WASHINGTON - The combination of Merck's ruzasvir and uprifosbuvir correlated with reduced efficacy in patients with hepatitis C genotype 3 with or without cirrhosis, according to a presentation at The Liver Meeting 2017.
Eric Lawitz, MD, of the University of Texas Health Science Center, Texas Liver Institute in San Antonio, presented phase-2, open-label data on the NS5A inhibitor ruzasvir 180 mg combined with NS5B inhibitor uprifosbuvir 450 mg for 12 weeks. He noted that a combination with a lower dose of ruzasvir correlated with "suboptimal efficacy" in a previous data set.
Eligible participants were either treatment-naive or had previously received treatment with interferon with or without ribavirin. The researchers included patients with or without compensated cirrhosis. Most patients were Caucasian, men and aged 50 years or older.
The analysis included 267 participants with HCV genotype 1 to 4 and a cohort of 219 participants with genotypes 1 to 6. This included 47 patients with genotype 1a, 28 with genotype 1b, 50 with genotype 2, 61 with genotype 3, 56 with genotype 4, three with genotype 5, and 22 with genotype 6.
The overall rate of sustained virologic response was 90%, according to Lawitz. "This includes eight patients who failed for administrative reasons," he said. "The modified SVR12 rate is 92%."
Nineteen patients relapsed and two patients discontinued due to adverse events. "Importantly, 14 of the 19 virologic relapsers were genotype 3 patients," Lawitz said. Three of these relapses had genotype 1a disease. "There was no impact on genotype 1b, 2, 3, 4, 5 or 6 on efficacy regardless of cirrhosis status or baseline resistance-associated substitutions."
Overall, 76% of patients with genotype 3achieved SVR. Patients with NS5A resistance had an overall SVR of 74%.
Further, there was no statistical difference between SVR rates in patients with cirrhosis and those without cirrhosis, according to Lawitz. However, he noted that the rate among patients with cirrhosis was 68% vs. 80% for those without cirrhosis.
"Turning our attention to safety, adverse events were frequent, but drug-related adverse events were infrequent, at 33%," he said, adding that there were seven serious events, none of which investigators determined to be drug-related.
"The overall efficacy of the two-drug regimen of ruzasvir 180 mg and uprifosbuvir 450 mg is suboptimal as a pangenotypic regimen," Lawitz concluded. "There was lower efficacy in genotype 3. Lower efficacy was seen both in cirrhosis and non-cirrhosis. Baseline resistance-associated substitutions accounted for many, but not all, of the virologic failures. There was potential impact of a baseline Y93 RAS." - by Rob Volansky
For more information: Lawitz E, et al. Abstract 61. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.
Tig said
Nov 1, 2017
Yep, that’s the same information I’ve been reading and hearing for awhile now. You can almost determine the best treatments by the manufacturers information on these stock pages. The investors often know more than most about the future of these drug protocols in development. Follow the money....
Canuck said
Nov 1, 2017
I agree with you Tig - here's a tidbit I did not post earleir (kinda dry for most I think ), but .... now that we are on the subject of markets again ...
Johnson & Johnson and Merck & Co. Inc. have both recently halted development of drugs to treat hepatitis C (HCV), with no plans to work on any others. This capitulation leaves the market largely split between Gilead Sciences Inc., AbbVie Inc., and a drug Merck already has on the market.
This is a smart retreat for Merck and J&J. The HCV market is well past its peak. Both of their new therapies would have been very late; AbbVie and Gilead both had new drugs approved this year. Their best hope likely would have been to compete on price in a market that's been warring over price for a while.
And the market is continually shrinking -- existing medicines have already cured many people. That's good news for patients but not an especially appealing prospect for drugmakers looking to invest in new treatments.
It's telling that J&J and Merck both retreated after the FDA approved AbbVie's new HCV medicine Mavyret in early August. The drug is particularly effective -- it works in all genetic subtypes of the disease and can cure many people more quickly than most other drugs. It's also cheaper than competing therapies. J&J and Merck may have realized they couldn't keep up with it on price. Insurers will likely use Mavyret's low cost to wring discounts from competitors.
