Emily Hayes

Genentech Inc. and partner OSI Pharmaceuticals Inc. are set to pursue a broader label for Tarceva (erlotinib) in the United States as a first-line treatment of advanced non–small cell lung cancer with epidermal growth factor receptor mutations, after reporting positive top-line results in that setting from a phase III European study.

On Jan. 28, Genentech announced that compared with platinum-based chemotherapy, the EGFR inhibitor Tarceva was shown to improve progression-free survival in an interim analysis of the EURTAC study of 178 newly-diagnosed advanced NSCLC patients who had tested positive for the mutations. Furthermore, safety was in line with Tarceva’s profile. In light of the efficacy and safety results, the trial was halted early on the recommendation of its independent data monitoring committee.

Tarceva is currently approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. An estimated 10% of NSCLC carries the EGFR mutations and according to Genentech a first-line indication would mean Tarceva could emerge as the first-choice for that sliver of the patient population, ahead of chemotherapy and other drugs approved for first-line NSCLC.

Genentech’s parent company, Roche, had already submitted a bid to expand the drug’s label to the European Medicines Agency in June 2010.

Then, in November 2010, Roche announced that it was sublicensing a diagnostic assay for EGFR mutations from Genzyme Corporation and collaborating with OSI on the development of a PCR- based companion diagnostic test to identify people with non–small cell lung cancer that harbors EGFR activating mutations.

Genentech and OSI plan to talk to the Food and Drug Administration about possibilities for a first-line indication in NSCLC and also for the companion diagnostic test in development, but timing on these discussions has not yet been decided.

It’s unclear whether the drug would be submitted to the FDA simultaneously with a diagnostic test, which was the case in a recent approval of a new, narrow indication for Herceptin in a particular type of gastric cancer.

The test in development by Roche and OSI was not the same diagnostic used in the EURTAC study, which was designed and sponsored by the Spanish Lung Cancer Group. Genentech said it still needs to validate the test used in the EURTAC study using samples from the trial, prior to talks with FDA. It’s also unclear at this time whether another study beyond EURTAC would be needed to expand the U.S. label.

Genentech did not disclose the magnitude of the benefit for progression-free survival – the primary end point – in the EURTAC trial. Secondary end points include overall survival, 1-year survival, objective response rate, and safety profile.

In the SATURN trial of Tarceva as a maintenance therapy for NSCLC, the drug showed only a modest PFS benefit for NSCLC patients overall (12.3 weeks for the drug versus 11.1 weeks for placebo). Its use as a maintenance treatment has proven controversial since the FDA approved the indication despite a negative vote by an advisory committee.

However, SATURN showed dramatically better results for patients who had EGFR mutations. In this subgroup, which accounted for 11% of the total population, PFS was 44.6 weeks for the treated group versus the 11 weeks for placebo. Based on the data, some physician surveys have suggested more willingness to use Tarceva as a maintenance treatment in the case of EGFR mutations.

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

Genentech Inc. and partner OSI Pharmaceuticals Inc. are set to pursue a broader label for Tarceva (erlotinib) in the United States as a first-line treatment of advanced non–small cell lung cancer with epidermal growth factor receptor mutations, after reporting positive top-line results in that setting from a phase III European study.

On Jan. 28, Genentech announced that compared with platinum-based chemotherapy, the EGFR inhibitor Tarceva was shown to improve progression-free survival in an interim analysis of the EURTAC study of 178 newly-diagnosed advanced NSCLC patients who had tested positive for the mutations. Furthermore, safety was in line with Tarceva’s profile. In light of the efficacy and safety results, the trial was halted early on the recommendation of its independent data monitoring committee.

Tarceva is currently approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. An estimated 10% of NSCLC carries the EGFR mutations and according to Genentech a first-line indication would mean Tarceva could emerge as the first-choice for that sliver of the patient population, ahead of chemotherapy and other drugs approved for first-line NSCLC.

Genentech’s parent company, Roche, had already submitted a bid to expand the drug’s label to the European Medicines Agency in June 2010.

Then, in November 2010, Roche announced that it was sublicensing a diagnostic assay for EGFR mutations from Genzyme Corporation and collaborating with OSI on the development of a PCR- based companion diagnostic test to identify people with non–small cell lung cancer that harbors EGFR activating mutations.

