2 Minute Medicine Rewind September 18, 2017

Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval

There is current debate surrounding the high cost of many medications, as many groups have voiced opposition to high prices while others have argued that high prices are justified by the costs required for drug development. Previous studies have produced very different estimates for the cost of bringing a single drug to the US market. In this study, the investigators estimated the cost of developing a single anticancer drug by analyzing US Security and Exchange Committee (SEC) filings on 10 publicly traded pharmaceutical companies with only one US Food and Drug Administration (FDA) approved drug. The investigators analyzed the costs of developing single anticancer agents from 2006 and 2015 by manufacturers that had no other drugs on the market. Researchers found that the median time to develop a drug was 7.3 years (range 5.8 to 15.2 years). The median cost of development of a single anticancer drug in 2017 US dollars was $648.0 million (range $157.3 million to $1950.8 million. The mean cost of development was $719.8 million (95% CI $336.0 million to $1140.0 million). Combined, the ten drugs produced a total revenue of $67.0 billion from their time of approval to December 2016 or when the compound was sold. The median revenue for the companies in 2017 was $1658.4 million (range $204.1 million to $22,275.0 million). The mean revenue was $66,99.1 million (95% CI $403.0 million to $12,996.0 million). These results differ from a prior estimate of $2.7 billion for the development of a single drug, and suggest that the actual cost may be lower, which has potential implications for drug pricing. This study is limited, however, as it employed a small data set, focusing only on cancer drugs; results on cost and revenue cannot be extrapolated to other drug types. Furthermore, the authors had to estimate research and development costs as access to pharmaceutical company records was relatively limited. More precise analyses on the costs to bring drugs to market will require greater transparency from pharmaceutical companies.

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke

Studies have shown an association between patent foramen ovale (PFO) and cryptogenic strokes, which are strokes with obscure or unknown origin. It has been hypothesized that a PFO could allow emboli from the legs or other part of the body to travel from the right side of the heart to the left through the PFO, and be sent to the brain. In this randomized controlled trial, 663 patients who had a PFO and a recent cryptogenic stroke were randomized to PFO closure followed by antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation alone. The investigators studied the effect of these different therapies on fatal or nonfatal stroke occurrence. The investigators also tested for superiority of PFO closure plus antiplatelet therapy over antiplatelet therapy alone. Researchers found that after an average of 5.3 ± 2 years of follow-up, there were 0 strokes that occurred in the PFO closure group, compared to 14 strokes in the antiplatelet-only group (HR 0.03, 95% CI 0 to 0.26, p<0.001). Results also showed that a composite outcome of ischemic attack, systemic embolism, and stroke occurred in 3.4% of PFO closure patients in comparison to 8.9% of those in the antiplatelet-only group (HR 0.39, 95% CI 0.16 to 0.82, p=0.01). There were, however, major procedural complications in 5.9% of patients in the PFO closure group, and the rate of new-onset atrial fibrillation was 4.6% for the PFO closure group compared to 0.9% for the antiplatelet therapy-only group. Investigators were unable to statistically compare the antiplatelet group to the anticoagulant group due to a lack of statistical power. Taken together, the results from this study indicate that PFO closure in addition to antiplatelet therapy lowers the risk of stroke more than taking antiplatelet therapy alone, however PFO closure is associated with procedural complications and higher rates of atrial fibrillation. Further studies are needed to determine whether atrial fibrillation induced by PFO closure can increase the risk of stroke.

Percutaneous Coronary Intervention vs Coronary Artery Bypass Grafting in Patients With Left Main Coronary Artery Stenosis

The current standard of treatment for stenosis of the left main coronary artery (LMCA) is coronary artery bypass grafting (CABG). In recent years, percutaneous coronary intervention (PCI) has emerged as an alternative technique. Previous analyses comparing PCI with CABG have showed conflicting results, indicating the need for further analysis. In this systematic review and meta-analysis, investigators examined and synthesized the results of 4 randomized clinical trials (n=4394) compared PCI with drug-eluting stent (DES) versus CABG in patients with LMCA stenosis in order to compare the long-term safety of these interventions. The primary end point was a composite of all-cause death, myocardial infarction (MI) and stroke. Researchers found no significant difference between cumulative incidences of death, MI, or stroke (HR 1.06 for PCI versus CABG, 95% CI 0.85 to1.32, p=0.60). Results, however, did show that patients undergoing PCI were at a significantly higher risk of requiring repeat revascularization (HR 1.70, 95% CI 1.42 to 2.05, p<0.001). The results from this study suggest that PCI and CABG are associated with similar risks of death, MI, and stroke for patients undergoing revascularization of the LMCA, but that PCI has a higher risk of repeat revascularization.

