New drug Fentora

Cephalon Receives FDA Approval of FENTORA(TM) (fentanyl buccal tablet) for the Management of Breakthrough Pain in Patients with Cancer

Cephalon, Inc. (Nasdaq: CEPH) announced today that it has received approval from the U.S. Food and Drug Administration (FDA) to market FENTORA(TM) (fentanyl buccal tablet) [C-II] for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. FENTORA is the first and only buccal tablet approved for this indication and is the second new product to be marketed by Cephalon this year. Cephalon expects FENTORA to be available in the United States during the first week of October 2006.

"The approval of FENTORA not only allows us to extend our leadership position in the pain management arena, but also to provide a medication that is better designed to meet the needs of cancer patients with breakthrough pain," said Frank Baldino, Jr., Ph.D., Chairman and CEO. "Our longer-term clinical strategy is focused on developing FENTORA for patients with breakthrough pain associated with other conditions, including neuropathic pain and back pain."

Robert P. Roche, Jr., Executive Vice President, Worldwide Pharmaceutical Operations, added, "We are very excited to be providing clinicians and their patients with cancer with this innovative new treatment for breakthrough pain. With our recognized expertise in this area developed over many years, our dedicated pain sales force, and established relationships in the pain marketplace, we are well positioned for a successful launch of FENTORA."

Breakthrough pain is a common component of chronic pain characterized by its rapid onset, intensity, and relatively short duration. An estimated 800,000 cancer patients will experience breakthrough pain this year, based on data reported by the American Cancer Society.

"Research on breakthrough pain conducted over the past 15 years suggested that we needed to look beyond conventional short-acting opioids and evaluate new medications that could better manage the rapid onset of this often debilitating condition," said Russell Portenoy, MD, Chairman, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, in New York City, and a principal investigator in the FENTORA clinical trials. "The clinical trials of FENTORA confirm that it is safe and effective for cancer-related breakthrough pain, and may relieve pain faster than orally ingested opioids."

Conventional short-acting oral opioids, often used to treat breakthrough pain, are swallowed and absorbed in the gastrointestinal tract, which can take up to 30-45 minutes to take effect. With FENTORA's drug delivery technology, approximately half of the medicine is absorbed directly across the lining of the upper cheek, the buccal mucosa, and into the bloodstream more quickly than if it were swallowed and broken down by the liver in the gastrointestinal tract.

In placebo-controlled clinical trials, patients treated with FENTORA showed a statistically significant improvement on the primary end point, the Sum of Pain Intensity Differences (SPID30) (p<0.01)>

Cephalon will manufacture FENTORA in five dosage strengths: 100, 200, 400, 600, and 800 micrograms (mcg). FENTORA will be packaged in cartons containing twenty-eight tablets (seven child-resistant blister cards with four tablets in each card).

FENTORA

FENTORA is the first tablet formulation of the opioid fentanyl and the first new medication approved for the management of breakthrough pain in opioid-tolerant patients with cancer since 1998. Its proprietary OraVescent(R) drug delivery system was developed by Cephalon subsidiary CIMA LABS. FENTORA is covered by patents until 2019.

The sugar-free FENTORA tablet is placed between the upper cheek and gum above a rear molar tooth. When it comes into contact with saliva, FENTORA's delivery system generates a reaction leading to the release of carbon dioxide. It is believed that transient pH changes accompanying this reaction may optimize how well the tablet dissolves and how quickly the medicine passes across the buccal mucosa.

In clinical trials, FENTORA was generally well tolerated. Most adverse events occurring with FENTORA are typical opioid side effects. The most serious adverse events associated with all opioids are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. All patients should be followed for symptoms of respiratory depression. Opioid side effects should be expected and managed accordingly. The most common (greater than or equal to 10%) adverse events observed in clinical trials of FENTORA were nausea, vomiting, application site abnormalities, fatigue, anemia, dizziness, constipation, edema, asthenia, dehydration, and headache. Most side effects were mild to moderate in severity. No attempt was made to correct for concomitant use of around-the-clock opioids or cancer-related symptoms.

