Biotech products have suffered one setback after another this year -- from clinical trial blow-ups to FDA put-downs. This string of high-profile disappointments has also discouraged investors, who can too easily interpret the cumulative carnage as a sign that the entire biotech sector is having an inordinately difficult time coming up with winning products. Together with larger market forces at work this year, product difficulties and delays have driven down stock prices, dried up cash reserves and compelled many biotech firms to tighten their belts.
However, this is not the first time that the biotech sector has been down this road. There were so many product failures in 1994 that it went down in the record books as The Year of the Placebo. Then, too, drug candidates that were considered sure bets going into late-stage trials or before FDA advisory committees fell flat on their faces. Then, too, stock prices were depressed, forcing cash-strapped firms with product duds to re-examine their options. Yet, as we'll see, not even these dire circumstances can predict with absolute certainty that a once-promising therapeutic has met its end. For not all of those early failures were doomed: More than a few found new life and eventually gained marketing approval. At least one could become a blockbuster. |
"The placebo effect:" For any biotech company conducting clinical trials, this is a dreaded phrase, indeed. For not only does it mean the obvious -- that a firm's drug candidate has failed to demonstrate that it is more efficacious than the placebo in producing the sought-after clinical endpoint (or, in some cases, that it couldn't outperform the standard-of-care drug against which it's being tested) -- but also it can set off a series of events that eventually threaten that company's very existence.
The bad news can pummel a company's stock, slicing its value in half (or worse) in no time flat. Many investors, deciding that this firm is now farther than ever from reaching profitability, abandon the company all together. If the stock continues to lose ground, and drops below $1 for an extended period of time, it's in danger of being delisted from the Nasdaq National Market -- after which it drops off most everyone's radar screens.
Meanwhile, the company has to scramble to realign its research programs and cut costs. Those individuals who had worked on the now-failed drug candidate are let go, and the business is restructured to focus on the next best product in the pipeline. If money is really tight, the company will pare back even farther, reducing its head-count to but a few individuals. And, if a big pharma partner was conducting the clinical trials or otherwise vested in the outcome, it may terminate the collaboration, returning all product rights to the biotech but also withdrawing critical financial support.
Like the ever-widening ripples that form once a stone's been tossed into a pond, the effects of the placebo effect can be profound.
Not all biotech firms are so negatively affected. Well-heeled companies can often take a clinical setback in stride, especially if they have multiple drug candidates in the clinic, significant cash reserves to cushion the blow and a "kill early" philosophy, whereby development is terminated for any product that doesn't show a clear clinical benefit in Phase II trials.
Yet, when one biotech product after another comes up short, month after month, the entire sector suffers. That was certainly the case in 1994 (which we will examine in more detail later) -- a year that few in the biotech sector remember with fondness. And it's happening again in 2002 -- only more so.
As you'll note in the tables included in this article, some companies whose drugs have stumbled in Phase III trials -- or, in some cases, Phase IIs -- have not abandoned the product yet, but are busily exploring its use in alternate indications, or in sub-populations of patients who responded well in the trial. Other firms called an end to product development right there and then. Unfortunately, for many of these, the fallout has been significant -- they've either lost the support of a major partner or they've been forced to restructure -- or both.
All told, 30 separate biotech drugs failed to achieve statistical significance for their primary endpoints in Phase II or Phase III trials between January and late October. These product candidates, some of which are discussed below, span the gamut of disease indications -- from cancer to central nervous system disorders, from rheumatoid arthritis to infectious disease -- and also encompass a wide range of technology platforms -- from gene therapy to small molecules, from ribozymes to immune-based therapy.
Given the fact that nearly half the biotech medicines in development are aimed at treating cancer and cancer-related conditions (according to the Pharmaceutical Research and Manufacturers of America's [PhRMA] latest survey), it's not surprising that experimental cancer drugs have taken the biggest hit this year, accounting for 27 percent of failed late-stage trials. (These products are detailed in the table below.)
The eight cancer drugs that were not able to achieve their primary endpoints include a ribozyme, several vaccines, a few small molecule drugs and two monoclonal antibodies -- a showcase, of sorts, of biotech's leading-edge technology platforms.
