Shirley Haley

When the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee takes up the homozygous familial hypercholesterolemia therapy lomitapide on Oct. 17, the big question will be whether the company has enough data to convince regulators of the drug’s efficacy and safety, particularly in light of a liver toxicity signal that appears manageable but likely to set off warnings.

The lomitapide application, by Aegerion Pharmaceuticals, was supported by one single-arm, open-label, dose-escalating, phase III trial in 29 patients averaging 31 years of age with a mean LDL cholesterol of 337 mg/dL (353 mg/dL for the 23 completers), who already were on a variety of lipid-lowering therapies, including low-fat diet, statins, and removal of cholesterol from the blood via apheresis. In addition to the phase III data, Aegerion submitted a 1,000-patient safety database documenting patient exposure during phase I and phase II trials.

The company is asking to use the drug, which is administered orally in capsule form, as an add-on to diet and other lipid-lowering therapies in HoFH patients.

In the pivotal trial, patients were given up to 60 mg/day of lomitapide in addition to their other lipid-lowering treatment. In January, Aegerion reported 78-week data "consistent with earlier results," showing that baseline LDL cholesterol was reduced 40% on average at week 26, 44% at week 56, and 38% at week 75, all significant findings.

MTP-Is Block Lipoprotein Production

Homozygous familial hypercholesterolemia is a rare and challenging genetic disorder that affects an estimated 20,000 people in the United States and Europe. Patients inherit a mutation from both parents that triggers overproduction of atherogenic lipoproteins, which transport cholesterol through the bloodstream.

Lomitapide is the first of a new class of investigational lipid-lowering drugs known as microsomal triglyceride transfer protein inhibitors (MTP-Is). By blocking transfer of triglycerides to apolipoprotein B (the main protein component of LDL cholesterol), MTP-Is prevent the liver and intestines from producing and secreting lipoproteins, thus reducing circulating LDL levels.

Because of the unmet need, Aegerion, based in Cambridge, Mass., had asked for and anticipated 6-month priority review, but the FDA denied the request and defaulted to the regular 10 month user fee clock.

Potential Liver Tox May Have Raised a Flag

Mild to moderate gastrointestinal adverse events were the most commonly reported side effects in the lomitapide trial. Three patients discontinued the study because of GI events and three withdrew consent, all before week 26.

Perhaps of more concern to reviewers are reports that four of the remaining patients had consecutive aminotransferase elevations of 5-11 times the upper limit of normal during the first 56 weeks of the trial; during the final phase, no patients had consecutive elevations greater than 5 times ULN. Patients responded to temporary reductions in lomitapide dosing, and no one discontinued treatment because of liver function test elevations.

Potentially, the most problematic adverse effect associated with lomitapide is accumulation of liver fat. Hepatic fat content climbed from a mean baseline of 1.3% to 7.9% after 26 weeks of treatment, investigators reported at the American Heart Association meeting in 2009. In January, Aegerion reported that the 26-week average gain from a baseline of 1% was 9%, with 7.3% and 8.2% increases, respectively, at 56 and 78 weeks from a baseline of 1.2%.

Mipomersen

Also a first-in-class drug, mipomersen (Kynamro), an injectable anti-HoFH molecule from Isis Pharmaceuticals Inc. and partner Sanofi, works by preventing the formation of lipoproteins. The mipomersen New Drug Application was submitted March 29, a month after the lomitapide application was filed, but with the results of a 2-year, ongoing, open-extension study that followed patients from the phase III program.

Although elevated liver enzymes and dropout rates were problematic throughout mipomersen’s development, liver function apparently was not found to be a problem either in the phase III program (which tested the drug in different high-risk patient groups) or in the extension study (which followed 141 patients). Median liver-fat levels rose incrementally for the first year, but they plateaued and then fell to baseline as the liver adapted to the changes wrought by the medication, Genzyme said.

Although the FDA cannot compare lomitapide to another pending application, the experts on the advisory panel will almost certainly be familiar with the mipomersen profile.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

When the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee takes up the homozygous familial hypercholesterolemia therapy lomitapide on Oct. 17, the big question will be whether the company has enough data to convince regulators of the drug’s efficacy and safety, particularly in light of a liver toxicity signal that appears manageable but likely to set off warnings.

The lomitapide application, by Aegerion Pharmaceuticals, was supported by one single-arm, open-label, dose-escalating, phase III trial in 29 patients averaging 31 years of age with a mean LDL cholesterol of 337 mg/dL (353 mg/dL for the 23 completers), who already were on a variety of lipid-lowering therapies, including low-fat diet, statins, and removal of cholesterol from the blood via apheresis. In addition to the phase III data, Aegerion submitted a 1,000-patient safety database documenting patient exposure during phase I and phase II trials.

The company is asking to use the drug, which is administered orally in capsule form, as an add-on to diet and other lipid-lowering therapies in HoFH patients.

In the pivotal trial, patients were given up to 60 mg/day of lomitapide in addition to their other lipid-lowering treatment. In January, Aegerion reported 78-week data "consistent with earlier results," showing that baseline LDL cholesterol was reduced 40% on average at week 26, 44% at week 56, and 38% at week 75, all significant findings.

MTP-Is Block Lipoprotein Production

Homozygous familial hypercholesterolemia is a rare and challenging genetic disorder that affects an estimated 20,000 people in the United States and Europe. Patients inherit a mutation from both parents that triggers overproduction of atherogenic lipoproteins, which transport cholesterol through the bloodstream.

Lomitapide is the first of a new class of investigational lipid-lowering drugs known as microsomal triglyceride transfer protein inhibitors (MTP-Is). By blocking transfer of triglycerides to apolipoprotein B (the main protein component of LDL cholesterol), MTP-Is prevent the liver and intestines from producing and secreting lipoproteins, thus reducing circulating LDL levels.

Because of the unmet need, Aegerion, based in Cambridge, Mass., had asked for and anticipated 6-month priority review, but the FDA denied the request and defaulted to the regular 10 month user fee clock.

Potential Liver Tox May Have Raised a Flag

Mild to moderate gastrointestinal adverse events were the most commonly reported side effects in the lomitapide trial. Three patients discontinued the study because of GI events and three withdrew consent, all before week 26.

Perhaps of more concern to reviewers are reports that four of the remaining patients had consecutive aminotransferase elevations of 5-11 times the upper limit of normal during the first 56 weeks of the trial; during the final phase, no patients had consecutive elevations greater than 5 times ULN. Patients responded to temporary reductions in lomitapide dosing, and no one discontinued treatment because of liver function test elevations.

Potentially, the most problematic adverse effect associated with lomitapide is accumulation of liver fat. Hepatic fat content climbed from a mean baseline of 1.3% to 7.9% after 26 weeks of treatment, investigators reported at the American Heart Association meeting in 2009. In January, Aegerion reported that the 26-week average gain from a baseline of 1% was 9%, with 7.3% and 8.2% increases, respectively, at 56 and 78 weeks from a baseline of 1.2%.

Mipomersen

Also a first-in-class drug, mipomersen (Kynamro), an injectable anti-HoFH molecule from Isis Pharmaceuticals Inc. and partner Sanofi, works by preventing the formation of lipoproteins. The mipomersen New Drug Application was submitted March 29, a month after the lomitapide application was filed, but with the results of a 2-year, ongoing, open-extension study that followed patients from the phase III program.

