FDA Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development.

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.

Therapeutic innovation in Parkinson's disease: a 2020 update on disease-modifying approaches.

INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting more than 10 million patients worldwide. Despite increasing improvements in disease management, a huge medical need still exists as its relentless progression cannot be delayed by current treatments. Therefore, scientists, clinicians, and pharmaceutical companies are hunting new drugs with 'disease-modifying' properties. AREAS COVERED: This review concentrates on new therapeutics - excluding cell and gene therapies - under investigation for PD with 'disease-modifying' potential. This is a global, comprehensive picture of the current innovative drug pipeline, where the main preclinical and clinical data available are provided. Drug candidates presented include α-synuclein modulating agents, neuroprotective agents and neuroinflammation modulators, kinase modulators, neurotrophic factors, and drugs acting on emerging targets. EXPERT OPINION: There is excitement for agents with 'disease-modifying' properties and the authors found more than 130 assets, not including cell and gene therapies under investigation - most of them still in preclinical development - meaning that the science is progressing multiple, diverse new opportunities. Many limitations hamper the successful development of these drug candidates such as the translational accuracy of preclinical models, the current clinical development paradigm as well as the lack of biomarkers to be used in diagnosis and therapy management.

Safinamide's potential in treating nondystrophic myotonias: Inhibition of skeletal muscle voltage-gated sodium channels and skeletal muscle hyperexcitability in vitro and in vivo.

The antiarrhythmic sodium-channel blocker mexiletine is used to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or suboptimal response. Safinamide is an add-on therapy to levodopa for Parkinson's disease. In addition to MAOB inhibition, safinamide inhibits neuronal sodium channels, conferring anticonvulsant activity in models of epilepsy. Here, we investigated the effects of safinamide on skeletal muscle hNav1.4 sodium channels and in models of myotonia, in-vitro and in-vivo. Using patch-clamp, we showed that safinamide reversibly inhibited sodium currents in HEK293T cells transfected with hNav1.4. At the holding potential (hp) of -120 mV, the half-maximum inhibitory concentrations (IC50) were 160 and 33 µM at stimulation frequencies of 0.1 and 10 Hz, respectively. The calculated affinity constants of safinamide were dependent on channel state: 420 µM for closed channels and 9 µM for fast-inactivated channels. The p.F1586C mutation in hNav1.4 greatly impaired safinamide inhibition, suggesting that the drug binds to the local anesthetic receptor site in the channel pore. In a condition mimicking myotonia, i.e. hp. of -90 mV and 50-Hz stimulation, safinamide inhibited INa with an IC50 of 6 µM, being two-fold more potent than mexiletine. Using the two-intracellular microelectrodes current-clamp method, action potential firing was recorded in vitro in rat skeletal muscle fibers in presence of the chloride channel blocker, 9-anthracene carboxylic acid (9-AC), to increase excitability. Safinamide counteracted muscle fiber hyperexcitability with an IC50 of 13 µM. In vivo, oral safinamide was tested in the rat model of myotonia. In this model, intraperitoneal injection of 9-AC greatly increased the time of righting reflex (TRR) due to development of muscle stiffness. Safinamide counteracted 9-AC induced TRR increase with an ED50 of 1.2 mg/kg, which is 7 times lower than that previously determined for mexiletine. In conclusion, safinamide is a potent voltage and frequency dependent blocker of skeletal muscle sodium channels. Accordingly, the drug was able to counteract abnormal muscle hyperexcitability induced by 9-AC, both in vitro and in vivo. Thus, this study suggests that safinamide may have potential in treating myotonia and warrants further preclinical and human studies to fully evaluate this possibility.

Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease.

