EASL; Locteron(interferon) shows reduced rates of depression in HCV patients

OctoPlus' licensee Biolex presents Phase IIb results at EASL showing reduced rates of depression in HCV patients treated with Locteron


* Reuters is not responsible for the content in this press release.

Thu Mar 31, 2011 3:46am EDT

Locteron's next-generation controlled-release mechanism is designed to provide key tolerability and dosing advantages over currently marketed interferons

Locteron may address one of the most significant side effects associated with the use of current interferon products in the treatment of HCV

OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data show substantially reduced rates of depression in patients treated with Locteron, compared to current HCV treatments.

Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism and even show a significant advantage in depression related side effects. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression, compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments."

The following information was taken directly from Biolex' press release (see http://www.biolex.com/ ).

Results demonstrating reduced rates of depression from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. In SELECT-2, patients treated with Locteron within the expected commercial dose range experienced substantially lower rates of depression and depressive symptoms than patients treated with the PEG-Intron® control. Locteron, the only controlled-release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed pegylated interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.

In a survey of hepatitis C patients published in the Journal of Viral Hepatitis in 2010, depression was cited as the number one adverse event impacting patient adherence to treatment, and studies have shown that patients who develop depression during treatment have a reduced chance of achieving a cure. The expected progression of treatment for hepatitis C to triple and quad regimens with potentially shorter durations of treatment are unlikely to eliminate the problem of depression as the SELECT-2 results presented today show that the majority of all episodes of depression occur by the 12th week of treatment.

Locteron is administered once every other week and requires half as many injections as the currently marketed pegylated interferons, each of which are injected once per week. In SELECT-2, three different doses of Locteron were studied (320, 480 and 640 µg). All three doses of Locteron in SELECT-2 demonstrated viral kinetics and sustained virologic response (SVR) rates that were comparable with or exceeded the PEG-Intron control while also achieving a statistically significant reduction in flu-like adverse events and lower use of concomitant medications. The Company expects the commercial dose of Locteron to be in the 320 to 480 µg range as the SVR rates for these two doses were comparable with or exceeded the control, and the tolerability advantages (including lower discontinuation rates due to adverse events) were greatest within this dose range.

In SELECT-2, depression was assessed by two methods, including patient self reporting using a validated instrument and adverse event assessment performed by medical personnel at the clinical sites during weekly visits by the patients. The SELECT-2 results demonstrated that patients experienced depression early in the study, with 75% of cases occurring within the first 12 weeks of the trial under each of the reporting methodologies. Under both reporting methodologies, depression was less frequent for the Locteron doses encompassing the expected commercial dose range compared to the PEG-Intron control.

Throughout the 48 weeks of treatment in SELECT-2, patients self reported their status using the Beck Depression Inventory (BDI), one of the most widely used instruments for measuring the severity of depression. Higher BDI scores indicate more severe depressive symptoms. Mean BDI scores peaked by week 12 of treatment for all Locteron doses and for the PEG-Intron control group. The increase in peak mean BDI scores was substantially less for all three Locteron doses compared to the PEG-Intron group. In addition, the results demonstrated that fewer patients reported scores greater than 16 using the BDI (the threshold for mild depression) in the 320 and 480 µg Locteron dose groups compared to the PEG-Intron group.

Click on the link below for the full press release including tables.
Click here for the press release in PDF format

http://www.reuters.com/article/2011/03/31/idUS74643+31-Mar-2011+HUG20110331

AASLD:Locteron/interferon,less adverse flu-like effects

Nov 01, 2010 09:09 ET

OctoPlus' licensee Biolex presents significant tolerability advantages of Locteron at AASLD conference today

Locteron Phase IIb results include statistically significant reduction of flu-like adverse events confirmed by two independent reporting methods