Although elevated liver enzymes and dropout rates were problematic throughout mipomersen’s development, liver function apparently was not found to be a problem either in the phase III program (which tested the drug in different high-risk patient groups) or in the extension study (which followed 141 patients). Median liver-fat levels rose incrementally for the first year, but they plateaued and then fell to baseline as the liver adapted to the changes wrought by the medication, Genzyme said.

Although the FDA cannot compare lomitapide to another pending application, the experts on the advisory panel will almost certainly be familiar with the mipomersen profile.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

When the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee takes up the homozygous familial hypercholesterolemia therapy lomitapide on Oct. 17, the big question will be whether the company has enough data to convince regulators of the drug’s efficacy and safety, particularly in light of a liver toxicity signal that appears manageable but likely to set off warnings.

The lomitapide application, by Aegerion Pharmaceuticals, was supported by one single-arm, open-label, dose-escalating, phase III trial in 29 patients averaging 31 years of age with a mean LDL cholesterol of 337 mg/dL (353 mg/dL for the 23 completers), who already were on a variety of lipid-lowering therapies, including low-fat diet, statins, and removal of cholesterol from the blood via apheresis. In addition to the phase III data, Aegerion submitted a 1,000-patient safety database documenting patient exposure during phase I and phase II trials.

The company is asking to use the drug, which is administered orally in capsule form, as an add-on to diet and other lipid-lowering therapies in HoFH patients.

In the pivotal trial, patients were given up to 60 mg/day of lomitapide in addition to their other lipid-lowering treatment. In January, Aegerion reported 78-week data "consistent with earlier results," showing that baseline LDL cholesterol was reduced 40% on average at week 26, 44% at week 56, and 38% at week 75, all significant findings.

MTP-Is Block Lipoprotein Production

Homozygous familial hypercholesterolemia is a rare and challenging genetic disorder that affects an estimated 20,000 people in the United States and Europe. Patients inherit a mutation from both parents that triggers overproduction of atherogenic lipoproteins, which transport cholesterol through the bloodstream.

Lomitapide is the first of a new class of investigational lipid-lowering drugs known as microsomal triglyceride transfer protein inhibitors (MTP-Is). By blocking transfer of triglycerides to apolipoprotein B (the main protein component of LDL cholesterol), MTP-Is prevent the liver and intestines from producing and secreting lipoproteins, thus reducing circulating LDL levels.

Because of the unmet need, Aegerion, based in Cambridge, Mass., had asked for and anticipated 6-month priority review, but the FDA denied the request and defaulted to the regular 10 month user fee clock.

Potential Liver Tox May Have Raised a Flag

Mild to moderate gastrointestinal adverse events were the most commonly reported side effects in the lomitapide trial. Three patients discontinued the study because of GI events and three withdrew consent, all before week 26.

Perhaps of more concern to reviewers are reports that four of the remaining patients had consecutive aminotransferase elevations of 5-11 times the upper limit of normal during the first 56 weeks of the trial; during the final phase, no patients had consecutive elevations greater than 5 times ULN. Patients responded to temporary reductions in lomitapide dosing, and no one discontinued treatment because of liver function test elevations.

Potentially, the most problematic adverse effect associated with lomitapide is accumulation of liver fat. Hepatic fat content climbed from a mean baseline of 1.3% to 7.9% after 26 weeks of treatment, investigators reported at the American Heart Association meeting in 2009. In January, Aegerion reported that the 26-week average gain from a baseline of 1% was 9%, with 7.3% and 8.2% increases, respectively, at 56 and 78 weeks from a baseline of 1.2%.

Mipomersen

Also a first-in-class drug, mipomersen (Kynamro), an injectable anti-HoFH molecule from Isis Pharmaceuticals Inc. and partner Sanofi, works by preventing the formation of lipoproteins. The mipomersen New Drug Application was submitted March 29, a month after the lomitapide application was filed, but with the results of a 2-year, ongoing, open-extension study that followed patients from the phase III program.

Although elevated liver enzymes and dropout rates were problematic throughout mipomersen’s development, liver function apparently was not found to be a problem either in the phase III program (which tested the drug in different high-risk patient groups) or in the extension study (which followed 141 patients). Median liver-fat levels rose incrementally for the first year, but they plateaued and then fell to baseline as the liver adapted to the changes wrought by the medication, Genzyme said.

Although the FDA cannot compare lomitapide to another pending application, the experts on the advisory panel will almost certainly be familiar with the mipomersen profile.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Mifepristone has been approved for the treatment of the orphan disease Cushing’s syndrome, without a risk evaluation and mitigation strategy, despite the drug’s other use as an abortifacient, according to a statement by the Food and Drug Administration.

The FDA announced approval of the mifepristone formulation, to be marketed as Korlym, to control high blood sugar levels in adults with endogenous Cushing’s syndrome on Feb. 17. It is the first approval for Corcept Therapeutics Inc. and the first therapy available for the condition.

Corcept announced in December that the FDA would not require a risk evaluation and mitigation strategy (REMS) for the drug, also known as RU-486 and used for terminating pregnancy. Several factors figured into determining that Korlym would not require a REMS, the FDA explained in a release announcing the approval. Currently, there are no approved therapies for this debilitating form of Cushing’s, and a REMS might prove an impediment to treatment; the number of patients is small; the number of health care professionals involved is small and highly specialized, and they keep a close eye on patients; and the risks of Korlym treatment can be managed through physician and patient labeling, which includes a MedGuide.

In addition, the company has instituted a homegrown "elements to ensure safe use" plan of sorts by arranging to distribute Korlym through a central pharmacy. The FDA estimates that about 5,000 patients will be eligible for the treatment, which received orphan designation in 2007. According to Corcept, about 20,000 patients in the United States have Cushing’s syndrome, which manifests in many ways and can affect every organ of the body.

The distribution arrangement will ensure "the timely, convenient and appropriate delivery of the drug to Cushing’s patients or to the health care institutions where this therapy may be initiated," the agency said, noting that retail pharmacies are unlikely to keep adequate supplies of the drug on hand for the condition and a central pharmacy will give Cushing’s patients better access.

Endogenous Cushing’s syndrome is caused by overproduction of cortisol, a steroid hormone that increases blood sugar levels, by the adrenal glands; the syndrome commonly strikes people between the ages of 25 and 40. Korlym is approved for patients with Cushing’s who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery.

Korlym is a glucocorticoid receptor type II (GR-II) antagonist that blocks the cortisol receptor. Corcept, based in Menlo Park, Calif., is also studying mifepristone in a phase III trial as a therapy for psychotic depression. The company, which says it specializes in drugs for severe metabolic and psychiatric disorders, also has CORT 10829 in its portfolio of GR-II receptor antagonists, in studies for the prevention of antipsychotic-induced weight gain.

Though Korlym should never be used by pregnant women, pregnancy is extremely rare in Cushing’s syndrome patients because of the suppressive effect of cortisol on female reproduction, the FDA said. Nonetheless, Korlym will carry a boxed warning that the therapy will terminate a pregnancy.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Mifepristone has been approved for the treatment of the orphan disease Cushing’s syndrome, without a risk evaluation and mitigation strategy, despite the drug’s other use as an abortifacient, according to a statement by the Food and Drug Administration.

The FDA announced approval of the mifepristone formulation, to be marketed as Korlym, to control high blood sugar levels in adults with endogenous Cushing’s syndrome on Feb. 17. It is the first approval for Corcept Therapeutics Inc. and the first therapy available for the condition.

