Hepatitis B

May 1, 2017

Gilead Sciences released results of two ongoing phase III studies evaluating the safety and efficacy of daily Vemlidy (tenofovir alafenamide, TAF 25mg) in immune active patients and in patients switching from Gilead’s Viread (tenofovir disoproxil fumarate, TDF 300mg) for HBeAg-negative and HBeAg-positive chronic hepatitis B virus (HBV) infection with compensated liver disease. The two randomized, double-blinded studies (Studies 108 and 110) demonstrate continued advantages of treatment with Vemlidy over Viread between week 48 and week 96. Virologic response rates at week 96 were 90% (n=257/285) and 91% (n=127/140) in HBeAg-negative patients (Study 108) receiving Vemlidy and Viread, respectively. In HBeAg-positive patients (Study 110), virologic response rates at week 96 were 73% (n=423/581) and 75% (n=218/292) in the Vemlidy and Viread groups, respectively. In both studies, a greater percentage of patients taking Vemlidy achieved normalization of ALT levels relative to patients taking Viread as measured by both central laboratory criteria, and by the American Association for the Study of Liver Diseases (AASLD) criteria. Patients receiving Vemlidy also demonstrated ongoing benefits at week 96 in bone and renal safety parameters, including smaller declines from baseline in hip and spine bone mineral density (BMD) and smaller declines from baseline in estimated creatinine clearance compared with patients taking Viread in both studies. Similar rates of adverse events and low and similar rates of adverse events leading to discontinuation were observed in both treatment arms. Viral resistance analyses showed no resistance to Vemlidy or Viread at week 96.

May 16, 2016

Dynavax Technologies released results of a phase III trial comparing hepatitis B vaccine HEPLISAV-B with the vaccine Engerix-B in adults 18 to 70 years of age. HBV-23 was a randomized, observer-blinded, active-controlled, multicenter study. Participants were randomized to HEPLISAV-B or Engerix-B in a two to one ratio. They were stratified into two age groups, 18 to 39 years and 40 to 70 years. Two doses of HEPLISAV-B were given one month apart compared to the conventional Engerix-B regimen of three doses given over six months. HEPLISAV-B participants were followed for 52 weeks after the last dose, and Engerix-B participants were followed for 28 weeks after the last dose. HEPLISAV-B demonstrated statistically significant higher protection rates than Engerix-B in both age groups. The seroprotection rate in all participants who received HEPLISAV-B was 95% compared to 81% for Engerix-B. Of participants 18 to 39 years of age, 99% who received HEPLISAV-B and 93% who received Engerix-B were seroprotected. In participants 40 to 70 years of age, a larger difference in seroprotection rates was seen with the HEPLISAV-B rate of 95% compared to 79% for Engerix-B. The FDA has established September 15 as the Prescription Drug User Fee Act action date for the HEPLISAV-B Biologics License Application.

January 11, 2016

Gilead Sciences has reported results of two phase III studies (Studies 108 and 110) of tenofovir alafenamide (TAF) 25mg in treatment-naïve and treatment-experienced adults with HBeAg-negative and HBeAg-positive chronic hepatitis B virus (HBV) infection. Studies 108 and 110 are randomized, double-blind, 96-week clinical trials among 1,298 treatment-naïve and treatment-experienced patients with chronic HBV. In Study 108, 425 HBeAg-negative patients were randomized 2:1 to receive TAF (n=285) or Viread (n=140). In Study 110, 873 HBeAg-positive patients were randomized 2:1 to receive TAF (n=581) or Viread (n=292). In Study 108, evaluating HBeAg-negative patients, 94% (n=268/285) of patients receiving TAF and 92.9% (n=130/140; CI -3.6% to +7.2%, p=0.47) of patients receiving Viread achieved HBV DNA below 29 IU/mL at week 48. In Study 110, evaluating HBeAg-positive patients, 63.9% (n=371/581) of TAF patients and 66.8% (n=195/292; CI -9.8% to +2.6%, p=0.25) of Viread patients achieved HBV DNA below 29 IU/mL at week 48. Discontinuations due to adverse events were uncommon in both treatment arms (0.7% (n=2) for TAF v. 0.7% (n=1) for Viread in Study 108, and 1% (n=6) for TAF v. 1% (n=3) for Viread in Study 110). The most commonly reported adverse events in both studies included headache, upper respiratory tract infection, nasopharyngitis and cough, and occurred at similar rates in patients receiving either TAF or Viread. Gilead plans to submit regulatory applications for TAF for chronic HBV in the U.S. and the E.U. in the first quarter of 2016.

