November 9, 2010

Look out, your medicine is watching you

By Ben Hirschler
NEW YORK
Tue Nov 9, 2010 8:18am EST

NEW YORK (Reuters) - Novartis AG plans to seek regulatory approval within 18 months for a pioneering tablet containing an embedded microchip, bringing the concept of "smart-pill" technology a step closer.

The initial program will use one of the Swiss firm's established drugs taken by transplant patients to avoid organ rejection. But Trevor Mundel, global head of development, believes the concept can be applied to many other pills.

"We are taking forward this transplant drug with a chip and we hope within the next 18 months to have something that we will be able to submit to the regulators, at least in Europe," Mundel told the Reuters Health Summit in New York.

"I see the promise as going much beyond that," he added.

Novartis agreed in January to spend $24 million to secure access to chip-in-a-pill technology developed by privately owned Proteus Biomedical of Redwood City, California, putting it ahead of rivals.

The biotech start-up's ingestible chips are activated by stomach acid and send information to a small patch worn on the patient's skin, which can transmit data to a smartphone or send it over the Internet to a doctor.

Mundel said the initial project was focused on ensuring that patients took drugs at the right time and got the dose they needed -- a key issue for people after kidney and other transplant operations, when treatment frequently needs adjustment.

Longer-term, he hopes to expand the "smart pill" concept to other types of medicine and use the wealth of biometric information the Proteus chip can collect, from heart rate and temperature to body movement, to check that drugs are working properly.

Because the tiny chips are added to existing drugs, Novartis does not expect to have to conduct full-scale clinical trials to prove the new products work. Instead, it aims to do so-called bioequivalence tests to show they are the same as the original.

A bigger issue may be what checks should be put in place to protect patients' personal medical data as it is transmitted from inside their bodies by wireless and Bluetooth.

"The regulators all like the concept and have been very encouraging. But ... they want to understand how we are going to solve the data privacy issues," Mundel said.

A technology that ensures a patient takes his or her medicine and checks that it is working properly should deliver better outcomes and justify a higher price tag.

(Reporting by Ben Hirschler. Editing by Robert MacMillan)

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Bob Roehr

November 9, 2010 (Boston, Massachusetts) — Boceprevir is a protease inhibitor that targets the hepatitis C virus (HCV). When added to the standard of care (pegylated-interferon alfa-2b and ribavirin), boceprevir improved the sustained viral response (SVR) rate approximately 70% over standard of care alone, according to the final results from the SPRINT-2 trial, reported here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.

The SPRINT-1 findings were published in August, as reported by Medscape Medical News at that time.

Principal investigator Fred Poordad, MD, chief of hepatology at Cedars-Sinai Hospital in Los Angeles, California, presented the SPRINT-2 final results. The researchers evaluated the effect of the triple-drug regimen on patients with HCV genotype 1, and conducted a separate analysis of the treatment effect in black patients. SVR rates have been below 50% in HCV genotype 1 patients, especially in those of African descent, Dr. Poordad noted.

The study had a 3-group design that included a 4-week lead-in of standard of care before adding boceprevir, and response-guided therapy to determine the overall duration of therapy for responders. After the initial lead-in period, the control group received standard of care plus placebo for 44 weeks; the 44-week boceprevir group received boceprevir plus standard of care for 44 weeks; and the response-guided therapy group received boceprevir plus standard of care for 24 weeks, with an additional 20 weeks of standard of care only if HCV RNA was detectable during weeks 8 to 24. Patients with detectable HCV RNA at week 24 were withdrawn from the study.

The pegylated-interferon alfa-2b dose was 1.5 μg/kg subcutaneously once a week; ribavirin dose was weight-based (600 to 1400 mg/day) twice daily, orally; boceprevir dose was 800 mg orally 3 times a day.

The SVR in nonblack patients was 40% in the control group, 67% in the response-guided therapy group, and 68% in the 44-week boceprevir group.

Dr. Poordad said that although "the relapse rate in the control arm was 23%, it was less than 10% for patients receiving boceprevir."