Corcept announced in December that the FDA would not require a risk evaluation and mitigation strategy (REMS) for the drug, also known as RU-486 and used for terminating pregnancy. Several factors figured into determining that Korlym would not require a REMS, the FDA explained in a release announcing the approval. Currently, there are no approved therapies for this debilitating form of Cushing’s, and a REMS might prove an impediment to treatment; the number of patients is small; the number of health care professionals involved is small and highly specialized, and they keep a close eye on patients; and the risks of Korlym treatment can be managed through physician and patient labeling, which includes a MedGuide.

In addition, the company has instituted a homegrown "elements to ensure safe use" plan of sorts by arranging to distribute Korlym through a central pharmacy. The FDA estimates that about 5,000 patients will be eligible for the treatment, which received orphan designation in 2007. According to Corcept, about 20,000 patients in the United States have Cushing’s syndrome, which manifests in many ways and can affect every organ of the body.

The distribution arrangement will ensure "the timely, convenient and appropriate delivery of the drug to Cushing’s patients or to the health care institutions where this therapy may be initiated," the agency said, noting that retail pharmacies are unlikely to keep adequate supplies of the drug on hand for the condition and a central pharmacy will give Cushing’s patients better access.

Endogenous Cushing’s syndrome is caused by overproduction of cortisol, a steroid hormone that increases blood sugar levels, by the adrenal glands; the syndrome commonly strikes people between the ages of 25 and 40. Korlym is approved for patients with Cushing’s who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery.

Korlym is a glucocorticoid receptor type II (GR-II) antagonist that blocks the cortisol receptor. Corcept, based in Menlo Park, Calif., is also studying mifepristone in a phase III trial as a therapy for psychotic depression. The company, which says it specializes in drugs for severe metabolic and psychiatric disorders, also has CORT 10829 in its portfolio of GR-II receptor antagonists, in studies for the prevention of antipsychotic-induced weight gain.

Though Korlym should never be used by pregnant women, pregnancy is extremely rare in Cushing’s syndrome patients because of the suppressive effect of cortisol on female reproduction, the FDA said. Nonetheless, Korlym will carry a boxed warning that the therapy will terminate a pregnancy.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Mifepristone has been approved for the treatment of the orphan disease Cushing’s syndrome, without a risk evaluation and mitigation strategy, despite the drug’s other use as an abortifacient, according to a statement by the Food and Drug Administration.

The FDA announced approval of the mifepristone formulation, to be marketed as Korlym, to control high blood sugar levels in adults with endogenous Cushing’s syndrome on Feb. 17. It is the first approval for Corcept Therapeutics Inc. and the first therapy available for the condition.

Corcept announced in December that the FDA would not require a risk evaluation and mitigation strategy (REMS) for the drug, also known as RU-486 and used for terminating pregnancy. Several factors figured into determining that Korlym would not require a REMS, the FDA explained in a release announcing the approval. Currently, there are no approved therapies for this debilitating form of Cushing’s, and a REMS might prove an impediment to treatment; the number of patients is small; the number of health care professionals involved is small and highly specialized, and they keep a close eye on patients; and the risks of Korlym treatment can be managed through physician and patient labeling, which includes a MedGuide.

In addition, the company has instituted a homegrown "elements to ensure safe use" plan of sorts by arranging to distribute Korlym through a central pharmacy. The FDA estimates that about 5,000 patients will be eligible for the treatment, which received orphan designation in 2007. According to Corcept, about 20,000 patients in the United States have Cushing’s syndrome, which manifests in many ways and can affect every organ of the body.

The distribution arrangement will ensure "the timely, convenient and appropriate delivery of the drug to Cushing’s patients or to the health care institutions where this therapy may be initiated," the agency said, noting that retail pharmacies are unlikely to keep adequate supplies of the drug on hand for the condition and a central pharmacy will give Cushing’s patients better access.

Endogenous Cushing’s syndrome is caused by overproduction of cortisol, a steroid hormone that increases blood sugar levels, by the adrenal glands; the syndrome commonly strikes people between the ages of 25 and 40. Korlym is approved for patients with Cushing’s who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery.

Korlym is a glucocorticoid receptor type II (GR-II) antagonist that blocks the cortisol receptor. Corcept, based in Menlo Park, Calif., is also studying mifepristone in a phase III trial as a therapy for psychotic depression. The company, which says it specializes in drugs for severe metabolic and psychiatric disorders, also has CORT 10829 in its portfolio of GR-II receptor antagonists, in studies for the prevention of antipsychotic-induced weight gain.

Though Korlym should never be used by pregnant women, pregnancy is extremely rare in Cushing’s syndrome patients because of the suppressive effect of cortisol on female reproduction, the FDA said. Nonetheless, Korlym will carry a boxed warning that the therapy will terminate a pregnancy.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration’s decision to downsize the Risk Evaluation and Mitigation Strategies for romiplostim and eltrombopag shows that the agency is continuing its trend of moving away from an aggressive application of the drug safety tools, particularly when additional information comes in through the assessment process.

The FDA announced Dec. 6 that it would no longer require health care professionals, hospitals, specialty care facilities, and patients to enroll in a restricted access program in order to prescribe or receive the thrombocytopenia treatments and that physicians will no longer be required to complete periodic safety forms for patients receiving the therapies.

Pharmacies also will no longer be required to enroll in the programs or verify prescriber and patient enrollment before dispensing eltrombopag (Promacta, GlaxoSmithKline), an oral therapy covered under Medicare Part D.

Drug maker Amgen is hoping that the revision to the Risk Evaluation and Mitigation Strategies (REMS) will help it get romiplostim (marketed as Nplate) off the Centers for Medicare and Medicaid Services list for a potential Medicare National Coverage Determination.

Modified REMS for the two drugs will now include a communications plan to inform health care professionals about changes to the risk management program and to reinforce safety risks associated with each product. The patient Medication Guide will be separated from the REMS, but continue to be part of labeling.

The changes came after additional information was submitted under the REMS assessment process. The FDA has already shown a willingness to modify the programs based on incoming information, such as for golimumab and sacrosidase. And the agency has modified its approach to Medication Guides and REMS, no longer requiring all MedGuides to be linked to the REMS.

REMS Review Led to Labeling Changes

The FDA approved both romiplostim and eltrombopag in 2008 to treat adults with chronic immune thrombocytopenia – a rare autoimmune-mediated blood disorder that results in a low platelet count and associated bleeding risk – who have not responded to corticosteroids, immunoglobulins or splenectomy. The drugs work by stimulating bone marrow to produce needed platelets, but the process is not without risk.

Since the approvals, the FDA has monitored bone marrow changes of collagen deposition (reticulin), risk of blood clots, risk of developing blood-related cancers resulting from bone marrow stimulation, and the increased risk of low blood platelet count or bleeding after discontinuation. Eltrombopag also carries a boxed warning concerning the risk of liver toxicity. In addition to the reports required by the REMS, the drugs’ manufacturers have submitted data from ongoing clinical trials to clarify the safety profiles of their therapies.

The agency based the new labeling on both long-term safety data submitted from those trials and a determination that causality of adverse events in the individual case safety reports collected through the REMS was difficult to assign when the side effects of the therapies were mixed with the underlying medical conditions of the patients.

While REMS continue to be "vital tools" for FDA, "the agency remains committed to exercising a flexible and responsible regulatory approach" to ensure the programs are effective and efficient and not "resulting in an unnecessary burden on health care professionals and patients," Center for Drug Evaluation and Research Director Janet Woodcock said in a statement.

Will Labeling Changes Soften CMS’s Position on Romiplostim?