OBJECTIVE: The aim of the study was to evaluate electrophysiological effects of safinamide on the intrinsic and synaptic properties of striatal spiny projection neurons (SPNs) and to characterize the possible therapeutic antiparkinsonian effect of this drug in dopamine (DA) denervated rats before and during levodopa (l-DOPA) treatment. BACKGROUND: Current therapeutic options in Parkinson's disease (PD) are primarily DA replacement strategies that usually cause progressive motor fluctuations and l-DOPA-induced dyskinesia (LIDs) as a consequence of SPNs glutamate-induced hyperactivity. As a reversible and use-dependent inhibitor of voltage-gated sodium channels, safinamide reduces the release of glutamate and possibly optimize the effect of l-DOPA therapy in PD. METHODS: Electrophysiological effects of safinamide (1-100 µM) were investigated by patch-clamp recordings in striatal slices of naïve, 6-hydroxydopamine (6-OHDA)-lesioned DA-denervated rats and DA-denervated animals chronically treated with l-DOPA. LIDs were assessed in vivo with and without chronic safinamide treatment and measured by scoring the l-DOPA-induced abnormal involuntary movements (AIMs). Motor deficit was evaluated with the stepping test. RESULTS: Safinamide reduced the SPNs firing rate and glutamatergic synaptic transmission in all groups, showing a dose-dependent effect with half maximal inhibitory concentration (IC50) values in the therapeutic range (3-5 µM). Chronic co-administration of safinamide plus l-DOPA in DA-denervated animals favored the recovery of corticostriatal long-term synaptic potentiation (LTP) and depotentiation of excitatory synaptic transmission also reducing motor deficits before the onset of LIDs. CONCLUSIONS: Safinamide, at a clinically relevant dose, optimizes the effect of l-DOPA therapy in experimental PD reducing SPNs excitability and modulating synaptic transmission. Co-administration of safinamide and l-DOPA ameliorates motor deficits.

Safinamide inhibits in vivo glutamate release in a rat model of Parkinson's disease.

To investigate whether the reversible MAO-B inhibitor and sodium channel blocker safinamide impairs glutamate release under parkinsonian conditions in vivo, and this effect is dependent on MAO-B inhibition, safinamide (and rasagiline as a comparator) were administered to 6-hydroxydopamine hemilesioned rats, a model of Parkinson's disease, and haloperidol-treated rats, a model of neuroleptic-induced parkinsonism. A microdialysis probe was implanted in the dopamine-depleted dorsolateral striatum, globus pallidus, subthalamic nucleus or substantia nigra reticulata of 6-hydroxydopamine hemilesioned rats. Glutamate and GABA release was stimulated by reverse dialysis of veratridine, and safinamide or rasagiline were acutely administered before veratridine at doses inhibiting MAO-B >50%. A microdialysis probe was implanted in the substantia nigra reticulata of naïve rats to monitor glutamate and GABA release following acute haloperidol and safinamide administration. Safinamide inhibited the veratridine-evoked glutamate release in the globus pallidus and subthalamic nucleus but not in the striatum and substantia nigra. Moreover, it reduced pallidal and nigral GABA release. Conversely, rasagiline failed to modify the veratridine-induced glutamate and GABA release in the basal ganglia. Safinamide also inhibited the haloperidol-induced nigral glutamate release. MAO-B inhibitors safinamide and rasagiline differ in their abilities to inhibit depolarization-evoked glutamate release in the basal ganglia of parkinsonian rats. The ineffectiveness of rasagiline suggests that MAO-B inhibition does not contribute to the antiglutamatergic activity of safinamide. The glutamate-inhibiting action of safinamide within the subthalamo-external pallidal loop, which shows abnormal activity in Parkinson's disease, might contribute to its therapeutic actions of improving motor performance without provoking troublesome dyskinesia.

Long-Term Effects of Safinamide on Mood Fluctuations in Parkinson's Disease.

BACKGROUND: Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. OBJECTIVE: To investigate the effects of safinamide on mood over two-year treatment in PD patients with motor fluctuations. METHODS: This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. RESULTS: Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). CONCLUSION: The favorable effect of safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.

Metabotropic glutamate receptor 5: a target for migraine therapy.

