Cephalon Drug Gets Conditional OK
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Posted by Reuters on October 21, 2003 at 07:52:12:
Tuesday October 21, 7:26 am ET WASHINGTON (Reuters) - Cephalon Inc. (NasdaqNM:CEPH - News) said on Tuesday it received notice that U.S. regulators will approve wider marketing of Provigil, a drug that combats sleepiness, once certain conditions are met. The Food and Drug Administration said Provigil is "approvable" for treating excessive sleepiness due to shift work or obstructive sleep apnea, a disorder that causes severe snoring, according to a statement from Cephalon. The company said it remained on track to launch Provigil for the new uses in the first quarter of 2004. The drug is currently approved for treating narcolepsy, a rare condition that causes uncontrollable sleeping during waking hours. "We expect precise labeling language to be decided by year end, which keeps us on track to launch the new indications to a broader group of physicians with our expanded sales force early next year," Paul Blake, Cephalon's senior vice president of clinical research and regulatory affairs, said in a statement. Cephalon had sought the FDA's permission to promote Provigil even more widely to people with other causes of excessive sleepiness, including jet lag. Last month, an advisory panel split 4-4 on whether to recommend that use. Known generically as modafinil, Provigil targets a part of the brain that controls sleep and waking, but researchers do not know exactly how it works. Second-quarter sales of Provigil rose 40 percent to $69.5 million, the company said in August. In Cephalon's studies, Provigil helped people stay alert with only mild to moderate side effects such as headaches and was gentler than caffeine, which can make people jittery.  Summary Cephalon has developed and launched modafinil (Provigil), an alpha 1 adrenoceptor agonist under license from Lafon, for narcolepsy and idiopathic hypersomnia. It was first launched by Lafon in France in 1994 [173305]. A development and marketing agreement has been made with Nippon Shoji in Japan [289372], while marketing agreements have also been made with Dompe for Italy [290270] and Draxis for Canada [182331]. In addition, Cephalon is also developing modafinil for the potential treatment of sleep apnea [323039], fatigue associated with various neurological disorders, attention deficit hyperactivity disorder (ADHD), depression and circadian rhythm disorder [414510], [353372], [343435], [388926]. By March 2002, the drug was in phase II as an adjunct to antidepressant therapy, and for relief of symptoms associated with Alzheimer's and Parkinson's diseases [443544]. In November 2002, it was reported that Cephalon planned to initiate phase III trials for ADHD at the beginning of the 2003/2004 school year [470078]. In May 2003, Cephalon expected to start phase III studies in children with ADHD later in 2003 [490345]. ATTENTION DEFICIT HYPERACTIVITY DISORDER
In September 2002, Cephalon disclosed results from a multicenter study in 248 children aged between 6 and 13. In the 4-week, randomized, double-blind, placebo-controlled, parallel design study, children and adolescents with ADHD were assigned to one of four dose regimens of modafinil daily or placebo. All of the modafinil-treated groups showed a reduction in symptoms of ADHD. The greatest significance was achieved in the group assigned to 300 mg of modafinil once daily. The drug was generally well tolerated and side effects were consistent with those described in the product label. At this time, the complete study data were expected to be presented at a medical meeting in 2003 [463944]. In May 2003, the data were presented at the 156th annual meeting of the American Psychiatric Association, in San Francisco, CA [490345], [492385]. In November 2002, clinical data on modafinil were presented at the 32nd Neuroscience meeting in Orlando, FL. The randomized, double-blind trial involved 60 healthy young adult male volunteers who received either a single oral dose of placebo, 100 mg or 200 mg modafinil. Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop signal reaction time accompanied by a slowing in latency on a delayed matching to sample task, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects described were independent of dose, except for the effects seen with the Stop-Signal paradigm. In contrast to methylphenidate, there were no significant effects of drug on a paired associates learning task, spatial memory span task, spatial working memory and strategy task, rapid visual information processing or attentional set-shifting task [468812]. In July 2000, the results of a 113-patient, double-blind, placebo-controlled trial, designed to compare the safety and efficacy of 100 mg and 400 mg doses of modafinil Tablets [C-IV] to a placebo, showed that modafinil had no