The SVR in the black patient cohort was 23% in the control group, 42% in the response-guided therapy group, and 53% in the 44-week boceprevir group. "Relapse rates were slightly higher than [in nonblacks], roughly the same across all 3 arms, ranging from 12% to 17%," Dr. Poordad said.

"At the end of lead-in [week 4], the viral load measurement predicted quite well who would ultimately respond. Patients who had greater than a 1 log decline at the end of the lead-in phase, if they received boceprevir, ultimately had over an 80% SVR. The control arm had a 52% SVR," he reported.

"Conversely, patients who did not achieve a 1 log decline in the control arm had a 5% SVR; [it was] 29% to 39% in those receiving boceprevir."

Resistance mutations to boceprevir developed in 4% of the more rapid responders. Dr. Poordad said that "patients who had less than a 1 log decline at the end of lead-in ended up with 35% to 47% resistance using population sequencing. This is likely an underestimate of the overall development of resistance associated variants."

Adverse events were higher in the boceprevir groups than in the control group — most notably anemia (20% more likely) and dysgeusia (19% to 25% more likely). Discontinuation because of anemia was less than 2%, but erythropoetin (EPO) use was 19% more in the boceprevir groups than in the control group.

When pressed, Dr. Poordad noted that "this is a problem with all of the protease inhibitors." He said the sponsor provided EPO for use at the discretion of the physician, and acknowledged that most insurance carriers do not cover such use, which could affect clinical practice. He added that "there is an ongoing studying looking at SVR with and without EPO use."

Boceprevir has a low barrier to the emergence of resistance by the virus. The sponsor has adopted the strategy of a 4-week lead-in of standard of care to knock down levels of viremia before boceprevir is added, to minimize the risk of resistance emerging. Boceprevir and telaprevir share resistance points and cannot be rescued by the other, the researcher noted.

Medscape Medical News asked Michael Fried, MD, from the University of North Carolina at Chapel Hill, if it might make sense to re-evaluate patients at this point on whether those with a rapid virological response (HCV RNA <50 IU/mL at week 4) and undetectable HCV RNA level on standard of care really need a third drug.

He hedged a bit in responding: "The problem is that such a small percentage of patients have [rapid virological responses]. With genotype 1 in the United States, it might be 5%. But you have to wait and see what happens with the final results. Then you can adapt with your patient. I don't think it is appropriate to make blanket statements."

Scott L. Friedman, MD, a hepatologist at Mount Sinai School of Medicine in New York City, and immediate past president of AASLD, believes that third-party payers will play a role in determining the staging of therapy through what they are willing to cover. They will ask: "Do you really need to incorporate a very expensive new drug when you have a marker that tells you your standard of care is going to be highly effective?"

SPRINT-2 investigators are predicting that boceprevir will likely to be approved by the US Food and Drug Administration in 2011.

The SPRINT trials were sponsored by Schering-Plough, now part of Merck. Dr. Poordad and Dr. Fried report extensive financial ties with most of the major companies involved in HCV research. Dr. Friedman has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-4. Presented November 1, 2010.

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Bob Roehr

November 9, 2010 (Boston, Massachusetts) — The second wave of hepatitis C virus (HCV) protease inhibitors includes TMC435, an NS3/4A protease inhibitor being developed by Tibotec/Johnson & Johnson. The compound has a 40-hour half life, which makes it amenable to once-a-day dosing.

Michael Fried, MD, from the University of North Carolina at Chapel Hill, presented an interim 24-week analysis of the ongoing phase 2b Protease Inhibitor TMC435 Trial Assessing the Optimal Dose and Duration as Once Daily Anti-Viral Regimen (PILLAR) here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.

All 386 patients received a backbone regimen of standard of care, consisting of pegylated-interferon plus ribavirin, for 24 weeks, and were then randomized to add either 75 mg or 150 mg oral TMC435 once daily for 12 or 24 weeks. The fifth group received standard of care for only 48 weeks. Each study group consisted of 75 to 79 patients.

A response-guided treatment algorithm allowed patients in the TMC435 groups to discontinue therapy at week 24 "if they had HCV RNA [levels] less than 25 IU and were also undetectable at treatment weeks 12, 16, and 20. Patients who did not meet these virological criteria were eligible to continue pegylated-interferon and ribavirin for up to 48 weeks," Dr. Fried said. All patients are being followed for 72 weeks.