The monoclonals include Genentech Inc.'s Avastin (which targets vascular endothelial growth factor, VEGF) and Protein Design Labs Inc.'s Zamyl (which binds to the CD33 antigen on myeloid leukemia cells). Protein Design Labs won't be putting any more effort into its cancer drug candidate, but not so Genentech, which has a broad clinical program in full swing.
Late-Stage Clinical Failures: Cancer
|
Company
|
Product
|
Type
|
Indication
|
Failure To Achieve Primary Endpoint (Clinical Phase;
Date; Comments)
|
Subsequent Events
|
|
CANCER
|
|
Biomira, Merck KGaA
|
Theratope
|
Vaccine that contains synthetic form of cancer-associated carbohydrate
antigen Sialyl Tn
|
Metastatic breast cancer
|
Phase III (9/02)
(Interim analysis by Data Safety Monitoring Board found that data did
not meet predetermined statistical significance for primary or secondary
endpoint, but recommended that the trial should be completed to final
analysis)
|
Restructuring to focus on 2 lead products, including Theratope (10/02)
|
|
Dendreon
|
Provenge
|
Dendritic cell immunotherapy (patient's dendritic cells activated with
recombinant antigen derived from prostatic acid phosphatase)
|
Advanced hormone-resistant prostate cancer
|
Phase III (1/02; 8/02)
(Interim analysis inconclusive; full preliminary analysis showed vaccine
treatment did not reach primary endpoint in all patients, but did provide
benefit in subgroup)
|
------
|
|
Genentech
|
Avastin
|
Humanized anti-VEGF antibody
|
Relapsed metastatic breast cancer
|
Phase III (9/02)
(still being tested in other cancers; Phase IIIs in colorectal cancer
completed)
|
------
|
|
IntraBiotics Pharmaceuticals
|
Iseganan HCl
|
Synthetic analog of protegrin antimicrobial peptide
|
To prevent or reduce ulcerative oral mucositis in cancer patients undergoing
radiation therapy or high-dose chemotherapy
|
Radiation therapy:
Phase III (5/02)
(also failed to achieve secondary endpoint)
Chemotherapy:
Phase III (9/02)
(company is no longer pursuing oral mucositis indication)
|
Restructuring and reassessment of clinical program priorities (10/02)
|
|
Pharmacia (Sugen)
|
SU5416
|
Small molecule that blocks VEGFr (anti-angiogenesis)
|
Colorectal cancer
|
Phase III (2/02)
(company will not pursue further development)
|
------
|
|
Protein Design Labs
|
Zamyl
|
Humanized MAb that binds to CD33 antigen
|
Relapsed or refractory acute myeloid leukemia
|
Phase III (5/02)
(company will not pursue further development unless product can be partnered)
|
------
|
|
Ribozyme Pharmaceuticals, Chiron
|
Angiozyme
|
Synthetic ribozyme that targets VEGFr-1 (anti-angiogenisis; used as
monotherapy)
|
Metastatic breast cancer
|
Phase II (4/02)
(company will not pursue this product's use as a monotherapy)
|
Ribozyme Pharmaceuticals restructured organization and R&D programs
(8/02)
|
|
Vical
|
Allovectin-7
|
Vaccine consisting of gene for human leukocyte antigen (HLA-B7) complexed
with lipid
|
Metastatic melanoma (low-dose) and early-stage head and neck cancer
|
Phase III (9/02)
(Initial review by external consultant indicated study would not meet
statistical significance for primary endpoints in metastatic melanoma;
company will not continue this trial. Company also closed enrollment
in Phase II head and neck cancer trial and will not pursue further development)
|
------
|
In fact, even though the lead indication for Avastin is colorectal cancer, the Phase III trial in relapsed metastatic breast cancer patients was closely watched. Its failure reverberated throughout the biotech sector, too, for the product is the most clinically advanced of various drug candidates designed to block the new growth of the blood vessels that supply tumors (angiogenesis).
Avastin's inability to meet its primary endpoint in breast cancer raised further doubts as to whether anti-VEGF strategies will work (a debate that has been raging for years). Five months earlier, Ribozyme Pharmaceuticals Inc.'s drug candidate Angiozyme -- a ribozyme that targets the VEGF receptor -- came up short in a Phase II trial in patients with stage IV metastatic breast cancer. But the company was far from discouraged by these results, because for the first time it was able to demonstrate that ribozymes are biologically active in humans. Treatment with Angiozyme resulted in a statistically significant reduction in the levels of soluble VEGF receptor.
