Biotech Feature (issue 2): Biogenerics

Biogenerics

Index

1-Introduction and Regulatory Affairs
2-Erythropoietin
3-Somatotropin: human growth hormone (hGH)
4-Interferon
5-G-CSF and GM-CSF
6-Insulin
7-Thrombolytics

Download a PDF version of Biotech Feature: Biogenerics

Introduction and Regulatory Affairs

Seven major classes of branded recombinant protein products accounted for total sales of US$ 32 bln in the year 2005:

Erythropoietins: US$ 11.162 bln
Insulins: US$ 7.211 bln
Interferons: US$ 5.958 bln
G-CSF: US$ 3.968 bln
HGH: US$ 2.309 bln
FSH: US$ 970 mln.
Thrombolytics: US$ 300 mln

Although the individual products within the protein families are heterogenous, these protein product classes represent established markets with proven value of the therapeutic proteins. As such, many companies were attracted to use their technology for products with improved features, i.e. efficacy, safety, convenience or price leading to a fully packed pipeline of next generation products.

The stakeholders in the R&D activities related to these seven established protein product classes plus to that of thrombopoiesis stimulating agents are:

Innovator companies of first generation protein products;
Biogeneric companies in regulated markets;
Biogeneric companies in non-regulated or “off-patent” markets;
Drug delivery companies;
Device companies;
Next generation innovator companies.

Patent expiry for first generation protein products such as human growth hormone, insulin and G-CSF has already commenced, predominantly first in Europe and then in the US , and is Looking for more information about Biogenerics & Therapeutic Proteins progressively advancing to other territories and protein products. Patent expiration, thus, reduces the risk of law suites for patent infringement and stimulated companies to copy the success story of small molecule generics with biologics. Follow-on versions of previously approved recombinant biotechnology products most commonly are termed “ biogenerics ”, but equivalent terms are “ biosimilars ” or similar biological medicinal products in the terminology of the EMEA and follow-on versions of biologics (“ follow-on biologics ”, FoBs) in the terminology of the FDA.

While the development of a small molecule generic typically costs between US$ 2 and 5 mln, biogeneric costs are at least ten-fold higher due to more severe requirements in manufacturing and clinical development. This will prevent manufacturers and marketers of biogeneric proteins to sell the products as cheap as small molecule generics at price discounts of more than 50 %.. In fact, Novartis announced to sell its biogeneric Omnitrope at a 25 % discount (Wall Street Journal; June 1, 2006, page D8).

The first biogeneric protein approved in the European Union, the USA and in Australia is Sandoz' Omnitrope, a generic equivalent of Pfizer's Genitrope, a human growth hormone. Sandoz' NDA submitted to the FDA did not include phase II dose-finding studies and contained less toxicology. The NDA relied on demonstration of similarity to an approved product rather than clinical data for one of its indications. FDA acted within the confines of section 505(b)(2) of the Food, Drug, and Cosmetic Act )FDCA) which governs regulation of drugs filed under NDA. FDA stated that it had no statutory authority to address follow-on biologics governed by the Public Health Service Act (PHS).

In contrast, the European Medicines Evaluation Agency (EMEA) published a set of final guidelines on similar biological medicinal products ( link ) which came into effect on June 1, 2006 (or July 1, 2006 in the case of erythropoietin). The guidelines give guidance on quality, non-clinical and clinical issues. There are four product specific annexes for insulin, somatropin (hGH), erythropoietin and G-CSF which give guidance on specific non-clinical and clinical issues. A concept paper for interferon alpha is under consultation.