October 27, 2014

Hepatera reported results of two phase IIa studies of Myrcludex B in patients with chronic hepatitis B (HBV) and delta (HDV). A phase IIa trial investigating effects of several Myrcludex B doses in 40 patients with chronic HBV infection showed the drug was well-tolerated. A dose-dependent effect on HBV DNA was observed: >1 log10 HBV DNA decline at week 12 occurred in 6/8 (75%) patients receiving 10mg Myrcludex B, while this occurred less often in the remaining dose groups (7/40; 17%). The HBV DNA response was maintained in 10mg patients through week 24. In a phase IIa trial in chronic HDV infection with 24 patients, Myrcludex B was investigated as monotherapy v. combination with pegylated interferon alpha for 24 weeks; a control arm received pegylated interferon alpha alone. Myrcludex B was well-tolerated both as monotherapy and in combination with interferon. Myrcludex B has shown strong single agent efficacy against HDV. Six out of seven evaluable patients experienced >1 log10 HDV RNA decline at week 24; two patients became HDV RNA negative and in two others the values dropped below the limit of quantification. In the combination arm, all patients had HDV RNA decline and five were HDV RNA negative at week 24. Importantly, ALT normalized in four Myrcludex B monotherapy patients at week 24.

August 11, 2008

Dynavax and Merck issued positive results from a phase III trial of Heplisav for the treatment of hepatitis B. This study, dubbed PHAST (Phase 3 HeplisAv Short-regimen Trial) enrolled 2,427 subjects, aged 11 to 55 years, in Canada and Germany. The subjects received a two-dose regimen of Heplisav, administered at 0 and 1 month, or a three-dose regimen of Engerix-B, administered at 0, 1 and 6 months. The primary endpoint was the proportion of subjects who developed protective antibodies to hepatitis B after administration. Data revealed that 95.1% of subjects who received two doses of Heplisav developed protective antibodies to hepatitis B when measured at 12 weeks versus 81.1% of subjects who received three doses of Engerix-B when measured at 28 weeks. Further results re expected to be presented at an upcoming medical conference

July 2, 2007

Aspreva and Roche issued negative results from a phase III trial of CellCept for the treatment of lupus nephritis. This two-phase induction to maintenance study enrolled 370 subjects. It was designed as a randomized open label comparison of CellCept to intravenous cyclophosphamide (IVC) for the first six months (induction phase), followed by a double-blind comparison of CellCept to azathioprine for up to three years (maintenance phase). Treatment response in the induction phase was defined as a decrease in proteinuria and the stabilization or improvement of serum creatinine. Although response rates were similar between the two groups, the trial did not meet the primary endpoint of demonstrating that CellCept is superior to IVC in inducing treatment response. The response rate was 56.2% in the CellCept arm and 53% in the IVC arm. Treatment was well tolerated, with adverse events similar between the two arms. The maintenance phase of the trial is ongoing. Roche and Aspreva plan to further evaluate the data to determine the potential for a regulatory submission.

Gilead released positive results from a phase III trial of Viread for the treatment of "e" antigen (HBeAg)-positive chronic hepatitis B. This multi-center double-blind study, dubbed 103, enrolled 266 subjects who were randomized in a 2:1 ratio to receive either Viread (300 mg once daily) or Hepsera (10 mg once daily). The trial was designed to establish the non-inferiority of Viread to Hespera. The primary endpoint was the proportion of subjects with a complete response at week 48, defined by serum hepatitis B (HBV) DNA levels below 400 copies/mL and histologic improvement. This endpoint was achieved; 66.5% of subjects in the Viread arm had a complete response compared to 12.2% in the Hepsera arm (p less than 0.001), thus confirming non-inferiority. Adverse events were comparable between the two treatment arms. Based on the results, Gilead plans to file a NDA with the FDA and a MAA with the EMEA in the fourth quarter of 2007.

June 18, 2007

Gilead reported positive results from a phase III trial of Viread (tenofovir) for the treatment of chronic hepatitis B. This randomized, double-blind trial, dubbed 102, enrolled 375 subjects who were HBeAg-negative/anti-HBe positive. Subjects were placed in a 2:1 ratio to receive either tenofovir DF (300 mg once daily) or Hepsera, an FDA approved treatment (10 mg once daily), for 48 weeks. The primary endpoint was the proportion of subjects with a complete response at week 48, defined by serum HBV DNA levels below 400 copies/mL and histologic improvement characterized by at least a two point reduction in the Knodell necroinflammatory score. At 48 weeks, 70.8% of the subjects in the Viread arm had a complete response compared to 48.8% in the Hepsera arm (p less than 0.001). Adverse events were comparable between the two arms. A second phase III trial, Study 103, is currently underway, with results expected by the end of 2007.