Genentech and OSI plan to talk to the Food and Drug Administration about possibilities for a first-line indication in NSCLC and also for the companion diagnostic test in development, but timing on these discussions has not yet been decided.

It’s unclear whether the drug would be submitted to the FDA simultaneously with a diagnostic test, which was the case in a recent approval of a new, narrow indication for Herceptin in a particular type of gastric cancer.

The test in development by Roche and OSI was not the same diagnostic used in the EURTAC study, which was designed and sponsored by the Spanish Lung Cancer Group. Genentech said it still needs to validate the test used in the EURTAC study using samples from the trial, prior to talks with FDA. It’s also unclear at this time whether another study beyond EURTAC would be needed to expand the U.S. label.

Genentech did not disclose the magnitude of the benefit for progression-free survival – the primary end point – in the EURTAC trial. Secondary end points include overall survival, 1-year survival, objective response rate, and safety profile.

In the SATURN trial of Tarceva as a maintenance therapy for NSCLC, the drug showed only a modest PFS benefit for NSCLC patients overall (12.3 weeks for the drug versus 11.1 weeks for placebo). Its use as a maintenance treatment has proven controversial since the FDA approved the indication despite a negative vote by an advisory committee.

However, SATURN showed dramatically better results for patients who had EGFR mutations. In this subgroup, which accounted for 11% of the total population, PFS was 44.6 weeks for the treated group versus the 11 weeks for placebo. Based on the data, some physician surveys have suggested more willingness to use Tarceva as a maintenance treatment in the case of EGFR mutations.

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

Genentech Inc. and partner OSI Pharmaceuticals Inc. are set to pursue a broader label for Tarceva (erlotinib) in the United States as a first-line treatment of advanced non–small cell lung cancer with epidermal growth factor receptor mutations, after reporting positive top-line results in that setting from a phase III European study.

On Jan. 28, Genentech announced that compared with platinum-based chemotherapy, the EGFR inhibitor Tarceva was shown to improve progression-free survival in an interim analysis of the EURTAC study of 178 newly-diagnosed advanced NSCLC patients who had tested positive for the mutations. Furthermore, safety was in line with Tarceva’s profile. In light of the efficacy and safety results, the trial was halted early on the recommendation of its independent data monitoring committee.

Tarceva is currently approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. An estimated 10% of NSCLC carries the EGFR mutations and according to Genentech a first-line indication would mean Tarceva could emerge as the first-choice for that sliver of the patient population, ahead of chemotherapy and other drugs approved for first-line NSCLC.

Genentech’s parent company, Roche, had already submitted a bid to expand the drug’s label to the European Medicines Agency in June 2010.

Then, in November 2010, Roche announced that it was sublicensing a diagnostic assay for EGFR mutations from Genzyme Corporation and collaborating with OSI on the development of a PCR- based companion diagnostic test to identify people with non–small cell lung cancer that harbors EGFR activating mutations.

Genentech and OSI plan to talk to the Food and Drug Administration about possibilities for a first-line indication in NSCLC and also for the companion diagnostic test in development, but timing on these discussions has not yet been decided.

It’s unclear whether the drug would be submitted to the FDA simultaneously with a diagnostic test, which was the case in a recent approval of a new, narrow indication for Herceptin in a particular type of gastric cancer.

The test in development by Roche and OSI was not the same diagnostic used in the EURTAC study, which was designed and sponsored by the Spanish Lung Cancer Group. Genentech said it still needs to validate the test used in the EURTAC study using samples from the trial, prior to talks with FDA. It’s also unclear at this time whether another study beyond EURTAC would be needed to expand the U.S. label.

Genentech did not disclose the magnitude of the benefit for progression-free survival – the primary end point – in the EURTAC trial. Secondary end points include overall survival, 1-year survival, objective response rate, and safety profile.

In the SATURN trial of Tarceva as a maintenance therapy for NSCLC, the drug showed only a modest PFS benefit for NSCLC patients overall (12.3 weeks for the drug versus 11.1 weeks for placebo). Its use as a maintenance treatment has proven controversial since the FDA approved the indication despite a negative vote by an advisory committee.