CMS put romiplostim on its list of potential National Coverage Determination topics even before it was approved, expressing safety concerns regarding thrombopoiesis-stimulating agents because they lacked long-term safety data, an overhang that has irked Amgen. The company has argued that romiplostim’s comprehensive REMS program – the first to include a mandatory patient registry – and long list of postmarketing safety studies precluded the need for CMS to consider coverage restrictions.

It appears that the most recent REMS assessment, based on completed phase IV clinical studies, was how Amgen was able to convince the government to drop some of the most arduous restrictions.

"The Pink Sheet" and this news organization are owned by Elsevier.

The Food and Drug Administration’s decision to downsize the Risk Evaluation and Mitigation Strategies for romiplostim and eltrombopag shows that the agency is continuing its trend of moving away from an aggressive application of the drug safety tools, particularly when additional information comes in through the assessment process.

The FDA announced Dec. 6 that it would no longer require health care professionals, hospitals, specialty care facilities, and patients to enroll in a restricted access program in order to prescribe or receive the thrombocytopenia treatments and that physicians will no longer be required to complete periodic safety forms for patients receiving the therapies.

Pharmacies also will no longer be required to enroll in the programs or verify prescriber and patient enrollment before dispensing eltrombopag (Promacta, GlaxoSmithKline), an oral therapy covered under Medicare Part D.

Drug maker Amgen is hoping that the revision to the Risk Evaluation and Mitigation Strategies (REMS) will help it get romiplostim (marketed as Nplate) off the Centers for Medicare and Medicaid Services list for a potential Medicare National Coverage Determination.

Modified REMS for the two drugs will now include a communications plan to inform health care professionals about changes to the risk management program and to reinforce safety risks associated with each product. The patient Medication Guide will be separated from the REMS, but continue to be part of labeling.

The changes came after additional information was submitted under the REMS assessment process. The FDA has already shown a willingness to modify the programs based on incoming information, such as for golimumab and sacrosidase. And the agency has modified its approach to Medication Guides and REMS, no longer requiring all MedGuides to be linked to the REMS.

REMS Review Led to Labeling Changes

The FDA approved both romiplostim and eltrombopag in 2008 to treat adults with chronic immune thrombocytopenia – a rare autoimmune-mediated blood disorder that results in a low platelet count and associated bleeding risk – who have not responded to corticosteroids, immunoglobulins or splenectomy. The drugs work by stimulating bone marrow to produce needed platelets, but the process is not without risk.

Since the approvals, the FDA has monitored bone marrow changes of collagen deposition (reticulin), risk of blood clots, risk of developing blood-related cancers resulting from bone marrow stimulation, and the increased risk of low blood platelet count or bleeding after discontinuation. Eltrombopag also carries a boxed warning concerning the risk of liver toxicity. In addition to the reports required by the REMS, the drugs’ manufacturers have submitted data from ongoing clinical trials to clarify the safety profiles of their therapies.

The agency based the new labeling on both long-term safety data submitted from those trials and a determination that causality of adverse events in the individual case safety reports collected through the REMS was difficult to assign when the side effects of the therapies were mixed with the underlying medical conditions of the patients.

While REMS continue to be "vital tools" for FDA, "the agency remains committed to exercising a flexible and responsible regulatory approach" to ensure the programs are effective and efficient and not "resulting in an unnecessary burden on health care professionals and patients," Center for Drug Evaluation and Research Director Janet Woodcock said in a statement.

Will Labeling Changes Soften CMS’s Position on Romiplostim?

CMS put romiplostim on its list of potential National Coverage Determination topics even before it was approved, expressing safety concerns regarding thrombopoiesis-stimulating agents because they lacked long-term safety data, an overhang that has irked Amgen. The company has argued that romiplostim’s comprehensive REMS program – the first to include a mandatory patient registry – and long list of postmarketing safety studies precluded the need for CMS to consider coverage restrictions.

It appears that the most recent REMS assessment, based on completed phase IV clinical studies, was how Amgen was able to convince the government to drop some of the most arduous restrictions.

"The Pink Sheet" and this news organization are owned by Elsevier.

The Food and Drug Administration’s decision to downsize the Risk Evaluation and Mitigation Strategies for romiplostim and eltrombopag shows that the agency is continuing its trend of moving away from an aggressive application of the drug safety tools, particularly when additional information comes in through the assessment process.

The FDA announced Dec. 6 that it would no longer require health care professionals, hospitals, specialty care facilities, and patients to enroll in a restricted access program in order to prescribe or receive the thrombocytopenia treatments and that physicians will no longer be required to complete periodic safety forms for patients receiving the therapies.

Pharmacies also will no longer be required to enroll in the programs or verify prescriber and patient enrollment before dispensing eltrombopag (Promacta, GlaxoSmithKline), an oral therapy covered under Medicare Part D.

Drug maker Amgen is hoping that the revision to the Risk Evaluation and Mitigation Strategies (REMS) will help it get romiplostim (marketed as Nplate) off the Centers for Medicare and Medicaid Services list for a potential Medicare National Coverage Determination.

Modified REMS for the two drugs will now include a communications plan to inform health care professionals about changes to the risk management program and to reinforce safety risks associated with each product. The patient Medication Guide will be separated from the REMS, but continue to be part of labeling.

The changes came after additional information was submitted under the REMS assessment process. The FDA has already shown a willingness to modify the programs based on incoming information, such as for golimumab and sacrosidase. And the agency has modified its approach to Medication Guides and REMS, no longer requiring all MedGuides to be linked to the REMS.

REMS Review Led to Labeling Changes

The FDA approved both romiplostim and eltrombopag in 2008 to treat adults with chronic immune thrombocytopenia – a rare autoimmune-mediated blood disorder that results in a low platelet count and associated bleeding risk – who have not responded to corticosteroids, immunoglobulins or splenectomy. The drugs work by stimulating bone marrow to produce needed platelets, but the process is not without risk.

Since the approvals, the FDA has monitored bone marrow changes of collagen deposition (reticulin), risk of blood clots, risk of developing blood-related cancers resulting from bone marrow stimulation, and the increased risk of low blood platelet count or bleeding after discontinuation. Eltrombopag also carries a boxed warning concerning the risk of liver toxicity. In addition to the reports required by the REMS, the drugs’ manufacturers have submitted data from ongoing clinical trials to clarify the safety profiles of their therapies.

The agency based the new labeling on both long-term safety data submitted from those trials and a determination that causality of adverse events in the individual case safety reports collected through the REMS was difficult to assign when the side effects of the therapies were mixed with the underlying medical conditions of the patients.

While REMS continue to be "vital tools" for FDA, "the agency remains committed to exercising a flexible and responsible regulatory approach" to ensure the programs are effective and efficient and not "resulting in an unnecessary burden on health care professionals and patients," Center for Drug Evaluation and Research Director Janet Woodcock said in a statement.

Will Labeling Changes Soften CMS’s Position on Romiplostim?

CMS put romiplostim on its list of potential National Coverage Determination topics even before it was approved, expressing safety concerns regarding thrombopoiesis-stimulating agents because they lacked long-term safety data, an overhang that has irked Amgen. The company has argued that romiplostim’s comprehensive REMS program – the first to include a mandatory patient registry – and long list of postmarketing safety studies precluded the need for CMS to consider coverage restrictions.

It appears that the most recent REMS assessment, based on completed phase IV clinical studies, was how Amgen was able to convince the government to drop some of the most arduous restrictions.

"The Pink Sheet" and this news organization are owned by Elsevier.