Guideline Similar Biological Medicinal Products: http://www.emea.eu.int/pdfs/human/biosimilar/043704en.pdf

Guideline Non-Clinical and Clinical Issues: http://www.emea.eu.int/pdfs/human/biosimilar/4283205en.pdf

Guideline Quality Issues: http://www.emea.eu.int/pdfs/human/biosimilar/4934805en.pdf

Insulin annex: http://www.emea.eu.int/pdfs/human/biosimilar/3277505en.pdf

G-CSF annex: http://www.emea.eu.int/pdfs/human/biosimilar/3132905en.pdf

Somatropin (hGH) annex: http://www.emea.eu.int/pdfs/human/biosimilar/9452805en.pdf

EPO annex: http://www.emea.eu.int/pdfs/human/biosimilar/9452605en.pdf

Concept paper Interferon alpha: http://www.emea.eu.int/pdfs/human/biosimilar/724106en.pdf

The EMEA also finalized its New Framework for Scientific Advice & Protocol Assistance ( link ) which provides several improvements including faster delivery of advice (within 40 to 70 days), broader scope for requesting advice and more involvement of experts from the pre-submission phase. In addition, a 90 % fee reduction applies for micro, small and medium size companies. The new Framework will come into effect as of July 1, 2006 and will help to clarify open questions related to the development of biogenerics.

Apart from the European and US regulatory developments, first biogeneric R&D activities are reported in Japan (EPO), but the regulatory situation is not yet transparent.

Biogeneric development activities so far focus on copycats of first generation protein products, but in the case of hGH slow release versions of biogeneric hGH are in advanced clinical development in EU and US territories. Indian companies are already working on pegylated versions of biogeneric proteins and also started with development of biogeneric antibodies (rituximab).

Erythropoietin (EPO)

a) First generation Erythropoietin

Epoetins are recombinant human erythropoietins that have the same amino acid sequence as endogenous EPO. However, glycosylation varies and the three currently commercially available types of epoetin (alpha, beta and omega) contain a higher proportion of sialylated, acidic carbohydrate residues than endogenous EPO.

Patents for epoetin alpha are hold by Amgen & Kirin which market epoetin alpha under the brand Read more about Erythropoietin (EPO) Competitor Analysis name Epogen and ESPO, respectively. Epoetin alpha is also marketed by licensee Johnson & Johnson in the US as Procrit and in non-US territories as Eprex. Combined worldwide 2005-sales of epotein alpha were US$ 6.163 bln . Epoetin alpha is indicated for the treatment of anemia associated with chronic renal failure including patients on dialysis and not on dialysis.Epoetin alpha is also indicated for treatment of anemia in

zidovudine-treated HIV-infected patients,
cancer patients on chemotherapy, and
patients scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusion.

The European patent for epoetin alpha already has expired in 2004 and the US patent expired in 2004 (for gene) or will expire in 2013 (for compound).

Patents for epotein beta are hold by Roche and Chugai originating from Genetics Institute. The companies market epotein beta only in non-US territories under the brand name Neo-Recormon (Roche) and Epogin (Chugai), respectively. Consolidated epotein beta sales in 2005 were US$ 1.726 bln . Approved indications for epotein beta are basically the same as those for epoetin alpha. The European patent for epotein beta expired in 2006.

Both epoetin alpha and epoetin beta are produced in Chinese Hamster Ovary (CHO) cells while epotein omega is produced in Baby Hamster Kidney cells. Baxter acquired epoetein omega from Elanex Pharmaceuticals. Epoetin omega is marketed in more than 15 countries outside the US , but Baxter abandoned the development of epoetin omega (also known as Epomax) in Europe due to a change in priorities.

Epoetin delta was developed by Transkaryotic and Aventis in Europe and obtained European Marketing Authorisation. Shire Pharmaceuticals which acquired Transkaryotic Therapies, plans European market launch of Dynepo (epoetin delta) in the first half of 2007. Dynepo is procuded by gene activation technology in a “human cell line” as emphasized by Shire.

b) Second generation Erythropoietin

To maintain their market shares in the EPO business, both major players, i.e. Amgen and Roche, developed next generation EPO molecules with a longer duration of action, thus reducing the frequency of administration. Amgen achieved this goal by glycoengineering of EPO and obtained darbepoetin alfa (Aranesp or KRN321 at Kirin ). Aranesp was already approved in 2001 and achieved sales of US$ 3.273 bln in 2005. The increase of 32 % in 2005 sales of Aranesp over the previous year marks the increasing conversion from epoetin beta (decrease of 6 % for Epogen or 7 % for Procrit/Eprex). Roche's follow-up EPO-product CERA was recently filed in the US and in the European Union for renal anemia, but immediately caused Amgen to sue Roche over alleged violation of Epogen patents. The importation of Roche's pegylated EPO (= CERA: Continuous Erythropoiesis Receptor activator) into the USA also is subject of an investigation by the US International Trade Commission (ITC) in response to Amgen's filing.