Biolex Presents at AASLD Meeting Significant Tolerability Advantages of Locteron®, Its Next-Generation Interferon for Hepatitis C
Locteron Phase 2b Results Include Statistically Significant Reduction of Flu-Like Adverse Events Confirmed by Two Independent Reporting Methods; Locteron's Tolerability and Dosing Advantages and Strong Efficacy Make It a Highly Combinable Interferon for Use With Future Direct-Acting Anti-Viral Combinations

PITTSBORO, NC--(Marketwire - November 1, 2010) - Biolex Therapeutics, Inc. today announced positive results from two Phase 2b trials further demonstrating the strong anti-viral response and tolerability advantages of the 480 µg dose of Locteron® in the treatment of hepatitis C. In the Phase 2b trials, patients directly reported flu-like adverse events on a daily basis through an electronic patient-reported outcome (ePRO) system, and the results demonstrated a statistically significant reduction in the frequency and severity of flu-like adverse events and reduced use of concomitant (analgesic/antipyretic) medications for patients treated with Locteron compared to patients treated with the PEG-Intron® control. Locteron, controlled-release interferon alpha 2b, is designed to offer key advantages compared to currently marketed interferons as a core component of combination therapies for the treatment of hepatitis C. These advantages include reduced flu-like symptoms, reduced rates of depression, and a less frequent dosing regimen with half the number of injections. The "EMPOWER" Phase 2b ePRO results will be presented today in a late-breaker session at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

EMPOWER is a prospectively designed analysis of the combined results from two Phase 2b hepatitis C trials focusing on the 480 µg dose of Locteron (the middle dose of three Locteron doses evaluated in the two trials). Through 12 weeks of treatment, 50% of the patients in the Locteron 480 µg group achieved cEVR (undetectable HCV RNA) compared to 46% of the patients in the PEG-Intron group. As a result of its controlled-release mechanism, Locteron achieved strong efficacy results while being dosed half as frequently as PEG-Intron.

The AASLD presentation today includes for the first time results from the ePRO adverse-event reporting system where patients directly recorded their flu-like adverse events on a daily basis, providing greater insight into the patients' real world experiences with these side effects and the impact on their daily activities. In addition to the self-reporting by patients with the ePRO system, flu-like adverse events were also recorded using traditional weekly adverse event assessments performed by the clinical sites. Flu-like adverse events were predefined to include arthralgia, chills, fever, headache, and myalgia.

A substantial reduction in flu-like adverse events for patients treated with Locteron compared to PEG-Intron was evident even in the first week after initiation of treatment and continued through the 12-week time point through which the ePRO system was utilized. The reduction in flu-like adverse events during the week after the first injection supports the hypothesis that the slower rise to Cmax provided by the controlled-release mechanism of Locteron contributes to the tolerability advantages seen in multiple clinical trials. A comparison of the flu-like adverse event reporting by the clinical sites and by ePRO provide independent confirmation of the substantial benefits Locteron provided in reducing these side effects as outlined in the table below:


"The ePRO results being presented for the first time today are robust and provide important insight into the impact that flu-like adverse events have on patients' daily lives," said Patrick Marcellin, MD, PhD, Professor of Hepatology at the University of Paris and Head of the Viral Hepatitis Research Unit in Hôpital Beaujon, Clichy. "Treatment of hepatitis C is likely to progress to triple and quad therapies in which interferons are combined with one or more direct-acting anti-viral drugs. Locteron's advantages with regards to flu-like adverse events, depression and dosing frequency have the potential to enhance the overall tolerability of, and patient adherence to, these future combinations."

Consistent with the reduction in flu-like adverse events, less than half as many Locteron patients used concomitant medications (analgesics and antipyretics) compared to the usage of these medications by PEG-Intron patients during the study period as detailed below.



