RGLS : Regulus Therapeutics Stock Analysis and Research Report

2017-10-20 - by Asif, Contributing Analyst

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Regulus Therapeutics is a clinical-stage biopharmaceutical company focused on discovering and developing first-in-class drugs targeting micro RNAs to treat diseases with significant unmet medical need. Regulus was formed in 2007 when Alnylam Pharmaceuticals, Inc., or Alnylam, and Ionis Pharmaceuticals, Inc., or Ionis, contributed significant intellectual property, know-how and financial and human capital to pursue the development of drugs targeting micro RNAs pursuant to a license and collaboration agreement. Its most advanced program, under its strategic alliance with Sanofi, is RG-012, an anti-miR targeting miR-21 for the treatment of Alport syndrome, a life-threatening kidney disease driven by genetic mutations, currently with no approved therapy available.

micro RNAs are naturally occurring ribonucleic acid, or RNA, molecules that play a critical role in regulating key biological pathways. Scientific research has shown that an imbalance, or dysregulation, of micro RNAs is directly linked to many diseases. Furthermore, many different infectious pathogens interact and bind to host microRNA to survive. To date, over 500 micro RNAs have been identified in humans, each of which can bind to multiple messenger RNAs that control key aspects of cell biology. Since many diseases are multi-factorial, involving multiple targets and pathways, the ability to modulate multiple pathways by targeting a single micro RNA provides a new therapeutic approach for treating complex diseases.

RNA plays an essential role in the process used by cells to encode and translate genetic information from DNA to proteins. RNA is comprised of subunits called nucleotides and is synthesized from a DNA template by a process known as transcription. Transcription generates different types of RNA, including messenger RNAs that carry the information for proteins in the sequence of their nucleotides. In contrast, micro RNAs are RNAs that do not code for proteins but rather are responsible for regulating gene expression by modulating the translation and decay of target messenger RNAs. By interacting with many messenger RNAs, a single micro RNA can regulate the expression of multiple genes involved in the normal function of a biological pathway. Many pathogens, including viruses, bacteria and parasites, also use host micro RNAs to regulate the cellular environment for survival. In some instances, the host micro RNAs are essential for the replication and/or survival of the pathogen. For example, miR-122 is a micro RNA expressed in human hepatocytes and is a key factor for the replication of the hepatitis C virus, or HCV.

Regulus believe that micro RNA therapeutics have the potential to become a new and major class of drugs with broad therapeutic application for the following reasons:

  • micro RNAs play a critical role in regulating biological pathways by controlling the translation of many target genes;
  • micro RNA therapeutics regulate disease pathways which may result in more effective treatment of complex multi-factorial diseases;
  • many human pathogens, including viruses, bacteria and parasites, use micro RNAs (host and pathogen encoded) to enable their replication and suppression of host immune responses; and
  • micro RNA therapeutics may be synergistic with other therapies because of their different mechanism of action.

Regulus believe it had assembled the leading position in the micro RNA field, including expertise in micro RNA biology and oligonucleotide chemistry, a broad intellectual property estate, relationships with key opinion leaders and a disciplined drug discovery and development process. Regulus is using its micro RNA expertise to develop chemically modified, single-stranded oligonucleotides that Regulus call anti-miRs to modulate micro RNAs and address underlying disease. Regulus believe micro RNAs may play a critical role in complex disease and that targeting them with anti-miRs may become a source of a new and major class of drugs with broad therapeutic application, much like small molecules, biologics and monoclonal antibodies.

Regulus believe that micro RNA biomarkers may be used to select optimal patient segments in clinical trials and to monitor disease progression or relapse. Regulus believe these micro RNA biomarkers can be applied toward drugs that it develop and drugs developed by other companies with which Regulus partner or collaborate. Regulus has completed a research collaboration with Biogen Inc. focused on the discovery of micro RNAs as biomarkers for multiple sclerosis and have also completed research for another leading, commercial-stage pharmaceutical company to explore micro RNAs as biomarkers for specific patient populations. Regulus also maintain several academic research collaborations focused on the identification of micro RNAs as biomarkers in multiple disease areas.

Development Stage Pipeline

Regulus currently has multiple programs in various stages of clinical and preclinical development.