Thus, in the short term, the current total EPO 2005-market of more than US$ 11 bln is subject of potential shifts of market shares from Amgen to Roche and to a lesser extent to Shire provided that Shire will launch its Dynepo in the first half of 2007 and Roche will obtain approval for renal anemia during the year 2007. The development of Aranesp in further indications such as anemia in patients with heart failure may compensate for the stagnation in EPO sales or potential loss of market shares in the future.

c) EPO Biogenerics in regulated markets

In contrast to the US FDA, the European Medicines Evaluation Agency has provided a rather clear regulatory framework of guidelines for “similar biological medicinal products” regarding quality and non-clinical and clinical issues with specific annexes for individual proteins. The erythropoietin specific annex comes into effect as of July 1, 2006. For the clinical part of EPO biosimilars, the guidance recommends a comparative single-dose pharmacokinetic study including pharmacodynamics. Furthermore, at least two adequately powered, randomized, parallel groou clinical trials should be conducted in a double-blind manner. Initial indication should be renal anemia, extrapolation to other approved indications might be possible. Safety of the biosimilar EPO should be demonstrated with at least 12-month comparative immunogenicity data. These data should be presented before marketing authorization. In addition, the EMEA provides Scientific Advice on development of biosimilars in a recently improved procedure.

While the US market still seems to be prohibitive for EPO biogenerics due to the Amgen patent position, the European field now is rather open for EPO biogenerics. The publicly known, most advanced EPO development in the European Union was conducted by German company Bioceuticals, a spin-off from generic company Stada which now has a 13 % stake in Bioceuticals, but holds marketing rights for the biosimilar EPO. The company has finalized development and plans submission of the regulatory file with the EMEA by June 2006 after a recent pre-submission meeting with the EMEA. Based on the timelines of recent biosimilar approvals by the EMEA, this might enable marketing authorization of the first European EPO biosimilar in the second half of 2007. DSM Biologics of The Netherlands is manufacturing Stada's biosimilar erythropoietin. Apart from Stada/Bioceuticals, there are nine further companies with biosimilar EPO projects in various stages of development in Europe .

However, the recent EMEA guidelines also contributed to the beginning of a consolidation process of the EPO biogeneric developments because development requires a higher than expected investment, and revenues from the European market will be rather limited. The European EPO market is considered to be about 20 to 25 % of the global EPO market. On the other hand, intensive partnering discussions are ongoing as companies attempt to enrich their renal/hemodialysis or oncology franchises with an EPO product.

Japan is not excempt from biogeneric developments, as the first development of a biogeneric EPO in Japan recently has been disclosed.

d) EPO biogenerics in non-regulated markets

As erythropoietin is a rather high price product, many countries with healthcare systems which cannot afford to pay Western prices, approved erythropoietin products originating from manufacturers which do not respect patent protection. Such biogeneric erythropoietin products primarily come from companies with a home base in South America , India , Korea and China . These products mainly serve to satisfy the EPO needs of emerging countries, but especially Indian companies are working to qualify the manufacturing of biogeneric EPO to meet European or FDA standards. As the local low price markets are rather small, these companies are aiming at Western markets in their long term business strategy.

e) Next generation Erythropoiesis Stimulating Agents (ESA)

The large EPO market is not only “attacked” by biogeneric EPO, but also by next generation erythropoiesis stimulating agents (ESA), among them also molecules which can be orally administered. The most advanced development of an oral ESA are a group of compounds originating from Fibrogen, now in co-development with Astellas for certain territories, now including Europe .

