Biopharmaceutical Products in the U.S. and European Markets

FDA Biopharmaceutical Product Approvals and Trends: 2011

2011 FDA Biopharmaceutical Approvals Were Low in Number and Economic Impact, But Include Many New Treatments and a Record Number of Orphan Approvals

by Ronald A. Rader, President
Biotechnology Information Institute

Background - Data are derived from the BIOPHARMA: Biopharmaceutical Products in the U.S. and European Markets Web database, the only information resource/reference specializing in biopharmaceuticals. See also the running list of recent years' approvals. [Earlier analyses include 2010; 2009; 2008; 1982-2008 analysis, and a related article from Gen. Eng. News].
These are the only analyses of FDA biopharmaceutical approvals using fully consistent criteria from year-to-year. 'Biopharmaceuticals' are pharmaceuticals with therapeutic indications manufactured using living organisms (biotechnology). This excludes 'drugs,' i.e., pharmaceuticals manufactured by chemical means, including synthetic drugs and and natural products derived from dead tissues (e.g., heparins) [1,2].

Summary

Figure 1 shows the number of full approvals of new biopharmaceutical products by year since 1982 (when the first recombinant protein was approved). Table 1 lists the product approvals.

Table 1. FDA Full Biopharmaceutical Approvals in 2011**
Product	Company	Date	Indication
VEGF Trap, rDNA (Eylea)	Regeneron Pharmaceuticals Inc.	11/18/2011	age-related macular degeneration
Asparaginase/Erwinia (Erwinaze)*	EUSA Pharma Inc.	11/18/2011	acute lymphoblastic leukemia
Cord blood stem cells (Hemacord)	New York Blood Center, Inc.	11/10/2011	hematopoietic stem cell transplantation
CD30 mAb, rDNA--monomethyl auristatin E (Adcetris)*	Seattle Genetics, Inc	8/19/2011	Hodgkin's lymphoma
Scorpion antitoxin/immunoglobulin, equine (Anascorp)*	Rare Disease Therapeutics Inc.	8/3/2011	scorpion stings
Fibroblasts, autologous (laViv)*	Fibrocell Science, Inc.	6/22/2011	nasolabial fold wrinkles (smile lines)
CTLA4-Ig, rDNA (Nulojix)*	Bristol-Myers Squibb	6/15/2011	kidney transplant rejection
Albumin, human (Kedbumin)*	Kedrion, S.p.A.	6/3/2011	multiple albumin supplementation indications
CTLA-4 Mab, rDNA/Medarex (Yervoy)*	Bristol-Myers Squibb	3/25/2011	melanoma
Adenovirus Type 4, 7 Vaccine Live, oral (Ardovax)	Teva Pharmaceuticals	3/16/2011	vaccination of U.S. military personnel only
B-cell-activating factor Mab, rDNA (Benlysta)	Human Genome Sciences Inc.	3/9/2011	systemic lupus erythematosus
Factor XIII, human (Corifact)*	CSL Behring	2/17/2011	Factor XIII deficiency

BIOPHARMA: Biopharmaceutical Products in the U.S. and European Markets

Discussion:

There were 12 full approvals for biopharmaceutical products in 2011. All of the qualifying products were approved as biologics (BLAs), except for 1 drug (NDA; Erwinaze, grandfathered as a drug). Only 4 of the 12 (33%) approvals were for recombinant proteins, a low number and percentage. This included 3 monoclonal antibody-based products.

Medical Advances/Novel Indications: A record number of biopharmaceuticals received approval for novel indications (diseases), including for indications for which no prior effective treatments were available and for indications for which there had been no new approvals for over a decade. But various approvals are more specific and limited than can be so simply described (Table 1), e.g., not for first-line use; and some of these products' sales are already much less than had been expected (e.g., Benlysta). We may be starting to see prior increased industry emphasis on orphan development finally coming to fruitiion in terms of product approvals. Treatment advances and innovations include:

Anascorp - the first therapeutic for scorpion stings

Benlysta - the first new treatment for lupus in over 50 years

Adcetris - the first new FDA-approved treatment for Hodgkin's lymphoma since 1977, and the first treatment for systemic anaplastic large cell lymphoma (ALCL)

Corifact - the first prophylactic treatment for Factor XIII deficiency

Nulojix - the first therapeutic for rejection of organ transplants in more than a decade

Hemacord - the first cord (hematopoietic stem cell) blood cells approved for transplantation

Yervoy - the first therapeutic showing survival benefit in advanced melanoma patients

laViv - the first live cellular product for treatment of nasolabial folds (smile lines)

Adenovirus vaccines - the first new adenovirus vaccines approved since 1980, with the prior vaccine withdrawn from the market. [These oral vaccines are only approved for use by the U.S. Dept. of Defense (DOD), which administers them to recruits reporting for boot camp. Administered together, these are considered to be a single combination vaccine].

