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Meeting Highlights

11th European Congress on Osteoporosis and Osteoarthritis and International Liver Congress 2011

46th European Association for the Study of the Liver
Walter Alexander

More than 5,500 participants from around the world gathered in Valencia, Spain, from March 23 to 26, 2011, to attend ECCEO, the largest annual event in Europe for the dissemination of significant clinical research in osteoporosis and osteoarthritis. New data for strontium ranelate in bone formation created the most “buzz” at the meeting, and based on this information, the manufacturer is seeking a partner for a licensing application in the U.S. Summaries from three key ECCEO presentations follow.

11th European Congress on Osteoporosis and Osteoarthritis

Strontium Ranelate (Protelos) and Bone Formation After 6 and 12 Months: Histomorphometric Analysis

  • Roland Chapurlat, MD, PhD, Hôpital Edouard Herriot, Lyon, France

After 12 months of treatment, bone formation was found to be significantly higher in postmenopausal women receiving strontium ranelate (Protelos, Servier) compared with those receiving alendronate (Fosamax, Merck). The effect increased during therapy, according to data from the largest bone biopsy study to date of strontium ranelate versus alendronate in this population.

“We know that most available drugs that we use in osteoporosis treat bone degradation, but strontium ranelate is notable and promising because it increases markers of bone formation,” Dr. Chapurlat said in a press briefing. “This translated into better bone health for these patients.”

Patients (n = 387) in the double-blind trial were randomly assigned to receive strontium ranelate 2 g/day (n = 256) or alendronate 70 mg/week (n = 131). All patients underwent transiliac bone biopsies at baseline and after six months or 12 months of treatment.

Researchers obtained 785 bone biopsies, and 84% of these were evaluable. They created 268 paired biopsies: 179 for strontium ranelate (90 for six months and 89 for 12 months) and 89 for alendronate (43 for six months and 46 for 12 months). Paired biopsies were used for the primary analysis. Baseline patient characteristics (age, lumbar score, and duration of menopause) were similar between the paired subjects.

The primary endpoint was the mean difference between treatment groups in mineralizing surfaces after six or 12 months. Dr. Charpulat reported that after six months, mineralizing surface, expressed as a percentage of bone surface (MS/BS), was 2.94% with strontium ranelate and 0.20% with alendronate, representing a highly statistically significant between-group difference of 2.73% (P < 0.001). The comparative treatment effect of strontium ranelate increased to 4.65% (P < 0.001) after 12 months, with patients achieving MS/BS values of 4.91% for strontium ranelate and 0.28% for alendronate.

Protelos is approved in Europe and is available in more than 50 countries. The research was supported by Servier.

Once-Yearly Zoledronic Acid (Zometa) After Hip Fracture in Men: The HORIZON–RFT Trial

  • Steven Boonen, MD, PhD, Professor of Medicine, Leuven University and Clinical Director, Leuven University Center for Metabolic Bone Diseases, Leuven, Belgium

Following repair of a low-trauma hip fracture, an annual infusion of zoledronic acid (Zometa, Novartis) 5 mg, initiated within 90 days, significantly increased total hip bone mineral density (BMD) in men.

“The new data showed consistently that men respond to this treatment as well as women,” said Dr. Boonen.

The Novartis-supported study was a subanalysis of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Recurrent Fracture Trial (HORIZON–RFT), a double-blind, placebo-controlled trial among 2,127 subjects with a recent low-trauma hip fracture.

Investigators randomly assigned 508 men 50 years of age or older to receive either once-yearly intravenous (IV) zoledronic acid 5 mg (n = 248) or placebo (n = 260) within 90 days after surgical hip repair. All patients received daily oral calcium (1,000 to 1, 500 mg) and vitamin D (800 to 1,200 IU).

Primary endpoints were changes in total hip BMD and the incidence of new clinical fractures at the 24th month.

Dr. Boonen reported that changes in total hip BMD at month 24 were significantly greater with zoledronic acid (3.81%; P = 0.0021) than with placebo. Notably, at month 24, total hip BMD increased with zoledronic acid but decreased with placebo (3.59% vs. −0.22%, respectively).

At one and three years, respectively, there were significantly greater increases in total hip BMD among subjects receiving zoledronic acid (2.01% and 7.06% at months 12 and 36, respectively; both P < 0.005 vs. placebo).

Thirty-six men (7.1%) had experienced new clinical fractures at month 24; 16 received zoledronic acid, and 20 received placebo. Cumulative 24-month clinical fracture event rates were 7.45% and 8.70% for zoledronic acid and placebo, respectively.

Adverse events (AEs) and serious AEs were comparable between the two treatment groups.