A comparison of the ePRO and clinic site reporting highlights the fact that flu-like adverse events may even be more important to patients than historically believed. The total flu-like adverse events reported directly by the patients using the ePRO system during the first 12 weeks of EMPOWER was more than four times greater than the total flu-like adverse events recorded by the clinical sites. Also of importance, patients rated 80% of their flu-like adverse events as moderate or severe in their ePRO reports, compared to the clinical site reporting in which only 13% of flu-like adverse events were rated as moderate or severe. Despite the apparent differences in sensitivity in the two adverse event reporting methods, the results from both the ePRO and weekly clinic visits independently confirm the reduction in flu-like adverse events for patients treated with Locteron compared to patients treated with PEG-Intron. Through the 12-weeks, the difference in flu-like adverse event counts was statistically significant when measured by both the ePRO and clinical site reporting methods (p < 0.001 for each). The relevance of flu-like adverse events was highlighted in a survey of hepatitis C patients published in the Journal of Viral Hepatitis in June 2010 in which depression and flu-like symptoms were cited as the two most important adverse events impacting patient adherence to treatment. Last week Biolex reported 48-week results from its SELECT-2 Phase 2b trial of Locteron demonstrating substantial reductions in depression compared to PEG-Intron. AASLD Presentation The EMPOWER ePRO and clinical-site tolerability results will be presented today by the lead author, Walker Long, MD, Chief Medical Officer and Vice President, Drug Development, Biolex Therapeutics, in the form of a poster titled "Adverse Event Reporting During HCV Treatment Via Weekly Clinic Visits Substantially Underestimates Flu Frequency & Severity Compared to Daily ePRO: Results From 133 Patients in EMPOWER." "The EMPOWER results are notable in that they show a statistically significant reduction of flu-like adverse events for Locteron confirmed by two sources, the clinical site assessments and the daily patient reporting of side effects through the ePRO System. The reductions in the percent of patients using analgesics and in overall analgesic use observed in the Locteron group provide additional support for improved tolerability on Locteron," said Dr. Long. "These results complement the positive results released last week from our SELECT-2 Phase 2b trial in which we showed statistically significant reductions in flu-like adverse events for three different Locteron doses, and substantial reductions in depression for the Locteron 480 and 320 µg doses." About EMPOWER Study The objective of the EMPOWER study was to test the hypothesis that the 480 µg dose of Locteron dosed once every two weeks reduces flu-like symptoms but retains equivalent efficacy compared to PEG-Intron (1.5 µg/kg, administered every week). The 133 patients in the EMPOWER study were enrolled in two contributing Phase 2b trials: SELECT-2, a Phase 2b dose-finding trial evaluating the 320, 480 or 640 µg doses of Locteron versus PEG-Intron. The 480 STUDY, a Phase 2b trial evaluating the 480 µg dose of Locteron versus PEG-Intron. All patients in both trials were treatment-naïve-genotype-1 subjects with chronic hepatitis C, and all patients were also treated with weight-based ribavirin. A total of 30 sites participated in the two trials (14 sites in the US, 11 in Europe, and five in Israel). Locteron Overview Locteron, controlled-release interferon alpha 2b, is designed to offer key advantages compared to currently approved products, including reduced flu-like symptoms and rates of depression, and cutting in half the number of injections required. In contrast to Locteron, the currently approved products, Pegasys® and PEG-Intron, are immediate-release products that lack a controlled-release mechanism. The two-drug combination of interferon alpha and ribavirin serves as the current standard of care for the treatment of hepatitis C. The launch of the first direct-acting anti-viral (DAA) product, projected for 2011, will transform treatment of genotype-1 patients to a triple-drug therapy (interferon plus ribavirin plus DAA) and substantially raise cure rates. Other recent triple or quad drug combinations with interferon (including interferon plus ribavirin plus two DAA agents) have shown promise in early clinical testing, further solidifying the continued role of interferon in the treatment of hepatitis C. It is estimated that worldwide sales of interferon products for the treatment of hepatitis C will approach $6 billion by 2016. Locteron incorporates an advanced controlled-release drug delivery technology that allows dosing once every two weeks, more convenient than Pegasys and PEG-Intron, each of which require dosing every week. More importantly, Locteron's controlled-release mechanism results in the gradual release of interferon alpha 2b to patients over the duration of two weeks and avoids the early peak plasma levels of the active interferon that characterize the pegylated interferons. This controlled-release mechanism is designed to reduce the frequency and severity of flu-like symptoms and depression commonly experienced by patients treated with pegylated interferons. Locteron is an investigational therapeutic candidate and has not been approved for sale by the United States Food and Drug Administration or by any international regulatory agency. About Biolex Therapeutics Biolex is a biopharmaceutical company that uses its patented LEX System(SM) to develop follow-on biologics, hard-to-make therapeutic proteins and to optimize monoclonal antibodies. The LEX System is a novel technology that genetically transforms the aquatic plant Lemna to enable the production of biologic product candidates. The company's product candidates are designed to provide best-in-class efficacy/tolerability profiles while incorporating proven mechanisms of action. Biolex's lead product candidate, Locteron®, is in Phase 2b clinical testing for the treatment of chronic hepatitis C. Biolex has also developed two other product candidates that capitalize on the benefits of the LEX System. BLX-155 is a direct-acting thrombolytic designed to dissolve blood clots in patients. BLX-301 is a humanized anti-CD20 antibody glyco-optimized for the treatment of non- Hodgkin's B-cell lymphoma and other diseases.

