afraidofsurgery
Well-known member
Here's a new article in Medscape about the anticoagulant pipeline. FYI only. I'm not holding my breath. Sorry if the formatting didn't come out right, seems I can't attach a pdf document?
Patty
New Oral Anticoagulants Raise Hopes for Warfarin Replacement
from Heartwire ? a professional news service of WebMD
Sue Hughes
Information from Industry
Antibiotic Treatment for Many Outpatient and Inpatient Bacterial Infections
Learn more about high-dose, short-course therapy, including PK/PD parameters, clinical benefits, and doctor and patient benefits.
December 8, 2006 (Gothenburg, Sweden) - A host of potential new oral anticoagulant agents, which could become much-needed replacements for warfarin and could also be used as an alternative to heparins or other antithrombin agents, are making good progress in development, with at least two agents now in phase 3 trials.
But experts are cautious following the fall from glory of the first such agent to be developed--ximelagatran--which actually reached the market in Europe but was swiftly withdrawn because of liver toxicity. Nevertheless, as there are so many new compounds in development, researchers are optimistic that this time at least one or two will succeed and provide the millions of patients who are--or should be--taking warfarin with a much more user-friendly treatment.
The two agents furthest on in development are the factor IIa inhibitor dabigatran (Boehringer Ingelheim) and the factor Xa inhibitor rivaroxaban (Bayer and Ortho-McNeil). Several other companies also have orally available factor Xa inhibitors in earlier clinical development, including Bristol-Myers Squibb, Lilly, Yamanouchi, and DuPont, and there are also other agents with different mechanisms in the pipeline, including a factor IXa inhibitor, TTP889 (TransTech Pharma), and an orally active glycosaminoglycan enhancer, odiparcil (SmithKline Beecham).
These agents are initially being developed for the prevention of thrombosis in orthopedic-surgery patients, but both dabigatran and rivaroxaban are also now starting late-stage trials for the prevention of stroke in atrial-fibrillation patients (as a replacement for warfarin) and in the treatment of acute coronary syndromes. Researchers in the field are optimistic that these agents will become easier-to-use alternatives to warfarin.
One of the leaders in this field, orthopedic surgeon Dr Bengt Eriksson (Sahlgrenska University Hospital, Gothenburg, Sweden), told heartwire: ?I am hopeful that at least one of these new agents will reach the market within the next two to three years for the prevention of venous thromboembolism after major orthopedic surgery, and then these agents will gradually replace current anticoagulants.?
Rivaroxaban in orthopedic surgery
The latest phase 2 data on rivaroxaban in orthopedic-surgery patients was published in the November 28, 2006 issue of Circulation [1]. This study, led by Eriksson, compared various oral doses of rivaroxaban with subcutaneous enoxaparin in 873 patients undergoing elective total-hip replacement. Study drugs were given for five to nine days after surgery.
Results showed no significant dose-response relationship for rivaroxaban in terms of efficacy, which the authors say can be explained by the higher-than-expected efficacy achieved in the lower-dose groups. There was, however, a significant dose-response relationship in terms of bleeding.
Rivaroxaban phase 2 dose-ranging study vs enoxaparin in orthopedic-surgery patients Drug
DVT/PE/mortality (%)
Major postop bleeding (%)
Rivaroxaban
5 mg 14.9
2.3
10 mg 10.6
0.7
20 mg 8.5
4.3
30 mg 13.5
4.9
40 mg 6.4
5.1
Enoxaparin 40 mg
25.2
1.9
DVT=deep-venous thrombosis
PE=pulmonary embolism
The researchers conclude: ?Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total-hip replacement, with the convenience of once-daily oral dosing and without the need for coagulation monitoring. When both efficacy and safety are considered, these results suggest that 10-mg rivaroxaban once daily should be investigated in phase 3 studies.?
Eriksson adds: ?These data show that we could be another step closer to the clinical reality of an oral, once-daily anticoagulant that is not associated with limitations of current standard therapies such as regular monitoring or administration by injection."
In an accompanying editorial [2], Drs Kenneth Mahaffey and Richard Becker (Duke University, Durham, NC) say that ?novel anticoagulant pharmacotherapies such as rivaroxaban, developed toward carefully chosen targets with attractive characteristics (oral administration, once-daily dosing, rapid onset of action, an intermediate offset rate, and no requirement for routine coagulation monitoring) herald an exciting time in cardiovascular research."