RG-012: In 2015, Regulus completed a Phase I study to evaluate the safety, tolerability, and pharmacokinetics, or PK, of subcutaneous dosing of RG-012 in healthy volunteers. Forty healthy volunteer subjects were enrolled in this first-in-human, single ascending dose study. In May 2017, Regulus completed a Phase I multiple-ascending dose, or MAD, study in 24 healthy volunteers (six-week repeat dosing) to determine safety, tolerability and PK of RG-012 prior to chronic dosing in patients. In both Phase I studies, RG-012 was well-tolerated, and there were no serious adverse events, or SAEs, reported. Regulus also continue to enroll Alport syndrome patients in its global ATHENA natural history of disease study, which is designed to characterize the disease-related decline of renal function (as measured by established blood markers for renal function) in these patients over time. In mid-2017, Regulus is planning to initiate HERA, the Phase II randomized (1:1), double-blinded, placebo-controlled study evaluating the safety and efficacy of RG-012 in 40 Alport syndrome patients. In parallel, a renal biopsy study is also planned to evaluate RG-012 renal tissue PK, target engagement and downstream effects on genomic disease biomarkers. Data from the renal biopsy study is anticipated by year-end and interim data from HERA is anticipated mid-2018.

RGLS4326: In December 2016, Regulus nominated RGLS4326 as a clinical candidate targeting microRNA-17 (miR-17) for the treatment of autosomal dominant polycystic kidney disease, or ADPKD. IND-enabling toxicology, repeat pharmacology and manufacturing work have been completed as scheduled to support regulatory submissions as part of the investigational new drug, or IND, package. Regulus anticipate filing an IND or foreign equivalent regulatory filing by the end of 2017.

RG-101: In June 2016, Regulus received verbal notice from the U.S. Food and Drug Administration, or FDA, that its IND for RG-101 for the treatment of chronic HCV infection was placed on clinical hold. The FDA initiated the clinical hold after a second RG-101 treated patient experienced an SAE of jaundice. In December 2016, Regulus submitted a complete response to the FDA’s initial request for information, which included identification of a potential mechanism of hyperbilirubinemia. Regulus also submitted a proposal to mitigate this risk. In January 2017, Regulus received written communication from the FDA that the clinical development program for RG-101 remained on clinical hold. The FDA requested the complete safety and efficacy data from on-going RG-101 clinical and preclinical studies before reconsidering the clinical hold. The FDA also requested additional expert review of liver safety data considering the proposed mechanism of hyperbilirubinemia. In June 2017, Regulus announced its plan to discontinue clinical development of RG-101 upon completion of the follow-up phase of the remaining RG-101 clinical study, which occurred in July 2017. Comprehensive preclinical investigation and detailed analysis of clinical data from the RG-101 program have identified the direct inhibition of a hepatocyte conjugated bilirubin transporter as the likely mechanism for the cases of hyperbilirubinemia in the RG-101 program. Regulus believe that a combination of factors, including inhibition of conjugated bilirubin transport by RG-101, impaired baseline bilirubin transport in HCV patients and the preferential uptake of RG-101 by hepatocytes contributed to this mechanism. Additional patient-specific contributing factors cannot be excluded. Applying the learnings from the RG-101 program, alternative compounds targeting miR-122 have been identified that maintain potent HCV antiviral activity while lacking inhibition of the bilirubin transporter. Regulus believe these compounds have the potential for rapid clinical proof-of-concept of a novel, markedly shortened treatment regimen for HCV and will be considered for further development pending an updated global commercial market assessment for HCV.

RG-125(AZD4076): In June 2017, AstraZeneca delivered written notice of their election to terminate the collaboration and license agreement. Effective upon the termination of the agreement, AstraZeneca’s rights with respect to RG-125(AZD4076) for the treatment of non-alcoholic steatohepatitis, or NASH, in Type 2 Diabetes/Pre-diabetes will revert to it. In accordance with the Agreement, the termination will become effective in June 2018, which is 12 months following the date of delivery of the notice by AstraZeneca.

RGLS5040: In November 2016, Regulus nominated RGLS5040 as a clinical candidate targeting micro RNA-27 (miR-27) for the treatment of cholestatic diseases. In June 2017, Regulus discontinued development of RGLS5040 based on a positioning of the compound with respect to the competitive landscape coupled with the results from repeat pharmacology studies as part of IND-enabling work. Regulus continue to work on developing therapeutics for genetic forms of cholestatic disease as part of its overall research activities targeting unmet diseases of the liver and kidney.

Preclinical Pipeline

A major focus of its preclinical research is targeting dysregulated micro RNAs implicated in diseases of high unmet medical need where Regulus know it can effectively deliver to the target tissue or organ, such as the liver and kidney. Multiple micro RNAs have been identified as being dysregulated in NASH and these are in the process of target validation including the evaluation of tool compounds in animal models of NASH. Profiling of primary tumor cells from glioblastoma multiforme, or GBM, a rapidly fatal form of brain cancer, has identified miR-10b as a micro RNA target with the potential to inhibit tumor growth. Regulus is investigating local and systemic delivery of anti-miR-10b oligonucleotides in preclinical models to evaluate potential for advancing this program to clinical testing in GBM. Regulus also have early discovery programs investigating additional micro RNA targets for infectious diseases.

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