Wednesday, October 22, 2014

Anti-MiR122 Therapeutic Stuns HCV World with Single-Dose Efficacy Results

This morning, Regulus Therapeutics greeted us with amazing results from a phase I study of RG-101, an anti-microRNA 122 oligo for the treatment of HCV infection.  The results show that in the exploratory HCV-infected patient subgroup, a single dose of 2mg/kg of RG-101 resulted in a mean viral load reduction of 4.1log on day 29.  All responded with viral declines, with 6 and 3 of the 14 patients with viral levels below the level of quantitation on days 29 and 57, respectively.   

These results even exceed my own wildest imaginations (as discussed here yesterday) and I’m amazed how much this virus, in all patients, seems to have come to rely on this host-derived microRNA for replication and/or genome stabilization.

It is not clear whether increasing the dose to 4mg/kg, the pre-planned upper dose in the HCV-infected cohort for which dosing is ongoing will bring any additional benefit given that the biomarker data (host genes targeted by miR-122) from the healthy volunteers showed a plateau already at 2mg/kg, indicating the power of this GalNAc chemistry approach.  My guess is that the main benefit from a higher dose would be a decrease in response variability.

Interestingly, IL-28 status, frequently a predictor of treatment success, did not influence the results, nor did HCV genotype seem to have an impact (small numbers).  This further supports that RG-101 could fill some of the more attractive opportunities in the current HCV market.   

Regarding safety, mild and transient injection site reactions seemed most significant with no serious adverse events in the entire study, including the healthy volunteer cohorts (up to 8mg/kg).  This is also consistent with data for Alnylam’sALN-TTRsc which uses a similar GalNAc chemistry and where multiple doses up to 10mg/kg had been tolerated, with injection site reactions, especially at 10mg/kg, being the main safety finding.   

So what’s it all worth?  The results position RG-101 to facilitate a 4-week HCV dosing regimen (compared to typically 8-12 weeks currently), potentially in combination with a single direct-acting antiviral such as Olysio by Johnson&Johnson.  One or two injections maximum.  Great compliance, potentially pan-genotypic, ideal for the busy practicing physician who does not have the time nor inclination to know the ins and outs of each DAA.

In dollar terms, I’d like to think that with this drug profile, this overlooked compound and company are worth as much as what Merck recently paid for HCV drug developer Idenix: $3.85B. The market valuation of Regulus before the news: $300M.  Needlessly to say that I'm long the stock.

PS: GSK once had rights to a precursor compound of RG-101 which it did not exercise.  Importantly, at the time, Regulus’ anti-miR122 compound was not GalNAc-enabled.  This would have necessitated much more frequent dosing and higher dosages and resulted in less potent and more protracted viral declines, i.e. something that would not have been competitive in the current HCV marketplace.  But as often the case with Big Pharma and cutting-edge technology, today’s data clearly shows them wrong.  It has to be said though that GSK more or less got out of HCV which also would have explained GSK’s decision RE anti-miR122.

PPS: Congrats to Peter Sarnow and Catherine Jopling who in 2005 made the mind-boggling discovery that HCV relies on a microRNA for its replication.  I hope they will be handsomely rewarded for it.


Anonymous said...

While I will grant you, this is OK proof of concept for them, your suggestion it has any meaning in HCV is so ridiculous.

Some actual commentary worth reading.

"The early data appears, in our view, to not offer any meaningful role in the future treatment of Hep C and represents a minimal risk to Gilead given products with similar Phase 1 profiles have been completely dropped from the development pipeline," Skorney said. He added, "Speculation about a single dose cure is completely without merit."

Skorney further said RG-101 data looks about as competitive as dead interferons. "We believe the 4.1 number is all the market sees, not the 29 days it takes to get there," he commented. "While this drug has clear antiviral activity, it does not appear in any way superior to a number of other injectable drugs, most notably some of the recent interferons... Interferon lambda has been all but abandoned by Bristol despite what we see as a similar clinical profile to Regulus"

He said anything can get to 4 log10 at four weeks, relevance of exponentially quicker activity still uncertain. "Hep C cures are essentially at 100% with daily pills, so simply achieving viral suppression is meaningless. In order to play a role in the future of therapy, we believe an agent would have to match current therapy (Harvoni) or reduce the duration of current therapy. Harvoni is the combination of two drugs: sofosbuvir, which reduces viral loads by 4.7 log10 within 7 days, and ledipisvir, which reduces viral loads by 3.3 log10 within 3 days. We still think it is a very open ended question how short the duration can be when you add another oral component with similar rapid antiviral activity, much less an exponentially slower injectable antiviral."

