September 23, 2010

New TB Vaccine Enters Clinical Testing

23 September 2010

Colorized scanning electron micrograph of Mycobacterium tuberculosis bacteria. Source: CDC/ R. Butler; J. CarrAt an international gathering of TB vaccine researchers in Tallinn, the Aeras Global TB Vaccine Foundation announced it will initiate a clinical trial of an investigational live recombinant tuberculosis vaccine to be led by researchers at Saint Louis University in St. Louis, Missouri, USA. The announcement was made at the Second Global Forum on TB Vaccine Development.

Building on more than a decade of global scientific research, Aeras scientists have engineered a new investigational vaccine, called AERAS-422, which will undergo clinical trials to evaluate its properties for interrupting TB at all stages of infection, including initial infection, latency and reactivation.

“Moving our lead in-house vaccine from the laboratory into clinical testing is an important milestone for Aeras and its partners. Finding a potential replacement for the currently available TB vaccine, which was invented almost 90 years ago, is a primary goal in our mission,” said Thomas G. Evans, MD, Aeras’ Chief Scientific Officer. “Based on data from pre-clinical studies, we are cautiously optimistic about the potential of this vaccine candidate to be safer and more immunogenic than the currently available vaccine.”

The new vaccine, called AERAS-422, is a modernized version of the currently used TB vaccine – Bacille Calmette Guérin (BCG). BCG is widely viewed as insufficient in preventing pulmonary TB, and this trial is part of a wider global effort to develop safer and more immunogenic TB vaccines that would be effective against all forms of TB.

AERAS-422 has been modified with an endosome escape mechanism and over-expresses three key proteins: 85A, 85B and Rv3407. The bacterium that causes TB hides inside cells. Therefore, the endosome escape mechanism is designed so that the proteins will escape an internal compartment of the cell and be more efficiently presented to the immune system to elicit a greater protective response in the body.

“The TB epidemic continues to become more complex and difficult to control, especially in South Africa where resistance to available TB treatments is on the rise,” said Bernard Fourie, PhD, Chief Scientific Officer of Medicine in Need and Managing Director of Mend South Africa. “The scientific community has made developing a safer and more effective TB vaccine a priority and we are pleased that there is progress in the field.”


Weight-Based Dosing Best for New HCV Drug

By Michael Smith, North American Correspondent, MedPage Today Published: September 23, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

When given in doses based on weight, an investigational prodrug of ribavirin had efficacy comparable to ribavirin in chronic hepatitis C but with less hemolytic anemia, researchers reported.

In a phase IIb trial, the drug -- taribavirin -- yielded early response rates that were statistically identical with those achieved with ribavirin when both drugs were given with pegylated interferon alfa-2b, according to Fred Poordad, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

At the same time, two of the tested doses of the drug caused significantly less anemia (at P<0.05) than ribavirin, they reported online in Hepatology.

Taribavirin, formerly known as viramidine, is a nucleoside analogue and oral prodrug of ribavirin that is converted to ribavirin in the body. But its structural difference from the older drug means that it is less likely to enter and damage red blood cells, the researchers noted.

Indeed, in earlier studies using a fixed dose of taribavirin, that benefit was demonstrated, but efficacy was inferior to that of ribavirin, they said. Analysis suggested that the fixed-dose approach, as well as selection of inadequate doses, was responsible for the lack of efficacy.

To clarify the issue, Poordad and colleagues tested three doses of taribavirin -- 20, 25, or 30 mg per kilogram a day -- against ribavirin at 800 to 1,400 mg a day in 278 treatment-naïve patients with genotype 1 hepatitis C.

The primary efficacy endpoint was early virologic response, defined as the proportion of patients with at least a two-log decrease from baseline in serum hepatitis C RNA levels after two weeks of therapy. The researchers also looked at sustained virologic response after 48 weeks of therapy.

The main safety endpoint was the proportion of patients with hemoglobin less than 10 grams per deciliter at any time during the study.