Dr. Boonen noted that despite differences in other comorbidities between the men and women during the 24 months of the HORIZON trial, there was no significant sex-related difference in the efficacy of zoledronic acid in fracture prevention.

Five Years of Denosumab (Prolia) In Postmenopausal Osteoporosis: First Two Years of FREEDOM Trial Extension

  • Socrates Papapoulos, MD, Professor of Medicine, Leiden University Medical Center, Leiden, The Netherlands

Therapy with denosumab injection (Prolia, Amgen) in postmenopausal women with osteoporosis for five years safely maintained the reduction in bone turnover seen at three years, with bone mineral density (BMD) increasing as time passed. These findings were reported from an ongoing, open-label extension study of the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months (FREEDOM) trial.

“Denosumab remained well tolerated, showing an adverse events profile similar in years 4 and 5 of the extension study to that observed in the three years of the placebo-controlled FREEDOM study,” said Dr. Papapoulos.

FREEDOM investigators enrolled 70.2% of the original cohort of 4,550 patients in the extension, including 2,343 patients receiving denosumab (the long-term group) and 2,207 placebo crossover subjects who began denosumab treatment in the extension (the de novo group).

For the long-term FREEDOM patients receiving denosumab, the new findings represent five years of denosumab treatment. For the FREEDOM placebo/de novo group, the findings represent two years of denosumab treatment. The extension period is scheduled to continue for another five years. During the open-label extension, all subjects received denosumab 60 mg every six months as well as calcium and vitamin D daily.

During the fourth and fifth years of the extension, denosumab treatment in the long-term group resulted in further cumulative increases of 1.9% and 1.7% in the lumbar spine, respectively, and in further cumulative increases of 0.7% and 0.6% in total hip BMD, respectively. All measures showed significant improvement (P < 0.0001) compared with the long-term group at baseline in the extension study.

After five years of denosumab therapy, the long-term group achieved total BMD increases of 13.7% in the lumbar spine and 7% in the total hip. During the first two years of denosumab treatment, the de novo group achieved a BMD increase of 7.9% in the lumbar spine and 4.1% in the total hip (P < 0.0001 for both), compared with measures at baseline in the extension.

New vertebral and nonvertebral fracture rates were below those reported earlier in the FREEDOM placebo group. Treatment with denosumab also led to a rapid reduction of carboxyterminal collagen (CTC) cross-links, a marker of bone turnover, in both groups.

Reporting drug safety during the extension period, Dr. Papapoulos noted that rates of AEs were lower for denosumab in the extension trial than in the three years of FREEDOM. In the extension trial, the AE rate was 83.4% for long-term subjects, with 18.9% reported as serious. In the de novo group, 82.8% reported AEs; among these, 19.4% were serious.

In FREEDOM, 92.8% of denosumab subjects reported AEs, with serious AEs occurring at a rate of 25.8%. In the FREEDOM placebo group, rates of overall AEs and serious AEs were 93.1% and 25.1%, respectively.

Dr. Papapoulos emphasized the positive safety findings after two years of the extension trial.

“We saw no cumulative effect in the incidence of adverse events with the prolongation of treatment,” he said. “Importantly, the rates for infections and malignancies at five years have not increased,” he added.

He concluded, “Denosumab treatment for two years in the crossover group confirmed the original findings of FREEDOM.”

The research was supported by Amgen.

International Liver Congress 2011

46th European Association For the Study of the Liver

At this year’s International Liver Congress/EASL meeting, interest was high for sessions on two protease inhibitors for hepatitis C viral infection, both granted priority review status by the FDA. Launches for both boceprevir (Victrelis) and telaprevir (VX-950), although still subject to FDA approval, are widely anticipated for June of this year. More than 8,000 delegates attended the meeting in Berlin from March 30 to April 2, 2011.

Boceprevir (Victrelis) Plus Standard of Care In Hepatitis C Virus Genotype 1 Infection: Subgroup Analysis of HCV SPRINT-2 And HCV RESPOND-2

  • Savino Bruno, MD, Azienda Ospedaliera Fatebenefratellie Oftalmico, Internal Medicine and Liver Unit, Milan, Italy

HCV genotype 1 infection is the most common and least responsive form of HCV. Recently published phase 3 results from two studies—HCV RESPOND-2 (Re-treatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol-2) and HCV SPRINT-2 (Serine Protease Inhibitor Therapy-2), respectively—showed significantly increased rates of sustained viral responses with the addition of boceprevir (Victrelis, Merck) to the standard of care.1 Standard care consists of peginterferon (pegylated interferon) alfa-2b (PegIntron) plus ribavirin (Rebetol), Schering/Merck) in both treatment-naive patients and in those with previously treated HCV infections. Sustained viral response is defined as undetectable HCV–RNA counts at 24 weeks of therapy and is considered to represent a cure.