But Wall Street analysts continue to underestimate the drug's impact. Their 2020 sales estimates for Gilead and Merck's HCV drugs have barely budged since its approval. They expect only modest sales for Mavyret, while forecasting continued dominance for Gilead and a profitable niche for Merck's Zepatier.
IntellaTurn's insight:
The number of new HCV drug patients in the U.S. this year may fall as much as 35 percent from 2016, Gilead has estimated. That decline is not reversible. HCV is a slow-moving disease; the sickest patients have already been treated, and healthier ones are more likely to hold off on getting these expensive medicines.
Tig said
Oct 31, 2017
If you follow the stock market, the pharmaceutical industry is in a bit of turmoil. There have been so many new effective drugs into the HCV market, most of them 95+% effective and growing. Merck has been losing market opportunities in other areas as well as their work on NS5a/b drugs. I think they are rounding up their collective wagons and reserving ammo (cash) for other endeavors, including stockholders.
Canuck said
Oct 31, 2017
Further to the very recent announcement (September 2017) that Merck IS dropping further phase 3 trials/development of their triple uprif/grazo/ruz, it's just weird, in that, just only this spring, there was no "wind" of this happening!
Below is a press release from Merck earlier in 2017, as recent as (April 2017), and yet (now) Merck has gone completely silent on the matter of all this former/prior phase 1 and 2 hard work (multiple trials, Crest and C-Surge NCT 02332720 and NCT 02613403 respectively) researching this potentially good uprif (their new NS5B!)/grazo/ruz triple. Dropped like a hot potato it would seem!
Merck is currently off to the annual Washington "The Liver Meeting" (that is occurring right now in (October 2017), and they are only going to be presenting info on their stellar "Zepatier"? Why?
Just odd ... both Merck and Janssen developed their own "new" NS5B's for their triples (just ignore, if you can, the possible merits of their triples, or, the possible merits of any of their other individual drugs in their triple trials for a moment), to me, alone, any "new" effective NS5B is big news!, as it competes with Gilead's NS5B SOF - all that new Merck and Janssen 5B R&D just dropped??, coincidental? that both these companies new 5B's have been shoved unused to the back of the shelf, in the same breath that Gilead was successful in renewing/extending their SOF patents to 2029?? About Access to Sofa
Not understanding leads me to negative speculation - just pondering, out loud.
(Press release from Merck - April 2017)
Merck Announces New Phase 2 Data on Investigational Triple Combination Therapy MK-3682B for Chronic Hepatitis C
APRIL 22, 2017
Findings Presented at The International Liver Congress 2017 (TM) Show High Rates of Sustained Virologic Response (SVR12) in Genotype 1 Patients for Whom Direct-Acting Antiviral Therapy Had Previously Failed
KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the first sustained virologic response1 (SVR) results 12 weeks after completion of therapy (SVR12, considered virologic cure) from C-SURGE, an ongoing, open label Phase 2 clinical trial evaluating MK-3682B [uprifosbuvir (MK-3682)2/grazoprevir3/rusazvir4], the company's investigational triple-combination therapy in treatment-experienced patients with hepatitis C virus (HCV) genotype (GT) 1 infection for whom treatment with approved direct-acting antiviral regimens had failed. The study showed that 100 percent (43/43) of patients who completed 16 weeks of treatment plus ribavirin (RBV) achieved SVR12 and 100 percent (49/49) of patients who completed 24 weeks of treatment achieved SVR12 (abstract PS-159). These results will be presented today at The International Liver Congress 2017.
"Despite the significant progress made to address the worldwide epidemic of chronic hepatitis C infection, there remains a need for additional treatment options," said Dr. Heiner Wedemeyer, lead study investigator and research group leader in the department of gastroenterology, hepatology and endocrinology at Hannover Medical School, Germany. "We are encouraged by the high virologic cure rates in the difficult-to-treat patients observed in the C-SURGE study and look forward to further evaluation of this investigational triple-combination therapy."