As well, recent findings in the field have shown that anti-angiogenesis drugs must be used in combination with other therapies to achieve a clinically meaningful response. Not surprisingly, Ribozyme Pharmaceuticals and its partner Chiron Corp. are forging ahead with more clinical trials -- they've already completed enrollment in a Phase II trial testing Angiozyme in combination with a standard chemotherapy regimen in patients with metastatic colorectal cancer, the results of which are expected by year-end.
Dendreon Corp. scored another first in the clinic by demonstrating that dendritic cell immunotherapy is able to provide a clinical benefit in many patients with advanced hormone-resistant prostate cancer. For those men with less aggressive forms of the disease (a Gleason score of 7 or less, which comprise about 75 percent of all hormone-resistant patients), the therapy provided a statistically significant delay in the time to disease progression. Unfortunately, patients with a Gleason score of 8 did not benefit from the treatment, causing the first Phase III trial to miss its primary endpoint. Still, the company gained one very important piece of information: It now knows which patient group to target.
Dendritic cell-based immunotherapy is a new twist on the cancer vaccine approach to treating disease: Like the others, it's intended to trigger an immune response against a particular tumor. Unlike the others, it employs a patient's own dendritic cells -- specialized immune system cells found in the skin (where large populations reside), lymph nodes and elsewhere, that present antigens to T cells. These cells are activated with a recombinant antigen (for prostate cancer, the antigen is prostatic acid phosphatase) in order to trigger an immune reaction once injected back into the patient.
While ribozymes and dendritic cells represent cutting-edge, and still unproven, therapeutic approaches to treating disease, monoclonal antibodies have already demonstrated their prowess: Herceptin, Remicade, Rituxan and Synagis spring to mind, each of which racked up well north of $300 million in 2001 sales. (see the Signals article, "Solid Gold Sales," for details.)
According to the PhRMA's new survey, 20 percent of the biotech drugs in development (pending FDA approval as well as in the clinic) are monoclonal antibodies. In the cancer arena, then, monoclonals are fairly represented among the failures. But in the fields of psoriasis, rheumatoid arthritis, Crohn's disease and ulcerative colitis, they predominate: Six of the eight drug candidates that failed to achieve their primary endpoints in these therapeutic indications are monoclonal antibodies. (See the table that follows for details.)
In psoriasis, for instance, all three experimental drugs on the list are antibodies: Abgenix Inc.'s anti-interleukin-8 monoclonal, Idec Pharmaceuticals Corp.'s anti-CD80 primatized antibody and Protein Design Labs' anti-interleukin-2 antibody (which is FDA-approved for treating kidney transplant rejection). In all three cases, the sponsoring companies dropped product development at Phase II, citing insufficient efficacy to warrant further development. And Abgenix -- which had earlier found that the same monoclonal didn't work well enough in treating patients with rheumatoid arthritis -- discontinued its other clinical programs on ABX-IL8, including in metastatic melanoma and chronic obstructive pulmonary disease.
Late-Stage Clinical Failures: Crohn's Disease/Ulcerative Colitis; Rheumatoid Arthritis; Psoriasis
|
Company
|
Product
|
Type
|
Indication
|
Failure To Achieve Primary Endpoint (Clinical Phase;
Date; Comments)
|
Subsequent Events
|
|
CROHN'S DISEASE/ULCERATIVE COLITIS
|
|
Celltech Group, Biogen
|
CDP 571
(a.k.a. Humicade)
|
Humanized anti-TNF antibody
|
Moderate-to-severe Crohn's disease
|
Two Phase IIIs (7/02)
(demonstrated efficacy in secondary endpoints)
|
Companies will review collaboration following additional analysis of
data and guidance from regulatory authorities on the product's potential
use as an acute treatment in active Crohn's (7/02)
