New Biotech Medicines: 16 Approved And 19 In The Queue

Despite the burgeoning list of therapeutic proteins, monoclonal antibodies and other biologic compounds that have become part and parcel of the physician's armamentarium, most new medicines approved by the FDA continue to be drugs. In 2000, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), 33 new medicines received FDA's stamp of approval -- only six of these, or 18 percent, were biologics. The ratio was slightly better several years ago (in 1998), when 23 percent of new medicines were biologics. But it may never get to even 50 percent -- largely because many drug development firms are focused on creating orally available, small molecule therapeutics anyway. Whether it's by devising synthetic analogs of natural molecules that work even better than the original, or by creating a compound de novo (and, initially, in silico), biotech and big pharma companies alike often choose the road to drugs rather than biologics.
Biotechs Weigh In
In 2000, new medicines developed by biotechnology companies constituted about one-third of all approved products. According to PhRMA's list, these included four of the six biologics -- Protherics plc's rattlesnake antivenin CroFab; BioChem Pharma Inc.'s bladder cancer immunotherapy Pacis; Genetics Institute Inc.'s hemophilia A treatment ReFacto; and Genentech Inc.'s new clot-buster TNKase.

They also encompassed seven of the 27 new drugs -- Avanir Pharmaceuticals Inc.'s OTC cold sore remedy Abreva; Texas Biotechnology Corp.'s anticoagulant Acova; The Medicines Co. Inc.'s anticoagulant Angiomax; Celltech Group plc's leukemia drug Mylotarg; Cell Therapeutics Inc.'s leukemia therapy Trisenox; QLT PhotoTherapeutics Inc.'s macular degeneration treatment Visudyne; and Genzyme Corp.'s lipid-lowering product WelChol.

But five more biotech-sponsored products were not on the PhRMA's list. These included Unimed Pharmaceuticals Inc.'s testosterone gel AndroGel; Connetics Corp.'s dermatology foam Olux; Interneuron Pharmaceuticals Inc.'s premenstrual drug Sarafem; Ligand Pharmaceuticals Inc.'s treatment for lymphoma-associated lesions Targretin Gel; and InKine Pharmaceutical Co. Inc.'s colonoscopy product Visicol. (For details of these new products, see the table that follows.)