INTRODUCTION: Many patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine-specific target, the mGlu5 receptor. METHODS: We studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double-blind placebo-controlled, parallel group, clinical trial. RESULTS: The negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose-dependent manner, comparable to naratriptan, while the N-methyl-d-aspartate receptor blocker MK-801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment-emergent event at 48%. INTERPRETATION: Our findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.

A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.

BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease: a dose-finding study.

In advanced stages of Parkinson's disease, serotonergic terminals take up L-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of L-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks L-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against L-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of L-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with L-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of L-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to L-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias.

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model.

BACKGROUND: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model. METHODS: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). RESULTS: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy. CONCLUSION: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.

Rapid responders to frovatriptan in acute migraine treatment: results from a long-term, open-label study.

BACKGROUND: The chronic nature of migraine and the reliance on acute treatment constitute the basis of the present long-term, open-label study. OBJECTIVES: First, assessment of the tolerability and safety of frovatriptan, 2.5-7.5 mg taken orally over 24 hours, for the acute treatment of migraine, repeatedly over a 12-month period. Second, assessment of the efficacy and tolerability of a second, double-blind dose of 2.5-mg frovatriptan, compared with placebo, for nonresponse at 2 hours after treatment of moderate or severe headache with 2.5-mg frovatriptan. RESULTS: With regard to the first attack treated, 173 (36%) of the 486 subjects in the study did not take a second dose at 2 hours for nonresponse. At 2 hours and 4 hours, these "rapid responders" experienced a decrease in headache intensity from moderate or severe to mild or no pain in 84% and 98%, respectively ("headache response"). Six percent of them experienced recurrence of moderate or severe headache within 24 hours following a response at 4 hours and 12% took rescue medication. The response, measured in terms of median time to "complete migraine relief," was maintained over 30 subsequent migraine attacks, treated from attack 2 onwards over the course of 12 months. CONCLUSION: Frovatriptan provides a remarkably fast and high headache response in a subgroup of more than one-third of migraineurs, with a very low 24-hour headache recurrence and low rescue medication intake.

Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation.

OBJECTIVE: To evaluate, in a phase II study, the efficacy and safety of a topical eutectic mixture for premature ejaculation (TEMPE), a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine, as a treatment for PE. PATIENTS AND METHODS: Men with PE (Diagnostic and Statistical Manual-IV definition) aged 18-75 years were randomized into a double-blind, placebo-controlled study in the UK and the Netherlands. Efficacy variables included the mean change in intravaginal ejaculatory latency time (IELT) from baseline and the proportion of patients who achieved an IELT of > or = 4, > or = 3 or > or = 2 min on two occasions, and the effect of TEMPE on the index of ejaculatory control (IEC) and sexual quality-of-life (SQoL) scores of patients and their partners. Safety and adverse event data were also collected. Fifty-four patients were randomized and received study treatment. RESULTS: The observed mean change in IELT from baseline to the end of the treatment period was 3.8 min in the TEMPE group and 0.7 min in the placebo group, and when adjusted for baseline and centre was 2.4 times higher in the TEMPE than the placebo group (P < 0.01). The efficacy of TEMPE in increasing IELT was further supported by positive trends in the other efficacy endpoints. The proportion of men who had an IELT time > or = 2, > or = 3 or > or = 4 min on two occasions after treatment was 11/20 (55%), 8/20 (40%) and 5/25 (20%) in the TEMPE group, and 8/23 (35%), 3/23 (13%) and 3/23 (13%) in the placebo group, respectively, although these differences were not statistically significant. Improvements in IEC and SQoL (male and female) scores also showed trends towards greater efficacy for TEMPE than placebo. In all, 35 of 42 (83%) patients considered the spray easy to use. Mild to moderate local numbness occurred in three (12%) of the TEMPE-treated patients but did not lead to discontinuation. CONCLUSION: Topical treatment with TEMPE produced a statistically and clinically significant increase in IELT compared with placebo, and resulted in positive trends in ejaculatory control and SQoL. TEMPE was considered easy to use and was well tolerated. The data support the conduct of further large-scale studies to establish the utility of TEMPE as a first-line treatment for PE.