|
|
Incara Development
(Incara Pharmaceuticals/Elan JV)
|
Deligoparin
|
Ultra low molecular weight heparin
|
Ulcerative colitis
|
Phase II/III (9/02)
(also failed to achieve secondary endpoint; company discontinued product
development)
|
Incara stock delisted from Nasdaq; moved to OTC Bulletin Board (9/02)
|
|
Millennium Pharmaceuticals, Genentech
|
MLN02
|
Humanized MAb that binds to T-cell integrin alpha4beta7
|
Mild-to-moderate Crohn's disease
|
Phase II (9/02)
(secondary endpoint was achieved in high-dose cohort; also in Phase
IIs for ulcerative colitis)
|
------
|
|
RHEUMATOID ARTHRITIS
|
|
Abgenix
|
ABX-IL8
|
Fully human MAb that blocks activity of IL-8
|
Active rheumatoid arthritis
|
Phase IIa (1/02)
(insufficient efficacy to support further development in this indication)
|
------
|
|
Genmab
|
HuMax-CD4
|
Fully human MAb to CD4 receptor
|
Active rheumatoid arthritis
|
Phase II (9/02)
(company is winding down program; won't recruit more subjects for ongoing
Phase III trial)
|
------
|
|
Serono
|
Interferon-beta-1a
|
Recombinant interferon-beta-1a (Rebif)
|
Active rheumatoid arthritis
|
Phase II (5/02)
(company discontinued product development in this indication)
|
------
|
|
PSORIASIS
|
|
Abgenix
|
ABX-IL8
|
Fully human MAb that blocks activity of IL-8
|
Moderate-to-severe psoriasis
|
Phase IIb (5/02)
(company discontinued all clinical plans for this product, including
in other indications)
|
------
|
|
Idec Pharmaceuticals
|
IDEC-114
|
Primatized anti-B7-1 (CD80) MAb
|
Moderate-to-severe psoriasis
|
Two Phase IIs (9/02)
(insufficient efficacy to support further development)
|
------
|
|
Protein Design Labs
|
Zenapax
|
Humanized MAb that binds to Tac subunit of high-affinity IL-2 receptor
|
Moderate-to-severe psoriasis (maintenance therapy following cyclosporine
treatment)
|
Phase II (3/02)
(company will not pursue this indication)
|
------
|
These were wise decisions -- especially in psoriasis, a disease that has successfully defeated scores of drug candidates over the years. (For more details, see the Signals article, "The Heartbreak Of Psoriasis.") Yet, a few biotech products have already won this challenge (or nearly so): Biogen Inc.'s Amevive, a fusion protein, has been recommended for approval by an FDA advisory committee and could get the agency's nod by mid-March 2003. And Amgen Inc.'s Enbrel, another fusion protein, which was approved for treating psoriatic arthritis in January 2002, is reportedly being used off-label for psoriasis.
It makes sense, since both conditions are generally considered to be immune-mediated inflammatory disorders -- as are rheumatoid arthritis (RA) and Crohn's disease. Centocor Inc.'s Remicade, an anti-tumor necrosis factor (TNF) monoclonal, has been approved to treat both Crohn's and RA, and the company's testing it in psoriasis. Amgen, naturally, is also testing Enbrel in psoriasis.
And scores of other similar products are in the clinic -- as evidenced in the above table. Although not one was able to achieve statistical significance for its primary endpoint, two -- Celltech Group plc's anti-TNF antibody and Millennium Pharmaceuticals Inc.'s anti-T cell integrin, both for Crohn's disease -- exhibited strong results on secondary measures. It's a good bet that we haven't heard the last of them.
Interestingly, monoclonal antibody-based drug platforms don't seem to hold much appeal for the many biotech companies that are developing therapies for infectious diseases, central nervous system disorders, cardiovascular disease, eye disorders and other indications.
Of the 14 products that came up short in clinical trials for these diseases this year, not one is a monoclonal. (And, according to the PhRMA's survey only about 10 monoclonal antibodies are even in development in these indications.) Rather, they represent a mixture of small molecules, recombinant proteins, soluble receptors, antibiotics and other types of compounds.
Here, too, the setbacks have been significant -- not only for the products themselves, but also for many of their developers.