Two products received approval for a cancer indications, following 1 in 2010 and none in 2007, 2008 or 2009 (3 in the past 5 years). This is despite a large number of cancer-targeting biopharmaceuticals, particularly monoclonal antibodies, reported to be in development and often hyped as expected to revolutionize patient care and provide the industry with much-needed revenue, including new blockbusters. However, growth in the number of cancer-targeted biopharmaceutical approvals has yet to materialize as a distinct trend.

Some of these products are not new in terms of availability and use in the U.S. (further limiting the impact of 2011 approvals). Anascorp has been available for years for emergency use, including supply by CDC; Erwinaze (as Erwinase) has been available for decades for patients allergic to the prior E. coli-derived enzyme, including supply by NCI/NIH; the adenovirus vaccines (considered to be a single combination vaccine) are replacements for vaccines that the Dept. of Defense (DOD) had previously purchased, but had neglectfully (in hindsight) let their manufacture and approvals lapse; and the equivalents of Hemacord (stem cells transplantation) and IaViv (patient's own fibroblasts), like other individualized blood processing-based treatments, have been available to patients through custom processing rather than as approved products (with approvals supporting consistent manufacture, marketing and insurance coverage). And the adenovirus vaccine is only approved for DOD inoculation of new recruits entering boot camp.

Medical Advances/Orphan Approvals: A record number (8) and percentage (66%) of all 2011 approval, received approval with orphan designation (granting 7 years of market exclusivity). These are shown in Table 1. Although these products are major advances for affected patients and the nation's health care system, the markets for most of these are inherently limited, including many approvals being other than for first-line use and more limited than can be briefly described (in Table 1)

Active Agent Novelty: Among the 12 biopharmaceuticals receiving full approval in 2009, all but one, a high purity human-derived albumin product (Kedbumin), are considered New Biopharmaceutical Entities (NBEs), i.e., are new, unique, distinct products, particularly in terms of molecular structure, composition or source. Such high percentages of NBEs, indicative of innovation, among biopharmaceutical approvals is not unusual. Precedents in terms of novel active agent approvals include:

Adcetris - an immunotoxin (antibody-cytotoxin conjugate) involving an antibody for a novel target, CD30. linked to a novel cytotoxin, auristatin E; The only immunotoxin currently approved by FDA;

Eylea - an antibody-like "trap" molecule composed of VEGF receptors linked to a human antibody framework;

Yervoy - the first CTLA-4 monoclonal antibody, fully human

Benlysta - the first monoclonal antibody against a soluble B-lymphocyte stimulator, BLyS (BAFF; TALL-1), fully-human

Nulojix - a CTLA-4 receptor-antibody framework fusion protein (differing by several amino acids compared to Orencia)

Anascorp - the first scrorpion immune globulin/antitoxin product [equine F(ab)2 fragments]

Corifact - the first Factor XIII product approved in the U.S., human plasma-derived

Erwinase - the first non-E. coli-derived version of asparaginase;

Hemacord - the first cord blood cells approved for stem cell transplantation;

laViv - the first autologous (patient's-own) fibroblasts product

Adenovirus vaccine - live oral vaccines, replacing ones approved in 1980 but no longer manufactured

A record number (5) of recombinant antibody, antibody-like or antibody portion-containing products received approval (including Nulojix and Eylea, a VEGF "trap" molecule). We may finally be starting to see industry's considerable investments on the development of recombinant antibody and antibody-like products paying off in terms of products entering the market. Another product, Anascorp, involves human plasma-dervied antibodies.

Other Findings:

All approvals involved biologics receiving BLAs, except for Erwinaze, regulated as a drug and receiving an NDA.
As in 2010 and 2009, there were no approvals of biogeneric-like biopharmaceuticals, i.e., no relevant 505(b)(2) generic drug approvals and no biologics approved as biosimilars, despite the law (BPCIA) authorizing biosimilar approvals having been passed well over a year ago.
There were no mainstream vaccines approved in 2011 (with the adenovirus vaccines only approved for limited military use).
The BIOPHARMA: Biopharmaceutical Products in the U.S. and European Markets Web database reports over 50 products with applications currently pending with FDA or expected to be filed in 2011; a number slightly less but in line with those reported in recent years.

Economic and Industry Impacts:

2011 was a poor year in terms of the projected economic impact of approved products, with a low number of approvals and the sales of the many approved products with orphan or other limited, e.g., not first-line or other mainstream, indications providing only small niche markets. Yervoy and Benlysta have been the only approved products cited as potential blockbusters (>$1 billion/year), and Nulogix has been reported to potentially attain sales of over $500 million/year. But already, sales of some have been considerably well below expectations, e.g., Benlysta had only $52 million in sales after nearly 9 months on the market, while Yervoy, which was approved later, had about $350 million sales in 2011. The other 9 products approved will attain much smaller markets.