However, SATURN showed dramatically better results for patients who had EGFR mutations. In this subgroup, which accounted for 11% of the total population, PFS was 44.6 weeks for the treated group versus the 11 weeks for placebo. Based on the data, some physician surveys have suggested more willingness to use Tarceva as a maintenance treatment in the case of EGFR mutations.

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

The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The recombinant inhaled insulin product Afrezza has received a complete response letter from the Food and Drug Administration, drug developer MannKind Corp. announced Jan. 19.

The company says it hopes that with a major protocol change, studies that are already off the ground will satisfy the letter’s requirements.

The phase III trials supporting the Afrezza application had been done with the company’s "MedTone" delivery device, but the company plans to commercialize the next-generation whistle-shaped "Dreamboat" device instead.

The main concern of the FDA’s Center for Drug Evaluation and Research is MannKind’s use of in vitro performance and clinical pharmacology data to bridge the next-generation inhaler to the phase III trials conducted using the older MedTone inhaler, MannKind explained in a statement. Two clinical studies of Afrezza will be needed with the new inhaler: one in type 2 diabetes, and one in type 1 disease. Moreover, at least one of these trials must also have an arm of patients using the MedTone inhaler to allow for head-to-head comparisons.

The complete response letter is unlikely to surprise industry observers, as the inhaled delivery had raised concerns about pulmonary safety and the product had previously received a complete response letter. Regulatory and commercial hurdles for the product have been known to be high.

A request for new trials is typically seen as one of the more damaging outcomes of a complete response letter, with potential to cause major delay to the product-launch timetable and commercial viability.

During a call with investors, MannKind executives declined to say exactly how long it will take to satisfy new requirements and resubmit its application. "We believe we can readily address these additional requests," said CEO Alfred Mann. But analysts don’t necessarily agree. In a Jan. 19 note entitled "Afrezza’s Gasping For Air," J.P. Morgan biotechnology analyst Cory Kasimov described the complete response terms as "onerous" and predicted a delay of at least a year in the "best-case scenario."

Mr. Mann described the letter as a surprise, noting that the company thought it had enough bridging data for the next-generation device. In October, company executives had indicated that they expected no new requests from the FDA.

The ball is already rolling on two phase IIIB trials of the next-generation device, compared with insulin analogs (Affinity-1 in type 1 diabetes, and Affinity-2 in type 2 diabetes, the latter of which has started enrolling patients).

The protocols for these studies had already been submitted to the FDA and are very similar to what was requested in the complete response letter, executives maintained. However, the design of one study will need to be modified to include an arm using the MedTone inhaler to satisfy the complete response letter.

On top of the trials, the FDA also wants more information about performance characteristics, usage, handling, shipment, and storage of Dreamboat. Furthermore, the agency has requested an update of safety information related to Afrezza and information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap, and cartons.

In terms of the two phase III trials now needed for approval, the FDA has indicated that after an adequate titration of study medication, there should be at least 12 weeks of relatively stable insulin dosing at the end of the treatment period. The length of the titration period in the Affinity trials is 4 weeks, and the treatment period is 12 weeks. According to current protocols, each Affinity trial has 143 patients per arm. MannKind believes that the Affinity studies would meet the requirements of the FDA, based on the wording of the complete response letter. But this is subject to discussion with the agency.

In response to analyst questions, Mr. Mann insisted that the Affinity trials do not have to be halted pending talks with the FDA, and defended the likely strategy of using ongoing trials rather than starting from scratch to satisfy the demands of the complete response letter.

One possibility is to randomize patients in one of the Affinity studies to the MedTone arm, and then start dosing later to catch up with the other study arms, executives said.

The company also clarified that the agency has not requested that the new device prove to be superior to the old one, although it could show lesser negative effects on pulmonary function, which would be a positive signal.

Asked about the possibility that MedTone would outperform the next-generation device, Mr. Mann said simply, "It won’t be superior. Dreamboat is clearly superior in many ways."

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

Emily Hayes is with “The Pink Sheet” which, along with this newspaper, is published by Elsevier.

A long-acting formulation of exenatide has failed to pass muster with the Food and Drug Administration, which is asking the manufacturer Amylin for its most recent clinical trial results and a new QT prolongation analysis.