Late-Stage Clinical Failures: Cardiovascular; Central Nervous System
|
Company
|
Product
|
Type
|
Indication
|
Failure To Achieve Primary Endpoint (Clinical Phase;
Date; Comments)
|
Subsequent Events
|
|
CARDIOVASCULAR
|
|
Actelion, Genentech
|
Tracleer
|
Small molecule, dual action endothelin receptor antagonist
|
Chronic heart failure
|
Phase III (2/02)
|
------
|
|
Avant Immunotherapeutics
|
TP10
|
Soluble complement receptor 1
|
Adults undergoing high risk cardiac surgery
|
Phase II (2/02)
(company discontinued product development until it can be partnered)
|
------
|
|
Corvas International, Pfizer
|
UK-279,276
|
Recombinant neutrophil inhibitory factor
|
Reperfusion injury associated with ischemic stroke
|
Phase IIb (4/02)
|
Pfizer terminated the collaboration (6/02);
Corvas restructured to focus on other programs (7/02)
|
|
Emisphere Technologies
|
Oral heparin (liquid)
|
Anticoagulant
|
Prevention of deep vein thrombosis in hip replacement surgery patients
|
Phase III (5/02)
(company cancelled a planned follow-up trial and is no longer pursuing
the drug formulation used in this trial)
|
Restructured; will develop solid form of oral heparin (5/02)
|
|
MediGene
|
Etomoxir
|
Small molecule that inhibits a key enzyme of mitochondrial fatty acid
oxidation
|
Congestive heart failure
|
Phase II (6/02)
(product failed to demonstrate sufficient efficacy to warrant further
development)
|
Company decided to spin off its drug discovery program in cardiology
(8/02) and teamed with Evotec OAI to form the new company, Genovation
(10/02)
|
|
CNS
|
|
Angiotech Pharmaceuticals
|
Paxceed
|
Micellar paclitaxel
|
Multiple sclerosis
|
Phase II (2/02)
(company stopped product development in this indication)
|
------
|
|
Titan Pharmaceuticals, Novartis Pharma
|
Ilopterine
|
Serotonin/dopamine receptor antagonist
|
Schizophrenia
|
Phase III (7/02)
|
Partners are evaluating strategic alternatives (7/02)
|
For instance, when Corvas International Inc.'s stroke drug UK-279,276 (recombinant neutrophil inhibitory factor) failed to meet its primary endpoint in a Phase II trial being conducted by Pfizer Inc., the pharma partner dropped the program and terminated the collaboration. Corvas regained the exclusive, worldwide development and commercialization rights for the drug candidate, but apparently decided that the product wasn't worth pursuing in other indications. A month later, Corvas had realigned its R&D programs and reduced its staff by nearly 40 percent.
Cubist Pharmaceuticals Inc. lost a partner, too, when its lead anti-infective drug candidate Cidecin couldn't outperform the standard of care in two Phase III trials in community-acquired pneumonia. The combined data from the two studies demonstrated that Cidecin's clinical success rate was 80 percent, compared to ceftriaxone's 88 percent. Shortly thereafter, Cubist's European marketing partner Gilead Sciences Inc. terminated its licensing agreement for Cidecin, apparently because Cubist is now pursuing a more focused indication for Cidecin -- in complicated skin and soft tissue infections -- and Gilead wishes to focus on promoting its own products.
Late-Stage Clinical Failures: Infection; Other
|
Company
|
Product
|
Type
|
Indication
|
Failure To Achieve Primary Endpoint (Clinical Phase;
Date; Comments)
|
Subsequent Events
|
|
INFECTION
|
|
BioCryst Pharmaceuticals
|
Peramivir
|
Influenza neuraminidase inhibitor (oral)
|
Influenza A and B treatment
|
Phase II (6/02)
(company discontinued product development)
|
Restructured to focus on other programs (7/02)
|
|
Cubist Pharmaceuticals
|
Cidecin
|
Daptomycin for injection
|
Community-acquired pneumonia
|
Two Phase IIIs (1/02; 8/02)
(company discontinued product development for this indication)
|
Gilead Sciences terminated its agreement to commercialize the product
in Europe (9/02)
|
|
The Medicines Co.
