Regulus to Present Updated Data Supporting RG-101 as Novel microRNA Therapeutic for the Treatment of HCV at The Liver Meeting® 2015 (AASLD)

-Phase I Clinical Data will be Featured in Viral Hepatitis Plenary Session-

LA JOLLA, Calif., Oct. 2, 2015 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ:RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, announced today that two abstracts related to RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 ("miR-122") for the treatment of chronic Hepatitis C Virus (HCV) infection, were accepted for presentation at The Liver Meeting®, the 66th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), to be held November 13-17, 2015 in San Francisco, CA.

Viral Hepatitis Plenary Session, November 17, 2015, 8:45am - 9:00am: A Single Dose of RG-101, a GalNAc-Conjugated Oligonucleotide Targeting miR-122, Results in Undetectable HCV RNA Levels in Chronic Hepatitis C Patients at Week 28 of Follow-up

Investigators will present extended follow-up data from the Phase I clinical study of RG-101 demonstrating that a single subcutaneous administration of either 2 mg/kg or 4 mg/kg of RG-101 as monotherapy resulted in HCV RNA levels below the limit of quantification in 6/22 patients with various HCV genotypes at week 28 of follow-up.

Poster Presentation, November 17, 2015, 8:00am - 12:00pm: Treatment with the Anti-miRNA122 Oligonucleotide RG-101 Results in a Decrease in IP-10 but Does Not Affect the Levels of Other Cytokines in Patients with Chronic Hepatitis C

Investigators will present data examining immunological changes observed in the plasma of patients who received a subcutaneous administration of RG-101 in the completed Phase I study.
Results demonstrated that HCV patients had significantly higher IP-10 levels at baseline compared to healthy controls. In HCV patients who received a subcutaneous administration of RG-101, a significant decline was observed in IP-10 serum concentrations compared to baseline, and RG-101 did not trigger a systemic immune activation

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HCV Drugs —Alan Franciscus, Editor-in-Chief

In this month’s column, there is more good news about drugs in development.  Achillion is developing a potential treatment for genotype 1 that could shorten treatment time to 6 weeks.  However, there is also some disappointing news from the Food and Drug Administration (FDA)—they are rescinding the “breakthrough therapy designation” for hepatitis C drugs.  Other news which is also disappointing is that the ‘one-shot’ cure for hepatitis C does not look as if it is going to pan out.  Finally, data released from a small trial with sofosbuvir, pegylated interferon and ribavirin to treat genotype 2 and 3 shows that it may help cure some people with genotype 3 and advanced liver disease.

 

Achillion
Achillion has had HCV drugs in development for almost as long as the HCV Advocate has been reporting on HCV inhibitors.  Their latest drug and clinical trial—ACH-3102—combined with sofosbuvir (brand name Sovaldi)—was given to 12 HCV genotype 1 treatment-naïve patients for 6 weeks.  One hundred percent (12 of 12 patients) achieved SVR 12 (virologic cure).  Achillion is exploring additional trials with their other HCV inhibitors and perhaps shorter treatment durations (4 and 6 weeks).  Don’t pin all your hopes on this though—there were only 12 patients in the trial.  The combination should be studied in more people and the theory of treating for 4 or 6 weeks needs to be tested.  However, it is worth keeping an eye on.

FDA
The FDA is rescinding its “breakthrough therapy designation status” from Bristol-Myers Squibb for Daclatasvir and Merck for its combination of elbasvir (MK-8742) and grazoprevir (MK-5712). “Breakthrough therapy designation status” is given to drug(s) that demonstrate a substantial improvement over existing therapies.  Now that we have drugs that can cure over 90% of people with genotype 1 the newer drugs are unlikely to improve the cure rates.  The standard time it takes the FDA to review an application for approval is about 10 months.  Based on this it is unlikely that any new HCV drugs will be approved until 2016—at least for genotypes 1, 2 and 4.  This is unfortunate because it limits treatment choices for patients, and it affects the price of drugs already on the market.  What about genotype 3?  There is clearly a need for better therapies with shorter treatment durations.

Regulus
We have been following an on-going study of RG-101 as a possible treatment for genotype 1 that would require only one shot—yes you read that right – a possible one-shot treatment.  In a small study (2 mg/kg) dose, it was reported that 6 of 14 patients were undetectable 57 days after receiving the shot.  However, unfortunately, after 12 weeks that number dropped to only 4 patients.  Regulus started another study at a higher dose of RG-101 (4 mg/kg), but even at the higher dose the interim results (9 of 14 patients undetectable 57 days post-shot) cure rates were not as high as the current standard of care.