Phase 3 now under way
Based on these and other phase 2 data, phase 3 trials have now been started with rivaroxaban 10 mg once daily. The first of these--the RECORD study--is under way in the prevention of venous thromboembolism (VTE) after elective major orthopedic surgery, and it is planning to enroll more than 10 000 patients. The first approval filings for rivaroxaban in this indication are planned for late 2007 in Europe and 2008 in the US. A large phase 3 trial (ROCKET) of rivaroxaban in atrial fibrillation patients is also now being planned, to be run out of Duke University, and studies of the drug in ACS are being coordinated by the TIMI group.
Lead investigator of the RECORD study, Dr Alexander Turpie (McMaster University, Hamilton, ON), told heartwire that he was very excited about rivaroxaban and the other oral agents in development. ?We are all excited--these drugs look terrific--but we won?t know for sure until we see large-scale trial results. We have been here before--we were all very excited about ximelagatran and that was much further advanced when it bit the dust, so we have to be cautious."
Spotlight on liver effects
Ximelagatran, which had been touted as the blockbuster replacement for warfarin, was refused approval in the US and was spectacularly removed from the market in Europe shortly after its launch there because of liver toxicity, so this will be a particular focus for the new crop of oral anticoagulants in development. In the current phase 2 study with rivaroxaban reported in Circulation, the incidence of increased aminotransferase levels after short-term exposure to rivaroxaban did not exceed that observed with enoxaparin. However, an undesired effect on liver-function tests was noted in two patients receiving rivaroxaban. One patient had an increase in alanine aminotransferase (ALT) and bilirubin early during treatment, and another had an early rise in ALT that persisted during follow-up.
The authors note that neither of these patients had clinical symptoms suggestive of impaired liver function, but they add, ?It is not possible to draw definite conclusions to elucidate the causes of these raised liver enzymes, and further studies are required to determine whether there is a relationship with rivaroxaban."
Turpie suggested that the fact that there are now a whole group of different oral agents in development makes him optimistic that at least one will be successful. ?It?s hard to differentiate between them all at the moment--but hopefully a few of them will make it past the finishing line," he commented.
Enormous market
And there is certainly a big incentive for the companies developing these agents to get them to the market, as there is very large patient population who would benefit from an oral anticoagulant without the worry and inconvenience of monitoring. Turpie commented to heartwire: ?There are millions of patients currently taking warfarin who would prefer not to have to undergo monitoring, and there is another significant number who should take warfarin but don?t because they can?t manage the monitoring. As well as for AF patients, warfarin is indicated for many ACS patents, so the need for a simple and safe oral drug is enormous."
Will dabigatran get there first?
The other agent that is in phase 3 trials, dabigatran, is actually slightly nearer the market than rivaroxaban, with its phase 3 trials in orthopedic-surgery patients near completion, and phase 3 trials in AF already under way. Dabigatran belongs to the same class as ximelegatran, so it will be scrunitized even more carefully for liver toxicity.
Becker agrees that these drugs look very promising. ?They could be used across the board for both venous and arterial thrombotic conditions--as a replacement for warfarin as chronic therapy and instead of heparin in acute situations, so there is a huge market. It is very exciting," he told heartwire. ?If these drugs can do away with the need for monitoring and dose titration, which it looks as though they can, they will revolutionize this area of medicine. I believe that the number of patients getting treatment would increase by at least 15% to 20%."
Becker explained that dabigatran and rivaroxaban have different targets in the coagulation cascade, and it is not known if factor Xa inhibitors will be better than factor IIa inhibitors or vice versa. ?It is possible to put forward arguments for both targets, and we won?t know if one is better until we see the phase 3 results,? he said.
Becker said that it was not known for sure whether the hepatotoxicity associated with ximelagatran was a class effect or not. ?It is still not clear what caused the liver toxicity with ximelagatran--we still don?t know what the mechanism was, so we don?t know for sure that it isn?t a class effect. We therefore have to be vigilant with similar drugs. We learned a lot from ximelagatran--we learned that we have to be aware of off-target toxicity, and we need thousands of patients for this to show up. But based on the amount of effort going into developing these agents and the large amount of drugs now in clinical trials, I would say it is very likely that we will have an a replacement for warfarin in the not-too-distant future,? he added.
Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114:2374-2381.
Mahaffey KW and Becker RC. The scientific community?s quest to identify optimal targets for anticoagulant pharmacotherapy. Circulation 2006; 114:2313-2316.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
--------------------------------------------------------------------------------
Sue Hughes is a journalist for Medscape. She joined theheart.org, a website recently acquired by WebMD, in 2000. She was previously science editor of Scrip World Pharmaceutical News. Graduating in pharmacy from Manchester University, UK, she started her career as a hospital pharmacist before moving as a journalist to a UK pharmacy trade publication. She can be reached at [email protected].
