Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.

OBJECTIVE: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). METHODS: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. RESULTS: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. CONCLUSIONS: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study.

OBJECTIVE: To investigate the potential efficacy, safety, and tolerability of daily use of CH-1504 in patients with active rheumatoid arthritis (RA). US National Institutes of Health database no. NCT00658047. METHODS: In our phase II randomized double-blind double-dummy study, patients naive to methotrexate (MTX; n = 201) and having moderate to severe RA received either CH-1504 (0.25 mg, 0.5 mg, or 1.0 mg once-daily oral doses) or MTX (titrated to 20.0 mg once-weekly oral doses). All received weekly 10-mg folate supplementation. Efficacy and safety were assessed at 2, 4, 8, and 12 weeks, with a treatment-free followup at 16 weeks. Safety and tolerability were assessed. Primary efficacy endpoint was proportion of patients achieving ACR20 response at Week 12. Secondary endpoints included difference from baseline in the 28-joint Disease Activity Score (DAS28) and individual components of the American College of Rheumatology (ACR) composite index. RESULTS: Demographic characteristics were similar in all treatment groups: mean age 54.3 ± 11.4 years, female sex 87%, mean baseline DAS28 6.6 ± 0.9. At Week 12, CH-1504 demonstrated comparable efficacy compared to MTX as measured by ACR20, DAS28, and ACR composite core-set measures, including tender and swollen joints. No dose-response relationship was observed. Adverse events across treatment groups were mild. Liver enzyme levels increased from baseline to Week 16 in the MTX group, with qualitatively lesser increases in the CH-1504 groups. Two patients in the MTX group withdrew because of gastrointestinal-related adverse events. CH-1504 appeared safe and well tolerated at all dose levels. CONCLUSION: CH-1504 has comparable efficacy to MTX and is safe and well tolerated. Metabolically stable antifolates are a promising therapeutic option that warrants further study.

Pegylation of interferon alfa: structural and pharmacokinetic properties.

The attachment of a polyethylene glycol (PEG) polymer to a protein or peptide is becoming increasingly common within the pharmaceutical industry as a way of altering the activity of the parent molecule. Significant improvements in biological activity with PEG molecules have been seen with several licensed drugs, allowing for product life cycle management, as well as with experimental compounds in development that have pharmaceutical properties making them suitable candidates for pegylation. Among the various disease states that have been targeted for the study of drugs incorporating pegylation technology, the treatment of chronic hepatitis C with interferon-based compounds offers significant potential for clinical impact. Two separate compounds, peginterferon alfa-2a (PEGASYS) and peginterferon alfa-2b (PEG-Intron) are now both approved for use alone and in combination with ribavirin for the treatment of chronic hepatitis C. However, the different PEG moieties attached to the native protein, the site of attachment and the type of bond involved lead to vast differences with respect to the pharmacokinetics (including absorption, biodistribution, metabolism and elimination) and pharmacodynamics of these two compounds. This article discusses the differences that exist between these compounds, which may lead to different clinical profiles for their use in the treatment of patients with hepatitis C.

Use of peginterferon alfa-2a (40 KD) (Pegasys) for the treatment of hepatitis C.

Thrice-weekly interferon alfa-2b plus ribavirin has been the standard of care for chronic hepatitis C; however, a majority of patients fail to achieve a sustained virological response with this treatment. Peginterferon alfa-2a (40 KD), interferon alfa-2a conjugated to a 40 kDa branched polyethylene glycol moiety, exhibits sustained absorption and reduced renal clearance, resulting in antiviral pressure throughout a once-weekly dosing schedule. Peginterferon alfa-2a (40 KD) has superior virological efficacy to interferon alfa-2a, and elicits histological improvements in patients with and without sustained virological response. Peginterferon alfa-2a (40 KD) is effective in patients infected with viral genotype 1 and those with liver cirrhosis. Viral RNA measurements at 12 weeks can be used to predict the probability of achieving sustained virological response to peginterferon alfa-2a (40 KD) therapy. Peginterferon alfa-2a (40 KD) has comparable safety to interferon alfa-2a. The addition of ribavirin to peginterferon alfa-2a (40 KD) further enhances the therapeutic benefit for patients with hepatitis C.