In these studies, all patients receiving boceprevir were treated with a four-week lead-in of peginterferon alfa-2b at 1.5 mcg/kg per week and an investigational dose of ribavirin (600–1,400 mg/day) prior to the addition of boceprevir 800 mg three times daily. Patients were randomly assigned to one of three arms:

  • Arm 1 received placebo plus peginterferon alfa-2b/ribavirin (PR) for 48 weeks (PR48)
  • Arm 2 received boceprevir plus PR (boceprevir/PR48)
  • Arm 3, a response-guided therapy (RGT) group, received boceprevir plus PR and, in some, placebo plus PR, determined by HCV–RNA responses at the eighth week (boceprevir/RGT).

Dr. Bruno noted that patients with advanced liver disease who have received PR commonly experience lower virological response rates and more AEs than patients with less fibrosis. This group often experiences more disease progression, decompensation, hepatocellular carcinoma, and liver-related mortality. To determine the effects of disease severity on responses to therapy and safety, Dr. Bruno and colleagues conducted a subgroup analysis of patients who were enrolled in SPRINT-2 and RESPOND-2. Patients were stratified according to their fibrosis and cirrhosis status.

Disease severity was rated via Metavir fibrosis scores as follows: F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = portal fibrosis with few septa, F3 = numerous septa without cirrhosis, and F4 = cirrhosis. Among the 1,097 patients (mean age, 49 years) in SPRINT-2, 100 had advanced disease (F3 and F4). Among 403 patients (mean age, 53 years) in RESPOND-2, 78 had advanced disease.

Dr. Bruno reported that among previously treated patients in SPRINT-2 with milder disease (F0, F1, and F2), sustained viral response rates were 67% for both boceprevir-containing regimens and 38% for PR48. In the F3 and F4 groups, these rates were 41% and 52% for boceprevir/RGT and boceprevir/PR48, respectively, and 38% for PR48. The 38% sustained viral response rate for the placebo group, Dr. Bruno commented, was unusually high.

“We presume that this may be explained by the low number of patients in the study,” he said.

In patients with scores of F0, F1, and F2, relapse rates were 9% for each of the boceprevir groups and 22% for PR48. Among patients with F3 and F4 scores, relapse rates were 18% for boceprevir/RGT, 12% for boceprevir/PR48, and 25% for PR48.

In treatment-naive patients in RESPOND-2, sustained viral response rates were 66% and 67% for the two boceprevir-containing regimens and 23% for PR48 in the F0, F1, and F2 scoring groups. In the more severely ill F3 and F4 groups, sustained viral response rates were 44% for boceprevir/RGT, 68% for boceprevir/PR48, and 13% for PR48. Relapse rates were 33% in both placebo groups and 12% and 10% for the F0, F1, and F2 groups receiving boceprevir/RGT and boceprevir/PR48, respectively. In patients with F3 and F4 scores, relapse rates were 28% for boceprevir/RGT and 16% for boceprevir/PR48.

Lead-in response status by week 4 strongly predicted ultimate responses in the F3 and F4 patients. Although 77% and 87% of early responders achieved sustained viral responses (≥1.0 log10 decline in HCV–RNA levels) in the SPRINT-2 and RESPOND-2 boceprevir/PR48 groups, no patients among those with below a 1.0 log10 decline in the PR48 group achieved sustained viral responses in either trial by week 4.

In SPRINT-2, patients with F0, F1, and F2 scores and F3 and F4 patients with a sustained viral response by week 8 (early responders) achieved high ultimate sustained viral response rates (98% for boceprevir/RGT and 96% for boceprevir/PR48, respectively, and 75% for boceprevir/RGT and 92% for boceprevir/PR48, respectively). Sustained viral response rates in those with positive HCV–RNA status at week 8 were in the 75% range for F0 to F2 scores and in the range of 54% for F3 and F4 scores.

In RESPOND-2, the pattern was similar; however, sustained viral response rates were lower, down to approximately 25% for late responders with scores of F3 and F4.

Serious AEs experienced with the boceprevir-containing regimens were reported in 11% of patients with F0 to F2 scores and in 15% of patients with F3 and F4 scores. The discontinuation rate was approximately 12.5% for both regimens. The most common AEs attributed to boceprevir were anemia (in 50%) and dysgeusia (in 42.5%).