Breakthrough Pain

Approximately 50 million Americans suffer from chronic pain, a condition that often consists of two distinct components: persistent pain, which is pain that is continuous throughout the day, and breakthrough pain, which is a transitory flare of moderate-to-severe pain in patients with otherwise stable persistent pain. Breakthrough pain can reach peak intensity in as little as three minutes and typically lasts for 30 to 60 minutes. It may occur during a specific activity, spontaneously with no apparent cause, or when the dose of the persistent pain medicine wears off. An estimated 64 percent of all cancer patients treated for persistent pain -- and up to 74 percent of patients treated for persistent pain from other conditions such as low back pain, diabetic neuropathy, and osteoarthritis -- will experience breakthrough pain. Breakthrough pain can have a profound impact on an individual's physical and psychological well-being and is often associated with a more severe and difficult to treat pain condition. It can increase the economic burden on both patients and the healthcare system.

IMPORTANT WARNINGS AND SAFETY INFORMATION

FENTORA contains fentanyl, an opioid agonist and a Schedule II-controlled substance, with an abuse liability similar to other opioid analgesics. FENTORA can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing FENTORA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

FENTORA is indicated for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine/day, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Because life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients, FENTORA is contraindicated in the management of acute or postoperative pain. This product is not indicated for use in opioid non-tolerant patients.

Patients and their caregivers must be instructed that FENTORA contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep all tablets out of the reach of children. (See Information for Patients and Their Caregivers contained within the prescribing information for disposal instructions.)

Due to the higher bioavailability of fentanyl in FENTORA, when converting patients from other oral fentanyl products, including oral transmucosal fentanyl citrate (OTFC and Actiq(R)), to FENTORA, do not substitute FENTORA on a mcg-per-mcg basis and adjust doses as appropriate. (See DOSAGE AND ADMINISTRATION contained within the prescribing information.)

FENTORA is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.

Full prescribing information about FENTORA, including boxed warning, is available from http://www.FENTORA.com or Cephalon Professional Services and Medical Information (1-800-896-5855)

http://www.cephalon.com or by calling 1-800-896-5855.

In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Cephalon's current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs; development of potential pharmaceutical products, including any future indications for FENTORA; interpretation of clinical results, including the results of the clinical trials of FENTORA; prospects for regulatory approval; market prospects for its products, including the timing of the availability of FENTORA and the ability of the company to successfully launch this product; sales and earnings guidance; and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as "anticipate," "estimate," "expect," "project," "intend," "plan," "believe" or other words and terms of similar meaning. Cephalon's performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, regulatory and political conditions affecting the biotechnology and pharmaceutical industries as well as more specific risks and uncertainties facing Cephalon such as those set forth in its reports on Form 8-K, 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Cephalon does not intend to update publicly any forward-looking statement, except as required by law. The Private Securities Litigation Reform Act of 1995 permits this discussion.

SOURCE Cephalon, Inc.

Lenalidomide and DVd

Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy.

Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, Reed J, Faiman B, Ellis Y, Brand C, Srkalovic G, Andresen S, Knight R, Zeldis J, Hussein MA.

Cleveland Clinic Cancer Center Myeloma Research Program, Cleveland Clinic, Cleveland.

BACKGROUND: Lenalidomide is active and well tolerated in relapsed and refractory multiple myeloma. We conducted a phase I/II trial of the combination of lenalidomide and chemotherapy to evaluate the safety and efficacy of the combination. METHODS: The 62 patients enrolled received liposomal doxorubicin 40 mg/m(2) i.v. and vincristine 2 mg i.v. on day 1, dexamethasone 40 mg p.o. on days 1-4 (DVd), and lenalidomide on days 1-21 in 28-day cycles. Primary end points were maximum tolerated dose (MTD) of lenalidomide with DVd chemotherapy and overall response rate (ORR) by Southwest Oncology Group criteria of the combination. Findings: The median age was 62 years, 70% of patients were males and 65% had refractory multiple myeloma. The MTD of lenalidomide with DVd chemotherapy was 10 mg and the dose-limiting toxicity was non-neutropenic sepsis. After 7.5 months of median follow-up, the ORR of the combination was 75%, with 29% of patients achieving a complete or near complete remission. The median progression-free survival was 12 months, while the median overall survival has not yet been reached. Interpretation: The combination of lenalidomide and DVd chemotherapy was well tolerated and resulted in high response rates in this mostly refractory patient population. Evaluation of this combination in newly diagnosed patients is warranted.