Biotech Company Products Approved By The FDA In 2000 (First-Time Approvals Only)
Product Name
(active ingredient)		 Company (s)
(Developer; Marketer)		 Product Description Indication
Approval Date
Abreva
(docosanol 10% cream)		 Avanir Pharmaceuticals; SmithKline Beecham Long-chain alcohol that interferes with viral entry into cells Topical treatment for recurrent cold sores (herpes simplex infection); OTC medication
7/00
Acova
(formerly Novastan; argatroban)		 Texas Biotechnology; SmithKline Beecham Anticoagulant; synthetic small molecule derived from arginine; acts as direct inhibitor of thrombin Prevention or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT)
6/00
AndroGel
(testosterone)		 Unimed Pharmaceuticals (subsidiary of Solvay Pharmaceuticals) Testosterone Testosterone replacement therapy in males with testosterone deficiency
2/00
Angiomax
(formerly Hirulog; bivalirudin)		 The Medicines Co. (licensed from Biogen); Innovex Synthetic thrombin inhibitor based on hirudin (natural anticoagulant secreted by leeches) Anticoagulant for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty
12/00
CroFab
(crotalidae polyvalent immune Fab [ovine])		 Protherics; Savage Laboratories Mixture of 4 different monospecific antivenins (immunoglobulin fragments produced in sheep) Management of patients with minimal or moderate North American crotalid envonomation (rattlesnake antivenin)
10/00
Mylotarg
(gemtuzumab ozogamicin)		 Celltech Group; Wyeth-Ayerst (AHP) Humanized anti-CD33 monoclonal antibody, conjugated with calicheamicin (chemotherapy) Relapsed acute myeloid leukemia in CD33+ patients who are 60+ years old and are not candidates for cytotoxic chemotherapy
5/00
Olux
(clobetasol proprionate; 0.05% foam)		 Connetics (licensed from Soltec Research Pty.) High-potency corticosteroid (foam formulation) Short-term, topical, treatment of moderate-to-severe dermatoses of the scalp
5/00
Pacis
(BCG, live)		 BioChem Pharma; UroCor Live attenuated mycobacteria (Bacillus Calmette-Guerin) Immunotherapy for bladder cancer
3/00
Refacto
(antihemophilic factor recombinant)		 Genetics Institute; Wyeth-Ayerst (AHP) (purchased rights from Pharmacia & Upjohn 8/97) Recombinant Factor VIII SQ; albumin-free Hemophilia A; also short-term prophylaxis to reduce frequency of spontaneous bleeding episodes
3/00
Sarafem
(fluoxetine HCl)		 Interneuron Pharmaceuticals; Eli Lilly Synthetic compound (same active ingredient as Prozac) that increases brain serotonin levels Premenstrual dysphoric disorder
7/00
Targretin Gel
bexarotene)		 Ligand Pharmaceuticals Synthetic retinoid analog (selectively activates retinoid X receptors) Topical treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma
6/00
TNKase
(tenecteplase)		 Genentech;Boehringer Ingelheim Bioengineered variant of Activase (tissue plasminogen activator) Single-bolus thrombolytic agent, to be administered over 5 seconds; treatment of acute myocardial infarction
6/00
Trisenox
(arsenic trioxide)		 Cell Therapeutics Arsenic; induces apoptosis Acute promyelocytic leukemia in relapsed and refractory patients
9/00
Visicol
(sodium phosphate)		 InKine Pharmaceutical Sodium phosphate (tablet formulation) Cleansing of bowel prior to colonoscopy
9/00
Visudyne
(verteporfin)		 QLT PhotoTherapeutics; CIBA Vision Photodynamic therapy (light-activated drug) Treatment of wet form of age-related macular degeneration
4/00
Welchol
(formerly CholestaGel; colesevelam HCl)		 Genzyme (GelTex Pharmaceuticals); Sankyo; Parke Davis Non-absorbed polymer that binds bile acids in the intestine (lipid-lowering) Administered alone or in combination with an HMG-CoA reductase inhibitor (statin), for reducing elevated LDL cholesterol in patients with hypercholesterolemia
5/00

Given the amount of time it takes to develop new therapeutics -- not to mention the added months or years required to finally satisfy the FDA -- sixteen brand new medicines in one year isn't a bad track record for the biotech sector. Many of these new biotech products are aimed at niche markets, and may never reach blockbuster status, while others could be on the road to significant sales in the future. For, as biotech companies have demonstrated time and again, a product first approved for a narrow indication can grow in prominence as it's found to be effective in treating other indications and larger patient populations.



In 2000, the following biotech medicines -- each already being marketed for at least one ailment -- garnered further approval:

