Regulus Completes RG-101 Enrollment in Phase II Combination Study For HCV

Regulus Completes RG-101 Enrollment in Phase II Combination Study

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SOURCE Regulus Therapeutics Inc.

- Additional studies on track for enrollment in H12016 with multiple data read-outs expected throughout 2016 -

LA JOLLA, Calif., Jan. 21, 2016 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced key 2016 programmatic goals to advance RG-101, Regulus' wholly-owned therapy for the treatment of HCV. RG-101 is a GalNAc-conjugated anti-miR targeting miR-122, a host factor for HCV infection. Regulus' Phase II program and development strategy for RG-101 includes evaluating RG-101 in combination studies with different approved direct-acting anti-HCV agents (DAAs), in combination with an investigational oral DAA that can be formulated into a Long Acting Parenteral formulation for injection (LAP) providing the potential for a single-visit therapy, and in certain underserved HCV patient populations.

"Regulus begins 2016 with a multi-faceted clinical development plan for RG-101 in both Europeand the United States which we believe, if successful, will position our lead microRNA therapeutic well against the backdrop of the rapidly evolving HCV landscape," said Paul Grint, M.D., President and CEO of Regulus. "Regulus aims to enhance the value of RG-101 by maturing its profile in combination with oral agents and in certain underserved patient populations and we look forward to reporting results from multiple studies throughout 2016."

Phase II DAA Combination Studies:
Enrollment Complete in Phase II Combination Study; Interim Results in mid-Feb. Regulus announced today that patient enrollment is now complete in an ongoing Phase II study evaluating the combination of RG-101 with multiple approved DAAs. Treatment-naïve patients chronically infected with genotypes 1 or 4 were randomized to one of three treatment arms (n=78). Patients receive a single subcutaneous injection of 2 mg/kg of RG-101, followed by 28 days of once/daily DAAs Harvoni®, Olysio®, or Daklinza®, followed by an additional subcutaneous injection of 2 mg/kg of RG-101 on Day 29. Regulus is planning to report interim results from this study in mid-February 2016 in time for submission for potential publication at the European Association for the Study of the Liver (EASL) annual meeting. Primary endpoint results for sustained viral response data 12 weeks following conclusion of treatment (SVR12) are anticipated to be disclosed late in Q2 2016.
GSK Combination Study on Track; Data by Year-End 2016. In March 2016, Regulus plans to initiate a multi-center, open-label Phase II study evaluating the combination of a single subcutaneous injection of 4 mg/kg of RG-101 and daily oral administrations of 20 mg of GSK2878175, an investigational non-nucleoside NS5B polymerase inhibitor, for up to 12 weeks in treatment-naïve patients chronically infected with HCV genotypes 1 and 3. Concurrently, GSK will work on developing a "LAP" formulation of GSK2878175 as a single intra-muscular injection, providing the potential for a single-visit therapeutic treatment for HCV that could improve patient compliance through reduced dosing intervals and potentially extend opportunities for HCV therapeutic intervention. This LAP formulation of GSK2878175 may be used in additional clinical trials together with RG-101 following completion of the planned Phase II study, although any additional studies are not covered by the current collaboration agreement. Regulus expects to report safety and efficacy data from the GSK Phase II study before the end of 2016.

IND-Opening Study for Underserved HCV Population(s):
Clearance Received from US FDA to Initiate First Study in US; Enrollment Ongoing, Data by YE 2016. Regulus announced today that enrollment has commenced in a multi-center, open label, non-randomized Phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of 2 mg/kg of RG-101 in subjects with severe renal insufficiency or end-stage renal disease (ESRD) to healthy control subjects, and further explore RG-101 in hepatitis C infected subjects with severe renal insufficiency or ESRD. The Phase I study is designed to have three treatment arms (n=24): (i) healthy volunteers (n=8); (ii) patients with severe renal impairment or ESRD (n=8); and (iii) HCV patients with severe renal impairment or ESRD (n=8). Enrollment is expected to be complete in the first half of 2016 with efficacy data from the HCV/severe renal impairment or ESRD arm anticipated in the second half of 2016.

About microRNAs
The discovery of microRNAs in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 800 microRNAs have been identified in the human genome, and over two-thirds of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNA expression, or function, has been shown to be significantly altered or dysregulated in many disease states, including oncology, fibrosis, metabolic diseases, immune-inflammatory diseases and HCV. Targeting microRNAs with anti-miRs, chemically modified, single-stranded oligonucleotides, offers a unique approach to treating disease by modulating entire biological pathways and may become a new and major class of drugs with broad therapeutic application.

Study details microRNA’s role as a double agent during Hep C infection

Study details microRNA’s role as a double agent during Hep C infection
March 12, 2015 | SCIENCE NEWS

In the battle between a cell and a virus, either side may resort to subterfuge. Molecular messages, which control the cellular machinery both sides need, are vulnerable to interception or forgery. New research at Rockefeller University has revealed the unique twist on just such a strategy deployed by the liver-infecting Hepatitis C virus – one that may help explain the progression of liver disease and that the researchers suspect may be found more widely in the world of disease-causing viruses.

