- Email: [email protected]
1999 a Disappointing Year for Biotech Approvals
BIOTECHNOLOGY UPDATE
1999 a Disappointing Year for Biotech Approvals Peggy Piascik
The most recent Ph annaceutical Research and Manufacturers of America (PhRMA) survey of biotechnology products, published in April 1998, estimated the number of biotechnology medications in development at 350 products and the number of approved products at 54. 1 Biotechnology drug approvals have made considerable progress since Humulin became the first biotech therapeutic agent in 1982. In recent years the Food and Drug Administration (FDA) has made a significant effort to speed up the drug approval process. The Food and Drug Administration Modernization Act of 1997 established performance goals for FDA review of new medications. According to the goals, priority drugs, those that represent significant therapeutic gains, are to be reviewed within 6 months of receiving a New Drug Application (NDA) or Biologic License Application (BLA), the application filed on behalf of biologic products. Standard drugs are to be reviewed within a 12-month period after the application is filed. FDA made significant progress tOward meeting 1999 performance goals with an average
Vol. 40, No.2
March/April 2000
approval time for all drugs of 12.6 months. Biotech drug approvals were down for 1999, back to approval levels seen in 1995 and 1996 (see Table 1). Review periods for biotech drugs were uninspiring, as well. Two products designated as standard drugs were approved in 18 and 34.5 months, versus the designated 12-month goal, and two products designated as priority drugs were approved in 7.3 and 13.9 months, versus the 6-month goal set by the agency. These data appear to indicate that the process is working more efficiently for traditional drugs than for biologic agents. Therapeutic biotech agents approved in 1999 include the following: • Denileukin diftitox (Ontak-Seragen) was approved in February for treatment of persistent or recurrent cutaneous T-cell lymphoma where the cells express the CD25 portion of the IL-2 receptor. This agent was described in detail in a recent issue of JAPhA. 3 • Two blood products for hemophiliacs: - Coagulation Factor VIla (NovoSeven-Novo Nordisk) was approved in March for
treatment of bleeding episodes in hemophilia A or B when patients have inhibitors to Factor VIII or IX. - Antihemophilic factor/ von Willebrand factor complex (Human) (Humate-P-Centeon Pharma) was approved in April for treatment and prevention of bleeding in hemophilia A. It was also approved for use in treatment and prevention of spontaneous bleeding in von Willebrand disease. • Interferon alfa-n 1, lymphoblastoid (WellferonGlaxo W ellcome) was approved in March for treatment of chronic hepatitis C in patients ~ 18 years of age without decompensated liver disease. The new indications approved for existing biologics in 1999 include: • Etanercept (EnbrelImmunex Corp.)-indication expanded to include treatment of poly-articular course juvenile rheumatoid arthritis. • Epoetin alfa (EpogenAmgen Inc. )-approved for pediatric use. • Infliximab (RemicadeCentocor Inc. )-approved for reduction in signs and symptOIns of rheumatoid arthritis in patients who have had an inad-
equate response to methptrexate (MTX). • Interferon alfa-2 (RoferonA-Hoffman-La-Roche)-,recei ved approval for a new dosage regimen of 6 MID three times weekly for 12 weeks followed by the standard regimen for an additional 12 to 36 weeks. • Interferon alfacon-1 (Infergen-Amgen Inc.)-indication expanded to include subsequent treatment of hepatitis C-infected patients who have tolerated an initial course of therapy with Infergen for 48 weeks. The new rheumatoid arthritis indication for Remicade is particularly interesting. This product was first approved in 1998 for treatment of Crohn' s disease. Remicade is a monoclonal antibody that binds to tumor necrosis factor a (TNFa) and prevents this cytokine from contributing to the inflammatory response. Rheumatoid arthritis, like Crohn's disease, is an atnoimmune disease mediated by TNF. Animal studies in transgenic mice with polyarthritis demonstrated the ability of Remicade to produce healing in eroded joints. Remicade is given in
Table 1. Approved Biotechnology Products Fiscal Year
Vaccine
Total
4
5
0
6
Therapeutic
1995 1996
6
1997
10
1998
11
0
11
3
3
6
1999
11
Adapted from: Reference 2.