Somatotropin: human Growth Hormone (hGH)

a) First generation somatotropins

Somatotropin is the recombinant form of human growth hormone (hGH) and contains the Read more about Human Growth Hormone (hGH) identical 191 amino acid sequence as that of pituitary gland-produced hGH. Most of the commercially available somatotropins are produced in bacterial cells ( E.coli ) except one which is produced in mouse C127 mammalian cells. Before availability of recombinant somatotropin, hGH was derived human cadavers but was associated with the risk of contamination with the Jakob-Creutzfeldt disease-causing agent. FDA approved indications include the long-term treatment of growth failure due to growth hormone deficiency in children and adults, the treatment of short stature in Turner syndrome, idiopathic short stature, short bowel syndrome and AIDS wasting.

There are six major manufacturers and marketers of somatotropin in the regulated markets:

Company	Brand names of somatotropin	2005 sales (vs. 2004) (US$ mln.)
Pfizer	Genotropin	808 (+ 9.8 %)
Novo Nordisk	Norditropin	444 (+ 19.5 %)
Eli Lilly	Humatrope	414.4 (- 4 %)
Genentech	Nutropin	365 (+ 3.1 %)
Serono	Saizen / Zorbtive / Serostim	276.9 (+ 3%)
Ferring & Dainippon Sumitomo & SciGen	Zomacton, TEV-Tropin, Bio-Tropin, Growject, Sci-Tropin	> 50

Total 2005-sales of the five major branded somtatropin products was US$ 2.308 bln and grew 6.8 % over the previous year.

Ferring purchased Biotechnology General (BTG), the global biologics manufacturing business from Savient Pharmaceuticals in 2005, including somatropin and the manufacturing facility in Israel . After settlement of a patent dispute and granting of cross-licenses, Ferring's somatropin was launched in the USA via Gate Pharmaceuticals, a divison of Teva Pharmaceutical Industries.

b) Dosing convenience of somatotropin

None of the established sellers of first generation somatotropin so far has launched a next generation version of somatotropin. As in the case of insulin which also requires regular injections, somatotropin companies first have introduced improved presentation formats and injection devices. Available presentation formats include:

Lyophilized powder;
Lyophilized powder in two-chamber cartridge;
Single-use syringe-device with two chambers;
Ready-to-use liquid in vial or pen-cartridge;
Liquid formulation in pre-filled cartridge delivery device;
Pre-filled disposable pen-device;
Needle-free devices.

Apart from use of somatotropin in ethical indications, hGH is subject of numerous off-label uses such as an “anti-aging factor” and as an “enhancing agent” for bodybuilders and athletes due to its ability to increase lean body mass and muscle tissue.

c) First generation biogeneric hGH in regulated markets

Patents of somatotropin in the US and Europe already expired and, thus, are no hurdle for development and commercialization of biogeneric hGH. Somatropin is the precedent-setting case of a biogeneric protein. Novartis' generic subsidiary Sandoz which now has biologicals manufacturing capabilities for bacterial and mammalian cell line-produced proteins in Austria, succeeded in getting regulatory approval for its biogeneric somatotropin, called Omnitrope, in Australia, the European Union and in the USA. Omnitrope was already launched in Australia at an initial discount of 10 % and was announced to be available in Western markets at a 25 % discount price. E.coli -produced Omnitrope will be available as a lyophilised powder with water for injection for treatment of growth disorders in children in adults. A second biogeneric somatotropin also received Marketing Authorisation Approval from the European Commission. Switzerland-based BioPartners licensed-in Valtropin (biogeneric somatotropin) from Korean LG Life Science which submitted an NDA to the FDA in December 2005. LG Life Sciences' somatropin is produced in yeast. Another somatotropin is in the pre-registration phase for US submission and under European development and further hGH biogeneric versions in clinical development or available as active pharmaceutical ingredient.