Led jointly by Charles Rice, the Maurice R. and Corinne P. Greenberg Professor in Virology and head of the Laboratory of Virology and Infectious Disease and Robert Darnell, Senior Attending Physician, Robert and Harriet Heilbrunn Professor, and head of the Laboratory of Molecular Neuro-oncology, the research is described today (March 12) in Cell. It employed a powerful combination of techniques to map the interactions between the virus and a small piece of genetic material – known as miRNA-122 – that is produced almost exclusively by liver cells, which normally use it to regulate expression of their own genes.

Messages intercepted: When researchers looked at sites on liver cell genomes where the gene-regulating molecule miRNA-122 binds, they found that infected cells (red) had fewer of the normal interactions with miRNA-122 compared to uninfected cells (blue). 

This suggests the virus alters gene expression by sponging up miRNA-122.

“It is well known that once inside a liver cell, the hepatitis C virus must bind to miRNA-122 in order to establish a persistent infection. We found an unanticipated consequence of this interaction: By binding to miRNA-122, the virus acts like a sponge, soaking up these gene-regulating molecules,” says first author Joseph Luna, a graduate student with a joint appointment in the labs. “Our experiments showed this has the effect of skewing gene activity in infected liver cells.”

The fight between an infecting virus and its host is often viewed as proteins fighting like soldiers. And soldiers on both sides must have orders, in this case the genetic information responsible for the production of proteins, Luna explains. This is where miRNA-122 comes in. It is amicroRNA, a type of RNA encoded into the genome for the purpose of turning down the expression of genes. It does this job by guiding a complex of silencing proteins to an RNA transcript of a gene so as to prevent it from being turned into a protein. In this way, miRNA-122 appears to help control a number of normal functions, including cholesterol and iron metabolism, as well as circadian rhythms.

But miRNA-122 is also necessary for hepatitis C virus. Once in a liver cell, the viral RNA binds with miRNA-122, which stabilizes and protects the virus so it can replicate. Over the long term, the hepatitis C virus infections can lead to scarring of the liver and liver cancer.

In order to explore how the hepatitis C virus and miRNA-122 interact and the repercussions for the host liver cells, the researchers used a technique known as cross-linking and immunoprecipitation (CLIP), developed over the past 12 years by the Darnell lab, which was targeted to find Argonaute, one of the proteins involved in silencing. This way, they captured the miRNA-122/Argonaute complexes and the sections of RNA transcript to which they bound. They then sequenced those RNA transcripts to see what genetic instructions they represented.

“One microRNA can have hundreds of targets, but most often studies are driven by anecdotes focused on single interactions. By combining CLIP and RNA sequencing, however, we were able to take a global perspective and map out all of miRNA-122’s interactions across both the viral and infected host genomes,” says study author Robert Darnell, who is also a Howard Hughes Medical Institute Investigator. “The result is a rigorously constructed picture of what is actually going on in the cell.”

Their maps showed a peak in miRNA-122 binding at one end of the viral genome, confirming previous work; miRNA-122 also interacted with the virus in a number of other places, for which the significance is not yet known. When the researchers looked at miRNA-122 interactions in an infected cell, they found lower levels as compared to uninfected cells. What’s more, a look at the expression of genes regulated by miRNA-122 confirmed this microRNA was less active because those genes had higher levels of activity.

“What if chronic low levels of miRNA-122 prompt changes that, over years, contribute to liver damage and cancer? This could be a molecular link between the viral infection and the pathologies associated with hepatitis C,” Luna says. “More work on miRNA-122 targets in hepatitis C-infected patients may clarify why some go on to develop liver cancer and others don’t.”

The hepatitis C virus isn’t the only virus known to alter gene expression in host cells by sponging up their microRNAs. Human cytomegalovirus and herpesvirus saimiri, which infects New World monkeys, employ a similar strategy, producing RNAs specifically to bind up host microRNAs. But, unlike the others, the hepatitis C virus must bind to a microRNA to replicate, and when it does so, the new viral genomes sop up even more miRNA-122, creating a positive feedback.

“We suspect these three cases may just be the tip of the iceberg, that other viruses – perhaps those that replicate much more ferociously – may use similar microRNA-sponging strategies,” study author Charles Rice says. “The techniques we used will make it possible to investigate the use of this strategy in an unbiased way.”

MicroRNAs and hepatitis C virus: Toward the end of miR-122 supremacy

Review
MicroRNAs and hepatitis C virus: Toward the end of miR-122 supremacy

Thomas W Hoffmann, Gilles Duverlie and Abderrahmane Bengrine

Virology Journal 2012, 9:109 doi:10.1186/1743-422X-9-109
Published: 12 June 2012
Abstract (provisional)

The most common etiologic agents causing chronic hepatitis are hepatitis C and B viruses (HCV and HBV, respectively). Chronic infection caused by HCV is considered one of the major causative agents of liver cirrhosis and hepatocellular carcinoma worldwide. In combination with the increasing rate of new HCV infections, the lack of a current vaccine and/or an effective treatment for this virus continues to be a major public health challenge. The development of new treatments requires a better understanding of the virus and its interaction with the different components of the host cell. MicroRNAs (miRNAs) are small non-coding RNAs functioning as negative regulators of gene expression and represent an interesting lead to study HCV infection and to identify new therapeutic targets. Until now, microRNA-122 (miR-122) and its implication in HCV infection have been the focus of different published studies and reviews. Here we will review recent advances in the relationship between HCV infection and miRNAs, showing that some of them emerge in publications as challengers against the supremacy of miR-122.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

http://www.virologyj.com/content/9/1/109/abstract