Full Press Release Details
We are a clinical-stage
biopharmaceutical company focused on discovering and developing first-in-class drugs targeting microRNAs to treat diseases with significant unmet medical
need. We were 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 microRNAs pursuant to a license and collaboration agreement. Our most advanced program, under our 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.
microRNAs 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 microRNAs is directly linked to many diseases. Furthermore, many different infectious pathogens interact and bind to host microRNA to survive. To date, over 500
microRNAs 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 microRNA provides a new therapeutic approach for treating complex diseases.
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, microRNAs 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 microRNA 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 microRNAs to regulate the cellular environment for survival. In some instances, the host microRNAs are essential for the replication and/or survival of the
pathogen. For example, miR-122 is a microRNA expressed in human hepatocytes and is a key factor for the replication of the hepatitis C virus, or HCV.
We believe that microRNA therapeutics have the potential to become a new and major class of drugs with broad therapeutic application
for the following reasons:
We believe we have assembled the leading position in the microRNA field, including expertise in microRNA biology and
oligonucleotide chemistry, a broad intellectual property estate, relationships with key opinion leaders and a disciplined drug discovery and development process. We are using our microRNA expertise to develop chemically modified,
single-stranded oligonucleotides that we call anti-miRs to modulate microRNAs and address underlying disease. We believe microRNAs 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.
We believe that microRNA biomarkers may be used to select optimal patient segments in clinical trials and to monitor
disease progression or relapse. We believe these microRNA biomarkers can be applied toward drugs that we develop and drugs developed by other companies with which we partner or collaborate. We have completed a research collaboration with
Biogen Inc. focused on the discovery of microRNAs as biomarkers for multiple sclerosis and have also completed research for another leading, commercial-stage pharmaceutical company to explore microRNAs as biomarkers for specific
patient populations. We also maintain several academic research collaborations focused on the identification of microRNAs as biomarkers in multiple disease areas.
Development Stage Pipeline
have multiple programs in various stages of clinical and preclinical development.
RG-012: In 2015, we 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, we 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. We also continue to enroll Alport syndrome patients in our 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, we are 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, we 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 application, or IND, package. We anticipate filing an IND or foreign equivalent regulatory filing
RG-101: In June 2016, we received verbal notice from the U.S. Food and
Drug Administration, or FDA, that our 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, we submitted a complete response to the FDA s initial request for information, which included identification of a potential
mechanism of hyperbilirubinemia. We also submitted a proposal to mitigate this risk. In January 2017, we 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, we announced our plan to discontinue clinical development of
RG-101 upon completion of the follow-up phase of the remaining RG-101 clinical study, which is expected to occur 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. We 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. We 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 to us of its election to
terminate the clinical development program for RG-125(AZD4076) for the treatment of non-alcoholic steatohepatitis, or NASH, in Type 2
Diabetes/Pre-diabetes. Pursuant to the terms of our August 2012 collaboration and license agreement with AstraZeneca, AstraZeneca s rights with respect to
RG-125(AZD4076) will revert to us when the termination becomes effective in June 2018.
RGLS5040: In November 2016, we nominated RGLS5040 as a clinical candidate targeting
microRNA-27 (miR-27) for the treatment of cholestatic diseases. In June 2017, we 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. We continue to work on developing therapeutics for genetic forms of cholestatic
disease as part of our overall research activities targeting unmet diseases of the liver and kidney.
Preclinical Pipeline
A major focus of our preclinical research is targeting dysregulated microRNAs implicated in diseases of high unmet medical need where we
know we can effectively deliver to the target tissue or organ, such as the liver and kidney. Multiple microRNAs 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 microRNA target with
potential to inhibit tumor growth. We are 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. We also have early discovery programs investigating additional microRNA targets for infectious diseases.
Our microRNA Product Platform
We believe we are the leading company in the field of microRNA therapeutics and are uniquely positioned to leverage oligonucleotide
technologies developed by us and our founding companies.
We view the following as providing a competitive advantage for
our microRNA product platform:
Our Development Candidates
developing single-stranded oligonucleotides, which are chemically synthesized chains of nucleotides that are mirror images of specific target microRNAs. We incorporate proprietary chemical modifications to enhance drug properties such as
potency, stability and tissue distribution. We refer to these chemically modified oligonucleotides as anti-miRs. Each anti-miR is designed to bind with and inhibit a specific microRNA target that is
up-regulated in a cell and that is involved in the disease state. In binding to the microRNA, anti-miRs correct the dysregulation and return diseased cells to their healthy state. We have
demonstrated the potential therapeutic benefit of inhibiting microRNA-122 in humans with RG-101 in HCV patients. In addition to these human proof-of-concept results, we have demonstrated therapeutic benefits of our anti-miRs in over 20 different preclinical models of human diseases.
