In mid-May, approximately 15,000 clinicians, researchers, and physicians learned about the latest advances in gastroenterology at Digestive Disease Week (DDW) held in Washington, DC. The annual meeting is cosponsored by four organizations: the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract. Key highlights from the meeting that focus on research related to pharmaceuticals and gastrointestinal (GI) disorders are presented in this article.
HCV–HIV coinfection. Twelve weeks of treatment with an interferon- and ribavirin-free regimen of sofosbuvir (Sovaldi—Gilead) and daclatasvir, an investigational agent by Bristol-Myers Squibb (BMS), achieved sustained virological response in almost all treatment-naive and treatment-experienced patients who were coinfected with the hepatitis C virus (HCV) and HIV, according to results from the ALLY-2 trial (abstract 901d).
The ALLY-2 trial was a Phase III, open-label clinical trial that randomized 151 treatment-naive and 52 treatment-experienced patients with HCV (genotypes 1–4) coinfected with HIV-1 on a broad range of antiretroviral regimens into three cohorts.
Treatment-naive patients were randomized 2:1 to 12 or 8 weeks of treatment with daclatasvir 30–90 mg plus sofosbuvir 400 mg once daily. Treatment-experienced patients received daclatasvir 30–90 mg plus sofosbuvir 400 mg once daily for 12 weeks. In both groups, daclatasvir was dose adjusted for concomitant antiretroviral therapy. The majority of patients had HCV genotype 1 (83%), were male (87%), and were white (62%).
For the primary endpoint of sustained virological response at 12 weeks (SVR12) among genotype 1 treatment-naive patients, combination treatment with daclatasvir plus sofosbuvir resulted in an SVR12 of 96%. In addition, SVR12 among genotype 1 treatment-experienced patients was 98%. Responses were lower after 8 weeks of therapy, at 76% in treatment-naive patients with HCV genotype 1. The SVR12 rates were 100% for genotypes 2–4 in both treatment-naive and treatment-experienced patients; again rates were lower after 8 weeks of treatment in the treatment-naive population. No treatment-related serious adverse events or discontinuations related to adverse events were observed in the trial.
“The results of ALLY-2 signal that nearly all HIV–HCV coinfected patients in the study could be cured of hepatitis C with a 12-week regimen on daclatasvir and sofosbuvir,” said David Wyles, MD, ALLY-2 Lead Investigator and Associate Professor of Medicine in the Department of Medicine, Division of Infectious Diseases, University of California San Diego, in a BMS news release.
“The trial demonstrated the dosing flexibility afforded by the daclatasvir–sofosbuvir regimen did not require alteration of HIV medications because of potential drug–drug interactions,” Wyles continued. “This is a paramount consideration for clinicians treating this patient population.”
BMS announced that FDA has accepted its New Drug Application (NDA) for review for use of daclatasvir in combination with sofosbuvir for the treatment of chronic HCV.
Treatment-experienced patients. In patients infected with HCV genotypes 1, 4, or 6 who experienced treatment failure with prior peginterferon plus ribavirin therapies, treatment with an investigational combination of grazoprevir (NS3/4A protease inhibitor) plus elbasvir (NS5A replication complex inhibitor) with or without ribavirin for 12 to 16 weeks resulted in sustained viral response (SVR) rates of 92%–99%, according to results from the C-EDGE trial (abstract 901f).
The C-EDGE trial is an ongoing, Phase III study involving 420 patients with or without cirrhosis and infected with HCV genotypes 1, 4, or 6 who experienced treatment failure with prior peginterferon plus ribavirin therapies. The patients were randomized to 12 or 16 weeks of treatment of grazoprevir plus elbasvir with or without ribavirin. The majority of patients were male (65%), 35% had cirrhosis, 5% were coinfected with HIV, and 18% were black. Previous responses to peginterferon plus ribavirin were relapse in 35% of patients, partial response in 22%, and null response in 43%.
The trial results showed that SVR rates of up to 99% were achieved in patients receiving treatment with grazoprevir plus elbasvir plus ribavirin for 16 weeks, including 100% in those with cirrhosis (n = 37/37) and 98% in prior null responders (n= 44/45).
In the other groups, SVR rates were 94% for those treated with grazoprevir plus elbasvir with or without ribavirin for 12 weeks and 92% for those treated with 16 weeks of grazoprevir plus elbasvir alone. Common adverse events observed in the trial were fatigue (23%), headache (20%), and nausea (11%).
“Patients with comorbidities and varying treatment experiences represent important segments of the chronic hepatitis C population in need of additional innovative treatment options,” said Eric Lawitz, MD, Vice President, Scientific and Research Development, Texas Liver Institute, and Clinical Professor of Medicine, University of Texas Health Science Center, San Antonio, in a Merck news release. “These findings are important because they demonstrate that a single pill of grazoprevir/elbasvir taken once-daily achieved consistently high rates of SVR12 in the patient populations studied,” he added.