PMID: 16980599 [PubMed - as supplied by publisher]

Thalidomide use in Multiple Myeloma

Long-term results of thalidomide in refractory and relapsed multiple myeloma with emphasis on response duration.

Cibeira MT, Rosinol L, Ramiro L, Esteve J, Torrebadell M, Blade J.

Hematology Department, Institute of Hematology and Oncology, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Villarroel, Barcelona, Spain.

Objective: Thalidomide administered as a single agent produces a response rate of about 40% in patients with refractory or relapsed multiple myeloma (MM). The aim of our study was to determine the quality and duration of such responses. Patients and methods: Forty-two consecutive patients with refractory (20) or relapsed (22) MM were given thalidomide as a single agent at our institution. Most of them (70%) had previously received two or more lines of therapy, and 38% had undergone autologous stem cell transplantation. Results: Eighteen patients (43%) responded to thalidomide [11 minimal responses (MR) and seven partial responses (PR)] according to the European Marrow Transplant Registry (EBMT) criteria. The median time to response was 3 months and the median duration of therapy in responding patients was 9 months. Treatment was discontinued because of toxicity in 10 responding patients. The toxicity mainly led to peripheral neuropathy and fatigue. At the time of this analysis, all responding patients had progressed except one who remains in continued stable PR. The median time to progression was 15.6 months (range 1.3 to 70+), with a trend towards a longer duration for patients who achieved PR vs. MR (21.2 vs. 11.2 months, P = 0.11). The median duration of response was 12.4 months (range: 0.3-67+) (17.2 months for PR vs. 9.7 months for MR, P = 0.11). Conclusion: These results show that the effect of thalidomide in refractory/relapsed MM can be sustained, particularly in patients who achieve a greater degree of response, and support the finding that this drug can be used for maintenance therapy.

PMID: 16978238 [PubMed - as supplied by publisher]

Regular analgesic use and risk of multiple myeloma

Department of Epidemiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, United States; Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY, United States.

Analgesic use has been implicated in the chemoprevention of a number of solid tumors, but to date no previous research has focused on the role of analgesics in the etiology of multiple myeloma (MM). We conducted a hospital-based case-control study of 117 patients with primary, incident MM and 483 age and residence matched controls without benign or malignant neoplasms. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY, and completed a comprehensive epidemiological questionnaire. Participants who reported analgesic use at least once a week for at least 6 months were classified as regular users; individuals who did not use analgesics regularly served as the reference group throughout the analyses. We used unconditional logistic regression analyses to compute crude and adjusted odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Compared to non-users, regular aspirin users were not at reduced risk of MM (adjusted OR=0.99; 95% CI 0.65-1.49), nor were participants with the highest frequency or duration of aspirin use. A significant risk elevation was found for participants who were regular acetaminophen users (adjusted OR=2.95; 95% CI 1.72-5.08). Further, marked increases in risk of MM were noted with both greater frequency (>7 tablets weekly; adjusted OR=4.36; 95% CI 1.70-11.2) and greater duration (>10 years; adjusted OR=3.26; 95% CI 1.52-7.02) of acetaminophen use. We observed no evidence of a chemoprotective effect of aspirin on MM risk, but observed significant risk elevations with various measures of acetaminophen use. Our results warrant further investigation in population-based case-control and cohort studies and should be interpreted with caution in light of the limited sample size and biases inherent in hospital-based studies.

PMID: 16962170 [PubMed - as supplied by publisher]

Long-term results focusing on the effect of the degree of response on survival and relapse pattern after transplantation

Nordic Myeloma Study Group.