Randomized, placebo-controlled comparison of early use of frovatriptan in a migraine attack versus dosing after the headache has become moderate or severe.

OBJECTIVE: To evaluate whether frovatriptan would provide greater relief if given early during a migraine attack. RESEARCH DESIGN AND METHODS: Adults with a history of migraine of at least 1 year, and who had 2-8 headaches in the previous month were recruited from 19 US centres for a prospective, placebo-controlled crossover study over 2 migraine attacks. Dose 1 was taken at the onset of mild migraine headache, Dose 2 was taken at least 2 h later if the headache progressed to moderate/severe. Patients were randomized to receive Dose 1 frovatriptan then Dose 2 placebo or Dose 1 placebo followed by Dose 2 frovatriptan. Treatment order was reversed for the second attack. This schedule enabled a comparison of frovatriptan with placebo and a comparison of early and later treatment with frovatriptan. MAIN OUTCOME MEASURES: Freedom from pain at 2 h for frovatriptan versus placebo as Dose 1; use of Dose 2 and/or rescue medication, pain severity, functional impairment and headache recurrence. RESULTS: In 241 patients who each treated 2 migraine attacks, Dose 1 frovatriptan was more effective than placebo in terms of the proportion of patients who were pain free at 2 h (28% vs 20%, p = 0.04). This benefit was sustained up to 4 h post-dose (p = 0.003). Early use of frovatriptan significantly reduced re-medication (p < 0.001). Twenty-four-hour headache recurrence was low in both early (4%) and later use (6%) groups. Sustained pain-free response occurred in 40% of frovatriptan early use patients compared with 31% of later use patients (p < 0.05). Early use prevented headache progression: 69%-78% had mild/no headache 2-4 h after Dose 1 frovatriptan compared with 54%-63% taking Dose 1 placebo (p < 0.001). Early use reduced pain burden and functional disability (p < or = 0.001). More patients rated early use of frovatriptan as excellent or good (57% vs 46%). CONCLUSIONS: Early use of frovatriptan resulted in a higher, earlier and sustained pain-free response, prevented progression to moderate/severe headache and reduced pain burden and functional disability.

A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine.

BACKGROUND: Menstrually associated migraine (MAM) is often prolonged and difficult to manage with conventional therapies. Frovatriptan is a new selective 5HT(1B/1D) receptor agonist indicated for short-term management of migraine. It has a long half-life and good tolerability. These characteristics suggest that frovatriptan may be useful for the intermittent prevention of MAM. METHODS: The study was a randomized, double-blind, placebo-controlled, three-way crossover design. Patients treated each of three perimenstrual periods (PMPs) with placebo, frovatriptan 2.5 mg QD, and frovatriptan 2.5 mg BID. The 6-day treatment started 2 days before the anticipated start of MAM headache. The primary efficacy endpoint was incidence of MAM headache during the 6-day PMP. RESULTS: The population comprised 546 women (mean age, 37.6 years). Use of frovatriptan reduced the occurrence of MAM headache. The incidence of MAM headache during the 6-day PMP was 67% for placebo, 52% for frovatriptan 2.5 mg QD, and 41% for frovatriptan 2.5 mg BID. Both frovatriptan regimens were superior to placebo (p < 0.0001), and the BID regimen was superior to the QD regimen (p < 0.001). Both frovatriptan regimens also reduced MAM severity (p < 0.0001), duration (p < 0.0001), and the use of rescue medication (p < 0.01 QD; p < 0.0001 BID) in a dose-dependent manner. The incidence and type of adverse events for both regimens were similar to placebo and consistent with those reported for short-term migraine management. CONCLUSION: Frovatriptan given prophylactically for 6 days was effective in reducing the incidence of menstrually associated migraine. More than half of patients who used frovatriptan 2.5 mg BID had no menstrually associated migraine headache during the 6-day perimenstrual period. The findings are consistent with the long duration of action and good tolerability of frovatriptan observed in short-term migraine management.