On May 28, Merck announced that it had submitted an NDA to FDA for grazoprevir/elbasvir (100 mg/50 mg) for the treatment of adult patients with chronic HCV genotypes 1, 4, or 6 infection.
Two investigational agents, PF-00547659 by Pfizer and GS-5745 by Gilead, show promising results for patients with moderate to severe ulcerative colitis, according to data from two late-breaking abstracts presented at DDW (901a and Tu2056).
A Phase II trial known as the TURANDOT study was designed to determine the optimal dose for PF-00547659, a monoclonal antibody that acts directly on MAdCAM, to induce remission in patients with moderate to severe ulcerative colitis who have experienced treatment failure with at least one prior therapy.
MAdCAM is a cell adhesion molecule expressed mainly by intestinal venules. Its role in the intestinal inflammatory response has been previously demonstrated in animal models, with inhibition resulting in improvement of colitis. A total of 357 patients were enrolled and randomized to one of four doses of the investigational agent (7.5 mg, 22.5 mg, 75 mg, and 225 mg) or placebo, with therapy administered every 4 weeks for a total of three doses.
Results for the primary endpoint of clinical remission at week 12, based on the total Mayo score, and varying secondary endpoints showed that the greatest efficacy signal was derived from the 22.5-mg and 75-mg doses. Clinical remission rates were 16.7% and 15.5% for the 22.5-mg and 75-mg doses, respectively, compared with 2.7% in the placebo group (P < 0.05). The clinical remission rates in the 7.5-mg and 225-mg groups were 11.3% and 5.7%, respectively.
The investigators noted that patients who had experienced previous treatment failure with an anti–tumor necrosis factor agent had poorer responses than those who had not received such therapies. In terms of safety, the findings were unremarkable, and no cases of progressive multifocal leukoencephalopathy occurred.
A multicenter, double-blind, Phase Ib study was conducted in 50 patients with moderate to severe ulcerative colitis to assess the efficacy and safety of GS-5745, an IgG4 monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). MMP9 is a type IV collagenase that is upregulated in patients with ulcerative colitis and is associated with mucosal injury. Patients were randomized to placebo or varying doses of GS-5745 given intravenously (0.3 mg/kg, 1.0 mg/kg, 2.5 mg/kg, and 5.0 mg/kg at days 0, 7, 14, 21, and 28) or as a once-weekly subcutaneous dose of 150 mg given on days 0, 7, 14, 21, and 28.
Clinical response was 43% for the entire cohort of patients given active treatment compared with 13% in the placebo group. Clinical response rates ranged from 38% to 50% for the varying doses. Remission occurred in 14% of patients given active treatment compared with no patients in the placebo group, and mucosal healing occurred in 33% and 25% of these groups, respectively.
Rates of adverse events and serious adverse events were low in the active treatment group and comparable with rates observed in the placebo group, and only one patient given active treatment discontinued because of an adverse event.
Results from a Phase II study support the use of naldemedine, a novel peripherally acting mu-opioid receptor antagonist being developed by Shionogi, for the management of opioid-induced constipation in patients with chronic noncancer pain (abstract 901e).
A total of 244 patients with chronic noncancer pain with opioid-induced constipation were randomized in a 1:1:1:1 ratio to receive naldemedine 0.1 mg, 0.2 mg, or 0.4 mg given once daily or placebo for 4 weeks. Eligible patients were those who had received chronic opioid treatment for at least 3 months prior to the study and had less than three spontaneous bowel movements (SBM) per week during the screening period. The primary efficacy endpoint for the study was change from baseline in the frequency of SBM per week to the last 2 weeks of the treatment period.
Results showed a statistically significant improvement in the primary efficacy endpoint for patients using naldemedine at doses of 0.2 mg (3.37 SBM; P = 0.0014) and 0.4 mg (3.64 SBM; P = 0.0003) compared with placebo (1.42 SBM). In addition, significantly more patients given naldemedine 0.2 mg or 0.4 mg were classified as responders, compared with placebo-treated patients.
The drug was generally well tolerated at all doses, with gastrointestinal disorders such as abdominal pain, diarrhea, flatulence, and nausea the most commonly reported adverse effects. The investigators noted that on the basis of these findings, the 0.2-mg dose of naldemedine was selected to move into Phase III clinical trials.
The 2015 DDW meeting was packed with data on the latest advances in GI research. Only a small number of studies relevant to pharmacists were presented in this overview. Additional information from the 2015 DDW meeting can be accessed online at www.ddw.org.