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease

Many patients with chronic obstructive pulmonary disease (COPD) have an eosinophilic phenotype, where their peripheral-blood differential eosinophil count is 2% or more. Previous studies have suggested a pathogenic role for eosinophils in COPD exacerbations. Mepolizumab is a human monoclonal antibody that decreases eosinophil counts by blocking interleukin-5. In this paper, two randomized control trials were conducted, where a total of 1512 patients with COPD on maintenance therapy were randomized to receive mepolizumab or placebo to study the effect on the annual rate of moderate or severe COPD exacerbations. In the METREX trial, 837 patients with COPD were stratified according to blood eosinophil count and randomized to 100 mg of mepolizumab or placebo. In the METREO trial, 675 patients with COPD and high blood eosinophil counts were randomized to receive 100 mg of mepolizumab, 300 mg of mepolizumab, or placebo. Based on the results of the METREX trial, the mean annual rate of COPD exacerbations for patients with a high eosinophilic phenotype was 1.40 for the 100 mg mepolizumab group and 1.71 for the placebo group (RR 0.82, 95% CI 0.68 to 0.98, p=0.04). When patients without high eosinophilic phenotypes were included in the METREX analysis, the rate of exacerbations did not differ significantly between groups. For the METREO study, the mean annual rate of COPD exacerbations was lower for the groups on mepolizumab in comparison to placebo, but the differences were not statistically significant. Overall, results from the METREX trial indicate that 100 mg mepolizumab can reduce rates of moderate or severe COPD exacerbations in patients with high eosinophilic counts who are already receiving maximal inhaled glucocorticoid-based triple inhaled maintenance therapy. This result supports the hypothesis that blood eosinophils have a role in COPD exacerbations.

Identification of ALK rearrangements in malignant peritoneal mesothelioma

Malignant peritoneal mesothelioma is a rare and aggressive tumour arising from peritoneal, pleural or pericardial lining, with approximately 10% developing in the peritoneum. While mesothelioma has been found to be associated with exposure to asbestos, less commonly with therapeutic radiation for prior malignancy, and BAP1 tumour predisposition syndrome, there remain cases without identifiable causes. In this case series study, 88 consecutive patients with peritoneal mesothelioma were studied to investigate anaplastic lymphoma kinase (ALK) rearrangements and characterize mutations in these tumours. Researchers reviewed clinicopathologic characteristics and performed immunohistochemistry studies for ALK in all peritoneal mesotheliomas retrieved. In all ALK-positive cases, ALK rearrangement was confirmed by fluorescence in situ hybridization (FISH). Researchers found that 11 cases (13%) were ALK-positive. Of these 11 cases, 8 had focal and weak expression, while 3 had diffuse and strong expression. Among cases that were focal weak ALK-positive, no ALK rearrangement was detected by FISH or next-generation sequencing. In strong diffuse ALK-positive cases, FISH confirmed ALK rearrangements, and next-generation sequencing identified novel fusion partners ATG16L1, STRN and TPM1. Patients with ALK rearrangement were more likely to be female and were younger (p=0.02), however did not significantly differ with respect to other clinicopathologic characteristics. No asbestos fibers were identified in patients with ALK rearrangement. In addition, while overall survival did not significantly differ with ALK rearrangement (HR 0.5, 95% CI 0.1 to 1.8, p=0.29) or ALK protein expression (HR 1.5, 95% CI 0.6 to 4.2, p=0.40), patients with weak focal ALK expression did have shorter overall survival when compared to patients with absent or diffuse strong ALK expression (p=0.03). Researchers were therefore able to identify several unique ALK rearrangements in a subset of patients with peritoneal mesothelioma. This may have important implications in the development of targeted therapy in patients with malignant peritoneal mesothelioma.

Image: PD

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