigated at Memorial Sloan Kettering includes the study of retinoblastoma genes and those that affect programmed cell death, including bax,bcl-2, and mdm-2. Disturbances in the function of these genes may be markers for aggressive forms of bladder cancer or help locate sites where the cancer is at risk for metastising.

Other treatments that have shown early promise include a new proprietary mycobacterial cell wall-DNA complex (MCC) trademarked under the name Urocidin by Belleville, Ontario-based Bioniche. Early data, according to the company, show MCC’s mechanism of action kills non-invasive bladder cancer cells directly while helping to stimulate the body’s own immune system response. Urocidin was granted fast-track status by the FDA. Clinical trials comparing the efficacy of Urocidin as a first-line therapy in non-invasive bladder cancer to traditional BCG therapy are expected to commence at Memorial Sloan Kettering and other cancer centers within the next few months.

Oncologists are also looking at drugs currently used in the treatment of other types of cancer for potential use in bladder cancer patients. One Phase II trial is looking at whether the addition of bevacizumab, a drug currently used to treat advanced colon cancer, can boost the effectiveness of gemcitabine and carboplatin, a combination chemotherapy treatment used in the treatment of advanced bladder cancer by interrupting tumor angiogenesis. And an oral chemotherapeuticl drug currently used to treat kidney cancer, Sunitinib (sutent A) is being studied for its effectivness against metastatic bladder cancer.

Word of the new therapies was welcome news to attendees at a recent bladder sup¬port group for patients and their caregivers held at Memorial Sloan-Kettering’s Sidney Kimmel Center for Prostate and Urologic Cancers, many of whom wondered aloud why standard bladder cancer treatments hadn’t progressed beyond BCG for some time compared to the advances in the treatment of other cancers. Bladder cancer is diagnosed in 38,000 men and 15,000 women in the U.S. each year, according to the National Cancer Institute, and is the fourth most common cancer in men and the eighth most common in women. Risk factors are hard to pin down, although the cancer rarely occurs in people under 40 years old and seems more prevalent in smokers.

— Diane West

â–º Doctor’s Own Brush With Bladder Cancer Gives Him Uniqe Insight to Patients’ Challenges Geriatrician’s experience heightens his awareness of he quality-of-life issues patients face during bladder cancer treatment

Like many proud parents in this time of year, Dr. Monte Peterson talks proudly about the upcoming graduation of his son from New York’s Syracuse University. “He started off in journalism,” the tall, soft-spoken doctor says, “but decided to go into graphic design instead.” Another son is at John Hopkins University studying chemistry. “They couldn’t be more different,” he smiles, “and my wife and I are very proud of both of them.”

Dr. Peterson, a devoted geriatrician at St. Vincent’s Hospital in New York, says he has always had an affinity for older people. “I grew up on a farm in Iowa in a town predominately made up of people of Swedish decent, and I can tell you Swedes are among the longest-living people in the world,” he says. “My parents were around 40 years old when I was born, and I was very close to my maternal grandmother, so I became very interested in geriatric care and primary care of older adults at a young age.”

Because of the age of the patients he sees—many are in their mid 80’s and 90’s—Dr. Peterson has been involved in the care plan of bladder cancer several times. But he never thought he would one day be sharing the same battle.

He says it started with the usual signs earlier this year—frequent and painful urination—which the doctor initially chalked up to prostatitis, not an unusual occurrence for a man of his age. “I wasn’t thinking it was bladder cancer,” he says, “because I’m only 54 and I’ve never smoked. It’s much more common in older people, so it wasn’t a diagnosis at the top of my list.” Nonetheless, Dr. Peterson trusted his colleagues judgment as he underwent more and more diagnostic tests.

“That was the first thing I took away from the experience,” he says. “I’m definitely more sensitive to how difficult it is to wait for the results of tests, no matter what they are.”

Unfortunately, in Dr. Peterson’s case, the tests ultimately proved positive for bladder cancer.

Acknowledging the old adage that doctors can be some of the 'worst’ patients, Dr. Peterson decided not to involve his colleagues in the continuance of his care, a decision he says they ‘graciously’ understood. Instead, he went to Dr. Harry Herr at Memorial Sloan-Kettering Cancer Center. There, it was determined his best course of treatment would be having the transurethral resection of the bladder tumor (TURBT) followed by a course of BCG treatment. After his TURBT, Dr. Peterson was sent home with a Foley catheter overnight.

“I have to tell you, it was pretty uncomfortable,” he says, “so now I know what that’s like. Especially standing up—I was seeing stars. I made it through the night, but I took it out myself the next morning after checking with staff from the hospital.” Dr. Peterson says the pain and discomfort of the catheter was among the strongest experiences he gained. While he had always urged his interns and residents to avoid inserting catheters in elderly patients if there were any alternative, he urges them to do so even more.

He also said he tells patients to take it easy when recovering from procedures. “I tried to go back to work the day after my first rigid cystoscopy and learned that my need to go to the bathroom every 15 to 20 minutes wasn’t going to let me make it on the subway, let alone be conducive to seeing patients,” he says.

Like any other patient, Dr. Peterson said he read everything he could about his condition as well as some inspirational reading to keep him positive. It’s been two weeks since he finished his last BCG treatment, and so far, so good.

“Sometimes I forget I have bladder cancer,” he says, “so I’m cautiously optimistic. But you’re never home free. Once it’s out, you’re still never safe against it returning, and that one of the most frustrating things. And the initial symptoms can be so subtle.” Yet the rate of bladder cancer is increasing, and Dr. Peterson is encouraged by the public’s growing awareness of the disease. The Bladder Cancer Advocacy Network (www.bcan.org), for example, has become very active.

As for himself, the upbeat, piano-playing athletic doctor has decided to take his own challenge one day at a time, one diagnosis at a time. While more than satisfied with the quality of care he himself is receiving, he offers some insight to oncologists.

“My main advice,” he says, “would be to imagine themselves on the other side of the desk.”

— Diane West