SELECT-2 study:Phase IIb results for Locteron

OctoPlus announces publication of key Phase IIb results for Locteron which confirm Locteron's improved tolerability up to 60 weeks into the SELECT-2 study28.10.2010, Leiden, the Netherlands

Additional tolerability results from two Phase IIb trials of Locteron
to be presented at AASLD conference next week

OctoPlus N.V. (“OctoPlus” or the “Company”) (Euronext: OCTO) announces that its licensee Biolex Therapeutics today has published positive interim results at week 60 of the Phase IIb trial, 12 weeks after completion of 48 weeks of treatment with Locteron®. The results are consistent with the existing clinical results for Locteron and confirm Locteron’s improved tolerability profile.

Simon Sturge, CEO of OctoPlus, says: “These positive results further demonstrate the value of our PolyActive® technology and show that Locteron’s targeted benefits are sustained in the long term, up to 12 weeks after the end of treatment. Based on increasing evidence we believe that interferon alpha will remain a core component of future hepatitis C treatment regimens, and these positive results position Locteron as a key product in hepatitis C therapy.“

The following information was taken directly from Biolex’ press release, for detailed results we refer to www.biolex.com .

Biolex Therapeutics, Inc. announced positive efficacy, safety and tolerability results from its 72-week SELECT-2 Phase 2b dose-finding Phase 2b trial of Locteron, Biolex’s lead product candidate for the treatment of hepatitis C. For each of the three Locteron doses tested in SELECT-2, the percentage of patients who maintained undetectable levels of virus at week 60 of the trial, 12 weeks after completion of 48 weeks of treatment (SVR12), were comparable with or exceeded the response rate for the PEG-Intron® control. As a result of its controlled-release mechanism, Locteron was dosed half as frequently as PEG-Intron. PEG-Intron is one of two currently marketed pegylated interferon products for the treatment of hepatitis C, a market that currently exceeds US$ 2.5 billion in worldwide sales.

Additional results from SELECT-2 demonstrated the substantial tolerability advantages of Locteron. Patients treated with each of the three Locteron doses in SELECT-2 reported a statistically significant reduction in flu-like adverse events (p<0 data-blogger-escaped-.001="" data-blogger-escaped-br="" data-blogger-escaped-compared="" data-blogger-escaped-peg-intron="" data-blogger-escaped-the="" data-blogger-escaped-to="">group. Accordingly, Locteron patients in all three dose groups used less concomitant medications (analgesics and antipyretics) than the PEG-Intron patients during the study period. Lastly, patients receiving the two lower doses of Locteron experienced lower rates of depression and discontinuations due to adverse events than patients receiving PEG-Intron.