The Phase 2 C-SURGE study enrolled 94 patients who were randomized to receive a once-daily regimen of MK-3682B for either 16 weeks with RBV (n=45) or 24 weeks without RBV (n=49); one patient in the 16-week arm withdrew prior to starting treatment. Of the 93 patients who received treatment (full analysis set), 57 had previously received a regimen of ledipasvir/sofosbuvir (LDV/SOF) for 12 to 24 weeks, 14 had previously received LDV/SOF for 8 weeks and 22 had previously received ZEPATIER® (elbasvir and grazoprevir) for 12 weeks. Seventy-eight patients who received treatment had at least one baseline NS5A resistance-associated substitution (RAS) at positions 28, 30, 31 or 93. Eighty patients who received treatment in C-SURGE had GT1a infection, and 40 patients had compensated cirrhosis. In the full analysis set, 98 percent of patients who received MK-3682B for 16 weeks with RBV (43/44) and 100 percent of patients who received MK-3682B for 24 weeks without RBV (49/49) achieved SVR12.
Results from the modified full analysis set, which excludes one patient in the 16-week arm who withdrew after three doses of treatment, show that 100 percent of patients receiving treatment with MK-3682B for 16 weeks with RBV (43/43) and 100 percent of patients receiving treatment with MK-3682B for 24 weeks without RBV (49/49) achieved SVR12.
Across the combined treatment arms, the most common adverse events (AEs) reported in the full analysis set were fatigue (35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%). There were no drug-related serious AEs, and no patients discontinued treatment due to a drug-related AE.
SVR8 results from the C-SURGE study were previously presented at The Liver Meeting® 2016.
About MK-3682B
MK-3682B is Merck's investigational triple-combination therapy in Phase 2 development for the treatment of chronic HCV infection. MK-3682B combines an HCV nucleotide analogue NS5B polymerase inhibitor (uprifosbuvir, MK-3682), an HCV NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A inhibitor (ruzasvir, MK-8408).
Canuck said
Oct 17, 2017
This was another recent drop out too! Janssen's triple with their new NS5B (AL-355)! C.
Looks like Merck is going after different markets and dropping out of the HCV drug business. Zepatier is their last. Not a bad finish! It has cured a lot of people.
Some late feedback on Mercks new NS5B (uprif) and NS5A (ruz) - now a non-contender/further trials dropped?
Helio - November 8, 2017 - From the Liver Meeting
Combined ruzasvir, uprifosbuvir shows suboptimal HCV pangenotypic efficacy
WASHINGTON - The combination of Merck's ruzasvir and uprifosbuvir correlated with reduced efficacy in patients with hepatitis C genotype 3 with or without cirrhosis, according to a presentation at The Liver Meeting 2017.
Eric Lawitz, MD, of the University of Texas Health Science Center, Texas Liver Institute in San Antonio, presented phase-2, open-label data on the NS5A inhibitor ruzasvir 180 mg combined with NS5B inhibitor uprifosbuvir 450 mg for 12 weeks. He noted that a combination with a lower dose of ruzasvir correlated with "suboptimal efficacy" in a previous data set.
Eligible participants were either treatment-naive or had previously received treatment with interferon with or without ribavirin. The researchers included patients with or without compensated cirrhosis. Most patients were Caucasian, men and aged 50 years or older.
The analysis included 267 participants with HCV genotype 1 to 4 and a cohort of 219 participants with genotypes 1 to 6. This included 47 patients with genotype 1a, 28 with genotype 1b, 50 with genotype 2, 61 with genotype 3, 56 with genotype 4, three with genotype 5, and 22 with genotype 6.
The overall rate of sustained virologic response was 90%, according to Lawitz. "This includes eight patients who failed for administrative reasons," he said. "The modified SVR12 rate is 92%."
Nineteen patients relapsed and two patients discontinued due to adverse events. "Importantly, 14 of the 19 virologic relapsers were genotype 3 patients," Lawitz said. Three of these relapses had genotype 1a disease. "There was no impact on genotype 1b, 2, 3, 4, 5 or 6 on efficacy regardless of cirrhosis status or baseline resistance-associated substitutions."
Overall, 76% of patients with genotype 3 achieved SVR. Patients with NS5A resistance had an overall SVR of 74%.
Further, there was no statistical difference between SVR rates in patients with cirrhosis and those without cirrhosis, according to Lawitz. However, he noted that the rate among patients with cirrhosis was 68% vs. 80% for those without cirrhosis.