Idenix issued positive results from a phase II trial of valopicitabine for the treatment of hepatitis C. This three-arm, partially blinded, randomized trial enrolled 117 treatment naïve, HCV genotype-1 subjects. Subjects in arm A received 200 mg/day of valopicitabine and pegylated interferon alpha 2a; subjects in arm B received 200 mg/day of valopicitabine, weight-based dosing of ribavirin, and pegylated interferon alpha 2a; and subjects in arm C received placebo, weight- based dosing of ribavirin and pegylated interferon alpha 2a (standard of care). The primary endpoint was to assess pharmacokinetic and pharmacodynamic drug-drug interaction between valopicitabine and ribavirin after 36 days of treatment. This was achieved; valopicitabine and ribavirin when administered alone or together were within the range of 80% to 125%, indicating the lack of interaction. The secondary endpoints of antiviral activity, safety and tolerability were met as well. In the subjects treated with triple combination therapy (arm B), 72.2% achieved HCV PCR-negativity, compared to 61.5% of subjects treated with the standard of care (arm C). Treatment was generally well tolerated, with three discontinuations due to adverse events. Based on the results, Idenix plans to move forward with the development of valopicitabine combination therapy.

April 3, 2006

Idenix and Novartis issued additional positive interim results of a phase III trial of telbivudine, for the treatment of chronic hepatitis B (CHB) infections, at the International Liver Congress in Shanghai. One-year data indicated that the drug significantly reduced HBV DNA levels by 6.22 log10, vs. 5.4 log10 for treatment with lamivudine (p<0.001). The drug also produced significantly higher rates of undetectable viral levels (70% vs. 43%; p<0.001) and clinical responses (HBV DNA levels below 5 log 10 copies/ml plus HBeAg loss or ALT normalization; 87% vs. 64%; p<0.001). This ongoing, randomized, double-blind study enrolled 332 Chinese CHB patients, the majority of whom were HBeAg-positive (n=290/332). Subjects were to receive treatment with telbivudine or the approved drug lamivudine through 2 years.

November 21, 2005

Valeant announced interim results of a phase II trial of pradefovir mesylate, for the treatment of hepatitis B (HBV) infections. Data from a planned interim analysis at 24 weeks indicated that 3 trial doses of the drug produced evidence of superiority to the approved drug Hepsera (adefovir dipivoxil), with a significantly greater portion of patients achieving undetectable viral load (<400 c/ml) at 10mg, 20mg and 30mg daily. Peak reduction was also superior, with a 5.02 log10 drop in viral titers from baseline for the 30 mg group, compared to 3.66 log10 for Hepsera (p<0.001). This open-label, randomized, multiple dose study enrolled 242 HBV patients at 21 sites in the US, Taiwan, Singapore and Korea; subjects received daily treatment with 10 mg Hespera or one of four regimens of pradefovir (5, 10, 20 or 30 mg) for 48 weeks.

August 8, 2005

Novartis and Idenix reported positive interim results of their phase III "GLOBE" trial of telbivudine, their oral nucleoside under investigation for the treatment of hepatitis B (HBV) infections. One-year data indicated that the drug met its primary composite efficacy endpoint, demonstrating statistical non- inferiority to the approved HBV treatment lamivudine, reducing serum HBV DNA load to below 100,000 copies/ml, and either improving liver function or reducing detectable hepatitis B e-antigen. This ongoing, randomized, double-blind, placebo-controlled study enrolled 1350 HBV patients across 130 sites worldwide, who were to receive either telbivudine (600 mg) or lamivudine (100 mg) daily for 2 years. Based on these interim results, the company announced plans to file an NDA to the FDA by the end of 2005, and an MAA to the EMEA in Q1 2006.

July 25, 2005

Valeant Pharmaceuticals, under license from Metabasis, reported positive interim results of a phase II study of their oral adefovir pro-drug pradefovir, for the treatment of hepatitis B (HBV) infections. Study data superiority in reducing mean viral load at 24 weeks; the magnitude of superiority was dose dependent (-3.39 log10 copies/ml, p=0.262 for 5 mg/day regimen; -4.22, p=0.012 for 10 mg/day; -4.33, p=0.004 for 20 mg/day; -5.02, p<0.001 for 30 mg/day; vs. -3.66 for approved therapy). No incidences of nephrotoxicity or serious adverse events were observed, and incidence of overall adverse events was not dose dependent and was similar across all study cohorts. This open-label, randomized, controlled multiple-dose study enrolled 242 HBV patients across 21 sites in the United States, Taiwan, Singapore and Korea. Subjects received one of 4 doses of pradefovir (5 mg, 10 mg, 20 mg or 30 mg) daily or approved treatment with Hespera (adefovir) (5 mg twice daily) for 48 weeks.