The Food and Drug Administration’s Oncologic Drugs Advisory Committee is broaching the topic of trials and end points for drugs to treat a segment of the prostate cancer population that is apparently getting rarer as diagnoses become more accurate.

ODAC will meet Sept. 14 to discuss the topic. The FDA’s agenda for the session notes there are no drugs currently approved to treat men with nonmetastatic castration-resistant prostate cancer who have a rising prostate-specific antigen level despite being on androgen-deprivation therapy. ADT is not approved for these patients, and labeling for the class added a warning last October for increased risk of diabetes and certain cardiovascular diseases.

ADT suppresses testosterone, which drives tumor growth, but side effects, in addition to impotence, include osteoporosis and metabolic syndrome, which gave rise to the warnings in labeling for the class. The overall area of prostate cancer is one where, until the last several months, few new treatments were reaching the market.

The committee is questioning whether approval of a new therapy in conjunction with continued ADT would be appropriate for patients with nonmetastatic CRPC.

What makes ODAC’s seemingly simple announcement complicated, said ASCO Cancer Communications Committee Chair Dr. Nicholas Vogelzang, is that "the entity of rising PSA is common, the entity of castrate resistance is common, but nonmetastatic is rare."

In reality, most of the time "nonmetastatic is a mixture of people whose x-rays are missed or not adequately looked at by the radiologist, and it’s a shrinking field" as imaging techniques grow more sophisticated. For example, Dr. Vogelzang said, the new PET F-18 imaging technique (which uses the tracer fluorine-18), "when applied to that population, shows a lot of little spots in the bone that are often missed in the regular bone scan."

However, he said, it could be argued that in men who fit the narrow definition, who’ve had ADT and their PSA is rising, it takes 2-2½ years for new spots to show up under regular imaging. That’s "an end point FDA might find acceptable." Dr. Vogelzang practices at the Comprehensive Cancer Centers of Nevada.

The more urgent unmet need in prostate cancer, in Dr. Vogelzang’s opinion, is in men whose PSAs are rising and who are not castrate resistant. "The elephant in the room" is men who have their prostate removed or radiated and their PSA is rising. "They don’t want to undergo medical or surgical castration. They’re perfectly fine. They have life expectancies we can measure in a decade, maybe more. And they don’t want to lose their testosterone. Who would blame them? Nobody."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration’s Oncologic Drugs Advisory Committee is broaching the topic of trials and end points for drugs to treat a segment of the prostate cancer population that is apparently getting rarer as diagnoses become more accurate.

ODAC will meet Sept. 14 to discuss the topic. The FDA’s agenda for the session notes there are no drugs currently approved to treat men with nonmetastatic castration-resistant prostate cancer who have a rising prostate-specific antigen level despite being on androgen-deprivation therapy. ADT is not approved for these patients, and labeling for the class added a warning last October for increased risk of diabetes and certain cardiovascular diseases.

ADT suppresses testosterone, which drives tumor growth, but side effects, in addition to impotence, include osteoporosis and metabolic syndrome, which gave rise to the warnings in labeling for the class. The overall area of prostate cancer is one where, until the last several months, few new treatments were reaching the market.

The committee is questioning whether approval of a new therapy in conjunction with continued ADT would be appropriate for patients with nonmetastatic CRPC.

What makes ODAC’s seemingly simple announcement complicated, said ASCO Cancer Communications Committee Chair Dr. Nicholas Vogelzang, is that "the entity of rising PSA is common, the entity of castrate resistance is common, but nonmetastatic is rare."

In reality, most of the time "nonmetastatic is a mixture of people whose x-rays are missed or not adequately looked at by the radiologist, and it’s a shrinking field" as imaging techniques grow more sophisticated. For example, Dr. Vogelzang said, the new PET F-18 imaging technique (which uses the tracer fluorine-18), "when applied to that population, shows a lot of little spots in the bone that are often missed in the regular bone scan."

However, he said, it could be argued that in men who fit the narrow definition, who’ve had ADT and their PSA is rising, it takes 2-2½ years for new spots to show up under regular imaging. That’s "an end point FDA might find acceptable." Dr. Vogelzang practices at the Comprehensive Cancer Centers of Nevada.

The more urgent unmet need in prostate cancer, in Dr. Vogelzang’s opinion, is in men whose PSAs are rising and who are not castrate resistant. "The elephant in the room" is men who have their prostate removed or radiated and their PSA is rising. "They don’t want to undergo medical or surgical castration. They’re perfectly fine. They have life expectancies we can measure in a decade, maybe more. And they don’t want to lose their testosterone. Who would blame them? Nobody."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration’s Oncologic Drugs Advisory Committee is broaching the topic of trials and end points for drugs to treat a segment of the prostate cancer population that is apparently getting rarer as diagnoses become more accurate.

ODAC will meet Sept. 14 to discuss the topic. The FDA’s agenda for the session notes there are no drugs currently approved to treat men with nonmetastatic castration-resistant prostate cancer who have a rising prostate-specific antigen level despite being on androgen-deprivation therapy. ADT is not approved for these patients, and labeling for the class added a warning last October for increased risk of diabetes and certain cardiovascular diseases.

ADT suppresses testosterone, which drives tumor growth, but side effects, in addition to impotence, include osteoporosis and metabolic syndrome, which gave rise to the warnings in labeling for the class. The overall area of prostate cancer is one where, until the last several months, few new treatments were reaching the market.

The committee is questioning whether approval of a new therapy in conjunction with continued ADT would be appropriate for patients with nonmetastatic CRPC.

What makes ODAC’s seemingly simple announcement complicated, said ASCO Cancer Communications Committee Chair Dr. Nicholas Vogelzang, is that "the entity of rising PSA is common, the entity of castrate resistance is common, but nonmetastatic is rare."

In reality, most of the time "nonmetastatic is a mixture of people whose x-rays are missed or not adequately looked at by the radiologist, and it’s a shrinking field" as imaging techniques grow more sophisticated. For example, Dr. Vogelzang said, the new PET F-18 imaging technique (which uses the tracer fluorine-18), "when applied to that population, shows a lot of little spots in the bone that are often missed in the regular bone scan."

However, he said, it could be argued that in men who fit the narrow definition, who’ve had ADT and their PSA is rising, it takes 2-2½ years for new spots to show up under regular imaging. That’s "an end point FDA might find acceptable." Dr. Vogelzang practices at the Comprehensive Cancer Centers of Nevada.

The more urgent unmet need in prostate cancer, in Dr. Vogelzang’s opinion, is in men whose PSAs are rising and who are not castrate resistant. "The elephant in the room" is men who have their prostate removed or radiated and their PSA is rising. "They don’t want to undergo medical or surgical castration. They’re perfectly fine. They have life expectancies we can measure in a decade, maybe more. And they don’t want to lose their testosterone. Who would blame them? Nobody."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration has approved Brilinta (ticagrelor), but the antiplatelet drug will carry a boxed warning that taking the agent with more than 100 mg/day of aspirin decreases its effectiveness, thus ending the saga of the poor performing North American subgroup in the PLATO trial.

The approval had previously been held up by the mysteriously poor performance of North American patients in PLATO (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome), the 43-country, 18,624-patient pivotal trial. The subgroup experienced a nonsignificant 27% increased risk, whereas non-U.S. results showed a significant 19% risk reduction. The company has laid the discrepancy to the difference in aspirin prescribing practice, but FDA reviewers, although swayed by the efficacy of the drug, didn’t buy into this theory and asked for additional analyses of PLATO in a December 2010 "complete response" letter.