benefit in reducing the symptoms of ADHD compared to placebo therapy although the drug was generally well tolerated. The company had planned to pursue label expansion of modafinil in the areas of excessive sleepiness and fatigue [377139], but had not made a decision to discontinue the development for ADHD. Cephalon confirmed that other studies were underway for ADHD as of August 2000 [377827]. In May 2000, results of a phase I study describing the effects of modafinil as a treatment for ADHD were presented at the 153rd Annual Meeting of the American Psychiatric Association. Modafinil was compared to dextroamphetamine and placebo in 22 adults with ADHD. A dose of 200 mg per day modafinil produced a significant reduction in the symptoms of ADHD, similar to that seen with 20 mg dextroamphetamine [367201]. Results of a 6-week, 180-patient, phase II trial of modafinil in ADHD were expected by early August 2000 [376026]. At this time, Cephalon was conducting studies with modafinil in adults with ADHD at seven academic centers in the US. In addition, the company had initiated a pharmacokinetic study and intended to initiate a dose-ranging study in children by the middle of 2000, as a prelude to a phase III study in children with ADHD [367201]. SLEEP DISORDERS In December 2002, Cephalon received marketing approval in the UK to expand the label of modafinil to treat excessive daytime sleepiness in patients with obstructive sleep apnea/hypopnea syndrome [474476]. In November 2000, Cephalon revealed its intention to submit a comprehensive sNDA for modafinil for the treatment of excessive sleepiness due to a variety of medical conditions, including circadian rhythm disorder. The first filing was expected at the end of 2001 [388926]. Cephalon received an approvable letter from the FDA in December 1997, for the treatment of excessive daytime sleepiness associated with narcolepsy [273272]. In December 1998, Cephalon received clearance from the US FDA for the marketing of modafinil tablets for this indication [310277]. It was launched in the US in February 1999 [311628], [315289]. The NDA had been submitted in December 1996 [229644]. In February 1999, Cephalon launched modafinil in the Republic of Ireland for the treatment of narcolepsy [313210]. In May 1999, modafinil was launched in Austria as Provigil [325806]. It was launched as Provigil in Italy in June 2000 [370010]. By November 2002, Cephalon had completed a trial in 209 patients with shift work sleep disorder, which showed that modafinil improved wakefulness and clinical condition. At this time, the company intended to file a sNDA by the end of 2002 [468343]. In December 2002 a sNDA requesting marketing approval was filed with the FDA, with results of this expected in late 2003 [498297]. In November 2001, Cephalon published in the American Journal of Respiratory and Critical Care Medicine data on an investigational randomized, double-blind, placebo-controlled, parallel group study, in which 157 patients were treated with nasal continuous positive airway pressure (nCPAP) plus placebo or nCPAP plus modafinil tablets for 4 weeks. With a score of 15 or greater on the Epworth Sleepiness Scale (ESS), 45% patients were classified as severely sleepy. Those receiving modafinil and nCPAP achieved greater improvements in wakefulness; 51% achieved a normalized ESS score of less than 10, compared to 27% of patients receiving nCPAP and placebo. Patients administered modafinil plus nCPAP also showed a significant reduction in their tendency to fall asleep, as measured by the multiple sleep latency test (MSLT). In this study, nCPAP use did not differ between the two treatment groups. Adverse events reported were predominantly mild-to-moderate [427906]. Draxis filed an NDA in Canada in August 1997. In September 1997, the Canadian HPB requested additional data pertaining to the manufacturing of modafinil. Full data were filed in November 1997 [264669], [274529], [276373]. The Canadian HPB approved modafinil (as Alertec) in March 1999 for the treatment of excessive daytime sleepiness in patients with narcolepsy [316800]. The product was launched in June 1999 [326650]. By August 1996, Cephalon had filed a registration application with the CPMP [215899]. Modafinil was launched in the UK in March 1998, and is the first non-amphetamine treatment for narcolepsy to be available in the UK [280010]. Cephalon has completed two US phase III trials for the treatment of hypersomnia with narcolepsy. Results from the second phase III trial of modafinil demonstrated that it had a significant benefit in increasing patient's ability to stay awake as measured by the maintenance of wakefulness test (MWT), and in improving patient's overall condition as measured by the clinical global impression of change (CGI-C), the 2 primary endpoints of the study. The double-blind, placebo-controlled study of 