|
CTV-05
|
Strain of lactobacillus
|
Bacterial vaginosis
|
Phase II (3/02)
(company discontinued product development)
|
------
|
|
OTHER
|
|
Insmed, Taisho Pharmaceutical
|
INS-1
|
D-chiro inositol carbohydrate derivative (insulin sensitizer)
|
Type II diabetes and polycystic ovary syndrome
|
Phase II (9/02)
(company stopped product development in both indications)
|
Restructured to focus on other drug candidates (9/02)
|
|
Inspire Pharmaceuticals, Allergan, Santen Pharmaceutical
|
INS365 Ophthalmic
|
Nucleotide that activates the P2Y2 receptor on the surface of the eye
|
Dry eye syndrome
|
Two Phase IIIs (1/02, 6/02)
(In 1st trial, product did not meet primary efficacy objective; in 2nd
trial, it demonstrated a statistically significant result for objective
endpoint but insignificant result for subjective endpoint; Inspire has
started a 3rd Phase III trial)
|
------
|
|
ISTA Pharmaceuticals
|
Vitrase
|
Highly purified hyaluronidase
|
Severe vitreous hemorrhage
|
Two Phase IIIs (3/02)
(demonstrated efficacy in secondary endpoints)
|
Company submitted rolling NDA (starting 1/02), including clinical section
based on secondary endpoints
|
|
Miravant Medical Technologies, Pharmacia
|
SnET2
|
Tin ethyl etiopurpurin (photodynamic therapy)
|
Wet form of age-related macular degeneration
|
Two Phase IIIs (1/02; 8/02)
(Although treatment did not reach primary endpoint in all patients,
it did provide benefit in subgroups)
|
Pharmacia terminated the collaboration (3/02);
Miravant delisted from Nasdaq, now trades on OTC Bulletin Board (7/02);
Company will discuss results with FDA and is seeking new partner (8/02)
|
Miravant Medical Technologies Inc. suffered a similar fate when its investigational photodynamic therapy failed to meet the primary efficacy endpoint in two Phase III trials in patients with the wet form of age-related macular degeneration. Two months later, Miravant's development partner Pharmacia Corp. terminated the collaboration and returned all product rights to the drug, SnET2. This gave Miravant the opportunity to analyze the trial data; the company identified certain patient subsets that did respond positively to the treatment and at last report intended to meet with the FDA to discuss the trial results. As well, since SnET2 is Miravant's most significant dug asset, it's seeking another partner to help carry development forward (and signed a letter of intent with Bausch & Lomb to this end in June). Despite these developments, the firm's stock never recovered from the initial blow delivered in January when the Phase III trial results were announced, and in July it started trading on the OTC Bulletin Board.
These product candidates -- as well as the others detailed above -- are all victims of the placebo effect. And now, their fate is uncertain. A few, which have shown efficacy in particular subgroups of patients, may eventually become full-fledged products if they prove their worth in newly designed trials. Others have been shelved, but could be brought back to life if the right corporate partner -- or the right therapeutic indication -- comes along. No doubt some have been abandoned for good, and will never see the light of day again.
The answers lie down the road, but whatever they turn out to be, one thing's for certain: History has shown us that it's way too early to count them out.
Take, for instance, Amgen's rheumatoid arthritis (RA) drug Kineret. This product, a recombinant interleukin-1 receptor antagonist, is looking to be a real winner. Yet, in 1994, it was an abysmal failure.
Or consider The Medicines Company's anticoagulant Angiomax. This drug, a synthetic thrombin inhibitor based on hirudin (a natural anticoagulant secreted by leeches) is the firm's flagship product today, reaping $24 million in net revenues for the first nine months of 2002. In 1994, however, it stumbled in a Phase III trial and was dropped by its developer.
Then there's MedImmune Inc.'s oncology drug Ethyol, which garnered $55 million in sales over the first three quarters of 2002. In 1994, an FDA advisory committee voted it down.
And Bio-Technology General Corp.'s (BTG) weight-gain product Oxandrin (oxandrolone, a testosterone analog), which is its best-selling product, also suffered a setback in 1994. At that time, BTG withdrew its NDA for this product (then called Hepandrin) for treating alcoholic hepatitis after the FDA said that the data in the company's application were not sufficient for approval.
Indeed, 1994 was another terrible year in the annals of biotech product development: At least a dozen drug candidates blew up in advanced trials and another six were rejected by FDA advisory committees. That may not be as many as we've had in 2002, but then the number of products in development was less back then (the PhRMA counted 143 biotech drugs in development in August 1993, 234 in March 1995 and 371 in October 2002). Moreover, many of the firms that had been developing these drugs were so adversely affected by the failures -- and the subsequent fall-out -- that they could no longer stand alone. Most were acquired.
In fact, that's what happened to Synergen Inc. after Antril, its lead product for treating severe sepsis, failed to demonstrate statistical significance in mortality in a Phase III trial. This was a huge setback for Synergen, and not just because its stock price dropped like a stone. The company cut its expenses in half by laying off more than 50 percent of its workforce and shutting down two major manufacturing facilities. But even that wasn't enough to save the firm. Five months later, Amgen bought what was left for $263 million -- and eventually revived Antril, which has now found a place in Amgen's portfolio as the RA drug Kineret.