In contrast to the more demanding clinical development requirements for biosimilar EPO by the EMEA, the specific annex for non-clinical and clinical issues of somatotropin asks for a single-dose cross-over pharmacokinetic study with subcutaneous administration. Clinical efficacy should be demonstrated in at least one adequately powered, randomized, parallel group clinical trial in a double-blind design in treatment-naïve children with growth hormone deficiency. Safety can be shown in this efficacy trial but the study has to provide 12-month comparative immunogenicity data.

d) Second generation hGH in regulated markets

The field of next generation somatotropin products with less frequent dosing is lead by biogeneric companies LG Life Science and BioPartners. The companies have a slow release formulation of biogeneric somatotropin in phase III development in Europe and the US . Next generation somatotropin products include

Slow-release formulations;
Long-acting protein forms of hGH;
Pegylated and glycopegylated hGH;
Fusion proteins including hGH;
Engineered hGH;
Drug delivery solutions;
Pulmonary delivery formulations;
Oral delivery formulations;
Transdermal delivery formulations;
Intranasal hGH delivery.

While some of these less-frequent or more-convenient dosing solutions just were evaluated for preclinical feasibility and are waiting for partners to develop them, others are already in clinical development and progressing rapidly.

e) Somatotropin in “off-patent” countries

A number of South American and especially Asian countries produces and sells first generation somatotropin in local markets and in other emerging countries or are just active in the bulk business. Most importantly, biogeneric somatostatin produced in Korea by LG Life Science received EMEA approval, thus highlighting the high level of GMP manufacturing capability in a previous “off-patent” country.

Interferon

a) Interferon alpha

Human alpha interferons are a family of naturally occurring signalling proteins. At least 23 of Read more about Interferon these alpha interferons comprising of 165 amino acids and weighing between 19 and 20 kD are recognised. Their therapeutic use is due to anti-viral, immunomodulatory and anti-proliferative effects.

Recombinant interferon alpha products nearly completely have replaced purified human interferon alpha products derived from human donor white blood cells. The two major classes of recombinant interferon products are interferon alpha and beta.

The two major players in the interferon alpha field are Schering-Plough with interferon alpha-2b and Roche with interferon alpha-2a. The patents for interferon alpha (gene) have expired in the US and are expiring in Europe country by country until 2007. Both companies have introduced long-acting pegylated versions of interferon into the market and are converting sales of their first generation products into those of the longer acting pegylated interferons.

Total sales of branded interferon alpha products in 2005 were US$ 2.113 bln .

Company	Branded product	2005 sales (vs 2004) US$ mln
Roche	Roferon-A	na
Roche	Pegasys	1075 (+ 17 %)
Schering-Plough	Intron A	287 (- 10 %)
Schering-Plough	Pegintron	751 (+ 26 %)

Interferons alpha are indicated for use alone or in combination with ribavirin for the

treatment of chronic hepatitis C (Pegintron and Pegasys) and chronic hepatitis B (Pegasys).

The Marketing Authorisation Application of the first biosimilar interferon alpha-2a already was submitted to the EMEA in 2004, but not yet recommended for approval. Teva Pharmaceuticals' biosimilar interferon alpha-2b already was approved in Lithuania (for Sicor Biotech UAB) and in other 17 countries, but Teva is awaiting clarification of the European regulatory pathway before taking a decision on its biogenerics strategy. The EMEA currently is in the consultation phase of its concept paper on biosimilar alpha-inteferon. The final annex guideline is expected to be approved by the Committee in the fourth quarter of 2007. While there are numerous first generation alpha-interferon products manufactured and sold in “off-patent” countries, the number of first generation biosimilar developments in the US and Europe is rather limited because the standard of therapy and of the market place now are pegylated interferons.

A number of competitors for the approved pegylated interferons are in clinical development with long-acting versions of interferon alpha. Among the technologies to achieve the prolonged action are a fusion protein (interferon + protein carrier) and several drug delivery systems (poly-amino acid nanoparticles, polymeric microspheres) and other slow-release formulations.

As clinical efficacy of pegylated interferon alpha still has considerable limitations, efforts are undertaken in the search for next generation interferon alpha molecules with improved activity. Means to achieve this goal are mutagenesis of interferon alpha-2 or other interferon alpha subtypes.

b) Interferon beta

The market for interferon beta products nearly is twice as large as that of interferons alpha. The three major players achieved total sales of US$ 3.845 bln in the year 2005 for use in treatment of multiple sclerosis.