The researchers found that:

• 43 patients in the 20-mg/kg (64.2%) had an early virologic response, as did 40 (57.1%) and 37 (54.4%) in the 25- and 30-mg/kg arms.

• At the same time, 36 ribavirin patients (51.4%) had an early virologic response, not significantly different from any of the taribavirin arms.

• Fewer patients on taribavirin required dose reductions (13% to 28%, depending on the dose) compared with 32% of ribavirin.

• The anemia rates were 13.4% and 15.7%, respectively, in the 20- and 30-mg/kg taribavirin arms, compared with 32.9% among ribavirin patients, significantly different at P<0.05 in both cases.

All told, 41% of patients in the three taribavirin arms completed treatment and follow-up, compared with 36% of the ribavirin patients, with 29% of those who dropped out citing lack of response as the reason and 20% citing adverse events.

The data suggest the drug "may be an effective agent" to substitute for ribavirin in the future, the researchers concluded.

On the other hand, the treatment picture is changing rapidly and could leave the drug with a "finite life cycle," according to Paul Kwo, MD and Rakesh Vinayek, MBBS, both of Indiana University in Indianapolis.

Taribavirin "may have a role in populations particularly sensitive to ribavirin-related anemia," they said in an accompanying editorial, and might be a "welcome addition" to the list of drugs available to treat hepatitis C.

But several clinical trials are beginning with combinations of direct-acting antiviral agents, with and without pegylated interferon, and protease inhibitors under development could also have lower rates of anemia, they said.

For those reasons, "the role of (taribavirin) remains less precisely defined," they argued.

The study was supported by Valeant Pharmaceuticals, which is developing the drug.

Poordad said he had no financial conflicts to report. Several authors are employees of the company.

Primary source: Hepatology
Source reference:
Poordad F, et al. "Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C" Hepatology 2010; DOI: 10.1002/hep.23827.

Additional source: Hepatology
Source reference:
Kwo PY, Vinayek R. "The next step for taribavirin" Hepatology 2010; DOI: 10.1002/hep.2395.

Also See: Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds

Regulus Therapeutics Secures Additional Patents on microRNA Therapeutics for the Treatment of Hepatitis C Virus (HCV) Infection

Sept. 23, 2010, 8:00 a.m. EDT

-- US and European Patent Offices Grant Claims Covering Use of anti-miR-122 Alone or In Combination with Other HCV Therapeutic Agents --

LA JOLLA, Calif., Sep 23, 2010 (BUSINESS WIRE) -- Regulus Therapeutics Inc. announced today that the European Patent Office (EPO) and United States Patent and Trademark Office (USPTO) have recently granted claims for microRNA-122 therapy in hepatitis C viral (HCV) infections. The EPO issued a Notice of Intent to Grant for an application in the 'Sarnow' patent series (European Patent Application No. 05749437.9) for claims covering the use of an antisense inhibitor of miR-122 for the treatment of HCV infection and related conditions, either alone or in combination with other HCV therapeutic agents. Additionally, the USPTO has recently allowed claims in a continuation application in the Sarnow patent series (US Serial No. 11/953,705), directed to methods of reducing HCV viral genome amount with an antisense inhibitor of miR-122 in combination with other HCV therapeutic agents. The Sarnow patent series, owned by Stanford University and licensed to Regulus, relates to the discovery and development of therapeutic products for HCV infection by inhibiting the liver-specific microRNA known as miR-122.

"We are very pleased that the Sarnow patent estate continues to generate patents worldwide. Notably, the claims capture uses of anti-miR-122 in combination with the therapeutic agents, such as interferon and ribavirin, which comprise the current standard of care for the treatment of HCV infection," said Garry E. Menzel, Ph.D., Executive Vice President Corporate Development and Finance of Regulus.