There is also the possibility that the single shot can be given in combination with 4 weeks of antiviral pills.  No side effect profile was given—an important issue since the current therapy has a low side effect profile.

Sofosbuvir/PEG/RBV
Current standard of care (SOC) treatment for genotypes 2 and 3 is the combination of sofosbuvir plus ribavirin.  The cure rates in the Phase 3 clinical trials of treatment-experienced patients with cirrhosis included:

• Genotype 2 = 88% (12 weeks)
• Genotype 3 = 60%  (24 weeks)

While the genotype 2 cure rates are impressive the genotype 3 rates were less than optimal and a 24-week course of treatment is a considerable period of time and expense.  Additional therapies are needed, but in this case perhaps interferon may be an option.

The current phase 2 study included 47 treatment-experienced patients—23 genotype 2 patients (14 with cirrhosis); 24 genotype 3 patients (12 with cirrhosis).  Treatment duration was 12 weeks.  The treatment was sofosbuvir, pegylated interferon (PEG) and ribavirin.

 

Genotype 2:  Cure rates = 93% (without cirrhosis); 96% (with cirrhosis).

The cure rates for genotype 2 were similar to the cure rates seen with sofosbuvir plus ribavirin—needless to say there is no need (or desire) to include PEG.

Genotype 3:  Cure rates = 83% with and without cirrhosis.

Clearly, much higher cure rates than 24 weeks of sofosbuvir plus ribavirin (without PEG).

There were 4 patients who had 5 serious side effects mostly related to interferon and ribavirin.

Adding pegylated interferon, however, may be an alternate therapy for genotype 3.  This regime is listed in the Guidance documents of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) for those who can tolerate 12 weeks of PEG therapy.

There are many therapies in development to treat genotype 3 (BMS, Gilead, Merck).  I hope that the FDA will recognize the need for newer therapies for genotype 3 that produce higher cure rates—especially for treatment-experienced patients with cirrhosis—that have fewer side effects and grant them “breakthrough therapy” designation.  That part of the articles about Merck and BMS losing their “breakthrough designation” status was not that clear.


http://hcvadvocate.org/news/newsLetter/2015/advocate0315.html#1

Hopes for single-dose Hepatitis C drug fade

Shares of Regulus fall but company, analysts still see promise 

LOS ANGELES (MarketWatch) — Shares of Regulus Therapeutics took it on the chin Monday after the biopharmaceutical company reported spotty results in tests for a drug designed to cure Hepatitis C with a single dose.

Regulus RGLS, +1.55%  shares dropped 10% to $15.15, as it appeared its drug, now designated as RG-101, will have to be accompanied by other treatments in many patients in order to cure Hepatitis C.

The company said RG-101 appeared to wipe out traces of the disease in four of 14 patients with a 2-milligram dose. This test was critical because it showed the drug’s ability to keep Hepatitis C at bay for 85 days. Patients who show no signs of Hepatitis C after 84 days are considered cured. 

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Regulus' experimental microRNA therapy RG-101 Update

All HCV Patients Treated with a Single SC Administration of 4 mg/kg of RG-101 Responded with Mean Viral Load Reduction of 4.8 log10 at Day 29 and 9/14 Patients are Below the Limit of Quantification at Day 57

 -Extended Follow-Up Shows 4/14 Patients Treated with a Single SC Dose of 2 mg/kg of RG-101 are Target Not Detected at Day 85 -

- Study Enrolled HCV Patients with Multiple Genotypes, Liver Fibrosis Status and Prior Treatment History -

- Conference Call Today at 8:00 a.m. EST to Discuss Results -

LA JOLLA, Calif., Feb. 9, 2015 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ:RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced top-line results from the 4 mg/kg cohort and additional results from the 2 mg/kg cohort in a completed clinical study evaluating RG-101, a wholly-owned, GalNac-conjugated anti-miR targeting microRNA-122 ("miR-122"), for the treatment of hepatitis C virus infection ("HCV").  Treatment with a single subcutaneous dose of 4 mg/kg of RG-101 as monotherapy resulted in significant and sustained viral load reductions in all patients, including difficult to treat genotypes, various liver fibrosis status and those who have experienced viral relapse after a prior IFN-containing regimen.  To date, RG-101 continues to have a favorable safety profile with no serious adverse events or discontinuations reported in the treated HCV patients.

Top-line results from the 4 mg/kg dose cohort:
In the 4 mg/kg dose cohort, 16 HCV patients were enrolled: 14 patients, 12 naive and 2 patients who experienced viral relapse after a prior IFN-containing regimen, received a single subcutaneous dose of 4 mg/kg of RG-101 as monotherapy, and 2 patients received placebo.