The FDA announced its approval of the blood thinner late on July 20. Brilinta, manufactured by AstraZeneca, is cleared to reduce cardiovascular death and heart attack in patients with acute coronary syndromes.

In clinical trials, Brilinta was more effective than Bristol-Myers Squibb/Sanofi’s Plavix (clopidogrel), "but that advantage was seen with aspirin maintenance doses of 75 to 100 mg once daily," Dr. Norman Stockbridge, director of the Center for Drug Evaluation and Research’s Cardiovascular and Renal Products Division, pointed out in the agency’s announcement.

The distinction between the maintenance dose and the limitation in the labeling is an important one. In the United States, physicians tend to prescribe high-dose aspirin more often than low-dose aspirin. That challenge will be partially addressed through the REMS (Risk Evaluation and Mitigation Strategy) that the FDA attached to the approval. The REMS requires the company to conduct educational outreach to alert physicians about the risk of using higher doses of aspirin, as well as provide a MedGuide to inform patients.

The educational efforts will be key to avoiding bleeding, which is already a known hazard of the class. It may also give physicians a reason not to switch their patients.

AstraZeneca said that in most cases, it expects 81 mg aspirin to be used. The company said it will focus for the next 12 months on the process of working with hospital formularies, protocol committees, and government and managed care reimbursement bodies, all of which are necessary steps to ensure that Brilinta will be adopted.

With this approval, ticagrelor is now available in 39 countries and is reimbursed in 7, AstraZeneca noted.

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration has approved Brilinta (ticagrelor), but the antiplatelet drug will carry a boxed warning that taking the agent with more than 100 mg/day of aspirin decreases its effectiveness, thus ending the saga of the poor performing North American subgroup in the PLATO trial.

The approval had previously been held up by the mysteriously poor performance of North American patients in PLATO (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome), the 43-country, 18,624-patient pivotal trial. The subgroup experienced a nonsignificant 27% increased risk, whereas non-U.S. results showed a significant 19% risk reduction. The company has laid the discrepancy to the difference in aspirin prescribing practice, but FDA reviewers, although swayed by the efficacy of the drug, didn’t buy into this theory and asked for additional analyses of PLATO in a December 2010 "complete response" letter.

The FDA announced its approval of the blood thinner late on July 20. Brilinta, manufactured by AstraZeneca, is cleared to reduce cardiovascular death and heart attack in patients with acute coronary syndromes.

In clinical trials, Brilinta was more effective than Bristol-Myers Squibb/Sanofi’s Plavix (clopidogrel), "but that advantage was seen with aspirin maintenance doses of 75 to 100 mg once daily," Dr. Norman Stockbridge, director of the Center for Drug Evaluation and Research’s Cardiovascular and Renal Products Division, pointed out in the agency’s announcement.

The distinction between the maintenance dose and the limitation in the labeling is an important one. In the United States, physicians tend to prescribe high-dose aspirin more often than low-dose aspirin. That challenge will be partially addressed through the REMS (Risk Evaluation and Mitigation Strategy) that the FDA attached to the approval. The REMS requires the company to conduct educational outreach to alert physicians about the risk of using higher doses of aspirin, as well as provide a MedGuide to inform patients.

The educational efforts will be key to avoiding bleeding, which is already a known hazard of the class. It may also give physicians a reason not to switch their patients.

AstraZeneca said that in most cases, it expects 81 mg aspirin to be used. The company said it will focus for the next 12 months on the process of working with hospital formularies, protocol committees, and government and managed care reimbursement bodies, all of which are necessary steps to ensure that Brilinta will be adopted.

With this approval, ticagrelor is now available in 39 countries and is reimbursed in 7, AstraZeneca noted.

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration has approved Brilinta (ticagrelor), but the antiplatelet drug will carry a boxed warning that taking the agent with more than 100 mg/day of aspirin decreases its effectiveness, thus ending the saga of the poor performing North American subgroup in the PLATO trial.

The approval had previously been held up by the mysteriously poor performance of North American patients in PLATO (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome), the 43-country, 18,624-patient pivotal trial. The subgroup experienced a nonsignificant 27% increased risk, whereas non-U.S. results showed a significant 19% risk reduction. The company has laid the discrepancy to the difference in aspirin prescribing practice, but FDA reviewers, although swayed by the efficacy of the drug, didn’t buy into this theory and asked for additional analyses of PLATO in a December 2010 "complete response" letter.

The FDA announced its approval of the blood thinner late on July 20. Brilinta, manufactured by AstraZeneca, is cleared to reduce cardiovascular death and heart attack in patients with acute coronary syndromes.

In clinical trials, Brilinta was more effective than Bristol-Myers Squibb/Sanofi’s Plavix (clopidogrel), "but that advantage was seen with aspirin maintenance doses of 75 to 100 mg once daily," Dr. Norman Stockbridge, director of the Center for Drug Evaluation and Research’s Cardiovascular and Renal Products Division, pointed out in the agency’s announcement.

The distinction between the maintenance dose and the limitation in the labeling is an important one. In the United States, physicians tend to prescribe high-dose aspirin more often than low-dose aspirin. That challenge will be partially addressed through the REMS (Risk Evaluation and Mitigation Strategy) that the FDA attached to the approval. The REMS requires the company to conduct educational outreach to alert physicians about the risk of using higher doses of aspirin, as well as provide a MedGuide to inform patients.

The educational efforts will be key to avoiding bleeding, which is already a known hazard of the class. It may also give physicians a reason not to switch their patients.

AstraZeneca said that in most cases, it expects 81 mg aspirin to be used. The company said it will focus for the next 12 months on the process of working with hospital formularies, protocol committees, and government and managed care reimbursement bodies, all of which are necessary steps to ensure that Brilinta will be adopted.

With this approval, ticagrelor is now available in 39 countries and is reimbursed in 7, AstraZeneca noted.

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are owned by Elsevier.

Iniparib, the potential first-in-class poly (adenosine diphosphate-ribose) polymerase inhibitor, failed to meet the coprimary end point of overall and progression-free survival in a pivotal phase III study of women with metastatic triple-negative breast cancer, drug developer Sanofi-Aventis reported after market close Jan. 27.

The results are particularly disappointing in light of stellar phase II findings presented at the San Antonio Breast Cancer Symposium in 2009 and published online Jan. 5 in the New England Journal of Medicine (N. Engl. J. Med. 2011;364:205-14). Sanofi-Aventis had planned to complete a Food and Drug Administration rolling new drug application for iniparib this quarter.

Despite the divergent outcomes, the designs of the two studies were very similar. "We need to do a complete look at the data, the patient populations, any differences that we can see between the phase II and the phase III," Dr. Paul Chew, Sanofi’s U.S. chief science officer and chief medical officer, said in an interview. "When we have that data we’ll present it at a major scientific meeting."

"We still feel that there is value in iniparib," Chew said. "We’re going to look at this data. We’re continuing the development in other tumors. And we’ll know more soon."

Besides breast cancer, iniparib is in phase II studies against ovarian, uterine, and brain cancers, and a phase III study in patients with advanced squamous non–small cell lung cancer launched in March 2010.

While several regimens are used off label, there are no approved treatments for triple-negative breast cancer, so called because those tumors are negative for three markers: estrogen receptor, progesterone receptor and HER2.

Can The Triple-Negative Claim Be Salvaged?