Regulus controls a broad and dominant patent estate related to microRNA therapeutics, including miR-122 therapeutic agents. These two new patents will further strengthen the Regulus-controlled patent estate surrounding miR-122 compositions and methods of use, which includes but is not limited to:

-- The 'Sarnow' patent claiming the use of anti-miR-122 to inhibit HCV replication (US Patent No. 7,307,067)

-- The 'Esau' patent claiming the use of anti-miRs targeting miR-122 as inhibitory agents (US Patent No. 7,683,036)

-- The 'Tuschl III' patent claiming compositions of matter for miR-122 and complementary oligonucleotides (US Patent No. 7,232,806)

-- The 'Manoharan' patent claiming antagomirs, including antagomirs targeting miR-122 (US Patent No. 7,582,744)

-- A recently granted Regulus-owned European application claiming the use of miR-122 antagonists for reducing cholesterol (EP Application No. 06813949.2)

miR-122 is a liver-expressed microRNA that has been shown to be a critical endogenous "host factor" for the replication of HCV, and anti-miRs targeting miR-122 have been shown to block HCV infection (Jopling et al. (2005) Science 309, 1577-81). In earlier work, scientists at Alnylam Pharmaceuticals and Isis Pharmaceuticals (Regulus' co-founders) demonstrated the ability to antagonize miR-122 in vivo using chemically modified single-stranded anti-miR oligonucleotides. Data from multiple preclinical studies have shown a robust HCV antiviral effect following inhibition of miR-122. Through a collaboration with GlaxoSmithKline, Regulus is developing a microRNA therapeutic targeting miR-122 for the treatment of HCV infection as its most advanced therapeutic program. Regulus plans to identify a clinical development candidate in the fourth quarter of 2010 and file an investigational new drug (IND) application in 2011.

About microRNAs

The discovery of microRNA in humans is one of the most exciting scientific breakthroughs in the last decade. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length that do not encode proteins but instead regulate gene expression. Nearly 700 microRNAs have been identified in the human genome, and more than one-third of all human genes are believed to be regulated by microRNAs. As a single microRNA can regulate entire networks of genes, these new molecules are considered the master regulators of the genome. microRNAs have been shown to play an integral role in numerous biological processes including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. Most microRNAs are conserved across multiple species indicating the evolutionary importance of these molecules as modulators of critical biological pathways. Indeed, microRNA expression or function has been shown to be significantly altered in many disease states, including cancer, heart failure and viral infections. Targeting microRNAs with anti-miRs, antisense oligonucleotide inhibitors of microRNAs, or miR-mimics, double-stranded oligonucleotides to replace microRNA function, opens the possibility of a novel class of therapeutics and a unique approach to treating disease by modulating entire biological pathways. To learn more about microRNAs please visit

About Regulus Therapeutics Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative new medicines based on microRNAs. Regulus is targeting microRNAs as a new class of therapeutics by working with a broad network of academic collaborators and leveraging oligonucleotide drug discovery and development expertise from its founding companies Alnylam Pharmaceuticals /quotes/comstock/15*!alny/quotes/nls/alny (ALNY 14.56, -0.11, -0.75%) and Isis Pharmaceuticals /quotes/comstock/15*!isis/quotes/nls/isis (ISIS 8.65, +0.08, +0.93%) . Regulus is advancing microRNA therapeutics towards the clinic in several areas including hepatitis C infection, cardiovascular disease, fibrosis, oncology, immuno-inflammatory diseases, and metabolic diseases. Regulus' intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus entered into a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus entered into a new collaboration with GlaxoSmithKline to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of Hepatitis C Viral infection. In June 2010, sanofi-aventis and Regulus entered into the largest-to-date strategic alliance on microRNA therapeutics focused initially on fibrosis. For more information, visit

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus' business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including the therapeutic potential of targeting microRNA-122. Any statement describing Regulus' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such party's forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause their results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of the management of Regulus, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus' programs are described in additional detail in each of Isis' and Alnylam's annual report on Form 10-K for the year ended December 31, 2009 and their most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from either Isis or Alnylam.

SOURCE: Regulus Therapeutics Inc.

Regulus Therapeutics
Zachary Zimmerman, Ph.D., 858-202-6300
Russo Partners
Heidi Chokeir, Ph.D., 619-528-2217