• In the 14 treated HCV patients, there was a mean viral load reduction of 4.8 log₁₀ at day 29 (range -5.8 to -3.0); and
• 9 out of 14 patients had HCV RNA levels below the limit of quantification ( < 15 IU/ml) ("BLOQ")  at day 57 and these patients will be followed up to six months to investigate the potential for viral cures following the single administration of 4 mg/kg of RG-101.

Extended follow-up results from the 2 mg/kg dose cohort:
In October 2014, Regulus reported interim efficacy and safety results and its first human proof of concept results from the 2 mg/kg cohort of the completed study evaluating RG-101 for the treatment of HCV. 

• At day 85, 4 out of 14 treated patients with varied genotypes, liver fibrosis status and treatment history were Target Not Detected ("TND"); 2 of the treated patients that were BLOQ at day 57 relapsed shortly thereafter; and
• Due to the longevity of the viral responses demonstrated, the protocol is being amended to add an additional year of follow up to investigate the potential for viral cures with one single administration of RG-101.

Summary of 2 mg/kg and 4 mg/kg dose cohort results:
Treatment with a single subcutaneous dose of either 2 mg/kg or 4 mg/kg of RG-101 as monotherapy has resulted in significant and sustained viral load reductions in all patients including difficult to treat genotypes, various liver fibrosis status and those who have experienced viral relapse after a prior IFN-containing regimen.  At day 57, 15 out of 28 patients treated with one single administration of either 2 mg/kg or 4 mg/kg of RG-101 had HCV RNA levels BLOQ and 12 out of these 15 treated patients were TND. 

"The profile of RG-101 has been significantly enhanced with these top-line data, making it an ideal pan-genotypic asset to investigate further in combination with all classes of oral agents to shorten the duration of treatment, increase patient compliance and maintain viral response, and also as monotherapy in certain underserved HCV populations," said Kleanthis G. Xanthopoulos, Ph.D., President and CEO of Regulus.  "With the promising data reported today, our confidence in our ability to treat diseases with microRNA therapeutics is higher than ever and we look forward to continuing to execute our 'Clinical Map Initiative' goals for RG-101 and our microRNA therapeutics pipeline."

"We continue to be pleased with the clinical results demonstrated with RG-101 and have a much more robust data set to inform our dual-track clinical development plans for Phase II," said Paul Grint, M.D., Chief Medical Officer of Regulus. "We have filed our pre-IND briefing book with the U.S. Food and Drug Administration and are working to file a Clinical Trial Application to conduct monotherapy and combination studies in multiple countries. In the second quarter of 2015, we look forward to initiating these studies and reporting full results from the completed study."

"These results demonstrate a significant breakthrough in the treatment of HCV," said Hendrik W. Reesink, M.D., Ph.D., Associate Professor in the Department of Gastroenterology and Hepatology at the Academic Medical Center in The Netherlands.  "These landmark studies were conducted with a high level of novelty and practical clinical importance.  All twenty-eight patients treated with one administration of RG-101 responded and more than 50% had HCV RNA levels below the lower limit of quantification at day 57.  I look forward to seeing RG-101 rapidly advance in Phase II to test its utility in combination with oral agents and possibly as monotherapy."

Conference Call & Webcast Information
Regulus will host a conference call and webcast at 8:00 a.m. Eastern Standard Time today to discuss the RG-101 results.  A slide presentation will also be available on Regulus' website, www.regulusrx.com to accompany the live webcast.  To access the call, please dial (877) 257-8599 (domestic) or (970) 315-0459 (international) and refer to conference ID 80841144.  To access the telephone replay of the call, dial (855) 859-2056 (domestic) or (404) 537-3406 (international), passcode ID 80841144.  The webcast and telephone replay will be archived on the company's website for ninety days following the call. 

About RG-101 for HCV
RG-101 is Regulus' wholly-owned, GalNAc-conjugated anti-miR targeting miR-122 for the treatment of HCV. Regulus has evaluated RG-101 in a completed clinical study conducted in the Netherlands. 58 healthy volunteers and 32 HCV patients with multiple genotypes, liver fibrosis status and treatment history were enrolled in the four part study: (i) a single ascending-dose study in which healthy volunteer subjects received a single subcutaneous dose of RG-101, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg and 8 mg/kg or placebo; (ii) a multiple-ascending dose study in which healthy volunteer subjects received a monthly single subcutaneous dose for four months of RG-101 or placebo; (iii) a single-dose drug-drug interaction study in which healthy volunteer subjects received a single subcutaneous dose of RG-101 in combination with simeprevir (OLYSIO™), an approved direct acting antiviral; and (iv) a single-dose study in which HCV patients received either a single subcutaneous dose of RG-101 or placebo at two doses, 2 mg/kg of RG-101 (the first dose cohort) or 4 mg/kg of RG-101 (the second dose cohort), to assess the safety and viral load reduction.  Dosing in part IV is complete and extended follow up is ongoing.  The primary objective is to evaluate safety and tolerability and the secondary objectives are to evaluate pharmacokinetics, viral load reduction and any impact an oral direct acting antiviral, such as simeprevir (OLYSIO™), may have on the pharmacokinetics of RG-101. 