Frovatriptan use in migraineurs with or at high risk of coronary artery disease.

OBJECTIVE: To investigate the cardiovascular effects of frovatriptan 2.5 mg during a migraine attack in patients with, or at high risk of, coronary artery disease. BACKGROUND: Rare occurrences of myocardial ischemia and coronary and peripheral vasospasm associated with the use of sumatriptan have triggered concern over the vasoconstrictor properties of the triptan class of drugs. METHODS: This randomized, double-blind, placebo-controlled, parallel-group study was conducted in 14 US private headache referral centers or clinics. Seventy-five patients, aged 18 years and older, with a history of migraine who were at high risk (Framingham score > or =14) of or who had previously documented coronary artery disease were evaluated. RESULTS: Incidence of clinically significant electrocardiogram changes was higher at all time points postdose with placebo than with frovatriptan, reaching statistical significance at 4 hours (40% versus 19%, P=.026). Similar proportions of patients had ischemia documented on Holter monitoring in the placebo (13%) and frovatriptan (11%) groups, and the incidence of arrhythmias was higher in the placebo group (11% versus 3%). There were no clinically significant changes in heart rate or blood pressure in either group. Adverse event profiles were similar for placebo and frovatriptan. CONCLUSIONS: In this exploratory study of migraineurs with, or at high risk of, coronary artery disease, frovatriptan 2.5 mg was well tolerated and not associated with an increase in cardiovascular monitoring abnormalities.

Consequences of transforming measures of efficacy for acute therapies: 5-HT agonists as a worked example.

OBJECTIVES: To examine whether the distributions of active and placebo response rates change after transformation into therapeutic gains, numbers needed to treat, and therapeutic ratios for 51 published clinical trials of 5-HT(1B/1D) agonists in the acute treatment of migraine. BACKGROUND: Acute migraine therapies have been compared using meta-analysis. Before pooling the results of noncontemporaneous clinical trials for meta-analysis, reconciliation of active response rates with concurrent placebo controls is done because of fluctuations in placebo response rates. The 3 common methods of reconciliation are to find for each clinical trial the therapeutic gain, the number needed to treat, or the therapeutic ratio. METHODS: Raw active and placebo response rates were tabulated and displayed as histograms. The distributions of the therapeutic gains, numbers needed to treat, and therapeutic ratios were similarly plotted. These distributions were then compared with normal distributions using chi-squared goodness-of-fit methodology. RESULTS: The distribution of active response rates was consistent with a normal distribution (passing a goodness-of-fit test). Placebo response rates were not normally distributed. The distribution of therapeutic gains failed a test of normality (P=.018), as did the numbers needed to treat (P <.001); the skews of these distributions were toward opposite ends of the scale for relative efficacy. The therapeutic ratios also failed a test for normality, but passed a test for log-normal distribution. CONCLUSIONS: Choice of transformation is a potential source of bias in meta-analysis of acute migraine therapies.

Migraine headache recurrence: relationship to clinical, pharmacological, and pharmacokinetic properties of triptans.