Excitement over the phase II data was based on results that were not a prespecified primary end point. Among the 61 women in the 123-patient trial randomized to receive iniparib plus gemcitabine and carboplatin, median overall survival was 12.3 months compared with 7.7 months for women in the chemo-alone group – a 43% reduction in risk of death. Median progression-free survival in the iniparib groups was 5.9 months, compared with 3.6 months for chemo, and the overall response rate was 52% compared with 32%.

The iniparib group also fared better on the specified end point of clinical benefit – complete or partial response or stable disease of at least 6 months. Of the women who received iniparib, 56% showed a clinical benefit, compared with 34% without iniparib.

Iniparib has fast-track status with the FDA, and Dr. Chew didn’t exclude the possibility of completing the oncologic’s rolling NDA with the phase II data in hand, then working on a new confirmatory phase III. "Once we have these data analyzed, we’re going to be talking very soon with the regulatory authorities both in the U.S. and in Europe in terms of what the next steps will be," he said.

The failed study enrolled 519 women with the tough-to-treat disease, who had received up to two previous lines of chemotherapy after their cancer spread. They were randomized to receive gemcitabine and carboplatin chemotherapy either alone or with iniparib.

While the iniparib results failed to reach statistical significance for the combined survival end point, a prespecified analysis of patients in the second- and third-line setting did show improvement, Sanofi said, raising the question of a possible claim for heavily pretreated patients. Dr. Chew called it "premature to comment on these first looks," however, and wouldn’t elaborate on the potential significance of those data.

The mechanism of action of iniparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, is not well understood, but PARPs are signaling enzymes involved in the repair of damaged DNA, and thwarting their activity results in selective destruction of tumor cells that have a certain DNA defect – a defect hypothesized to be found in the DNA of triple-negative cancer tumors.

Rapidly multiplying cancer cells have frequent disruptions in the DNA that they need to repair, Dr. Chew explained. When a PARP inhibitor is paired with chemotherapy agents that induce DNA damage, the effect is to "put a stick in the spokes" of DNA repair in those malignant cells, he said.

"You have a one-two punch if you administer chemotherapies that include or cause breaks in the DNA, then follow it up with another therapy that inhibits the repair. One might expect a potential at least additive benefit."

Among other PARP inhibitors under development are AstraZeneca’s olaparib, in development against a number of cancers, with regulatory filings in serious ovarian cancer and BRCA-associated breast cancers in 2014; Merck’s MK-4827, in phase I in advanced solid tumors; and Pfizer’s candidate PF-01367338, in phase II development in a number of cancers. BioMarin Pharmaceutical announced the launch of a phase I/II study of its candidate BMN-673 in advanced or recurrent solid tumors Jan. 11.

Originally published by "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

Iniparib, the potential first-in-class poly (adenosine diphosphate-ribose) polymerase inhibitor, failed to meet the coprimary end point of overall and progression-free survival in a pivotal phase III study of women with metastatic triple-negative breast cancer, drug developer Sanofi-Aventis reported after market close Jan. 27.

The results are particularly disappointing in light of stellar phase II findings presented at the San Antonio Breast Cancer Symposium in 2009 and published online Jan. 5 in the New England Journal of Medicine (N. Engl. J. Med. 2011;364:205-14). Sanofi-Aventis had planned to complete a Food and Drug Administration rolling new drug application for iniparib this quarter.

Despite the divergent outcomes, the designs of the two studies were very similar. "We need to do a complete look at the data, the patient populations, any differences that we can see between the phase II and the phase III," Dr. Paul Chew, Sanofi’s U.S. chief science officer and chief medical officer, said in an interview. "When we have that data we’ll present it at a major scientific meeting."

"We still feel that there is value in iniparib," Chew said. "We’re going to look at this data. We’re continuing the development in other tumors. And we’ll know more soon."

Besides breast cancer, iniparib is in phase II studies against ovarian, uterine, and brain cancers, and a phase III study in patients with advanced squamous non–small cell lung cancer launched in March 2010.

While several regimens are used off label, there are no approved treatments for triple-negative breast cancer, so called because those tumors are negative for three markers: estrogen receptor, progesterone receptor and HER2.

Can The Triple-Negative Claim Be Salvaged?

Excitement over the phase II data was based on results that were not a prespecified primary end point. Among the 61 women in the 123-patient trial randomized to receive iniparib plus gemcitabine and carboplatin, median overall survival was 12.3 months compared with 7.7 months for women in the chemo-alone group – a 43% reduction in risk of death. Median progression-free survival in the iniparib groups was 5.9 months, compared with 3.6 months for chemo, and the overall response rate was 52% compared with 32%.

The iniparib group also fared better on the specified end point of clinical benefit – complete or partial response or stable disease of at least 6 months. Of the women who received iniparib, 56% showed a clinical benefit, compared with 34% without iniparib.

Iniparib has fast-track status with the FDA, and Dr. Chew didn’t exclude the possibility of completing the oncologic’s rolling NDA with the phase II data in hand, then working on a new confirmatory phase III. "Once we have these data analyzed, we’re going to be talking very soon with the regulatory authorities both in the U.S. and in Europe in terms of what the next steps will be," he said.

The failed study enrolled 519 women with the tough-to-treat disease, who had received up to two previous lines of chemotherapy after their cancer spread. They were randomized to receive gemcitabine and carboplatin chemotherapy either alone or with iniparib.

While the iniparib results failed to reach statistical significance for the combined survival end point, a prespecified analysis of patients in the second- and third-line setting did show improvement, Sanofi said, raising the question of a possible claim for heavily pretreated patients. Dr. Chew called it "premature to comment on these first looks," however, and wouldn’t elaborate on the potential significance of those data.

The mechanism of action of iniparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, is not well understood, but PARPs are signaling enzymes involved in the repair of damaged DNA, and thwarting their activity results in selective destruction of tumor cells that have a certain DNA defect – a defect hypothesized to be found in the DNA of triple-negative cancer tumors.

Rapidly multiplying cancer cells have frequent disruptions in the DNA that they need to repair, Dr. Chew explained. When a PARP inhibitor is paired with chemotherapy agents that induce DNA damage, the effect is to "put a stick in the spokes" of DNA repair in those malignant cells, he said.

"You have a one-two punch if you administer chemotherapies that include or cause breaks in the DNA, then follow it up with another therapy that inhibits the repair. One might expect a potential at least additive benefit."

Among other PARP inhibitors under development are AstraZeneca’s olaparib, in development against a number of cancers, with regulatory filings in serious ovarian cancer and BRCA-associated breast cancers in 2014; Merck’s MK-4827, in phase I in advanced solid tumors; and Pfizer’s candidate PF-01367338, in phase II development in a number of cancers. BioMarin Pharmaceutical announced the launch of a phase I/II study of its candidate BMN-673 in advanced or recurrent solid tumors Jan. 11.

Originally published by "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

Iniparib, the potential first-in-class poly (adenosine diphosphate-ribose) polymerase inhibitor, failed to meet the coprimary end point of overall and progression-free survival in a pivotal phase III study of women with metastatic triple-negative breast cancer, drug developer Sanofi-Aventis reported after market close Jan. 27.

The results are particularly disappointing in light of stellar phase II findings presented at the San Antonio Breast Cancer Symposium in 2009 and published online Jan. 5 in the New England Journal of Medicine (N. Engl. J. Med. 2011;364:205-14). Sanofi-Aventis had planned to complete a Food and Drug Administration rolling new drug application for iniparib this quarter.

Despite the divergent outcomes, the designs of the two studies were very similar. "We need to do a complete look at the data, the patient populations, any differences that we can see between the phase II and the phase III," Dr. Paul Chew, Sanofi’s U.S. chief science officer and chief medical officer, said in an interview. "When we have that data we’ll present it at a major scientific meeting."