May 23, 2005

Idenix Pharmaceuticals reported positive data from a phase IIb trial of telbivudine, for the treatment of hepatitis B virus (HBV). Two-year results from the ongoing study indicated that monotherapy with the drug produced a 30 fold greater mean viral load reduction that approved therapy with lamivudine (71% vs. 32%, respectively; p<0.05). Telbivudine monotherapy also produced a significantly greater portion of subjects achieving normalization of liver enzymes than lamivudine (81% vs. 47%; p<0.05), and treatment failures occurred significantly less often (4.5% vs. 21%; p<0.05). This ongoing approved- therapy controlled extension study enrolled 104 subjects with HBV, who received telbivudine or lamivudine monotherapy or combination therapy with the two drugs for up to three years.

July 29, 2002

Study results indicate that Zadaxin (thymalfasin) effectively treats hepatitis B subjects in the immune-tolerant phase of viral infection. After 26 weeks of therapy and 52 weeks of follow-up observation, 15.6% of 32 subjects demonstrated a complete response to Zadaxin therapy in combination with famciclovir, a nucleoside analogue. In contrast, there were no responders among the 32 subjects in each group that received either famciclovir monotherapy or placebo. A successful response was defined as a sustained seroconversion of hepatitis B e-antigen and the disappearance of hepatitis B viral DNA. Zadaxin is being developed by SciClone Pharmaceuticals.

January 14, 2002

Positive results were reported from a phase I trial of ACH-126,443 (beta-L-Fd4C), an L-nucleoside analog with in vitro activity against chronic hepatitis B and human immunodeficiency virus. The trial was designed to evaluate six dose levels of the drug in healthy subjects. Pharmacokinetic results demonstrated ideal absorption of the compound into the bloodstream, and the data supports once daily dosing. ACH-126,443 is being developed by Achillion Pharmaceuticals.

Statistically significant preliminary results were reported from an ongoing phase III trial of Corixa's RC-529 synthetic adjuvant in combination with Rhein Biotech's hepatitis B vaccine. The trial was designed to compare vaccination with the hepatitis B vaccine plus the RC-529 adjuvant to vaccination with the vaccine alone in healthy adults who were not immune to hepatitis B virus (HBV). A total of 285 subjects received at least one vaccination, and 272 of these subjects were evaluated for efficacy. Results showed that there were significantly more subjects seroprotected after two immunizations with the hepatitis B vaccine plus RC-529 than with the vaccine alone (95.5% versus 82.1%). Analysis of secondary efficacy endpoints, such as seroconversion rates at days 30 and 60, also showed a statistically significant benefit in favor of the RC-529/vaccine combination.

January 7, 2002

Phase I/II trial results indicate that Novirio Pharmaceuticals' LdT produced a reduction of hepatitis B virus replication at all dose levels, and a median reduction of 3.63 log10 among subjects taking the highest dose evaluated to date (400 mg once-daily for four weeks). The randomized 30-subject trial was designed to evaluate the safety and short-term antiviral activity of LdT in adults with chronic hepatitis B, as well as assess optimal dosing levels for future trials. Results suggested greater than 1,000-fold reductions in serum virus load for subjects receiving daily LdT doses of 100 mg or more. Based on the increased antiviral activity observed with increasing LdT doses, along with positive safety results, the company is adding an additional subject cohort to the trial to evaluate higher dose levels.

Positive results from a phase I/II trial indicate that immunization with hepatitis B surface antigen, (HbsAg) co-administered with Dynavax's proprietary immunostimulatory DNA sequences (ISS), produced protective antibody levels in 31 of 32 subjects over all dose levels. During the two-month double-blind study, 48 subjects received two immunizations. After a single immunization at the highest dose tested, the vaccine produced protective antibodies in 88% of treatment subjects. Currently available vaccines for the treatment of hepatitis B require three vaccinations over a six-month period to achieve the response seen with this vaccine regimen. This combination vaccine is being jointly developed by Dynavax Technologies and Triangle Pharmaceuticals.