Patty
New Oral Anticoagulants Raise Hopes for Warfarin Replacement
from Heartwire ? a professional news service of WebMD
Sue Hughes
Information from Industry
Antibiotic Treatment for Many Outpatient and Inpatient Bacterial Infections
Learn more about high-dose, short-course therapy, including PK/PD parameters, clinical benefits, and doctor and patient benefits.
December 8, 2006 (Gothenburg, Sweden) - A host of potential new oral anticoagulant agents, which could become much-needed replacements for warfarin and could also be used as an alternative to heparins or other antithrombin agents, are making good progress in development, with at least two agents now in phase 3 trials.
But experts are cautious following the fall from glory of the first such agent to be developed--ximelagatran--which actually reached the market in Europe but was swiftly withdrawn because of liver toxicity. Nevertheless, as there are so many new compounds in development, researchers are optimistic that this time at least one or two will succeed and provide the millions of patients who are--or should be--taking warfarin with a much more user-friendly treatment.
The two agents furthest on in development are the factor IIa inhibitor dabigatran (Boehringer Ingelheim) and the factor Xa inhibitor rivaroxaban (Bayer and Ortho-McNeil). Several other companies also have orally available factor Xa inhibitors in earlier clinical development, including Bristol-Myers Squibb, Lilly, Yamanouchi, and DuPont, and there are also other agents with different mechanisms in the pipeline, including a factor IXa inhibitor, TTP889 (TransTech Pharma), and an orally active glycosaminoglycan enhancer, odiparcil (SmithKline Beecham).
These agents are initially being developed for the prevention of thrombosis in orthopedic-surgery patients, but both dabigatran and rivaroxaban are also now starting late-stage trials for the prevention of stroke in atrial-fibrillation patients (as a replacement for warfarin) and in the treatment of acute coronary syndromes. Researchers in the field are optimistic that these agents will become easier-to-use alternatives to warfarin.
One of the leaders in this field, orthopedic surgeon Dr Bengt Eriksson (Sahlgrenska University Hospital, Gothenburg, Sweden), told heartwire: ?I am hopeful that at least one of these new agents will reach the market within the next two to three years for the prevention of venous thromboembolism after major orthopedic surgery, and then these agents will gradually replace current anticoagulants.?
Rivaroxaban in orthopedic surgery
The latest phase 2 data on rivaroxaban in orthopedic-surgery patients was published in the November 28, 2006 issue of Circulation [1]. This study, led by Eriksson, compared various oral doses of rivaroxaban with subcutaneous enoxaparin in 873 patients undergoing elective total-hip replacement. Study drugs were given for five to nine days after surgery.
Results showed no significant dose-response relationship for rivaroxaban in terms of efficacy, which the authors say can be explained by the higher-than-expected efficacy achieved in the lower-dose groups. There was, however, a significant dose-response relationship in terms of bleeding.
Rivaroxaban phase 2 dose-ranging study vs enoxaparin in orthopedic-surgery patients Drug
DVT/PE/mortality (%)
Major postop bleeding (%)
Rivaroxaban
5 mg 14.9
2.3
10 mg 10.6
0.7
20 mg 8.5
4.3
30 mg 13.5
4.9
40 mg 6.4
5.1
Enoxaparin 40 mg
25.2
1.9
DVT=deep-venous thrombosis
PE=pulmonary embolism
The researchers conclude: ?Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total-hip replacement, with the convenience of once-daily oral dosing and without the need for coagulation monitoring. When both efficacy and safety are considered, these results suggest that 10-mg rivaroxaban once daily should be investigated in phase 3 studies.?
Eriksson adds: ?These data show that we could be another step closer to the clinical reality of an oral, once-daily anticoagulant that is not associated with limitations of current standard therapies such as regular monitoring or administration by injection."
In an accompanying editorial [2], Drs Kenneth Mahaffey and Richard Becker (Duke University, Durham, NC) say that ?novel anticoagulant pharmacotherapies such as rivaroxaban, developed toward carefully chosen targets with attractive characteristics (oral administration, once-daily dosing, rapid onset of action, an intermediate offset rate, and no requirement for routine coagulation monitoring) herald an exciting time in cardiovascular research."