"We still feel that there is value in iniparib," Chew said. "We’re going to look at this data. We’re continuing the development in other tumors. And we’ll know more soon."

Besides breast cancer, iniparib is in phase II studies against ovarian, uterine, and brain cancers, and a phase III study in patients with advanced squamous non–small cell lung cancer launched in March 2010.

While several regimens are used off label, there are no approved treatments for triple-negative breast cancer, so called because those tumors are negative for three markers: estrogen receptor, progesterone receptor and HER2.

Can The Triple-Negative Claim Be Salvaged?

Excitement over the phase II data was based on results that were not a prespecified primary end point. Among the 61 women in the 123-patient trial randomized to receive iniparib plus gemcitabine and carboplatin, median overall survival was 12.3 months compared with 7.7 months for women in the chemo-alone group – a 43% reduction in risk of death. Median progression-free survival in the iniparib groups was 5.9 months, compared with 3.6 months for chemo, and the overall response rate was 52% compared with 32%.

The iniparib group also fared better on the specified end point of clinical benefit – complete or partial response or stable disease of at least 6 months. Of the women who received iniparib, 56% showed a clinical benefit, compared with 34% without iniparib.

Iniparib has fast-track status with the FDA, and Dr. Chew didn’t exclude the possibility of completing the oncologic’s rolling NDA with the phase II data in hand, then working on a new confirmatory phase III. "Once we have these data analyzed, we’re going to be talking very soon with the regulatory authorities both in the U.S. and in Europe in terms of what the next steps will be," he said.

The failed study enrolled 519 women with the tough-to-treat disease, who had received up to two previous lines of chemotherapy after their cancer spread. They were randomized to receive gemcitabine and carboplatin chemotherapy either alone or with iniparib.

While the iniparib results failed to reach statistical significance for the combined survival end point, a prespecified analysis of patients in the second- and third-line setting did show improvement, Sanofi said, raising the question of a possible claim for heavily pretreated patients. Dr. Chew called it "premature to comment on these first looks," however, and wouldn’t elaborate on the potential significance of those data.

The mechanism of action of iniparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, is not well understood, but PARPs are signaling enzymes involved in the repair of damaged DNA, and thwarting their activity results in selective destruction of tumor cells that have a certain DNA defect – a defect hypothesized to be found in the DNA of triple-negative cancer tumors.

Rapidly multiplying cancer cells have frequent disruptions in the DNA that they need to repair, Dr. Chew explained. When a PARP inhibitor is paired with chemotherapy agents that induce DNA damage, the effect is to "put a stick in the spokes" of DNA repair in those malignant cells, he said.

"You have a one-two punch if you administer chemotherapies that include or cause breaks in the DNA, then follow it up with another therapy that inhibits the repair. One might expect a potential at least additive benefit."

Among other PARP inhibitors under development are AstraZeneca’s olaparib, in development against a number of cancers, with regulatory filings in serious ovarian cancer and BRCA-associated breast cancers in 2014; Merck’s MK-4827, in phase I in advanced solid tumors; and Pfizer’s candidate PF-01367338, in phase II development in a number of cancers. BioMarin Pharmaceutical announced the launch of a phase I/II study of its candidate BMN-673 in advanced or recurrent solid tumors Jan. 11.

Originally published by "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

This newspaper and “The Pink Sheet” are published by Elsevier.

The Food and Drug Administration has approved two new uses for trastuzumab with hormone therapy in HER2 overexpressing, node-positive or high-risk node-negative breast cancer, the agency announced.

The new approvals are for use of trastuzumab (a) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and docetaxel, and (b) as part of a regimen that includes docetaxel and carboplatin.

Genentech, which manufactures trastuzumab under the brand name Herceptin, submitted the two supplemental biologics license applications in June 2007 based on data from a Roche study that included an arm in which carboplatin was substituted for anthracyclines (doxorubicin and others) in an attempt to decrease the cardiotoxicity associated with that class.

Among other research, Genentech and Roche are studying trastuzumab in combination with bevacizumab for human growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer and for adjuvant HER2-positive breast cancer.

Herceptin, which was first approved in 1998, is the first humanized antibody approved for the treatment of HER2-positive metastatic breast cancer. It is designed to target and block the function of HER2 protein overexpression, and is indicated as a first-line treatment with paclitaxel and as monotherapy in second- and third-line therapy.

In 2006, trastuzumab gained approval in a regimen containing doxorubicin, cyclophosphamide, and paclitaxel for adjuvant treatment. In January, Herceptin was approved as a single agent for adjuvant treatment of HER2 overexpressing node-negative and node-positive breast cancer following multimodality anthracycline-based therapy.

This newspaper and “The Pink Sheet” are published by Elsevier.

The Food and Drug Administration has approved two new uses for trastuzumab with hormone therapy in HER2 overexpressing, node-positive or high-risk node-negative breast cancer, the agency announced.

The new approvals are for use of trastuzumab (a) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and docetaxel, and (b) as part of a regimen that includes docetaxel and carboplatin.

Genentech, which manufactures trastuzumab under the brand name Herceptin, submitted the two supplemental biologics license applications in June 2007 based on data from a Roche study that included an arm in which carboplatin was substituted for anthracyclines (doxorubicin and others) in an attempt to decrease the cardiotoxicity associated with that class.

Among other research, Genentech and Roche are studying trastuzumab in combination with bevacizumab for human growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer and for adjuvant HER2-positive breast cancer.

Herceptin, which was first approved in 1998, is the first humanized antibody approved for the treatment of HER2-positive metastatic breast cancer. It is designed to target and block the function of HER2 protein overexpression, and is indicated as a first-line treatment with paclitaxel and as monotherapy in second- and third-line therapy.

In 2006, trastuzumab gained approval in a regimen containing doxorubicin, cyclophosphamide, and paclitaxel for adjuvant treatment. In January, Herceptin was approved as a single agent for adjuvant treatment of HER2 overexpressing node-negative and node-positive breast cancer following multimodality anthracycline-based therapy.

This newspaper and “The Pink Sheet” are published by Elsevier.

The Food and Drug Administration has approved two new uses for trastuzumab with hormone therapy in HER2 overexpressing, node-positive or high-risk node-negative breast cancer, the agency announced.

The new approvals are for use of trastuzumab (a) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and docetaxel, and (b) as part of a regimen that includes docetaxel and carboplatin.

Genentech, which manufactures trastuzumab under the brand name Herceptin, submitted the two supplemental biologics license applications in June 2007 based on data from a Roche study that included an arm in which carboplatin was substituted for anthracyclines (doxorubicin and others) in an attempt to decrease the cardiotoxicity associated with that class.

Among other research, Genentech and Roche are studying trastuzumab in combination with bevacizumab for human growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer and for adjuvant HER2-positive breast cancer.

Herceptin, which was first approved in 1998, is the first humanized antibody approved for the treatment of HER2-positive metastatic breast cancer. It is designed to target and block the function of HER2 protein overexpression, and is indicated as a first-line treatment with paclitaxel and as monotherapy in second- and third-line therapy.

In 2006, trastuzumab gained approval in a regimen containing doxorubicin, cyclophosphamide, and paclitaxel for adjuvant treatment. In January, Herceptin was approved as a single agent for adjuvant treatment of HER2 overexpressing node-negative and node-positive breast cancer following multimodality anthracycline-based therapy.