Immunology and Biotherapies

Original Article from The New England Journal of Medicine — Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease

 

BACKGROUND

A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian–Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses.

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 METHODS

We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials, CYD14 and CYD15, and a phase 2b trial, CYD23/57. We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15.

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 RESULTS

Follow-up data were available for 10,165 of 10,275 participants (99%) in CYD14 and 19,898 of 20,869 participants (95%) in CYD15. Data were available for 3203 of the 4002 participants (80%) in the CYD23 trial included in CYD57. During year 3 in the CYD14, CYD15, and CYD57 trials combined, hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group. Pooled relative risks of hospitalization for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years, and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older. During year 3, hospitalization for severe dengue, as defined by the independent data monitoring committee criteria, occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group. Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3% (95% CI, 55.7 to 64.5) for all participants, 65.6% (95% CI, 60.7 to 69.9) for those 9 years of age or older, and 44.6% (95% CI, 31.6 to 55.0) for those younger than 9 years of age.

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 CONCLUSIONS

Although the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up, the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530, NCT01983553, NCT01373281, andNCT01374516.)

Via Krishan Maggon

Original Article from The New England Journal of Medicine — Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events

 

Abstract NEJM

 

BACKGROUND

Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy.

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 METHODS

We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.

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 RESULTS

At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02).

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 CONCLUSIONS

Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.)

Via Krishan Maggon

Perspective from The New England Journal of Medicine — Progress and Hurdles for Follow-on Biologics

 

The challenges to achieving savings from follow-on biologics are large but not insurmountable. First, market-entry hurdles should be low enough to ensure that enough companies compete to affect prices. Public investment in technological advances that can support biosimilar development, such as advancing knowledge about glycosylating human proteins in yeast, can aid all manufacturers. The FDA can help by promulgating product-specific guidance on how companies can demonstrate biosimilarity or interchangeability, to reduce the disadvantages for the first companies to try. Legislators may also need to reexamine the process for exchanging information about potentially infringing patents, to ensure that innovator manufacturers cannot unreasonably delay the process in order to extend their market exclusivity, and to prevent biosimilar manufacturers from entering into anticompetitive settlements. Such settlements have bedeviled the generic small-molecule drug industry but, since 2003, have had to be reported to the Federal Trade Commission for evaluation of their anticompetitive effects. This requirement may have to be extended to biologic drugs.

Innovative approaches will be required to ensure mandatory, rigorous postapproval research on the safety and effectiveness of biosimilars compared with their innovator predecessors in order to promote confidence in these new products. Over the long term, attention to both these areas will help ensure that U.S. patients benefit from appropriate price reductions for older biologic drugs that are essential for their clinical care. At the same time, fair but appropriately limited periods of exclusivity will reward the innovators of the original products while also spurring them to create new products rather than prolong exclusivity rights over older ones long after such monopolies should have come to a natural end.

Via Krishan Maggon