Efficacy of galcanezumab in patients with chronic migraine and a history of preventive treatment failure.

BACKGROUND: Efficacy of galcanezumab in chronic migraine has been demonstrated in a pivotal Phase 3 study. Here, we assess efficacy in patients who have failed ≥2 and ≥1 prior migraine preventives for efficacy and/or safety reasons, and in those who never failed. STUDY DESIGN/METHODS: REGAIN (NCT02614261) was a Phase 3, randomized, double-blind, placebo-controlled study in patients with chronic migraine. Patients were randomized 2:1:1 to receive placebo, galcanezumab 120 mg/240 mg once monthly during a double-blind treatment period lasting three months. Subgroup analyses were conducted among patients who failed ≥2 and ≥1 prior preventives and who never failed previously. Outcomes assessed were change from baseline in number of monthly migraine headache days, proportion of patients with ≥50% and ≥75% response (reduction in monthly migraine headache days), change in number of monthly migraine headache days with acute medication use and change in patient functioning per Migraine-Specific Quality of Life Questionnaire Role Function Restrictive (MSQ RF-R) domain score. RESULTS: Treatment with galcanezumab versus placebo resulted in significant improvements (p < 0.01) in overall reduction (Months 1-3) from baseline in the number of monthly migraine headache days in patients with prior failures (LS mean change [SE]: ≥2 prior failures: galcanezumab 120 mg: -5.35 (0.71); galcanezumab 240 mg: -2.77 (0.66); placebo: -1.01 (0.54); ≥1 prior failures: galcanezumab 120 mg: -5.53 (0.60), galcanezumab 240 mg: -3.53 (0.59); placebo: -2.02 (0.49). Similarly, significant results were seen with galcanezumab versus placebo for ≥50% and ≥75% response rates, reductions in acute medication use and improvements in MSQ RF-R domain score. In the subgroup with no prior preventive failures, results were statistically significant for the 240 mg galcanezumab group versus placebo on all outcome measures, and for the 120 mg group on the reduction in migraine headache days with acute medication use. There was also a higher placebo response observed in the patients with no prior preventive failures. CONCLUSION: Galcanezumab is consistently efficacious versus placebo in reducing monthly migraine headache days and several other key outcomes in patients with chronic migraine who have failed ≥2 or ≥1 preventives previously. In the subgroup with no prior failures, greater numerical differences were seen with galcanezumab, but statistical separation from placebo varied by dose and outcome. CLINICALTRIALS.GOV IDENTIFIER NUMBER: NCT02614261.

Economics of Inhaled Oxygen Use as an Acute Therapy for Cluster Headache in the United States of America.

BACKGROUND: Cluster headache (CH) is a primary headache disorder associated with low levels of diagnosis and high unmet medical need. The pain attacks, associated anxiety, and fear in anticipation of the attacks are extremely debilitating to a patient with CH. For acute therapy, treatment guidelines recommend inhalation of high flow oxygen during the period of an attack. However, the use of oxygen for treatment of CH remains largely underutilized. OBJECTIVES: The objectives of the study, which covered each of the US states, were to map the current market landscape of medical grade oxygen for use in CH and to develop a cost simulator based on a patient's needs and geography. METHODS: Desk research was undertaken to obtain price lists and product catalogs from wholesale and retail suppliers of medical grade oxygen across all US states. Base case scenarios for chronic and episodic forms of CH were assumed. A cost simulator was used to calculate the cost of oxygen use using inputs including the state in USA, tank size and price, exacerbations per year, duration of exacerbation, attacks per day, flow rate and duration of flow. Information was also collected to determine if healthcare insurers covered the costs of home oxygen use for CH. RESULTS: Out of the 42 US states where pricing information of medical grade oxygen was available from suppliers, in 38 states the annual cost of high-flow oxygen for a patient with episodic CH was estimated to be <$1000. In 39 states, the annual cost of high-flow oxygen for a patient with chronic CH was estimated to be <$5000. Most of the home oxygen suppliers were familiar with CH and stocked the special non-rebreather masks and regulators necessary for this condition. It was found that many of the private commercial healthcare insurance providers reimbursed the cost of oxygen use for CH. However, the US Centers for Medicare and Medicaid Services (CMS) maintains there is insufficient evidence for coverage and continues to deny coverage for US Medicare and Medicaid patients. CONCLUSIONS: Results from our study showed that the current costs for oxygen use as an acute therapy in CH are not prohibitively expensive for patients and healthcare insurance providers. Apart from CMS, many insurers do reimburse the cost of oxygen use for CH. Our study suggests that further research is needed to determine if a lack of physician awareness about treatments and ways to prescribe are barriers for patients to access the high-flow oxygen treatment.

P2Y receptor subtypes evoke different Ca2+ signals in cultured aortic smooth muscle cells.

Adenine and uridine nucleotides evoke Ca(2+) signals via four subtypes of P2Y receptor in cultured aortic smooth muscle cells, but the mechanisms underlying the different patterns of these Ca(2+) signals are unresolved. Cytosolic Ca(2+) signals were recorded from single cells and populations of cultured rat aortic smooth muscle cells, loaded with a fluorescent Ca(2+) indicator and stimulated with agonists that allow subtype-selective activation of P2Y1, P2Y2, P2Y4, or P2Y6 receptors. Activation of P2Y1, P2Y2, and P2Y6 receptors caused homologous desensitisation, while activation of P2Y2 receptors also caused heterologous desensitisation of the other subtypes. The Ca(2+) signals evoked by each P2Y receptor subtype required activation of phospholipase C and release of Ca(2+) from intracellular stores via inositol 1,4,5-trisphosphate (IP(3)) receptors, but they were unaffected by inhibition of ryanodine or nicotinic acid adenine dinucleotide phosphate (NAADP) receptors. Sustained Ca(2+) signals were independent of the Na(+)/Ca(2+) exchanger and were probably mediated by store-operated Ca(2+) entry. Analyses of single cells established that most cells express P2Y2 receptors and at least two other P2Y receptor subtypes. We conclude that four P2Y receptor subtypes evoke Ca(2+) signals in cultured aortic smooth muscle cells using the same intracellular (IP(3) receptors) and Ca(2+) entry pathways (store-operated Ca(2+) entry). Different rates of homologous desensitisation and different levels of receptor expression account for the different patterns of Ca(2+) signal evoked by each P2Y receptor subtype.

Ca(2+) signalling by P2Y receptors in cultured rat aortic smooth muscle cells.

BACKGROUND AND PURPOSE: P2Y receptors evoke Ca(2+) signals in vascular smooth muscle cells and regulate contraction and proliferation, but the roles of the different P2Y receptor subtypes are incompletely resolved. EXPERIMENTAL APPROACH: Quantitative PCR was used to define expression of mRNA encoding P2Y receptor subtypes in freshly isolated and cultured rat aortic smooth muscle cells (ASMC). Fluorescent indicators in combination with selective ligands were used to measure the changes in cytosolic free [Ca(2+)] in cultured ASMC evoked by each P2Y receptor subtype. KEY RESULTS: The mRNA for all rat P2Y receptor subtypes are expressed at various levels in cultured ASMC. Four P2Y receptor subtypes (P2Y1, P2Y2, P2Y4 and P2Y6) evoke Ca(2+) signals that require activation of phospholipase C and comprise both release of Ca(2+) from stores and Ca(2+) entry across the plasma membrane. CONCLUSIONS AND IMPLICATIONS: Combining analysis of P2Y receptor expression with functional analyses using selective agonists and antagonists, we isolated the Ca(2+) signals evoked in ASMC by activation of P2Y1, P2Y2, P2Y4 and P2Y6 receptors.