The FDA issued a complete response letter for the formulation, called Bydureon, the company announced last month. This is the agency's second complete response letter for Bydureon. The first, issued in March, had straightforward requirements, and Amylin responded within a month. However, the new request for a thorough QT prolongation study, which assesses effects on cardiac repolarization, could push the resubmission back by more than a year.

Complete response letters are not made public by the agency, and only the company can reveal contents at its discretion.

The FDA is also asking for results of a recently completed clinical trial, known as DURATION-5, which can be pulled together rapidly.

Amylin initially submitted the Bydureon new drug application (NDA) in May 2009, supported by the DURATION-1 head-to-head study of Bydureon vs. exenatide twice daily (Byetta), safety data from the DURATION-2 trial, and more than 7 years of clinical data.

DURATION-1 comprised 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs. Exenatide once-weekly showed a statistically significant improvement in hemoglobin A_1c of approximately 1.9% from baseline, compared with an improvement of 1.5% for Byetta. About three-fourths of the study subjects who were treated with the long-acting drug achieved a hemoglobin A_1c level of 7% or less.

Regulatory requirements for diabetes drugs have tightened since the Byetta program began, however. In 2008, the FDA issued guidelines requiring manufacturers to monitor potential for cardiovascular events in new diabetes drugs, but this was not an issue for the Bydureon application.

Since 2005, the FDA has required thorough QT prolongation studies to support all NDAs – for all therapeutic categories – and this was at the heart of the FDA's complete response letter. Prolongation of the QT interval may signify increased risk of cardiac arrhythmia, a recurrent safety concern for new drugs.

Amylin executives said that they conducted extensive preclinical and clinical QT prolongation studies on Byetta, but did not find any signs of risk. A QT prolongation study was also conducted to support the Bydureon filing. But the study consisted of administration of a single 10-mcg dose of Byetta in healthy volunteers, and did not have a control arm.

In addition, a QT assessment had been done for Bydureon as part of the DURATION-1 study, including patients with mild to moderate renal impairment, and showed no signs of QT prolongation.

The FDA now wants Amylin to analyze exposures higher than typical therapeutic levels of Bydureon in a controlled thorough QT (tQT) study.

“The complete response letter was the first indication that this was an approvability issue,” Amylin CEO Daniel Bradbury asserted during a conference call with investors and press.

Exenatide is cleared through the kidneys and the chief issue with Bydureon, which underlies regulators' concerns, appears to be that the drug persists in elevated levels in patients with renal impairment.

The agency has requested that the new tQT study include patients with pharmacokinetic concentrations consistent with levels seen in patients with renal impairment.

Emily Hayes is with “The Pink Sheet” which, along with this newspaper, is published by Elsevier.

A long-acting formulation of exenatide has failed to pass muster with the Food and Drug Administration, which is asking the manufacturer Amylin for its most recent clinical trial results and a new QT prolongation analysis.

The FDA issued a complete response letter for the formulation, called Bydureon, the company announced last month. This is the agency's second complete response letter for Bydureon. The first, issued in March, had straightforward requirements, and Amylin responded within a month. However, the new request for a thorough QT prolongation study, which assesses effects on cardiac repolarization, could push the resubmission back by more than a year.

Complete response letters are not made public by the agency, and only the company can reveal contents at its discretion.

The FDA is also asking for results of a recently completed clinical trial, known as DURATION-5, which can be pulled together rapidly.

Amylin initially submitted the Bydureon new drug application (NDA) in May 2009, supported by the DURATION-1 head-to-head study of Bydureon vs. exenatide twice daily (Byetta), safety data from the DURATION-2 trial, and more than 7 years of clinical data.

DURATION-1 comprised 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs. Exenatide once-weekly showed a statistically significant improvement in hemoglobin A_1c of approximately 1.9% from baseline, compared with an improvement of 1.5% for Byetta. About three-fourths of the study subjects who were treated with the long-acting drug achieved a hemoglobin A_1c level of 7% or less.

Regulatory requirements for diabetes drugs have tightened since the Byetta program began, however. In 2008, the FDA issued guidelines requiring manufacturers to monitor potential for cardiovascular events in new diabetes drugs, but this was not an issue for the Bydureon application.