§ Actimmune. InterMune Pharmaceuticals Inc.'s recombinant interferon gamma-1b was approved in February for treating patients with severe malignant osteopetrosis. The FDA first approved Actimmune in December 1990, for treating chronic granulomatous disease.
§ AmBisome. This product, a liposomal formulation of amphotericin B, was approved in July for treating cryptococcal meningitis in AIDS patients. Originally developed by NeXstar Pharmaceuticals Inc. (which merged with Gilead Sciences Inc. in July 1999), AmBisome first received FDA approval in August 1997 for treating presumed fungal infections in patients with fever of unknown origin. By that time, the drug had already been approved in 29 other countries.
§ Apligraf. Organogenesis Inc.'s living skin substitute was approved in June for treating diabetic foot ulcers. The product's first approval -- for treating venous leg ulcers -- came in February 1998.
§ Enbrel. Immunex Corp.'s breakthrough product for treating rheumatoid arthritis (RA) garnered its third label expansion in June. Enbrel, recombinant soluble p75 tumor necrosis factor receptor linked to human IgG1, is now approved as a first-line therapy for patients with moderately to severely active RA. It was first approved in November 1998 for use in combination with methotrexate, or as a monotherapy in patients who have failed other RA drugs. The FDA also approved Enbrel in May 1999 for treating juvenile RA.
§ Novantrone. Immunex also gained a broader market for its chemotherapy Novantrone. In October, the FDA approved this drug for treating secondary progressive multiple sclerosis. But Novantrone has been on the market in the U.S. since 1987, when it was approved for treating acute myelogenous leukemia. The FDA also approved its use in treating the pain associated with prostate cancer in November 1996.
§ Renagel Tablets. The FDA approved a new dosage and formulation of GelTex Pharmaceuticals' Renagel in July. The product, a non-adsorbed polymer for reducing serum phosphorus levels in hemodialysis patients with end-stage renal disease, was first approved in capsule form in November 1998, several years before GelTex was acquired by its partner Genzyme General.
§ Tamiflu. Gilead Sciences' neuraminidase inhibitor garnered FDA approval for preventing influenza A and B infections in adults and adolescents in November 2000; the following month, the FDA also approved the drug for treating acute influenza in children one year of age or older. Tamiflu was first approved for treating influenza in adults in October 1999.


Products In-Waiting
If 2000 was a relatively good year for biotech product approvals, then 2001 may be a great one. At the turn of the year, there were a total of 26 new drug applications (NDAs), biologics license applications (BLAs) and supplemental applications pending FDA review. (For details, refer to the table that follows.)


Biotech Products Under FDA Review

Product Name

Company (s) (Developer; Marketer)

Product Description

Indication (Sought)

Submission Type (Date)

Review Status; Details; Comments

Abarelix Depot

Praecis Pharmaceuticals; Amgen; Sanofi-Synthelabo

Synthetic peptide that acts as a gonadotropin-releasing hormone antagonist

Hormonally responsive prostate cancer

NDA

(12/00)

Assigned 6-month priority review status (1/01)

Acova
(a.k.a. Argatroban)

Texas Biotechnology; SmithKline Beecham

Anticoagulant; synthetic small molecule derived from arginine; acts as direct inhibitor of thrombin

Patients who have or who are at risk of developing heparin-induced thrombocytopenia (HIT) and are undergoing percutaneous coronary intervention

Supplemental NDA

(12/00)

Initially approved 6/00 (prevention or treatment of thrombosis in patients with HIT)

Alteplase
(a.k.a. Activase)

Genentech

Recombinant tPA

To restore function to central venous access devices that have become occluded or blocked

Supplemental BLA

(10/00)

Initially approved 11/87 (acute myocardial infarction)

Aranesp
(darbepoietin alfa)

Amgen; Kirin

Novel erythropoiesis-stimulating protein (2nd generation EPO)

Patients with chronic renal insufficiency and chronic renal failure

BLA

(12/99)

------

Atragen

Aronex Pharmaceuticals

Tretinoin (liposomal formulation of all-trans-retinoic acid)

Patients with acute promyelocytic leukemia for whom therapy with tretinoin is necessary but for whom IV administration is required

NDA

(12/98);

Non-approvable letter

(9/99);

Amendment to NDA

(7/00)

Non-approvable letter

(1/01)

Bexxar
(tositumomab, iodine I 131)

Corixa (Coulter Pharmaceutical); SmithKline Beecham

Murine monoclonal antibody against CD20 antigen on B cells, conjugated to I-131

Patients with relapsed or refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphoma

BLA

(7/99);

FDA requested reorganization of BLA

(8/99);

BLA resubmission

(9/00)

Assigned 6-month priority review status (10/00)

Campath
(alemtuzumab)

Millennium Pharmaceuticals (LeukoSite); Ilex Oncology; Berlex Laboratories (Schering AG)