These findings from SELECT-2 are of particular importance as a survey of hepatitis C patients published in the Journal of Viral Hepatitis in 2010 showed that depression and flu-like symptoms were cited as the two most important adverse events impacting patient adherence to treatment.

Response rates and tolerability results for SELECT-2 are outlined in the table in the PDF format of the press release.

“The strong viral response of Locteron achieved with once-every-two-week dosing is an improvement over current interferons, and I am impressed by the consistency of the flu-like effect across trials and different reporting methodologies,” said Nezam Afdhal, M.D., Chief of Hepatology at Beth Deaconess Medical Center, Harvard Medical School. “The reduction in symptoms of depression is quite promising and needs to be followed up in additional clinical evaluation. The Locteron safety and tolerability results are clearly important as recent clinical results demonstrate that interferon is likely to remain a core component of future treatment regimens that incorporate the new direct-acting anti-virals, highlighting the need for a more tolerable interferon to reduce the side-effect burden on patients from these multi-drug combinations and maximize their adherence to treatment.”

AASLD presentation
Biolex also announced today that new tolerability data from two Phase 2b trials of Locteron have been accepted for a late-breaker presentation on November 1, 2010 at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

For further information, please contact:
Rianne Roukema, Corporate Communications: telephone number +31 (71) 524 1071, or send an e-mail to Investor Relations at IR@octoplus.nl.

About Locteron
Locteron is a controlled release formulation of interferon alpha for the treatment of chronic hepatitis C. Locteron combines OctoPlus’ controlled release drug delivery technology PolyActive® with Biolex’ interferon alpha and is the most advanced product in clinical development incorporating one of OctoPlus’ proprietary drug delivery technologies. OctoPlus licensed its commercial rights to Locteron exclusively to Biolex in October 2008.

Locteron is an investigational therapeutic candidate and has not been approved for sale by the United States Food and Drug Administration or by any international regulatory agency.

About OctoPlus
OctoPlus is a drug delivery service company committed to the creation of improved pharmaceutical products that are based on OctoPlus’ proprietary drug delivery technologies and have fewer side effects, improved patient convenience and a better efficacy/safety balance than existing therapies. OctoPlus focuses on the development of long-acting, controlled release versions of known protein therapeutics, other drugs, and vaccines on behalf of its clients.

The clinically most advanced product incorporating our technology is Biolex Therapeutics’ lead product Locteron®, a controlled release formulation of interferon alpha for the treatment of chronic hepatitis C. OctoPlus licensed Locteron exclusively to Biolex in October 2008. Locteron is being manufactured for Biolex by OctoPlus and is currently in Phase IIb clinical studies.

In addition, OctoPlus is a leading European provider of advanced drug formulation and clinical scale manufacturing services to the pharmaceutical and biotechnology industries, with a focus on difficult-to-formulate active pharmaceutical ingredients.

OctoPlus is listed on Euronext Amsterdam by NYSE Euronext under the symbol OCTO. For more information about OctoPlus, please visit our website www.octoplus.nl.

This document may contain certain forward-looking statements relating to the business, financial performance and results of OctoPlus and the industry in which it operates. These statements are based on OctoPlus’ current plans, estimates and projections, as well as its expectations of external conditions and events. In particular the words “expect”, “anticipate”, “predict”, “estimate”, “project”, “plan”, “may”, “should”, “would”, “will”, “intend”, “believe” and similar expressions are intended to identify forward-looking statements. We caution investors that a number of important factors, and the inherent risks and uncertainties that such statements involve, could cause actual results or outcomes to differ materially from those expressed in any forward-looking statements. In the event of any inconsistency between an English version and a Dutch version of this document, the English version will prevail over the Dutch version.