"Turning our attention to safety, adverse events were frequent, but drug-related adverse events were infrequent, at 33%," he said, adding that there were seven serious events, none of which investigators determined to be drug-related.
"The overall efficacy of the two-drug regimen of ruzasvir 180 mg and uprifosbuvir 450 mg is suboptimal as a pangenotypic regimen," Lawitz concluded. "There was lower efficacy in genotype 3. Lower efficacy was seen both in cirrhosis and non-cirrhosis. Baseline resistance-associated substitutions accounted for many, but not all, of the virologic failures. There was potential impact of a baseline Y93 RAS." - by Rob Volansky
For more information: Lawitz E, et al. Abstract 61. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.
Yep, that’s the same information I’ve been reading and hearing for awhile now. You can almost determine the best treatments by the manufacturers information on these stock pages. The investors often know more than most about the future of these drug protocols in development. Follow the money....
I agree with you Tig - here's a tidbit I did not post earleir (kinda dry for most I think ), but .... now that we are on the subject of markets again ...
Oct 5, 2017 - Maelstrom (Link) ... The Hepatitis Drug Market Is Worse Than Wall Street Realizes
(graphs will not open below)
From www.bloomberg.com - October 5, 6:28 AM
Johnson & Johnson and Merck & Co. Inc. have both recently halted development of drugs to treat hepatitis C (HCV), with no plans to work on any others. This capitulation leaves the market largely split between Gilead Sciences Inc., AbbVie Inc., and a drug Merck already has on the market.
This is a smart retreat for Merck and J&J. The HCV market is well past its peak. Both of their new therapies would have been very late; AbbVie and Gilead both had new drugs approved this year. Their best hope likely would have been to compete on price in a market that's been warring over price for a while.
And the market is continually shrinking -- existing medicines have already cured many people. That's good news for patients but not an especially appealing prospect for drugmakers looking to invest in new treatments.
It's telling that J&J and Merck both retreated after the FDA approved AbbVie's new HCV medicine Mavyret in early August. The drug is particularly effective -- it works in all genetic subtypes of the disease and can cure many people more quickly than most other drugs. It's also cheaper than competing therapies. J&J and Merck may have realized they couldn't keep up with it on price. Insurers will likely use Mavyret's low cost to wring discounts from competitors.
But Wall Street analysts continue to underestimate the drug's impact. Their 2020 sales estimates for Gilead and Merck's HCV drugs have barely budged since its approval. They expect only modest sales for Mavyret, while forecasting continued dominance for Gilead and a profitable niche for Merck's Zepatier.
IntellaTurn's insight:
The number of new HCV drug patients in the U.S. this year may fall as much as 35 percent from 2016, Gilead has estimated. That decline is not reversible. HCV is a slow-moving disease; the sickest patients have already been treated, and healthier ones are more likely to hold off on getting these expensive medicines.
If you follow the stock market, the pharmaceutical industry is in a bit of turmoil. There have been so many new effective drugs into the HCV market, most of them 95+% effective and growing. Merck has been losing market opportunities in other areas as well as their work on NS5a/b drugs. I think they are rounding up their collective wagons and reserving ammo (cash) for other endeavors, including stockholders.
Further to the very recent announcement (September 2017) that Merck IS dropping further phase 3 trials/development of their triple uprif/grazo/ruz, it's just weird, in that, just only this spring, there was no "wind" of this happening!
Below is a press release from Merck earlier in 2017, as recent as (April 2017), and yet (now) Merck has gone completely silent on the matter of all this former/prior phase 1 and 2 hard work (multiple trials, Crest and C-Surge NCT 02332720 and NCT 02613403 respectively) researching this potentially good uprif (their new NS5B!)/grazo/ruz triple. Dropped like a hot potato it would seem!
Merck is currently off to the annual Washington "The Liver Meeting" (that is occurring right now in (October 2017), and they are only going to be presenting info on their stellar "Zepatier"? Why?
