Pablito wrote:

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Thanks for the PDF Jimmy.  So the pebble moves forward an inch in our understanding of the science behind DAAs.  

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It does yes, maybe an inch. Kind of amazing to think forward to the time when folks will look back and wonder, "what's the big deal anyway?".

When my sister was a little girl she was an actual Poster Child for Polio.

Today when you mention Polio to someone in their 20's they look at you and say, "Wut?"

LOL

Pablito wrote:

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The science in this field moves fast, and it's interesting to see non-enzyme inhibitors being developed.

The 2 cases of jaundice is worrying.  The problem with long-acting injections is that you can't get rid of the drug from the system if a problem occurs.  If you get a reaction to a short-acting oral tablet you just stop taking it.

Interesting but I'd be sticking with the DAAs until further evidence is available.

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 I too would be doing a waiting game for this reason. That being said, we don't have any stats on the current DAA's that go back very far but yes, we can stop talking something if there seems to be a reaction.

SF

Pablito wrote:

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Tig - is there any way of accessing the article without registering to the site?

Pablo

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 Here you go brother.

JimmyK

I kind of like it.

The science in this field moves fast, and it's interesting to see non-enzyme inhibitors being developed.

The 2 cases of jaundice is worrying.  The problem with long-acting injections is that you can't get rid of the drug from the system if a problem occurs.  If you get a reaction to a short-acting oral tablet you just stop taking it.

Interesting but I'd be sticking with the DAAs until further evidence is available.

RC,

Yup, ya gotta wonder about this stuff.

One article said (don't see it now) that RG101 (alone) completely wiped out the load ... with ONE 4 mg. SHOT!, but then, the load crept back again for a relapse, thus they have been trialing it by coupling it with the new daa's, at first with the ONE 4 mg. shot (along with new daa's), and then it morphed to the TWO 2 mg. shots, at strategic intervals along with new daa's - a dif kettle off fish this RG stuff is, and a dif combo when coupled with the new daa's, for a dif kind of one/two/three knock-out punch. I really wonder if this stuff is ever going to be a go, or not, seems it was designed to be a "single drug cure", and this did not pan out, so, will be interesting to see if RG is really needed (for a triple) to effect short(er) duration/or more effective cures with the new daa's we have today. Without RG, the new daa's at 8 and 12 weeks are already working pretty good and short enough for many it seems (comparatively speaking). C.  

Hey tig,

Good info, glad you posted the one about RG101 - I was looking for that particular announcement, as I was going to include it with the following recent history on this RG101 stuff. RG keeps surfacing in the news. Parts of the RG trials are on hold, but the rest ran or are running, and (if I am not mistaken) RG may be have been running their drugs along with some of the grazo/elba trials? Historically, this is not the first time a concern about adverse affects have slowed down RG trials. I recall Matt and Mallani discussing this drug. 

RG-101 was also "mentioned" vaguely, recently,  in reference to it being administered along with sof/vel and/or other daa's to shorten treatment lengths - i.e. - 

 "Future attempts to shorten duration of DAA regimens to less than 8 weeks will probably require the addition of a host-targeting agent such as RG-101, an miR-122 antagonist, which has been shown to do so in the interim results of an ongoing phase 2 study."

Enrollment completed in Regulus' mid-stage study of RG-101 in HCV

Jan 21 2016, 09:56 ET | About: Regulus Therapeutics (RGLS) | By: Douglas W. House, SA News Editor

Regulus Therapeutics (RGLS -4.2%) announces that enrollment is now complete  in its Phase 2 clinical trial assessing the combination of RG-101 with multiple approved direct-acting antivirals [Gilead's HARVONI (ledipasvir/sofosbuvir), J&J'sOLYSIO (simeprevir), Bristol-Myers' Daklinza (daclatasvir)] in treatment-naive patients with HCV infection, genotypes 1 or 4.

78 patients have been randomized to receive a single subcutaneous injection of 2mg/kg of RG-101 followed by 28 days of once-daily oral antivirals (one of the three) followed by another subcutaneous injection of 2 mg/kg of RG-101 on Day 29. Interim results should be available in mid-February. Primary endpoint results (SVR12) should be announced in late Q2.

The company says its ultimate goal is to develop a single-visit combination therapy for HCV infection

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                                                                                                                  Shorter treatment course potentially on the horizon for Hepatitis C patients

April 15, 2016

Investigational treatment, RG-101 combined with direct-acting antivirals shows potential to be effective in Hepatitis C with a shorter than standard four week course

April 15, 2016, Barcelona, Spain: Data from a Phase 2 clinical trial show that an investigational injectable treatment known as RG-101 in combination with a four week course of oral direct-acting antiviral (DAA) treatment was well tolerated and resulted in high virologic response rates post-treatment among Hepatitis C (HCV) infected patients with genotypes 1 and 4, who had not been treated previously. The findings, presented today at The International Liver Congress 2016 in Barcelona, Spain are an interim analysis, with ongoing research to assess virologic response over a 48 week follow-up period to further assess the safety and efficacy of a four week treatment course.