Journal of the American Phannaceutical Association
269
BIOTECHNOLOGY UPDATE
conjunction with MTX. The dosing regimen is intravenous administration of 3 mg/kg at 0, 2, and 6 weeks. Treatment is given at 8-week intervals thereafter for a total of eight infusions the frrst year and six infusions in subsequent years. Approval was based on ATTRACT, a double-blind, placebo-controlled, randomized clinical trial of 428 patients at 34 clinical sites. At week 30 of the trial, 50% of patients treated with a combination of Remicade and MTX experienced reduction in signs and symptoms of rheumatoid arthritis compared with 20% of patients receiving MTX alone. Patients in the ATIRACT trial were described as difficult to manage, with a median duration of disease of 8.4 years. All patients were receiving MTX. Approximately onehalf of the patients had been receiving MTX for 3 or more years. Nearly half were classified with progressive, advanced disease and one-third had had prior joint surgery. The most common adverse effects noted during the ATTRACT trial were the same as those experienced by patients with Crohn's disease: upper respiratory tract infections, headache, nausea, sinusitis, rash, and cough. There was no increase in serious adverse effects or infections compared with treatment with MTX alone. The incidence of infusion reactions
270
was also low, 5 % compared with 2% for MTX alone. By the nature of its mechanism of action, Remicade is potentially useful for other autoimmune diseases. Additional potential uses of Remicade include psoriasis.
Significant Agents Awaiting Approval by FDA Manufacturers of the following biologic agents have filed license applications for approval. As of January 24th, FDA had not approved any of these agents. • Ancestim (StemgenAmgen Inc.) is an early acting blood cell growth factor recommended for use with filgrastim (Neupogen-Amgen Inc.) to increase the proportion of cancer patients reaching a peripheral blood progenitor cell (PBPC) target for transplantation. In July 1998 the Biological Response Modifiers Advisory Committee recommended approval of Stemgen to FDA. The agency is not bound by the recommendations of its advisory committees. In three large, randomized clinical trials, Stemgen in combination with Neupogen increased the number of PBPCs or stem cells in cancer patients. An increased proportion of patients attained the PBPC target. Patients achieving the PBPC target are more
Journal of the American Phannaceutical Association
likely to be successfully treated with intense, high-dose chemotherapy. Stem cells are mobilized by the regimen into the peripheral blood, collected, and frozen. Patients receive potentially toxic doses of chemotherapy. Stem cells are then reinfused into the patient along with Neupogen to shorten the recovery time for blood cells. This decreases the time period during which patients are at risk for serious side effects such as infection. Mild-to-moderate injectionsite reactions and systemic allergic-like reactions were the most common adverse effects during trials. These effects were minimized by pretreatment with antihistamines or bronchodilators. • TNK (TenecteplaseGenentech) is a selectively mutated version of natural tissue-plasminogen activator (tPA). The ASSENT-II Phase III clinical trial demonstrated that a single bolus injection of TNK is equivalent to natural tPA in reducing 30-day mortality. An advantage of this agent is administration of a single injection rather than an infusion. A license application was filed in July for treatment of acute myocardial infarction. • Bivalirudin (Hirulog-BiogenffMC; Cambridge, Mass.) is a direct thrombin inhibitor used as an anticoagulant for patients with unstable angina who are undergoing percuta-
neous transluminal coronary angioplasty. Bivalirudin is related to hirudin, a natural anticoagulant principle found in the saliva of medicinal leeches. Many other anticoagulant applications are possible for this product. The PhRMA survey lists an additional 13 products awaiting approval by FDA either as new approvals or new indications. In contrast to the past year's slowed rate, action on these applications by FDA during this year could make 2000 a banner year for biotech approvals. Peggy Piascik, PhD, is associate professor ofpharmacology & experimental therapeutics and pharmacy practice & science, College of Pharmacy, University of Kentucky, Lexington.
References 1. New Medicines in Development, 1998 Survey. Pharmaceutical Research and ManuAmerica. factu rers of Washington, DC: April 1998. Available at: http://www. phrma.org. Accessed January
31,2000. 2. Zoon KC. Biologics update '99 FDLI. Presented to CBER Recombinant DNA Advisory Committee on December 16, 1999. Available at: www. fda.gov. Accessed January
31,2000. 3. Piascik P. FDA Approves fusion protein for treatment of lymphoma. J Am Pharm Assoc. 1999:39;571-2.
4. Piascik P. New therapeutic monoclonal antibodies target kidney transplant rejection. J Am Pharm Assoc. 1998:
38;379-80.