Phase 3 now under way
Based on these and other phase 2 data, phase 3 trials have now been started with rivaroxaban 10 mg once daily. The first of these--the RECORD study--is under way in the prevention of venous thromboembolism (VTE) after elective major orthopedic surgery, and it is planning to enroll more than 10 000 patients. The first approval filings for rivaroxaban in this indication are planned for late 2007 in Europe and 2008 in the US. A large phase 3 trial (ROCKET) of rivaroxaban in atrial fibrillation patients is also now being planned, to be run out of Duke University, and studies of the drug in ACS are being coordinated by the TIMI group.
Lead investigator of the RECORD study, Dr Alexander Turpie (McMaster University, Hamilton, ON), told heartwire that he was very excited about rivaroxaban and the other oral agents in development. ?We are all excited--these drugs look terrific--but we won?t know for sure until we see large-scale trial results. We have been here before--we were all very excited about ximelagatran and that was much further advanced when it bit the dust, so we have to be cautious."
Spotlight on liver effects
Ximelagatran, which had been touted as the blockbuster replacement for warfarin, was refused approval in the US and was spectacularly removed from the market in Europe shortly after its launch there because of liver toxicity, so this will be a particular focus for the new crop of oral anticoagulants in development. In the current phase 2 study with rivaroxaban reported in Circulation, the incidence of increased aminotransferase levels after short-term exposure to rivaroxaban did not exceed that observed with enoxaparin. However, an undesired effect on liver-function tests was noted in two patients receiving rivaroxaban. One patient had an increase in alanine aminotransferase (ALT) and bilirubin early during treatment, and another had an early rise in ALT that persisted during follow-up.
The authors note that neither of these patients had clinical symptoms suggestive of impaired liver function, but they add, ?It is not possible to draw definite conclusions to elucidate the causes of these raised liver enzymes, and further studies are required to determine whether there is a relationship with rivaroxaban."
Turpie suggested that the fact that there are now a whole group of different oral agents in development makes him optimistic that at least one will be successful. ?It?s hard to differentiate between them all at the moment--but hopefully a few of them will make it past the finishing line," he commented.
Enormous market
And there is certainly a big incentive for the companies developing these agents to get them to the market, as there is very large patient population who would benefit from an oral anticoagulant without the worry and inconvenience of monitoring. Turpie commented to heartwire: ?There are millions of patients currently taking warfarin who would prefer not to have to undergo monitoring, and there is another significant number who should take warfarin but don?t because they can?t manage the monitoring. As well as for AF patients, warfarin is indicated for many ACS patents, so the need for a simple and safe oral drug is enormous."
Will dabigatran get there first?
The other agent that is in phase 3 trials, dabigatran, is actually slightly nearer the market than rivaroxaban, with its phase 3 trials in orthopedic-surgery patients near completion, and phase 3 trials in AF already under way. Dabigatran belongs to the same class as ximelegatran, so it will be scrunitized even more carefully for liver toxicity.
Becker agrees that these drugs look very promising. ?They could be used across the board for both venous and arterial thrombotic conditions--as a replacement for warfarin as chronic therapy and instead of heparin in acute situations, so there is a huge market. It is very exciting," he told heartwire. ?If these drugs can do away with the need for monitoring and dose titration, which it looks as though they can, they will revolutionize this area of medicine. I believe that the number of patients getting treatment would increase by at least 15% to 20%."
Becker explained that dabigatran and rivaroxaban have different targets in the coagulation cascade, and it is not known if factor Xa inhibitors will be better than factor IIa inhibitors or vice versa. ?It is possible to put forward arguments for both targets, and we won?t know if one is better until we see the phase 3 results,? he said.
Becker said that it was not known for sure whether the hepatotoxicity associated with ximelagatran was a class effect or not. ?It is still not clear what caused the liver toxicity with ximelagatran--we still don?t know what the mechanism was, so we don?t know for sure that it isn?t a class effect. We therefore have to be vigilant with similar drugs. We learned a lot from ximelagatran--we learned that we have to be aware of off-target toxicity, and we need thousands of patients for this to show up. But based on the amount of effort going into developing these agents and the large amount of drugs now in clinical trials, I would say it is very likely that we will have an a replacement for warfarin in the not-too-distant future,? he added.
Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114:2374-2381.
Mahaffey KW and Becker RC. The scientific community?s quest to identify optimal targets for anticoagulant pharmacotherapy. Circulation 2006; 114:2313-2316.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
--------------------------------------------------------------------------------
Sue Hughes is a journalist for Medscape. She joined theheart.org, a website recently acquired by WebMD, in 2000. She was previously science editor of Scrip World Pharmaceutical News. Graduating in pharmacy from Manchester University, UK, she started her career as a hospital pharmacist before moving as a journalist to a UK pharmacy trade publication. She can be reached at [email protected].