Humanized monoclonal antibody against CD52 antigen on T and B cells

Chronic lymphocytic leukemia in patients who have been treated with alkylating agents and who have failed fludabarine therapy

BLA

(12/99)

Advisory Committee recommended accelerated approval (12/00)

Ceplene
(formerly Maxamine; histamine dihydrochloride)

Maxim Pharmaceuticals

H2 receptor agonist

Adjuvant to interleukin-2 for treating patients with advanced metastatic melanoma with liver metastases

NDA

(7/00)

Advisory Committee voted not to recommend

(12/00);

FDA issued non-approvable letter (1/01)

Dermagraft

Advanced Tissue Sciences; Smith & Nephew

Human tissue-engineered replacement for dermal layer of skin (viable human dermal fibroblasts cultured on a bioresorbable scaffold)

Wound-healing in diabetic foot ulcers

PMA

(8/00)

PMA originally submitted 12/96;

Advisory Committee recommended approval (1/98), but FDA said PMA not approvable without data from additional clinical trial (6/98)

Dynepo
(gene-activated EPO)

Transkaryotic Therapies; Aventis Pharma

Human erythropoietin produced via gene activation (inserts DNA sequences into human cells, thus activating the endogenous human gene to stimulate EPO production)

Anemia in patients with chronic renal failure (both dialysis and non-dialysis patients)

BLA

(8/00)

------

Fabrazyme
(agalsidase beta)

Genzyme

Recombinant human alpha-galactosidase A

Enzyme replacement therapy for patients with Fabry disease

BLA

(6/00)

FDA said advisory committee review not necessary (11/00);

FDA requested clarification and additional data (12/00)

FluMist

Aviron; Wyeth-Lederle Vaccines (American Home Products)

Attenuated, cold-adapted live virus vaccine (intranasal)

To prevent influenza in children and adults

BLA

(10/00)

Delayed BLA submission due to manufacturing issues (11/99)

GL701

Genelabs Technologies

Adrenal hormone (dehydroepiandrosterone [DHEA])

Systemic lupus erythematosus

NDA (modular)

(5/00-9/00)

------

Kineret
(anakinra)

Amgen

Recombinant interleukin-1 receptor antagonist

Rheumatoid arthritis

BLA

(12/99)

------

LeuTech

Palatin Technologies; Mallinckrodt

Radiolabeled monoclonal antibody that binds specifically to white blood cells; for in vivo imaging of infection sites

Diagnosis of appendicitis in patients with equivocal signs and symptoms

BLA

(11/99)

Advisory Committee voted to recommend (7/00);

FDA asked for more manufacturing data

(9/00)

Natrecor
(nesiritide)

Scios

Recombinant B-type natriuretic peptide

Acute congestive heart failure

NDA

(4/98);

FDA requested further data

(4/99);

Amendment to NDA

(1/01)

------

OP-1 Implant

Curis (Creative BioMolecules); Stryker

Recombinant human osteogenic protein-1 in collagen matrix

Bone graft substitute for treating non-union fractures of the tibia

PMA (modular)

(4/98-6/99)

Non-approvable letter; FDA recommended new study

(1/01)

Peg-Intron
(peginterferon alfa-2b)

Enzon; Schering-Plough

Recombinant interferon alfa-2b modified with polyethylene glycol (PEG) to give it longer-acting properties

Chronic hepatitis C virus infection in patients 18 years or older with compensated liver disease

BLA

(12/99)

Approved

(1/01)

Pegasys
(peginterferon alfa-2a)

Hoffmann-La Roche

Recombinant interferon alfa-2a modified with PEG

Chronic hepatitis C virus infection in non-cirrhotic and cirrhotic patients with compensated liver disease

BLA

(5/00)

------

Relenza
(zanamivir)

Biota Holdings; Glaxo Wellcome

Neuraminidase inhibitor

Prevention of influenza A and B in adults

NDA

(9/00)

Initially approved 7/99 (treatment of influenza A and B in adults and children 12 years of age and older)