 The investigational treatment, RG-101 works on microRNA-122, which the virus uses to replicate. Drugs that interfere with miR-122 could inhibit HCV replication, acting earlier in the viral lifecycle than currently approved HCV protease, polymerase or NS5A inhibitors.¹ The current standard of care treatment in HCV consists of eight-12 weeks of DAA oral agents.²

 These early results indicate the potential for RG-101 with oral DAA combination therapy to provide an effective Hepatitis C regimen for patients with a short treatment course of just four weeks, said Dr Mihaly Makara from the Buda Hepatology Centre, Budapest, Hungary, and lead study author. We very much hope the long-term, 48-week follow-up data follows the same trend.

This international study enrolled 79 patients with chronic HCV, genotype 1 or 4 who had not previously received treatment. Each patient received a 2mg/kg injection of RG-101 on Day one, with a four week course of oral DAAs (either ledipasvir/sofosbuvir, simeprevir, or daclatasvir), following by a second 2mg/kg injection of RG-101 on Day 29. The mean baseline viral load among patients was 5.805 (log10) IU/mL.

Interim analysis showed that 97.4% (37/38) and 100% (14/14) of patients at eight and 12 weeks respectively had a high virologic response. This was determined by assessing HCV levels below the lower limit of quantification (<12 IU/mL), using the Abbot RealTimeHCV Assay, a consolidated HCV viral load and HCV genotype testing method.³

The combination therapy was generally well tolerated, with the majority of side effects reported being mild in nature, including headache and fatigue, reported in 11.4% of patients.

 It is encouraging to see a potential treatment combination on the horizon that could limit treatment duration for patients, said Professor Tom Hemming Karlsen, EASL Vice Secretary. We will be eagerly awaiting the 48 week follow-up data.

Regulus and Glaxo expand collaboration with mid-stage study of RG-101 and GSK2878175 as single-visit cure of HCV infection

Jun 1 2016, 08:45 ET | About: Regulus Therapeutics (RGLS) | By: Douglas W. House, SA News Editor 

Regulus Therapeutics (NASDAQ:RGLS) expands its clinical trial collaboration with GlaxoSmithKline (NYSE:GSK) for the development of RG-101 with a new randomized dose-ranging Phase 2 study assessing the combination of RG-101 and Glaxo's long-acting parenteral formulation of GSK2878175 as a potential single-visit cure for patients with chronic hepatitis C virus (HCV) infection. The trial, to be conducted outside the U.S., should commence in Q4.

The companies project the availability of interim data in H2 2017. If all goes well, a pivotal trial could start in late 2017.

Earlier this year, an open-label Phase 2 study commenced assessing a single injection of 4 mg/kg of RG-101 and daily oral doses of 20 mg of GSK2878175 for up to 12 weeks in treatment-naive patients infected with HCV genotypes 1 and 3. Interim data are expected in late Q4.

RG-101 is a microRNA therapeutic, specifically a GalNAc-conjugated anti-microRNA targeting microRNA-122. MicroRNAs are small bits of RNA, typically 20 - 25 nucleotides long, that do not encode proteins but regulate gene expression. Researchers believe as many as two-thirds of human genes are regulated by microRNAs.

GSK2878175 is a non-nucleoside NS5B polymerase inhibitor.

Previously: Regulus teams up with Glaxo in mid-stage HCV study (Nov. 3, 2015)

by Stacy Lawrence 

Jun 27, 2016 8:10pm

Given that the mechanism for these two events is uncertain at this time, the FDA considered it appropriate to issue a clinical hold, said Regulus CEO Dr. Paul Grint on a June 27 conference call regarding the clinical hold.

The company said it had received verbal notice from the FDA, but that it anticipates a formal clinical hold letter within 30 days. It said it will work with the agency to lift the clinical hold.

Regulus said that its three ongoing studies of RG-101 should not be affected, since all patients have been enrolled and already completed their single dose of the candidate.

The company reported positive top-line Phase II data for RG-101 in early June. And it was also slated to be in a Phase II trial in combination with partner GlaxoSmithKlines long-acting parenteral formulation of GSK2878175 starting in the fourth quarter; data from that trial were anticipated during the second half of next year. GSK just expanded a deal with Regulus earlier this month to conduct that trial.

In March, the pair started a Phase II study of RG-101 in combination with daily oral GSK2878175 for up to 12 weeks in treatment-naïve patients chronically infected with HCV genotypes 1 and 3. Dosing has been completed in that trial with interim data due before year end.

This latest serious adverse event was a case of jaundice that occurred in an ongoing Phase I trial, 117 days after receiving one dose of RG-101. The HCV patient had end-stage renal disease and was on dialysis.

Regulus said its unlikely that the latest event was related to RG-101, noting that the patient had Type 2 diabetes that was controlled with insulin, coronary artery disease, high cholesterol and high blood pressure and was on a dozen medications

A prior case of jaundice was reported in a Phase II combination trial earlier this year. That patient had one dose of RG-101 as well as four weeks of oral Daklinza that was followed by a second dose of RG-101 on day 29.

Once we receive the letter from the FDA, I'm sure there going to be additional analysis and things that we're going to have to perform and we will obviously make that our utmost priority and we'll turn everything round and provide it back to the FDA as fast as we can, summed up Grint on next steps for Regulus