The primary end point was sustained virologic response. Secondary end points included assessment of antiviral activity, viral breakthrough, safety, tolerability, and IL28B status. Patients were stratified by race and HCV genotype (1a vs 1b).

The study population had a strong female presence (44.8%), was predominately white (93.8%), had a median age of 46.5 years, and had a body mass index of 25.0 kg/m2. The viral load was high; in 85.8%, HCV RNA level was 800,000 IU/mL or higher. Cirrhosis was an exclusionary factor, but fibrosis was present in 13.7% of patients.

Dr. Fried said that all TMC435 groups "had a rapid and steep decline in HCV RNA during the first 4 weeks of treatment that was maintained throughout the 12- or 24-week dosing period."

A more than 5 log decline in viremia was recorded by week 2 in patients in the TMC435 groups, which was maintained throughout the course of treatment. In contrast, the control group showed a much slower slope of decline, needing about 8 weeks to achieve a 4 log decline, and it never achieved the same depth of decline in HCV RNA as the TMC435 groups.

The portion of patients with very low or undetectable HCV RNA (<25 IU/mL) at week 4 ranged from 88% to 96% in the TMC435 groups, compared with 16% in the control group. At week 12, undetectable HCV RNA was recorded in 91% of those randomized to 12 weeks of TMC435 treatment, 97% in those randomized to 24 weeks of TMC435, and 69% in those randomized to the control group, respectively. At week 24, the numbers were 94%, 97%, and 82%, respectively, he said.

"According to the response-guided treatment algorithm used in the study, between 79% and 86% of patients in the TMC435 arms were able to discontinue treatment at week 24 by achieving the defined biological response criteria," said Dr. Fried. Patients in the control group have not yet completed their longer course of therapy.

A subset of nearly half of the patients on TMC435, with sustained virologic responses ranging from 88% to 97%, had completed all treatment and were available for week 12 follow-up evaluation.

Viral breakthrough by week 24 occurred in 2.5% to 7.8% of the TMC435 groups, compared with 3.9% of the control group. There was no correlation between dose of the drug and breakthrough, although patients on the longer course of treatment did have lower rates of breakthrough.

A retrospective analysis by IL28B genotype showed that TMC435 did increase response rates across all genotypes, and it narrowed the differences between the 3 genetic variations. It also confirmed that those with the CC allele perform better than those with the CT or TT alleles. The higher dose of TMC435 appears to result in a slightly deeper suppression of viremia than the lower dose, particularly among those with the TT allele. Dr. Fried said.

Treatment breakthroughs "were mostly in the CT and TT [allelic] groups" and were less likely to occur in the higher-dose groups, Dr. Fried reported. Resistance was most often found at points "155, 80, and some unique ones at the 168 residue" of the HCV genotype, he added. This provides some encouragement that regimens containing TMC435 will help ameliorate some of the negative effects of the IL28B genotype."

Rates of discontinuation and adverse events with TMC435 were similar to those seen with standard of care alone. There were increases in bilirubin, particularly with the higher dose of TMC435; however, "most were considered to be grade 1" and generally were within the upper limit of normal. The bilirubin increase peaked around week 2 and then declined slightly over time. He said that "this suggests that the mild, reversible increase in bilirubin is not due to hepatotoxicity."

Planning for phase 3 studies is underway.

One member of the audience called the data "very clean and very encouraging," but he wondered if the increase in bilirubin might be an issue. Dr. Fried reiterated that "it was completely reversible and was not progressive during the course of therapy. It is clearly related to a transporter mechanism, as opposed to hepatotoxicity, so I don't think it is going to be a major issue."

Session cochair Douglas R. LaBrecque, MD, director of Liver Services at University of Iowa Health Care in Iowa City, later told Medscape Medical News that "relatively low levels of bilirubin by themselves are not dangerous. From the limited data, it appears that it went away as soon as therapy was done."

This study was sponsored by Tibotec. Dr. Fried reports ongoing research and consulting contacts with the sponsor and several competing companies. Dr. LaBrecque has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-5. Presented November 1, 2010.

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