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By Patrick Crutcher

Repligen Corporation (NASDAQ:RGEN) is another attractive biotech that has revenues, cash and pending data in early 2011. With pending Phase 2 and Phase 3 data, Repligen seems set for a transformative 2011. Specifically, it has two important clinical catalysts in Q1 2011: Phase 3 data for RG1068 (pancreatic imaging agent) and Phase 2b data for its bipolar drug (RG2417). Both of these catalysts have the potential to take RGEN to new levels in 2011. (See its 2010 annual report here.)

Phase 2a results demonstrated a statistically significant reduction in the symptoms of depression in patients receiving RG2417 (vs. placebo) on the MADRS and on the CGI-BP-C scale over the six-week course of the study. RG2417 was safe and well tolerated. Repligen has exclusively licensed this patent from McLean Hospital, the largest psychiatric facility of Harvard Medical School. RGEN intends on seeking a partner, since this drug has a potential $2 billion market. Positive results from this trial could result in significant appreciation of its value. Enrollment is complete in this trial and most clinical work should be done by the end of the year. Results are expected in early Q1 2011.

Another catalyst to look forward to in Q1 2011 is the re-analysis of images from its Phase 3 results of RG1068 in Pancreatic Imaging. RG1068 is a synthetic version of human secretin, a natural gastrointestinal hormone involved in the process of digestion. RG1068 was granted orphan drug status and fast track designation by the FDA. The use of RG1068 in combination with a non-invasive procedure such as MRI can improve the detection of abnormalities and increase the diagnostic quality of the MRI image of the pancreas.

Last year, it reported results from a large, multicenter study that showed significant advantages of using RG1068 with MRI over endoscopy (ERCP) alone; however, the study did not show statistical significance. This was in large part because of errors made by the contract research organization (CRO) during the analysis of trial data, namely, deviating from the trial protocol. Fortunately for Repligen, the FDA and EMA recognized these issues and agreed to have the Phase 3 re-read of the data.

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In our view, the data was largely positive and with a new, more robust protocol and CRO, the study should achieve its primary endpoint. Pooled data from all three radiologists resulted in a statistically significant improvement in sensitivity with RG1068 (p=0.005) with minimal loss in specificity. With the RG1068-enhanced MRI images, RGEN saw highly statistically significant (p<0.001) improvements on other endpoints like improvements in image quality, ability to see all three segments of the pancreatic duct, and physician confidence in their ability to identify pancreatic duct abnormalities, when compared to MRI alone. There were no serious adverse events (SAEs) associated with the RG1068-MRI procedures, compared to 55 SAEs associated with ERCP. Clearly, RG1068 offers advantages over ERCP, in terms of economics and patient care. RGEN has modeled the market for RG1068 at over $100 million.

Recently, Repligen received $1.4 million in research funding from the Muscular Dystrophy Association to support the ongoing development of RG3039 for Spinal Muscular Atrophy (SMA). RG3039, its lead compound, is an inhibitor of an RNA processing enzyme which targets increased production of SMN, a protein of deficient levels in patients with SMA. Repligen hopes to complete preclinical studies and advance RG3039 into human clinical testing in 2011. Additionally, it received orphan drug designation from the FDA for RG2833, a selective histone deacetylase 3(HDAC-3) inhibitor for the treatment of Friedreich’s ataxia. It hopes to move this into Phase 1 next year.

Repligen is the world’s biggest supplier of recombinant Protein A, necessary for the production of monoclonal antibodies. This year, Repligen entered into a five -year supply agreement with GE (NYSE:GE) Healthcare Bio-Sciences AB for recombinant Protein A. It has had a steady source of income from this, and is projecting $22-24 million in revenue for fiscal year 2011. Repligen has $50+ million in cash and significant insider/institutional ownership with about 30 million outstanding. We also feel strongly about management's ability to deliver positive results.

To help us better understand RG2417 for bipolar disorder, we contacted Repligen’s CEO and president, Walter C. Herlihy, with some questions regarding RG2417.