Today, Regulus reported additional results from the above study and plans to report full study results in the second quarter of 2015.

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 500 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.

Hepatitis C Virus Infection (HCV)
Hepatitis C is a result of a hepatocyte specific infection induced by the virus known as HCV.  Chronic HCV may lead to significant liver disease, including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Up to 185 million people are chronically infected with HCV worldwide, and more than 350,000 people die from HCV annually.  The CDC estimates that there are currently approximately 3.2 million persons infected with HCV in the United States.  HCV shows significant genetic variation in worldwide populations due to its frequent rates of mutation and rapid evolution. There are six genotypes of HCV, with several subtypes within each genotype, which vary in prevalence across the different regions of the world. The response to treatment varies from individual to individual underscoring the inadequacy of existing therapies and highlights the need for combination therapies that not only target the virus but endogenous host factors as well, such as microRNA-122.  Regulus believes that its' miR-122 antagonist, RG-101, may be a useful agent in emerging combination regimens to address difficult-to-treat genotypes and to potentially expand upon the current therapies available to clinicians treating HCV patients.

'Clinical Map Initiative' Goals for RG-101
Regulus' 'Clinical Map Initiative' outlines certain corporate goals to advance its microRNA therapeutics pipeline over the next several years.  To rapidly advance RG-101, Regulus is pursuing a Phase II dual-track clinical development strategy (i) to investigate RG-101 in combination with oral agents to potentially shorten treatment durations, optimize clinical outcomes and potentially improve responses in certain underserved HCV patient populations; and (ii) to investigate RG-101 further as a single agent to determine whether HCV viral cures are achievable with monotherapy treatment (single or multiple doses of RG-101).  In the near term, Regulus expects to file both a Clinical Trial Application and an Investigational New Drug application for RG-101 with the goal to initiate the above described studies in Europe and the United States in the second quarter of 2015.

About Regulus
Regulus Therapeutics Inc. (NASDAQ:RGLS) is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs.  Regulus has leveraged its oligonucleotide drug discovery and development expertise to develop a well-balanced microRNA therapeutics pipeline complemented by a maturing microMarkers^SM biomarkers platform and a rich intellectual property estate to retain its domain dominant leadership in the microRNA field.  Under its 'Clinical Map Initiative', Regulus is developing RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of chronic hepatitis C virus infection, and RG-012, an anti-miR targeting microRNA-21 for the treatment of Alport syndrome, a life-threatening kidney disease driven by genetic mutations with no approved therapy.  Regulus is also advancing several programs toward clinical development in orphan disease indications, oncology and fibrosis.  Regulus' commitment to innovation has resulted in multiple peer-reviewed publications in notable scientific journals and has resulted in the formation of strategic alliances with AstraZeneca and Sanofi and a research collaboration with Biogen Idec focused on microRNA biomarkers.  Regulus maintains its corporate headquarters in La Jolla, CA.

 For more information, please visit http://www.regulusrx.com.

Can Regulus Therapeutics Double Again on Next Hep-C Drug Trial Update?

BOSTON (TheStreet) -- Let's interrupt the non-stop (and frankly, repetitive) chatter about hepatitis C drug price wars and turn our attention again to Regulus Therapeutics and its experimental, injectable microRNA therapy RG-101.

New trial data from a group of hepatitis C patients treated with a higher dose of RG-101 are expected in early February, according to Regulus. The company's stock price doubled last October when the first slug of RG-101 data were announced, so it's a good time to review what we know about the drug and attempt to determine what the updated results might reveal.

RG-101 uses small (micro) snippets of RNA to disrupt the replication of the hepatitis C virus and lead to its elimination from the liver. Regulus views RG-101 as a potentially new way to treat hepatitis C with a single or even a few simple and easily tolerated injections. It's a controversial idea because the best hepatitis C therapy today are already considered to be incredibly convenient. Gilead Sciences'  Harvoni requires patients to take a single, daily pill for eight or 12 weeks. No injections are needed. Abbvie's   Viekira Pak is just as effective but with a few more pills. [RA Capital portfolio manager Peter Kolchinsky owns Regulus and wrote about the bull thesis for RG-101 earlier this month].

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