John Alam

Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection

BACKGROUND Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies. METHODS We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy). RESULTS The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation. CONCLUSIONS Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.)

A Viral Dynamic Model for Treatment Regimens with Direct-acting Antivirals for Chronic Hepatitis C Infection

We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.

Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders

Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg‐IFN‐alfa‐2a) and ribavirin (RBV). We conducted a randomized, double‐blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg‐IFN‐alfa‐2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg‐IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg‐IFN‐alfa‐2a and RBV, for 24 weeks. Patients with a 2‐log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg‐IFN‐alfa‐2a and RBV for a further 24 weeks, followed by 24 weeks of follow‐up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse‐event profiles for the MMPD combination groups were similar to that for Peg‐IFN‐alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. Conclusion: The addition of MMPD to Peg‐IFN‐alfa‐2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR. (HEPATOLOGY 2009.)

Impaired bioavailability of interferon beta-1a when administered intramuscularly by needle-free injection.

Intramuscular (IM) or subcutaneous (SC) drug administration of small molecules and protein has been demonstrated by use of needle-free jet injection methods. One device that achieves needle-free parenteral administration, BIOJECTOR, is commercially available and was evaluated for IM delivery of interferon beta-1a. Recombinant human interferon beta-1a (IFN beta-1a) is a glycosylated protein containing 166 amino acids and has a molecular weight of 22.5 kDa. Needle-free jet injection of IFN beta-1a with the BIOJECTOR was assessed in a human Phase I trial. The study was a randomized, open-label crossover in which 12 healthy subjects each received 60 microg of IFN beta-1a as an IM injection by standard needle administration and by needle-free jet injection. Blood samples for pharmacokinetic (serum activity, PK) and pharmacodynamic (serum neopterin, PD) determinations were collected through 144 hours post-dose. Mean serum antiviral activity AUC values for needle-free and standard needle injection were 218 and 531 U x h/ml, respectively; corresponding C(max) values were 19.7 and 29.0 U/ml. Median T(max) following both treatments was 12 hours. The relative bioavailability of IFN beta-1a, needle-free to standard needle injection, was 41.1% with 90% confidence limits of 24.4% to 69.3%. Mean serum neopterin E(AUC) values for needle-free and standard needle injection were 114 and 325 ng x h/mL, respectively; corresponding E(max) values were 2.3 and 5.6 ng/mL. The ratio of serum neopterin E(AUC), needle-free to standard needle, was 34.9% with 90% confidence limits of 23.4% to 52.1%. Injection site reactions were substantially more frequent following needle-free injection; however, systemic side effects were less frequent. Intramuscular needle-free jet injection and needle-based injection of a 22.5-kDa glycoprotein do not produce equivalent systemic PK or PD responses.

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

The aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimers disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters.

PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE THERAPEUTIC EFFECT OF ORAL P38 MAPK ALPHA ANTAGONISM ON EPISODIC MEMORY IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE (AD)

Background:Neflamapimod is an oral antagonist of p38a, a kinase implicated in inflammation-induced hippocampal synaptic dysfunction. Phase 2a clinical trials (one of 6and one of 12-weeks duration) with neflamapimod in early AD demonstrated improvement in measures of episodic memory (CTAD, 2016; AAIC, 2017). In the absence of a placebo control in these trials, a specific neflamapimod-driven treatment effect was indicated by pharmacokinetic-pharmacokinetic (PK-PD) modeling of the longer duration study that demonstrated a relationship between plasma drug concentration exposure and improvement in episodic memory (AAIC, 2017). We report herein additional PK-PD modeling analyses than reported previously and assessment of the robustness of the best-fit model. Methods: Fifteen patients with MCI due to AD or mild AD (MMSE 20-28) received neflamapimod at 40 mg or 125 mg twice daily for 12 weeks. Episodic memory function assessed with Wechsler Memory Scale (WMS)–IV, analyzed as Immediate-Recall composite and Delayed-Recall composites. Individual plasma drug exposure (Area-under-curve over dosing interval of 12 hours) was derived from a population pharmacokinetics analysis of the two phase 2a studies and used in the PK-PD analysis. Results: A series of models were assessed for episodic memory scores with a set of covariates drug exposure, patient characteristics and some baseline AD metrics. Drug exposure was a statistically significant predictor of the change from baseline of combined (immediate + delayed) recall score for the best-fit model (p-value < 0.0001, and r1⁄40.696). Separately, there was also an important relationship between the drug exposure and change from baseline of either immediate or delay recall score (both with p-value < 0.001). Finally, a sensitivity analysis of the bestfit model for change from baseline of combined immediate and delayed-recall was performed using the remove of one subject-at-time jackknife resampling approach to determine model robustness. The r values for the jackknife models ranged from 0.63 to 0.77, indicating that no one individual subject disproportionately influenced the result. Conclusions: PK-PD modeling indicates that there is a robust relationship between plasma drug concentration of neflamapimod and improvement in episodic memory, as assessed by immediate and delayed-recall on the WMS.