Just odd ... both Merck and Janssen developed their own "new" NS5B's for their triples (just ignore, if you can, the possible merits of their triples, or, the possible merits of any of their other individual drugs in their triple trials for a moment), to me, alone, any "new" effective NS5B is big news!, as it competes with Gilead's NS5B SOF - all that new Merck and Janssen 5B R&D just dropped??, coincidental? that both these companies new 5B's have been shoved unused to the back of the shelf, in the same breath that Gilead was successful in renewing/extending their SOF patents to 2029?? About Access to Sofa
Not understanding leads me to negative speculation - just pondering, out loud.
(Press release from Merck - April 2017)
Merck Announces New Phase 2 Data on Investigational Triple Combination Therapy MK-3682B for Chronic Hepatitis C
APRIL 22, 2017
Findings Presented at The International Liver Congress 2017 (TM) Show High Rates of Sustained Virologic Response (SVR12) in Genotype 1 Patients for Whom Direct-Acting Antiviral Therapy Had Previously Failed
KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the first sustained virologic response1 (SVR) results 12 weeks after completion of therapy (SVR12, considered virologic cure) from C-SURGE, an ongoing, open label Phase 2 clinical trial evaluating MK-3682B [uprifosbuvir (MK-3682)2/grazoprevir3/rusazvir4], the company's investigational triple-combination therapy in treatment-experienced patients with hepatitis C virus (HCV) genotype (GT) 1 infection for whom treatment with approved direct-acting antiviral regimens had failed. The study showed that 100 percent (43/43) of patients who completed 16 weeks of treatment plus ribavirin (RBV) achieved SVR12 and 100 percent (49/49) of patients who completed 24 weeks of treatment achieved SVR12 (abstract PS-159). These results will be presented today at The International Liver Congress 2017.
"Despite the significant progress made to address the worldwide epidemic of chronic hepatitis C infection, there remains a need for additional treatment options," said Dr. Heiner Wedemeyer, lead study investigator and research group leader in the department of gastroenterology, hepatology and endocrinology at Hannover Medical School, Germany. "We are encouraged by the high virologic cure rates in the difficult-to-treat patients observed in the C-SURGE study and look forward to further evaluation of this investigational triple-combination therapy."
The Phase 2 C-SURGE study enrolled 94 patients who were randomized to receive a once-daily regimen of MK-3682B for either 16 weeks with RBV (n=45) or 24 weeks without RBV (n=49); one patient in the 16-week arm withdrew prior to starting treatment. Of the 93 patients who received treatment (full analysis set), 57 had previously received a regimen of ledipasvir/sofosbuvir (LDV/SOF) for 12 to 24 weeks, 14 had previously received LDV/SOF for 8 weeks and 22 had previously received ZEPATIER® (elbasvir and grazoprevir) for 12 weeks. Seventy-eight patients who received treatment had at least one baseline NS5A resistance-associated substitution (RAS) at positions 28, 30, 31 or 93. Eighty patients who received treatment in C-SURGE had GT1a infection, and 40 patients had compensated cirrhosis. In the full analysis set, 98 percent of patients who received MK-3682B for 16 weeks with RBV (43/44) and 100 percent of patients who received MK-3682B for 24 weeks without RBV (49/49) achieved SVR12.
Results from the modified full analysis set, which excludes one patient in the 16-week arm who withdrew after three doses of treatment, show that 100 percent of patients receiving treatment with MK-3682B for 16 weeks with RBV (43/43) and 100 percent of patients receiving treatment with MK-3682B for 24 weeks without RBV (49/49) achieved SVR12.
Across the combined treatment arms, the most common adverse events (AEs) reported in the full analysis set were fatigue (35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%). There were no drug-related serious AEs, and no patients discontinued treatment due to a drug-related AE.
SVR8 results from the C-SURGE study were previously presented at The Liver Meeting® 2016.
About MK-3682B
MK-3682B is Merck's investigational triple-combination therapy in Phase 2 development for the treatment of chronic HCV infection. MK-3682B combines an HCV nucleotide analogue NS5B polymerase inhibitor (uprifosbuvir, MK-3682), an HCV NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A inhibitor (ruzasvir, MK-8408).
This was another recent drop out too! Janssen's triple with their new NS5B (AL-355)! C.
A "new?" NS5B - "AL-355"
Looks like Merck is going after different markets and dropping out of the HCV drug business. Zepatier is their last. Not a bad finish! It has cured a lot of people.
Merck‘s Out