Dr. Bruno concluded that boceprevir, when added to the standard of care, increased sustained viral response rates numerically in SPRINT-2 and significantly in RESPOND-2 for both previous nonresponders and relapsers.

“In patients with early response to boceprevir, the sustained viral response rates are very high, regardless of advanced fibrosis,” he said.

Boceprevir (Victrelis) Plus Peginterferon alfa-2a/Ribavirin in Re-treatment of Nonresponding And Relapsed Patients With Hepatitis C Virus Genotype 1 Infection

  • Steven Flamm, MD, Professor of Medicine and Surgery, Northwestern Feinberg School of Medicine, Chicago, Ill.

In patients with genotype 1 HCV infections, high sustained viral response rates were reported when Merck’s boceprevir (Victrelis) was added to peginterferon alfa-2b (PegIntron, PEG-2b) and ribavirin (Rebetol) in recently published findings from the phase 3 RESPOND-2 trial by Bacon et al.1 All patients included in RESPOND-2 had been nonresponders or relapsers with prior interferon plus ribavirin treatment. In about 75% of HCV cases, however, peginterferon alfa-2a (PEG-2a) (Pegasys, Genentech/Roche), a second and different interferon, is used in the U.S. and elsewhere, Dr. Flamm said in an interview.

No significant differences in rates of sustained viral response or tolerability were found between the two interferons in a recent large phase 3 HCV genotype 1 study by McHutchison et al.2

“The problem is that almost all of the phase 3 studies have paired the new protease inhibitors with peginterferon alfa-2b,” Dr. Flamm said. “This is the first large-scale trial to look at boceprevir with PEG-2a. It’s important to establish that boceprevir also works with this other pegylated product.”

In the double-blind, placebo-controlled trial, 201 relapsing and nonresponding patients with HCV genotype 1 infection were randomly assigned, in a 1:2 ratio, to two arms:

  • Arm 1 (controls, N = 67) received a four-week lead-in of PEG-2a/ribavirin, followed by placebo plus PEG-2a/ribavirin for 44 weeks.
  • Arm 2 patients (N = 134) received a four-week lead-in of PEG-2a/ribavirin, followed by boceprevir plus PEG-2a/ribavirin for 44 weeks.

Patients with detectable HCV–RNA counts at week 12 were withdrawn from treatment for virological futility. The primary endpoint was sustained viral response after 24 weeks of therapy. Significantly more patients achieved sustained viral responses with boceprevir plus PEG2a/ribavirin (64%) than with placebo plus PEG-2a/ribavirin (21%) (P < 0.0001). All of these rates were consistent with RESPOND-2 findings. Relapse rates were higher for controls (33%), compared with those receiving boceprevir plus PEG-2a/ribavirin (12%).

HCV–RNA levels, which became undetectable by week 8, were a strong predictor of sustained viral response. When that occurred, these rates were 89% for boceprevir plus PEG-2a/ribavirin and 44% for PEG-2a/ribavirin. For patients with detectable HCV–RNA levels at week 8, sustained viral response rates were 42% for boceprevir plus PEG-2a/ribavirin and 16% for PEG-2a/ribavirin.

Also consistent with RESPOND-2 results, responses at week 4 were even stronger predictors of sustained viral response (odds ratio, 6.6; P = 0.0023) than historical responses to treatment (odds ratio, 3.3; P = 0.0066).

Discontinuations and dose modifications resulting from AEs were higher for the patients receiving the boceprevir-containing regimen. Because of discontinuations for virological futility, however, the proportion of patients continuing with treatment at week 20 was substantially lower in the PEG-2a/ribavirin control arm (31% vs. 72% for boceprevir plus PEG-2a/ribavirin).

“Boceprevir is safe and effective with both peginterferon alfa-2a and 2b,” Dr. Flamm concluded.

He commented on the significance of the anticipated approval of this agent. “Many of these people are desperate, and there’s nothing else we can do for them until we have a new treatment,” he said.

Dr. Flamm disclosed that he has relationships with Merck, Vertex, Gilead, Achillion, Anadys, Pfizer, and Abbott.

Telaprevir for Hepatitis C Virus Genotype 1 Infection in Patients Not Responding to Peginterferon/Ribavirin: REALIZE Final Results

  • Stefan Zeuzem, MD, Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany
  • Mark Thursz, MD, Professor of Hepatology, Imperial College, London, UK; and Vice-Secretary, EASL Meeting

Treatment of HCV genotype 1 infection with the current standard of care—pegylated interferon alfa-2a (PEG-2a) (Pegasys) and ribavirin (Rebetol)—fails in about 60% of patients. Adding telaprevir (VX-950, Vertex) to PEG-2a/ribavirin has been found to substantially increase rates of sustained viral responses (Table 1).