MarchiApril2000 Vol. 40, No.2
1999 a Disappointing Year for Biotech Approvals Peggy Piascik
The most recent Ph annaceutical Research and Manufacturers of America (PhRMA) survey of biotechnology products, published in April 1998, estimated the number of biotechnology medications in development at 350 products and the number of approved products at 54. 1 Biotechnology drug approvals have made considerable progress since Humulin became the first biotech therapeutic agent in 1982. In recent years the Food and Drug Administration (FDA) has made a significant effort to speed up the drug approval process. The Food and Drug Administration Modernization Act of 1997 established performance goals for FDA review of new medications. According to the goals, priority drugs, those that represent significant therapeutic gains, are to be reviewed within 6 months of receiving a New Drug Application (NDA) or Biologic License Application (BLA), the application filed on behalf of biologic products. Standard drugs are to be reviewed within a 12-month period after the application is filed. FDA made significant progress tOward meeting 1999 performance goals with an average
Vol. 40, No.2
March/April 2000
approval time for all drugs of 12.6 months. Biotech drug approvals were down for 1999, back to approval levels seen in 1995 and 1996 (see Table 1). Review periods for biotech drugs were uninspiring, as well. Two products designated as standard drugs were approved in 18 and 34.5 months, versus the designated 12-month goal, and two products designated as priority drugs were approved in 7.3 and 13.9 months, versus the 6-month goal set by the agency. These data appear to indicate that the process is working more efficiently for traditional drugs than for biologic agents. Therapeutic biotech agents approved in 1999 include the following: • Denileukin diftitox (Ontak-Seragen) was approved in February for treatment of persistent or recurrent cutaneous T-cell lymphoma where the cells express the CD25 portion of the IL-2 receptor. This agent was described in detail in a recent issue of JAPhA. 3 • Two blood products for hemophiliacs: - Coagulation Factor VIla (NovoSeven-Novo Nordisk) was approved in March for
treatment of bleeding episodes in hemophilia A or B when patients have inhibitors to Factor VIII or IX. - Antihemophilic factor/ von Willebrand factor complex (Human) (Humate-P-Centeon Pharma) was approved in April for treatment and prevention of bleeding in hemophilia A. It was also approved for use in treatment and prevention of spontaneous bleeding in von Willebrand disease. • Interferon alfa-n 1, lymphoblastoid (WellferonGlaxo W ellcome) was approved in March for treatment of chronic hepatitis C in patients ~ 18 years of age without decompensated liver disease. The new indications approved for existing biologics in 1999 include: • Etanercept (EnbrelImmunex Corp.)-indication expanded to include treatment of poly-articular course juvenile rheumatoid arthritis. • Epoetin alfa (EpogenAmgen Inc. )-approved for pediatric use. • Infliximab (RemicadeCentocor Inc. )-approved for reduction in signs and symptOIns of rheumatoid arthritis in patients who have had an inad-
equate response to methptrexate (MTX). • Interferon alfa-2 (RoferonA-Hoffman-La-Roche)-,recei ved approval for a new dosage regimen of 6 MID three times weekly for 12 weeks followed by the standard regimen for an additional 12 to 36 weeks. • Interferon alfacon-1 (Infergen-Amgen Inc.)-indication expanded to include subsequent treatment of hepatitis C-infected patients who have tolerated an initial course of therapy with Infergen for 48 weeks. The new rheumatoid arthritis indication for Remicade is particularly interesting. This product was first approved in 1998 for treatment of Crohn' s disease. Remicade is a monoclonal antibody that binds to tumor necrosis factor a (TNFa) and prevents this cytokine from contributing to the inflammatory response. Rheumatoid arthritis, like Crohn's disease, is an atnoimmune disease mediated by TNF. Animal studies in transgenic mice with polyarthritis demonstrated the ability of Remicade to produce healing in eroded joints. Remicade is given in
Table 1. Approved Biotechnology Products Fiscal Year
Vaccine
Total
4
5
0
6
Therapeutic
1995 1996
6
1997
10
1998
11
0
11
3
3
6
1999
11
Adapted from: Reference 2.