We have identified and validated several microRNA targets across a number of disease categories and are working independently and
with our strategic alliance partner to optimize anti-miR development candidates. We intend to pursue a balanced approach between product candidates that we develop ourselves and those that we develop with partners. We intend to focus our own
resources on proprietary product opportunities in therapeutic areas where development and commercialization activities are appropriate for our size and financial resources. In therapeutic areas where costs are more significant, development timelines
are longer or markets are too large for our capabilities, we may seek to secure partners with requisite expertise and resources.
discovering and developing of first-in-class drugs based on our proprietary microRNA product platform. The key elements of our strategy are to (i) build
a meaningful clinical portfolio by advancing our current clinical programs and rapidly advancing our preclinical programs into clinical development; (ii) focus our resources on developing drugs for indications that represent significant unmet
medical need and where the development and commercialization activities are appropriate for our size and financial resources; (iii) selectively form strategic alliances to augment our expertise and accelerate development and commercialization;
(iv) develop microRNA biomarkers to support our therapeutic product candidates; and (v) maintain our scientific and intellectual leadership in the microRNA field.
In June 2010, we formed a strategic alliance with Sanofi to discover and develop microRNA therapeutics for fibrotic diseases. In
July 2012, we expanded the alliance to include potential microRNA therapeutics in oncology. The original research term for this strategic alliance expired in June 2013, upon which we and Sanofi entered into an option agreement pursuant
to which we granted Sanofi an exclusive right to negotiate the co-development and commercialization of certain of our unencumbered microRNA programs, for which Sanofi paid us an upfront option fee
of $2.5 million. In addition, Sanofi granted us an exclusive option to negotiate the co-development and commercialization of miR-21. In February 2014, we and Sanofi
extended our strategic alliance and Sanofi concurrently made a $10.0 million investment in our common stock. Under the terms of our extended alliance, Sanofi will have opt-in rights to our RG-012 clinical fibrosis program targeting miR-21 for the potential treatment of Alport Syndrome, our preclinical program targeting
miR-21 for oncology indications, and our preclinical programs targeting miR-221/222 for oncology indications, each of which is to be led by us. If Sanofi chooses to
exercise its option on any of these programs, Sanofi will reimburse us for a significant portion of our preclinical and clinical development costs and will also pay us an option exercise fee for any such program, provided that $1.25 million of
the $2.5 million upfront option fee paid to us by Sanofi in connection with the June 2013 option agreement will be creditable against such option exercise fee. In addition, we will be eligible to receive clinical and regulatory milestone
payments under these programs and potentially commercial milestone payments. We also continue to be eligible to receive royalties on microRNA therapeutic products commercialized by Sanofi and have the right to co-promote these products.
Under this strategic alliance, we are eligible to receive milestone payments
of up to $101.8 million for proof-of-concept option exercise fees (net of $1.25 million creditable, as noted above), $15.0 million for
clinical milestones and up to $300.0 million for regulatory and commercial milestones. In addition, we are entitled to receive royalties based on a percentage of net sales of any products from the
miR-21 and miR-221/222 programs which, in the case of sales in the United States, will be in the middle of the 10 to 20% range, and, in the case of
sales outside of the United States, will range from the low end to the middle of the 10 to 20% range, depending upon the volume of sales. If we exercise our option to co-promote a product,
we will continue to be eligible to receive royalties on net sales of each product in the United States at the same rate, unless we elect to share a portion of Sanofi s profits from sales of such product in the United States in lieu of
In August 2012, we formed a strategic alliance with AstraZeneca to discover and develop
microRNA therapeutics for cardiovascular diseases, metabolic diseases and oncology. In March 2015, we and AstraZeneca nominated RG-125(AZD4076), a GalNAc-conjugated anti-miR 103/107 oligonucleotide that
has been observed to improve insulin sensitivity and glucose tolerance in animal models as a clinical development candidate in NAFLD in patients with type 2 diabetes/pre-diabetes and we earned a