273 patients with narcolepsy was conducted at 21 medical centers in the US [274529]. Patients were randomized to receive qd doses of placebo, 200 mg or 400 mg of modafinil for 9 weeks, followed by a 2 week observation period. The treated patients stayed awake approximately 50% longer than patients who received placebo. A total of 60% of patients who received 400 mg modafinil and 57% of those who received 200 mg modafinil demonstrated improvement on the CGI-C scale compared to 37% of patients who received placebo. Modafinil was well tolerated at both doses. The most frequent adverse effects reported in both studies were mild, transient headache and dry mouth [274529]. Results from a Canadian phase III trial in 75 patients, given 200 mg or 400 mg daily over six weeks, showed that the drug significantly increased mean sleep latency, with the 200 mg and 400 mg doses, 40% and 54%, respectively, better than the placebo [207120]. Modafinil received US Orphan Drug status in March 1993 for narcolepsy [188929]. Modafinil acts via receptors in the brain that are thought to be associated with narcolepsy. The drug has no effect on night time sleep but significantly reduces the number of daytime sleep episodes [182331]. SLEEP APNEA
The indication is part of the company's strategy to expand the market beyond the narcolepsy population that it is currently approved for. By March 2002, modafinil was in phase III for sleepiness due to obstructive sleep apnea [443544]. In March 2000, the results of a 4-week, double-blind, placebo-controlled study of 157 patients showed that modafinil produced significant improvements in daytime sleepiness. In those that received modafinil, 40/50 reported improvements whereas only 21/61 placebo recipients experienced similar results. Adverse side effects included headache, nervousness, runny nose, nausea, anxiety and dizziness [359790]. Based upon the positive findings Cephalon has initiated an additional clinical trial in sleep apnea patients, with the intention of pursuing a label extension to include this indication [354404]. In April 1999, Cephalon initiated clinical studies in the US and UK of modafinil tablets in sleep apnea patients with excessive daytime sleepiness [323039]. In October 1999, modafinil was in phase II studies for sleep apnea in adults [343435]. FATIGUE ASSOCIATED WITH PD, MS, AD, ADHD AND CHEMOTHERAPY
In June 2003, clinical data on modafinil were presented at the 13th ENS meeting in Istanbul, Turkey. Patients with MS (n = 115) and a mean score of greater than 45 in the modified fatigue impact scale, were recruited in the 5-week multicenter, controlled study. Modafinil was administered daily (200 mg), which could be increased to 400 mg, by increments of 100 mg per week during the first 3 weeks. No differences were identified between active drug and placebo. A further open study conducted in 13 patients, (modafinil 200 to 400 mg) displayed a decrease in the fatigue scale after 1 month of treatment. However, 10 out of 13 patients discontinued the drug in the extension phase of the study due to side effects [498167]. Cephalon is also planning to conduct pilot studies to evaluate the efficacy of modafinil in reducing daytime sleepiness associated with Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis (MS), although it will not pursue FDA approval for all the indications. Two MS studies are being conducted at Ohio State University [313305]. In addition the company intends to examine the drug's effects in patients with ADHD [353372]; a study of ADHD in children is expected to begin in mid-2000. In October 1999, modafinil was in phase II studies for fatigue in MS and ADHD in adults [343435]. A phase II study of modafinil in patients with chemotherapy-related fatigue had been expected later in 2000. By March 2002, modafinil was in phase III for sleepiness due to MS fatigue [443544]. At the May 2000 Annual Meeting of the American Academy of Neurology, results of a 9-week trial evaluating modafinil involving 72 patients with severe fatigue and MS were reported. The patients received a placebo during the first two weeks and again during the final three weeks of the study. During weeks three and four, each patient received 200 mg of modafinil; during weeks five and six, the dosage was increased to 400 mg daily. After each phase of treatment, the patients were asked to evaluate their level of fatigue and sleepiness. Overall, patients reported significantly less fatigue when they took the 200 mg dose compared to the placebo. However, when patients took the 400 mg dose, some of them experienced side effects [364921]. Data presented at the 1999 Society for Neuroscience meeting from studies of fatigue associated with PD indicate that modafinil-induced CNS activation is independent of intact dopaminergic systems [344282].
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