BACKGROUND AND OBJECTIVES: Triptan use is associated with headache recurrence, and this has been cited as an important reason for patient dissatisfaction with the treatment. The mechanism by which recurrence occurs is not clear, and the incidence of recurrence varies with the triptan used. In order to explore the pharmacological and physiological interaction of triptans and migraine headache recurrence further, some specific clinical, pharmacological, and pharmacokinetic factors that might influence migraine recurrence were evaluated in a review of the major efficacy data for the drugs in the triptan class. These factors were 5-HT1B and 5-HT1D receptor activities, the pharmacokinetic elimination half-life of each triptan, and the clinical efficacy of each compound, determined by the proportion of patients with headache relief and the therapeutic gain over placebo. METHODS: Clinical data were derived from 31 triptan, placebo-controlled, major efficacy studies used in a previous meta-analysis. The mean recurrence rate, mean headache response, and therapeutic gain were calculated using the results from the individual clinical studies. Mean headache response and therapeutic gain were calculated at the time point used to define recurrence in each study. Data for binding affinity and potency were taken from a direct-comparison in vitro pharmacology study, and the elimination half-life quoted in the data sheet for each triptan was used. Rank correlation with recurrence rate was performed for each of the test parameters. RESULTS: Mean headache recurrence rates ranged from 17% for frovatriptan 2.5 mg to 40% for rizatriptan. Elimination half-life and recurrence were inversely correlated (r = -1.0, P =.0016). There was also a significant inverse correlation between 5-HT1B receptor potency and recurrence (r = -0.68, P =.034), but 5-HT1D receptor potency was not correlated with recurrence (r = -0.20, P =.54). In addition, the binding affinities for the 5-HT1B and 5-HT1D receptors were not correlated to headache recurrence. Importantly, it also was demonstrated that initial clinical efficacy was not correlated to headache recurrence. The correlation coefficient for headache response was 0.18 (P =.53) and for therapeutic gain, -0.11 (P =.71). CONCLUSION: The incidence of migraine headache recurrence varies between drugs in the triptan class. Migraine recurrence does not appear to be related to initial clinical efficacy, but is influenced by the pharmacological and pharmacokinetic properties of the individual triptans. The triptans with longer half-lives and greater 5-HT1B receptor potency had the lowest rates of headache recurrence.

Comparison of therapeutic gain with therapeutic ratio for the assessment of selective 5HT(1B/1D) agonist efficacy in migraine.

OBJECTIVE: Comparison of use of therapeutic gain (TG) and therapeutic ratio (TR) for relative assessments of selective 5HT(1B/1D) agonist efficacy in the acute treatment of migraine. BACKGROUND: Comparison of selective 5HT(1B/1D) agonist efficacy in the acute treatment of migraine is complicated by the impracticality of conducting high-quality head-to-head active comparator trials for all permutations of drug, dose, and route of administration; the clinical trials that are available are usually noncontemporaneous, and have fluctuating active and placebo response rates (ARR and PRR, respectively) for the necessarily subjective endpoints. The standard primary endpoint is conversion of headache score 2 (moderate pain) or score 3 (severe pain) into score 0 (no pain) or score 1 (mild pain) at a single timepoint (usually 2 or 4 hours postdose). Two principal methods have been used for comparison of ARR between studies: TG = ARR - PRR and TR = ARR/PRR. Secondary endpoints can be treated in the same way, although the 24-hour remedication rate is the only secondary endpoint that is subject to regulatory authority standardization. Does either TG or TR have an advantage over the other? METHODS: Efficacy data were collected from published sources and included pain score conversion at 2- and 4-hour, as well as 24-hour remedication rates. TG and TR were calculated for each endpoint, as shown above. The ranges of these variables were found from all observed measures. Correlations between TG and TR were found using least squares methods. The 95% confidence intervals (CI) for TG and TR were then found for all clinical trials, and for the whole range of observed PRR. RESULTS: Values for TR and TG generally were well correlated for pain score conversion at 2 hours postdose (n = 51 clinical trials). Deviations from this correlation were greatest for drugs that were evidently very efficacious. When standardized for the observed ranges of PRR and ARR, the 95% CI for TR were narrower than for TG. A subset of these studies also reported 4-hour data (n = 23 clinical trials), but the correlation between TR and TG was again good, with narrower 95% CI for TR than TG. For the 24-hour remedication data (n = 18 trials), PRR was less variable; TR and TG again correlated well, but there was little difference in their relative 95% CI. CONCLUSIONS: For comparison of drugs in noncontemporaneous studies, when PRR fluctuates, relative ranges for TR are narrower than for TG. For assessing single clinical trial results (ie, point estimates of efficacy) TR will generally be relatively nearer to its mean than TG. For both these reasons, TR is a more robust statistic than TG.