Dirk Haussecker said...

Skorney shows a lot of emotion regarding a drug he/his firm has no interest in. 1 shot combined with 28 days of Olysio, sounds like a very viable target product profile to me.

Anonymous said...

another useless attempt to pump your have no credibility.

Anonymous said...

Dirk you just don't know what you don't know about HCV. You are speaking as if you have lost your moorings in reality and purely on the basis of emotion. Investing in Regulus is a fool's errand. Today's event changes nothing. And an miR-122 approach will likely do little for sanctuaries (which are not hepatic).

Anonymous said...

...and Baird is talking their book. Lots of vested interests in maintaining Gilead's air of invincibility in HCV, and apparently many investors married to their GILD stock.

Keep fighting the good fight, Dirk. Biotech doesn't need another voice promoting incumbents.

Anonymous said...

This makes Benitec look like the chasers of fools gold.

A genuine disruptive technology that has the ability to cut down over $10bn of revenues to GILD in one go. No wonder their supporters wish to get out a different message.

Those controlling the purse of the public health spend will be interested too I guess.

Anonymous said...

Oops Gilead crowd is crowing. If they were really not worried they wouldn't be shouting. Short regulus for Pete's sake if you really believe your garbage.

Anonymous said...

Usual twitter suspects bashing Dirk. Next time ask for their credentials in Rnai or biotech training or investment track record or investment portfolio size. Lmao. Of course this data are early. But they are outstanding. I though Adam did a very fair write up.

Haters gonna hate.

Anonymous said...

Dirk, this is clearly an interesting result. Do not think that RG-101 will be able to realistically challenge GILDs franchise, but I'm sure that there still are quick bucks to be made in RGLS. The main focus should, however be on their other assets...

Regarding broader RNAi implications, how do you feel this success reflects on ARWRs DPC and especially on TKMRs LNP tech? One could think that the Glnac tech is turning out to be superior to the other delivery techs?

Anonymous said...

After the failed $116bn AZN bid, ongoing great data along with all the fun of the fair in biotech, PFE figures the best it can do is to mount a $11bn buyback.

They could buy ALNY AND ISIS for that and solve their pipeline woes in one go.

Anonymous said...

Dr. Yimin Hua, a Cure-SMA funded researcher from the Krainer lab at Cold Harbor Laboratory, presented experiments using antisense oligonucleotides that distribute to the central nervous system, or to the rest of the body, in severe SMA mice. His data indicated that the systemic delivery to the entire body yielded greater improvement in severe SMA mice, compared to CNS delivery alone. He is also exploring whether the chemical backbone of the oligonucelotide influences how well it works.

Anonymous said...

Arms for Asher - Fighting SMA Together

Have a beautiful music filled day!

This is a big deal for Asher to sit up and use his hands like this.

Rebecca Gill I still remember taking care of him when he was admitted at nemours. What a sweet boy! So happy to see him doing such amazing things! Go Asher!
1 · 7 hours ago
Arms for Asher - Fighting SMA Together Hey Rebecca!
Asher still continues to make gains! We definitely have Nemours and all the great work they are doing there to thank for his health. Hope you and yours is doing well.
3 hours ago

Anonymous said...

Dirk, I've been way heavy ISIS for years so until recently I had a contra-position. You're latest numbers are off the charts. Congrats. I've got some free money floating around so I'm hanging on your every word. I should have moved that 100g last week. Keep up the good work! Luv u babes!

Anonymous said...

Who is the likely purchaser in the RGLS shelf?

Am hoping this where PFE makes its post AZ move.

Am not hoping this shelf ends up like ARWR or TKMR.

Anonymous said...

PPMD Submits Letter to FDA Regarding Latest Sarepta Update

Today’s press release and investor call from Sarepta have sent a ripple of angst and sadness through our community. Moments ago, PPMD sent a letter to the FDA that reflects our organization’s belief that safety and rigor have been demonstrated throughout this process. Further, we believe that any strengthening of data packages that causes delays (as is now being requested by the FDA, as articulated in today’s press release and call) should ensure a streamlined, more expeditious approval process for follow-on exons.

As a community we believe exon-skipping drugs like eteplirsen hold potentially life-altering benefits, and must be moved forward as rapidly as possible. In addition, we believe eteplirsen to be a critical foundational therapy, restoring dystrophin and significantly slowing disease progression. We look forward to the mid-2015 submission and approval of eteplirsen and the consideration of approval of PMO (phosphodiamidate morpholino oligomer) as a class of drugs that will have the ability to slow/halt progression in a great many of the individuals living with Duchenne.