Journal of the American Phannaceutical Association
269
BIOTECHNOLOGY UPDATE
conjunction with MTX. The dosing regimen is intravenous administration of 3 mg/kg at 0, 2, and 6 weeks. Treatment is given at 8-week intervals thereafter for a total of eight infusions the frrst year and six infusions in subsequent years. Approval was based on ATTRACT, a double-blind, placebo-controlled, randomized clinical trial of 428 patients at 34 clinical sites. At week 30 of the trial, 50% of patients treated with a combination of Remicade and MTX experienced reduction in signs and symptoms of rheumatoid arthritis compared with 20% of patients receiving MTX alone. Patients in the ATIRACT trial were described as difficult to manage, with a median duration of disease of 8.4 years. All patients were receiving MTX. Approximately onehalf of the patients had been receiving MTX for 3 or more years. Nearly half were classified with progressive, advanced disease and one-third had had prior joint surgery. The most common adverse effects noted during the ATTRACT trial were the same as those experienced by patients with Crohn's disease: upper respiratory tract infections, headache, nausea, sinusitis, rash, and cough. There was no increase in serious adverse effects or infections compared with treatment with MTX alone. The incidence of infusion reactions
270
was also low, 5 % compared with 2% for MTX alone. By the nature of its mechanism of action, Remicade is potentially useful for other autoimmune diseases. Additional potential uses of Remicade include psoriasis.
Significant Agents Awaiting Approval by FDA Manufacturers of the following biologic agents have filed license applications for approval. As of January 24th, FDA had not approved any of these agents. • Ancestim (StemgenAmgen Inc.) is an early acting blood cell growth factor recommended for use with filgrastim (Neupogen-Amgen Inc.) to increase the proportion of cancer patients reaching a peripheral blood progenitor cell (PBPC) target for transplantation. In July 1998 the Biological Response Modifiers Advisory Committee recommended approval of Stemgen to FDA. The agency is not bound by the recommendations of its advisory committees. In three large, randomized clinical trials, Stemgen in combination with Neupogen increased the number of PBPCs or stem cells in cancer patients. An increased proportion of patients attained the PBPC target. Patients achieving the PBPC target are more
Journal of the American Phannaceutical Association
likely to be successfully treated with intense, high-dose chemotherapy. Stem cells are mobilized by the regimen into the peripheral blood, collected, and frozen. Patients receive potentially toxic doses of chemotherapy. Stem cells are then reinfused into the patient along with Neupogen to shorten the recovery time for blood cells. This decreases the time period during which patients are at risk for serious side effects such as infection. Mild-to-moderate injectionsite reactions and systemic allergic-like reactions were the most common adverse effects during trials. These effects were minimized by pretreatment with antihistamines or bronchodilators. • TNK (TenecteplaseGenentech) is a selectively mutated version of natural tissue-plasminogen activator (tPA). The ASSENT-II Phase III clinical trial demonstrated that a single bolus injection of TNK is equivalent to natural tPA in reducing 30-day mortality. An advantage of this agent is administration of a single injection rather than an infusion. A license application was filed in July for treatment of acute myocardial infarction. • Bivalirudin (Hirulog-BiogenffMC; Cambridge, Mass.) is a direct thrombin inhibitor used as an anticoagulant for patients with unstable angina who are undergoing percuta-
neous transluminal coronary angioplasty. Bivalirudin is related to hirudin, a natural anticoagulant principle found in the saliva of medicinal leeches. Many other anticoagulant applications are possible for this product. The PhRMA survey lists an additional 13 products awaiting approval by FDA either as new approvals or new indications. In contrast to the past year's slowed rate, action on these applications by FDA during this year could make 2000 a banner year for biotech approvals. Peggy Piascik, PhD, is associate professor ofpharmacology & experimental therapeutics and pharmacy practice & science, College of Pharmacy, University of Kentucky, Lexington.
References 1. New Medicines in Development, 1998 Survey. Pharmaceutical Research and ManuAmerica. factu rers of Washington, DC: April 1998. Available at: http://www. phrma.org. Accessed January
31,2000. 2. Zoon KC. Biologics update '99 FDLI. Presented to CBER Recombinant DNA Advisory Committee on December 16, 1999. Available at: www. fda.gov. Accessed January
31,2000. 3. Piascik P. FDA Approves fusion protein for treatment of lymphoma. J Am Pharm Assoc. 1999:39;571-2.
4. Piascik P. New therapeutic monoclonal antibodies target kidney transplant rejection. J Am Pharm Assoc. 1998:
38;379-80.
MarchiApril2000 Vol. 40, No.2