BioMedReports: Can you get me some information about the study design for the Phase 2b clinical trial of RG2417? Discussion about the power of the trial and the primary endpoint would be helpful .

Herlihy: The RG2417 Phase 2b study in patients with bipolar disorder is a double-blind, placebo-controlled trial designed to assess the efficacy of eight weeks of treatment with RG2417 or a placebo on the symptoms of bipolar depression as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). This study has enrolled 175 patients at 29 clinical sites within the United States, and we expect to report top-line results in the first quarter of 2011.

Essentially the study was powered using the data from the Phase 2a study. A difference in MADRS of three points with a standard deviation of 10 would be 80% powered with 55 completers in each treatment arm. With a 33% early termination rate, we will be powered after recruiting 165 patients.

The primary objective of this study is to assess the safety and efficacy of RG2417 on the symptoms of bipolar depression by demonstrating a greater improvement in the MADRS score of the patients receiving RG2417 when compared to placebo using a repeat measures statistic over the eight-week treatment period.

Patients are initially screened for a score of bipolar depression symptoms of greater than 20 on the MADRS, and subsequently confirmed to meet the criteria for bipolar depression using an alternate diagnostic tool to ensure that patients have the appropriate diagnosis for inclusion in the study. Evaluations for symptoms of depression are conducted at baseline and then weekly using the MADRS, a standardized, rater-administered scale, which has been used for numerous drug trials in bipolar disorder. In addition to the MADRS ratings, patients conduct a weekly self-assessment of their symptoms, which is used to cross check the fidelity of the MADRS raters.

Additional secondary and exploratory objectives include improvements in the Clinical Global Impression Scale, difference in the end of study MADRS scores, and a lack of increase in mania as measured by the Young’s Mania Rating Scale. The average baseline MADRS of the 175 patients recruited into this study was 31.3, compared to 30.4 in the Phase 2a study, and there has been a high degree of fidelity between the MADRS scores determined by the raters and the patient’s self-assessment of depression symptoms during the eight-week treatment period. To date, there have been no serious adverse events determined to be related to RG2417, which continues to support an advantageous tolerability and safety profile for the drug.

BioMedReports: Can you discuss the results from the Phase 2a study of RG2417?

Herlihy: The Phase 2a study was a multi-center study in which 83 patients received either RG2417 or a placebo twice a day for six weeks. Patients in the RG2417 and placebo groups were well matched in their symptoms at baseline with the exception of mania for which the RG2417 group mania score was significantly higher (p=0.01). The objective of the study was to assess the safety and efficacy of RG2417 on the symptoms of bipolar depression as measured by the co-primary endpoints, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression of Change in Bipolar Disorder scale (CGI-BP-C). Patients were evaluated at baseline and then weekly, using these standardized tools to assess change in their symptoms. Over the six-week treatment period, the study demonstrated a statistically significant improvement in the symptoms of depression in the patients receiving RG2417 when compared to placebo on the MADRS (p=0.01) and on the CGIBP-C (p=0.044). RG2417 was well tolerated. Retention rate of 74% in the RG2417 group was statistically different than the retention rate of 55% in the placebo group (p=0.05).

BioMedReports: If the results are positive, will RGEN take RG2417 into Phase 3? Any current talks or interest in this molecule?

Herlihy: We will partner RG2417 for the next stage of development and commercialization (this is a big pharma indication), and we are currently qualifying potential corporate partners.

BioMedReports: Repligen’s bioprocessing angle is very interesting. Is RGEN developing any new future products on this front?

Herlihy: Repligen is seeking to leverage its core competency in protein manufacturing through developing and commercializing new products that improve efficiency in biopharmaceutical manufacturing. This year we acquired a technology platform for the production of pre-packed, “plug and play” chromatography columns. This patented technology enables economical production of chromatography columns in a format that is ready for use in the production of a broad range of biopharmaceuticals including monoclonal antibodies, vaccines and recombinant proteins. We will continue to grow our bioprocessing product line through internal product development initiatives and acquisition of new products and technologies.

Disclosure: Long RGEN

Source: Repligen's Promising Potential in 2011