PPMD has also reached out to leadership at Sarepta to support the pathway forward for these trials and to work to ensure the approval and availability of an effective therapy to our Duchenne community at the earliest moment possible. As always we will report back to you with updates on next steps and anything we as a community can do to help this process.

Our Letter to the FDA:

The Duchenne community does not deserve to be politically manipulated by the FDA.

Anonymous said...

"$RGLS seems like the book has closed and only way to get number of desired shares is on open market."

Could mean this will be an expeditious affair with the raise being closed shortly.

If they could produce data like that in Alzheimers, what would PFE pay for access to that?

Anonymous said...

Duchenne mom: 'The only ones who are going to suffer are the kids'

Monday's news that the U.S. Food and Drug Administration is requiring more data than originally hoped before it will consider approval is a roadblock, to be sure. It will delay the application for approval — originally planned before the end of this year — for between six and nine months. When you're talking about a disease which quickly wastes away the muscles in young boys, leaving them wheelchair-bound by the age of 12, those few months are precious.

"I don't understand. There seems to be no desire at all to get an approved medication to these boys," said McSherry, whose own son is 19 and now attending Bridgewater State University. She points out that this is the third apparent change of heart by the FDA as to what Sarepta needs to do to be considered for approval. "They keep moving the goalposts. You can't hit a moving target."
The FDA's latest reason for requesting more data is that there were "discrepancies" at the research site conducting the trials. McSherry questions that assertion, considering the trial site, Nationwide Children's Hospital in Columbus, Ohio, and the overseeing physician, Jerry R. Mendell, are recognized globally as the top experts in Duchenne muscular dystrophy. "They're not questioning the data. They're questioning the methodology," she said.

Anonymous said...

RGLS priced at seventeen. Trading above with strength. If someone wants control, then they have to go to ALNY, ISIS and BIIB first. After that, they have to speak with Sanofi/GENZ, Takeda, GSK et. al.

Am sure ObamaCare administrators have an opinion on a therapy at half or less the cost of current options.

Meanwhile, someone else took a strong liking to MRNA in the last fifteen minutes or so. Might be here where the takeover originates.

Anonymous said...

If RGLS go down the CISCO path, it will be RGLS paper for MRNA paper. And that will just be the beginning.

Bacon, lettuce and tomato (BLT) entering capitulation territory. All that's missing is a bit of egg on the faces of French, Francis and Co.

Anonymous said...

Moms, Regulators, Biotech Startups, and the Battle Over a Potentially Life-Saving Drug

Aidan has Duchenne, the deadliest strain of muscular dystrophy. It’s inherited maternally on the X chromosome and mostly afflicts boys. Parents typically sense something is wrong when their sons at 3 or 4 don’t run around or they start falling for no obvious reason. Beginning in the legs, Duchenne destroys muscle, which is replaced by fat and scar tissue. Victims lose the ability to walk by adolescence. Eventually the disease causes cardiac and/or respiratory complications that lead to death by the mid-20s. One in 3,500 newborns has Duchenne, which translates to around 15,000 cases in the U.S. There’s no cure.
“Aidan doesn’t really understand yet,” his mother, Mindy, says, “but it’s basically a slow-motion death sentence.”
There’s reason to hope—not for a miracle, but for a reprieve.
“Why doesn’t the government let me have eteplirsen?” Austin asks when we meet. He waits for an answer, which I don’t have. His mother joins the conversation: “The FDA’s inaction,” she says, “is killing my son.”

Anonymous said...

Arms for Asher - Fighting SMA Together

Today was a powerful day. An unexpected powerful day. It was Asher's 5th injection for a trial drug that is proving to benefit SMA babies. This drug is not a cure, but it is an effective treatment. It is helping.
Last October Asher didn't move his legs, he only rolled his ankles; he couldn't roll over or sit up. Fast forward a year, he lifts his legs, rolls over, sits up, bears weight in his arms and legs, and more. Today is a powerful day.

I am praying for this power to blanket over all SMA families and help ease some of the pain our friends experience. The friends we have lost are not forgotten. We continue to hope we will stop losing more.

Anonymous said...

Perhaps someone knows how this works.

JPM conference finishes on the 14th.

Absent from the presentors list but present on the participants list RGLS says this:

LA JOLLA, Calif., Jan. 7, 2014 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus, will present a company overview at the 32nd Annual J.P. Morgan Healthcare Conference on Thursday, January 16, 2014 at 8:30 AM PST at the Westin St. Francis Hotel in San Francisco, CA.

Two days after its finished RGLS are going to present??

Anonymous said...

What year are you in?

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