The number of biopharmaceuticals approved and their economic impact need to increase to assure continued vitality of the (bio)pharmaceutical industry. It is now reported (e.g., by PhRMA and Burrill & Co.) that pharmaceutical R&D is about $70 billion, a record high, with likely about 40% ($27 billion) of this now involving biopharmaceuticals. More biopharmaceuticals with higher sales are needed to cover the costs of the record amounts being invested in biopharmaceutical R&D. This includes many of the largest international (Big Pharma) companies now investing nearly half or even more of their R&D in biopharmaceuticals (vs. drugs), with much of this going for development of monoclonal antibodies and cancer therapeutics. However, despite years of investment and hype, relatively few of these products are yet entering the market.

The reasons for low biopharmaceutical approvals remain unclear. It is easy to blame increased scrutiny and higher standards on the part of FDA, but there are no data to support this (with FDA handling of filings far from transparent). Recent findings from the BIO/BioMedTracker study of pharmaceutical approval rates indicate that products regulated as biologics have a relatively high overall success rate, 26%, i.e., 26% of biologics that enter trials eventually receive FDA approval for their primary/lead indication(s). This compares to 14% for New Molecular Entity (NME; fully novel) products regulated as drugs. So FDA does not appear to be holding biologics to significantly more difficult-to-attain standards compared to drugs. One can also cite the economic difficulties in recent years, which surely have restricted R&D budgets and likey reduced the number of products entering late-stage trials. Continued merging and purging among many of the largest pharmaceutical companies continues to result in R&D pipeline shrinkage. Besides there simply being fewer major players, mergers of large companies often result in their R&D pipelines being trimmed back to much the same or fewer projects than the acquiring company started with.

Starting in a few years, we can expect a significant increase in biopharmaceutical approvals. Even ignoring innovative products, this includes multiple biosimilar (approved through the new biosimilars pathway) and biobetter (follow-ons receiving full approval) products entering the market for just about most every currently successful product coming off patent in coming years. Thus, the number of recombinant proteins (130+) marketed in the U.S. and the number of companies involved could double in the next 5 years. Biosimilars (and biobetters and biogenerics) will bring more competition and lower prices, but these inherently me-to products will also result in market fragmentation; will not expand the biopharmaceutical market; do not provide new treatments, including for new indications; and with increased competition, sales levels and profit margins will be lower than with innovative products. Thus, commercialization of biosimilars (and biobetters and biogenerics) as current products go off-patent will expand the number of products and players, but not significantly advance the economic health of the (bio)pharmaceutical industry. But in the next few years, there will likely be filings involving newer classes of products, such as gene therapies, cancer vaccines, stem and other cellular therapies, RNAi, cultured tissue transplants and individualized biopharmaceuticals.

Industry and Country Developments

Some developments and findings related to companies and countries included:

Companies receiving their first U.S. biopharmaceutical approval, representing 1/2 of new approvals, are EUSA Pharma, Seattle Genetics, Rare Disease Therapeutics, Fibrocell Science, Kedrion and Teva.
A record number (4) and percentage (33%) of newly-approved biopharmaceuticals are manufactured outside the U.S. -- Erwinase (U.K.), Anascorp (Mexico), Kedbumin (Italy) and Corifact (Germany).
Anascorp (scorpion immunoglobulin), manufactured by Instituto Bioclon, S.A. (Mexico), became the first FDA-approved biopharmaceutical/biologic manufactured in Latin America (i.e., in N. or S. American other than the U.S. and Canada)
There were no approvals from any of the major long-established still-independent biopharmaceutical companies, such as Amgen and Biogen Idec.
Only one large international pharmaceutical (Big Pharma) company, Bristol-Myers Squibb (BMS), received any biopharmaceutical approvals in 2011, with BMS receiving two, both for recombinant monoclonal antibodies, with these two products expected to attain among the highest sales among 2011 approvals.
There were no approvals from any other large international pharmaceutical (Big Pharma) companies. This includes companies that many now consider to be biopharmaceutical companies, since biopharmaceuticals now account for the majority of their revenue and/or R&D pipeline, e.g., Genentech/Roche or Eli Lilly.
One company, BMS, received two approvals in 2011.
Teva, best known as the world's largest generic drug company, received its first biopharmaceutical approvals, but for adenovirus vaccine produced under federal contract for limited U.S. military use only.

Conclusions:

2011 was a good year for patient and health care advances, particularly biopharmaceutical approvals for some new and orphan indications. However, 2011 was poor in terms of the number of approvals and their projected economic impact. With many of the largest (bio)pharmaceutical companies, the major players, counting on biopharmaceuticals to provide their future profits, if the low number of approvals and their economic impact persist, the industry is headed for big trouble.

Have questions or comments, contact the author:
Ronald A. Rader
President and Author/Publisher of BIOPHARMA: Biopharmaceutical Products in the U.S. and European Markets
Biotechnology Information Institute
1700 Rockville Pike, Suite 400
Rockville, MD 20852
E-Mail: biotech@biopharma.com
Phone: 301-424-0255 (9AM-5PM, Eastern U.S.)

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