Since 2005, the FDA has required thorough QT prolongation studies to support all NDAs – for all therapeutic categories – and this was at the heart of the FDA's complete response letter. Prolongation of the QT interval may signify increased risk of cardiac arrhythmia, a recurrent safety concern for new drugs.

Amylin executives said that they conducted extensive preclinical and clinical QT prolongation studies on Byetta, but did not find any signs of risk. A QT prolongation study was also conducted to support the Bydureon filing. But the study consisted of administration of a single 10-mcg dose of Byetta in healthy volunteers, and did not have a control arm.

In addition, a QT assessment had been done for Bydureon as part of the DURATION-1 study, including patients with mild to moderate renal impairment, and showed no signs of QT prolongation.

The FDA now wants Amylin to analyze exposures higher than typical therapeutic levels of Bydureon in a controlled thorough QT (tQT) study.

“The complete response letter was the first indication that this was an approvability issue,” Amylin CEO Daniel Bradbury asserted during a conference call with investors and press.

Exenatide is cleared through the kidneys and the chief issue with Bydureon, which underlies regulators' concerns, appears to be that the drug persists in elevated levels in patients with renal impairment.

The agency has requested that the new tQT study include patients with pharmacokinetic concentrations consistent with levels seen in patients with renal impairment.

Emily Hayes is with “The Pink Sheet” which, along with this newspaper, is published by Elsevier.

A long-acting formulation of exenatide has failed to pass muster with the Food and Drug Administration, which is asking the manufacturer Amylin for its most recent clinical trial results and a new QT prolongation analysis.

The FDA issued a complete response letter for the formulation, called Bydureon, the company announced last month. This is the agency's second complete response letter for Bydureon. The first, issued in March, had straightforward requirements, and Amylin responded within a month. However, the new request for a thorough QT prolongation study, which assesses effects on cardiac repolarization, could push the resubmission back by more than a year.

Complete response letters are not made public by the agency, and only the company can reveal contents at its discretion.

The FDA is also asking for results of a recently completed clinical trial, known as DURATION-5, which can be pulled together rapidly.

Amylin initially submitted the Bydureon new drug application (NDA) in May 2009, supported by the DURATION-1 head-to-head study of Bydureon vs. exenatide twice daily (Byetta), safety data from the DURATION-2 trial, and more than 7 years of clinical data.

DURATION-1 comprised 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs. Exenatide once-weekly showed a statistically significant improvement in hemoglobin A_1c of approximately 1.9% from baseline, compared with an improvement of 1.5% for Byetta. About three-fourths of the study subjects who were treated with the long-acting drug achieved a hemoglobin A_1c level of 7% or less.

Regulatory requirements for diabetes drugs have tightened since the Byetta program began, however. In 2008, the FDA issued guidelines requiring manufacturers to monitor potential for cardiovascular events in new diabetes drugs, but this was not an issue for the Bydureon application.

Since 2005, the FDA has required thorough QT prolongation studies to support all NDAs – for all therapeutic categories – and this was at the heart of the FDA's complete response letter. Prolongation of the QT interval may signify increased risk of cardiac arrhythmia, a recurrent safety concern for new drugs.

Amylin executives said that they conducted extensive preclinical and clinical QT prolongation studies on Byetta, but did not find any signs of risk. A QT prolongation study was also conducted to support the Bydureon filing. But the study consisted of administration of a single 10-mcg dose of Byetta in healthy volunteers, and did not have a control arm.

In addition, a QT assessment had been done for Bydureon as part of the DURATION-1 study, including patients with mild to moderate renal impairment, and showed no signs of QT prolongation.

The FDA now wants Amylin to analyze exposures higher than typical therapeutic levels of Bydureon in a controlled thorough QT (tQT) study.

“The complete response letter was the first indication that this was an approvability issue,” Amylin CEO Daniel Bradbury asserted during a conference call with investors and press.

Exenatide is cleared through the kidneys and the chief issue with Bydureon, which underlies regulators' concerns, appears to be that the drug persists in elevated levels in patients with renal impairment.

The agency has requested that the new tQT study include patients with pharmacokinetic concentrations consistent with levels seen in patients with renal impairment.