Dose range-finding studies with frovatriptan in the acute treatment of migraine.

OBJECTIVE: To determine the optimum dose of frovatriptan for the acute treatment of migraine. BACKGROUND: Frovatriptan is a new triptan developed for the acute treatment of migraine. The dose-response characteristics and safety of frovatriptan have been investigated across a broad range of doses from 0.5 to 40 mg. DESIGN: Two randomized, placebo-controlled, double-blind, parallel-group trials, with a total of 1453 patients, were performed to determine the optimal dose of the 5-HT(B/1D)agonist, frovatriptan, for the acute treatment of migraine. The dose ranges studied were 2.5 to 40 mg in the high-dose study and 0.5 to 5 mg in the low-dose study. RESULTS: At 2 hours postdosing for initial moderate or severe headache (International Headache Society grades 2 or 3), there was an approximate two-fold difference in the proportion of patients taking frovatriptan doses of 2.5 to 40 mg with mild or no headache compared to placebo. Frovatriptan doses of 0.5 mg and 1 mg were not more effective than placebo at 2 hours postdose, and 2.5 mg was identified as the lowest effective dose for the relief of migraine and accompanying symptoms. Above 2.5 mg, no dose-response relationship was observed for any efficacy parameters. There was an increase in the incidence of adverse events from 10 mg and above, but the vast majority were rated as mild in severity and did not impact upon tolerability in a significant manner. CONCLUSIONS: Frovatriptan was well tolerated throughout the dose range of 0.5 to 40 mg. The 2.5-mg dose confers the optimal balance of efficacy and tolerability for the acute treatment of migraine.

Tolerability and safety of frovatriptan with short- and long-term use for treatment of migraine and in comparison with sumatriptan.

OBJECTIVE: To evaluate the tolerability and safety of frovatriptan 2.5 mg in patients with migraine. BACKGROUND: Frovatriptan is a new, selective serotonin agonist (triptan) developed for the acute treatment of migraine. Dose range-finding studies identified 2.5 mg as the dose that conferred the optimal combination of efficacy and tolerability. METHODS: The tolerability and safety of frovatriptan 2.5 mg were assessed during controlled, acute migraine treatment studies, including a study that compared frovatriptan 2.5 mg with sumatriptan 100 mg, as well as a 12-month open-label study during which patients could take up to three doses of frovatriptan 2.5 mg within a 24-hour period. Safety and tolerability were assessed through the collection of adverse events, monitoring of heart rate and blood pressure performance of 12-lead electrocardiogram, hematology screen, and blood chemistry studies. RESULTS: In the short-term studies, 1554 patients took frovatriptan 2.5 mg and 838 took placebo. In the 12-month study, 496 patients treated 13 878 migraine attacks. Frovatriptan was well tolerated in the short- and long-term studies with 1% of patients in the short-term studies and 5% of patients in the long-term study withdrawing due to lack of tolerability. The incidence of adverse events was higher in the frovatriptan-treated patients than in the patients who took placebo (47% versus 34%) and the spectrum of adverse events was similar. When compared to sumatriptan 100 mg, significantly fewer patients taking frovatriptan experienced adverse events (43% versus 36%; P=.03) and the number of adverse events was lower (0.62 versus 0.91), there were also fewer adverse events suggestive of cardiovascular symptoms in the frovatriptan group. Analysis of the entire clinical database (n=2392) demonstrated that frovatriptan was well tolerated by the patients regardless of their age, gender, race, concomitant medication, or the presence of cardiovascular risk factors. No effects of frovatriptan on heart rate, blood pressure, 12-lead electrocardiogram, hematology screen, or blood chemistry were observed. No patient suffered any treatment-related serious adverse event. CONCLUSIONS: Short- and long-term use of frovatriptan 2.5 mg was well tolerated by a wide variety of patients. Frovatriptan treatment produced an adverse events profile similar to that of placebo, and in a direct comparison study was better tolerated than sumatriptan 100 mg.