Department of Hematology, University Hospital, S-221 85 Lund, Sweden. Stig.Lenhoff@skane.se

BACKGROUND AND OBJECTIVES: From 1994 to 1997 we conducted a population-based, prospective study on intensive therapy in newly diagnosed symptomatic myeloma patients younger than 60 years, comparing their survival to that of a conventionally treated historic population. Long-term results are presented, including the impact of the degree of response on survival and relapse pattern after transplantation.
DESIGN AND METHODS: The prospective population was formed of 397 patients and the historic population of 313 patients. Both populations were calculated to comprise more than 75% of the expected number of new cases.
RESULTS: After a median follow-up of 7 years survival was longer in the prospective population than in the historic one (median 60 versus 39 months; p=0.0002). When comparing only patients eligible for intensive therapy the median survival was 63 versus 44 months (p<0.0001). Attaining a complete response was associated with prolonged event-free survival but not overall survival. The pattern of relapse after transplantation was heterogeneous but could be divided into four major groups; insidious, classical, plasmacytoma form and transformed disease. The median survival after relapse was 29 months. The relapse pattern and time to relapse predicted outcome. Patients relapsing with an insidious or classical form of disease with skeletal events only, or after a long lasting first response were likely to respond well to conventional salvage therapy. In contrast, relapse with multiple symptoms, transformed disease or a short duration of first response implied bad prognosis.
INTERPRETATION AND CONCLUSIONS: The relapse pattern after autologous transplantation is heterogeneous and response to salvage therapy is variable. The degree of response and event-free survival after transplantation are not reliable surrogate markers for survival.

PMID: 16956822 [PubMed - in process]

New multiple myeloma diagnostic method created

A Spanish researcher has proposed a genetic diagnostic method for multiple myeloma that permits earlier detection of the bone marrow cancer.

Borja Saez of the University of Navarra studied the genetic basis of the cancer, and the posterior development of cytogenetic diagnostic strategies for the detection of alterations with prognostic value.

Saez statistically analyzed cytogenetic changes in a group of multiple myeloma patients to determine associations between specific chromosomal changes and thus the description of a new classification of the disease.

In addition, the technique of hybridization in situ with fluorescence allowed him to identify new recurrent genetic changes that are involved in the appearance of this pathology.

Multiple myeloma is a disease which primarily affects people older than 60 years. According to Saez, the new method of diagnosis will enable detection of genetic alterations rapidly during the early stages of the disease, permitting its early diagnosis.

Idiotype-specific immunotherapy in multiple myeloma

Bogen B, Ruffini PA, Corthay A, Fredriksen AB, Froyland M, Lundin K, Rosjo E, Thompson K, Massaia M.

Institute of Immunology, University of Oslo, Rikshospitalet University Hospital N-0027 Oslo, Norway. bjarne.bogen@labmed.uio.no

Multiple myeloma (MM) remains a difficult-to-cure cancer and less than 20% of patients achieve long-term survival irrespective of the treatment delivered, including high-dose chemotherapy. Thus, new treatment modalities are urgently needed. Myeloma cells produce a monoclonal immunoglobulin (Ig) which is a truly tumor-specific antigen. The tumor-specific antigenic determinants are localized in the variable regions of the monoclonal Ig and are termed idiotopes (Id). Id-vaccination, i.e., vaccination with the autologous monoclonal Ig, has been performed in MM patients in order to elicit tumor-specific immune responses and possibly elimination of myeloma cells. However, clinical trials have not given the promising results obtained in mice. This review focuses on tolerance mechanisms that might hinder Id-specific immune responses in MM patients. New strategies for Id vaccination in MM are discussed.

Balloon Kyphoplasty Study

Two-Year Data Demonstrate Significant and Sustained Improvements in Back Function, Back Pain and Quality of Life

Kyphon Inc. announced today that results from the first multicenter long-term, prospective clinical study evaluating the benefits of balloon kyphoplasty treatment of osteoporotic spinal fractures were published in the September 1, 2006 issue of Spine. This latest study in the growing body of evidence for balloon kyphoplasty showed that patients experienced rapid and sustained improvement in back pain, back function and quality of life for two years post-procedure.