The phase 3 REALIZE trial (Re-treatment of Patients with Telaprevir-Based Regimen to Optimize Outcomes) evaluated telaprevir in 662 patients whose responses to prior PEG-2a/ribavirin therapy had been null or partial or who experienced relapse after an initial response. The primary objective was to evaluate the proportion of these patients achieving sustained viral responses, defined as undetectable plasma HCV–RNA counts at 24 weeks after the last planned intake of the study medication. The sustained viral response is considered to represent a cure for HCV infection.

Patients in REALIZE, an international, multicenter, double-blind, placebo-controlled trial, were assigned to one of two telaprevir-containing regimens or to a PEG-2a/ribavirin plus placebo group:

  • Arms 1 and 2: Regimens included 12 weeks of telaprevir 750 mg every eight hours plus PEG-2a 180 mcg/week plus ribavirin 1,000 to 1,200 mg/day, one with the four-week PEG-2a/ribavirin plus placebo lead-in (LIT12/PR48) and one followed by four weeks of PEG-2a/ribavirin plus placebo (T12/PR48). Both regimens were followed by PEG-2a/ribavirin in weeks 16 to 48.
  • Arm 3: Patients received PEG-2a/ribavirin plus placebo for 16 weeks, followed by PEG-2a/ribavirin in weeks 16 to 48 (PR48).
Follow-up continued for all arms until the sustained viral response was assessed at week 72.

Null responders, partial responders, and relapsed patients constituted approximately 28%, 19%, and 54% of the cohort, respectively. Nearly 50% of patients were in advanced stages of disease. The median age was 51 years, and 70% of the patients were men. Sustained viral response rates were significantly higher for those receiving the telaprevir regimen (see Table 1).

The four-week PEG-2a/ribavirin lead-in phase resulted in no reductions in virological failure or relapse rates and in no improvements in sustained viral responses. Relapse rates were 10% each for the two telaprevir-containing arms and 23% for the placebo/PR48 arm.

Sustained viral response rates were higher for prior partial responders (56.5% for telaprevir-containing regimens, 15% for PR48) than for prior null responders (31% for telaprevir-containing regimens, 5% for PR48).

Reporting the most common AEs during any treatment phase, Dr. Zeuzem said that fatigue occurred in 55% of those receiving T12/PR48, in 50% receiving LIT12/PR48, and in 40% receiving placebo/PR48. Pruritus affected 52% of the T12/PR48 patients, 50% of the LIT12/PR48 subjects, and 427% of patients receiving placebo/PR48.

Anal pruritus, anorectal discomfort, and hemorrhoids were reported in 28% of patients receiving T12/PR48, in 22% receiving LIT12/PR48, and in 8% receiving placebo/PR48. For each of these AEs and for anemia, rash, nausea, and diarrhea, the incidence was more than 10% greater in the telaprevir arms than in the placebo/PR48 arm.

Discontinuations of all study drugs during telaprevir treatment occurred in 29% of patients. The most common causes were rash (5% with T12/PR48, 4% with LIT12/PR48, and 0% with placebo/PR48) and anemia (2% with T12/PR48, 3% with LIT12/PR48, and 0% with placebo/PR48).

Dr. Zeuzem concluded, “Telaprevir plus PEG-2a/ribavirin was superior to PEG-2a/ribavirin alone in treatment-experienced populations, including prior relapsers, partial responders, and null responders.”

Dr. Thursz commented: “These are really exciting results for this particularly difficult-to-treat group of patients. Over 60% achieved a sustained viral response.”

Dr. Zeuzem disclosed that he has relationships with Abbott, Achillion, Anadys, Bristol-Myers Squibb, Gilead, iTherX, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, and Vertex. Dr. Thursz reported that he has no relevant industry relationships to disclose.

Table

Sustained Viral Response Rates in Prior Relapsed and Nonresponsive Patients In the REALIZE Trial

T12/PR48 LIT12/PR48 PR48 PValue vs. PR48
Prior relapse 83% 88% 24% P < 0.001 P < 0.001
Prior nonresponse 41% 41% 9% P < 0.001 P < 0.001

REALIZE = Re-treatment of Patients with Telaprevir-Based Regimen to Optimize Outcomes; T12/PR48 = 4 weeks of PEG-2a/ribavirin plus placebo; LIT12/PR48 = 4-week lead-in with PEG-2a/ribavirin plus placebo; PR48 = placebo plus peg-2a/ribavirin.

References

  1. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–1217.
  2. McHutchison JG, Lawitz E, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–593.erratum 2009;361:1027.