Remicade
(infliximab)

Centocor (J&J); Schering-Plough

Chimeric monoclonal antibody to tumor necrosis factor-alpha

Combination therapy with methotrexate for reducing joint damage in patients with rheumatoid arthritis

Supplemental BLA

(10/99)

Approved

(1/01);

Initially approved 8/98 (moderate-to-severe Crohn's disease)

Replagel
(agalsidase alfa)

Transkaryotic Therapies; Sumitomo Pharmaceuticals

Alpha galactosidase A

Enzyme replacement therapy for Fabry disease

BLA

(6/00)

FDA requested clarification and additional data (1/01)

Symlin
(pramlintide acetate)

Amylin Pharmaceuticals

Synthetic version of human hormone amylin

Adjunctive therapy to insulin for treating people with Type I or II diabetes who use insulin

NDA

(12/00)

------

Uniprost
(a.k.a., UT-15)

United Therapeutics

Analog of natural molecule prostacyclin

Pulmonary arterial hypertension

NDA (modular)

(8/00-10/00)

Granted 6-month priority review status (10/00);

FDA said advisory committee meeting not required (12/00)

Xolair
(a.k.a. Anti-IgE;
rhuMAb-E25)

Genentech; Tanox; Novartis

Recombinant humanized anti-IgE monoclonal antibody

Allergic asthma and seasonal allergic rhinitis

BLA

(6/00)

------

Zevalin
(ibritumomab tiuextan)

Idec Pharmaceuticals; Schering AG

Murine monoclonal antibody that targets CD20 antigen on B cell surface, conjugated to yttrium-90

(used in conjunction with Rituximab)

Radioimmunotherapy for treating low grade or follicular, relapsed or refractory, CD20-positive, B-cell non-Hodgkin's lymphoma and Rituximab-refractory follicular NHL

BLA

(11/00)

Granted 6-month priority review status (1/01)

Of those, two have already been approved (Peg-Intron, for treating chronic hepatitis C virus infection, and Remicade, for an additional indication in rheumatoid arthritis). Three more -- Atragen, Ceplene (formerly Maxamine) and OP-1 Implant -- have received non-approvable letters. This is the second time that Aronex Pharmaceuticals Inc. has received a non-approvable letter for its leukemia drug Atragen; it's the first time for both Maxim Pharmaceuticals Inc. -- which is developing Ceplene as an adjunct therapy with interleukin-2 for treating metastatic melanoma -- and Curis Inc.'s partner Stryker Corp. -- which intends to market OP-1 Implant as a bone graft substitute for treating non-union fractures of the tibia.

As history has demonstrated, a non-approvable letter is not necessarily the end of the line. Take Acova, Texas Biotechnology's synthetic anticoagulant for preventing or treating thrombosis in patients with heparin-induced thrombocytopenia (HIT). The company received a non-approvable letter for this drug in May 1998, but persevered and resubmitted its NDA in March 1999: It garnered FDA approval in June 2000.

Texas Biotechnology isn't the only biotech company to stick it out. Of the applications now pending, those submitted by Coulter Pharmaceutical Inc. (recently acquired by Corixa Corp.), Advanced Tissue Sciences Inc., Genzyme Corp., Palatin Technologies Inc., Scios Inc. and Transkaryotic Therapies Inc. have also been subject to revision at the FDA's request. (Refer to the table for details.) And Amylin Pharmaceuticals Inc. spent 13 years developing its lead diabetes drug, Symlin, for which it submitted an NDA in December. We'll see soon enough if such persistence pays.

Not counting the two supplements still pending (for Texas Biotechnology's Acova and Genentech's Alteplase), there are currently 19 biotech drugs in the queue for first-time approval. Interestingly, more than half of those are recombinant proteins, predominantly monoclonal antibodies. Will 2001 mark a turning point, in which biologics steal the show from drugs?

Jennifer Van Brunt-editor



originally published 02/02/2001


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