Kineret was approved for marketing in the U.S. in November 2001 -- to treat moderately to severely active RA in adults who have failed standard DMARD therapy -- and in Europe in March 2002. Although Amgen has not yet provided 2002 sales figures for Kineret (2001 sales were $12M), it's already confident enough in the drug's ability to penetrate the RA drug space that the company's filed a supplemental BLA for Kineret's use to inhibit the progression of structural damage in adults. Moreover, Amgen just reported positive results from trials of Kineret in treating juvenile RA.
The Medicines Co. licensed its flagship anti-coagulant product from Biogen, which had dropped product development in 1994 following Phase III trial results that were not statistically significant (compared to heparin) in angioplasty patients. The Medicines Co. took Hirulog, which it renamed Angiomax, back into the clinic and this time was successful, garnering the FDA's approval in December 2000 for Angiomax's use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.
MedImmune inherited Ethyol as part of its 1999 acquisition of U. S. Bioscience Inc. By that time, the FDA had approved the drug, which is a selective cytoprotective agent used to reduce toxicities associated with certain cancer chemo- and radiation therapies, in several specific indications. But in 1994, an FDA advisory committee had voted against it. The first FDA approval, for use in ovarian cancer patients, came in late 1995. Shortly thereafter, U.S. Bioscience assigned the U.S. marketing rights to Alza Corp. -- rights that MedImmune reacquired in September 2001, allowing it to build the market for Ethyol while recording 100 percent of U.S. sales.
Oxandrolone (the generic name for BTG's Oxandrin) was originally approved by the FDA in 1964 for weight gain following weight loss due to severe trauma, chronic infection or extensive surgery and in some patients who fail to gain or maintain normal weight without definite pathophysiological reasons. BTG acquired the rights to oxandrolone from G.D. Searle & Co. through the former's acquisition of Gynex Pharmaceuticals Inc. in 1993. Oxandrolone had been Gynex's lead product, and BTG intended to develop it for treating alcoholic hepatitis and testosterone deficiency in males (delivered sublingually). As previously mentioned, the FDA nixed BTG's NDA for the first indication in 1994; in 1998, it did the same for the second. Meanwhile, the company had wisely re-launched oxandrolone in the U.S. for its original approved indication. In 2001, Oxandrin racked up about $47 million in sales, or 54 percent of BTG's total product sales for the year.
There are other examples, too, of product failures that have turned into success stories. For instance, Ribi ImmunoChem Research Inc.'s melanoma vaccine Melacine, which flopped in late-stage trials in 1994, is now on the market in Canada and in Phase III trials in the U.S. The trials are being conducted by Corixa Corp., which acquired Ribi in 1999.
Also in 1994, Alpha 1 Biomedicals Inc. (which has since changed its name to RegeneRx Biopharmaceuticals Inc.) found that the immunomodulator thymosin alpha 1 (a synthetic form of the naturally occurring hormone) had failed to outperform the placebo in patients with chronic hepatitis B virus (HBV) infection. So, the company sold the product rights to SciClone Pharmaceuticals Inc. -- which named the product Zadaxin and now markets it in 30 countries worldwide. As well, Zadaxin is currently in multiple late-stage trials -- a Phase III hepatitis C virus trial in the U.S., a Phase III HBV trial in Japan, Phase II liver cancer trails in the U.S. and a Phase II/III cancer program in Europe.
While these products were reborn, arising from the ashes like the mythical Phoenix, others seem to have gone the way of the dodo bird -- including Regeneron Pharmaceuticals Inc.'s ciliary neurotrophic factor for treating Lou Gehring's disease, Telios Pharmaceuticals Inc.'s Argidene for foot ulcers, Gensia Inc.'s Protara for heart attacks, Cortech Inc.'s Bradycor for sepsis and Greenwich Pharmaceuticals Inc.'s Therafectin for rheumatoid arthritis. In fact, some of these companies are extinct, too.
And now we've come full circle. As occurred with 1994's failed products, there's little doubt that among the 30 biotech drugs that met their match in the clinic in 2002, some are phoenixes and others are dodos. But which is which? |