Company	Branded product	2005 sales (vs 2004) US$ mln
Biogen Idec	Avonex	1543 (+ 8.9 %)
Serono	Rebif	1270 (+ 16.4 %)
Schering AG	Betaferon / Betaseron	1032 (+ 10 %)

Although the first patents of interferon beta expired with others to follow (e.g Betaseron: 2008 in the US ), biogeneric developments are in their infancy. Apart from patent reasons, further causes may be that biogenerics companies such as Sandoz, Stada and BioPartners have prioritized other biogenerics such as hGH and EPO in their development portfolio. So far, first generation interferon beta products have not been improved, e.g. by pegylation to offer patients more convenience by less frequent administrations. Interferon beta players are increasing their sales by extending the labels for use of interferon beta, e.g. in very early phases suspicious of multiple sclerosis before clear clinical manifestation of the immune disease.

Next generation R&D activities are focused on prolonging the activity of interferon by pegylation and other drug delivery solutions as well as by genetic modification of the molecule.

Granulocyte Colony Stimulating Factor (G-CSF)

Human G-CSF is a single polypeptide chain protein of 174 amino acids with O -glycosylation at one threonine residue. Recombinant G-CSFs produced in E.coli (filgrastim, nartograstim) and in CHO (lenograstim). Compared to the human and to the mammalian cell culture derived G-CSF, Read more about G-CSF and GM-CSF Competitor Analysis the E.coli protein has an additional amino-terminal methionine and no glycosylation. The recombinant G-CSF molecule contains one free cysteinyl residue and two disulphide bonds. G-CSF products are primarily used for treatment of chemotherapy-induced neutropenia (or: infection in patients with non-myeloid malignancies having febrile neutropenia due to myelosuppressive anti-cancer drugs). The four different branded G-CSF products achieved total sales of US$ 4 bln in the year 2005:

Company	Generic name	2005 sales (vs. 2004) US$ mln
Amgen Kirin	Filgrastim	1216 (+ 3.5 % 143.5
Amgen	Pegfilgrastim	2288 (+ 31.5 %)
Chugai (Roche)	Lenograstim	279
Kyowa Hakko Kogyo	Nartograstim	41.5

While patents for first generation G-CSF of Amgen are about to expire, its pegylated G-CSF holds market exclusivity until 2013/15. Amgen not only succeeded in conversion of product sales from filgrastim to pegfilgrastim, but also expanded the total sales volume of the combined products. This was due to an extension of the label which now includes first-cycle use in moderate risk chemotherapy regimens.

As of June 1, 2006, the specific annex for G-CSF to the guideline on biosimilars of the European Medicines Evaluation Agency (EMEA) came into effect. The EMEA recommends conductance of single dose cross-over pharmacokinetic studies using subcutaneous and intravenous adminstrations. The absolute neutrophil count (ANC) is regarded as the relevant pharmacodynamic marker for the activity of recombinant G-CSF. The clinical efficacy should be studied in a comparative study of the prophylaxis of severe neutropenia after cytotoxic chemotherapy in a homogenous patient group. Safety data should be collected from a cohort of patients after repeated dosing in a comparative trial. The total follow-up of patients should be at least 6 months. Immunogenicity data should be collected according to the general guideline for biosimilars/non-clinical and clinical issues.

With the regulatory framework in place and patents of first generation recombinant G-CSF about to expire, several European companies are developing recombinant generic versions of filgrastim, two of them already approved for local markets. More than a dozen companies from South America and Asia are manufacturing and selling biogeneric filgrastim. Second generation biogenerics, i.e. pegylated recombinant G-CSF, are in development in India , China and Taiwan . Next generation G-CSF products from European and US are close to initation of phase I studies and include glycopegylated rhu G-CSF.

Insulin

Recombinant insulin was first produced by scientists in collaboration with Genentech in 1978. Today there are about 180 branded insulin products available worldwide representing an estimated requirement for 4,600 kg insulin product per year. The insulin market is dominated by the three major players Novo Nordisk, Eli Lilly and Sanofi-Aventis.

As conventional insulin therapy cannot accurately reproduce the endogenous secretion pattern of Read more about Insulin Competitor Analysis insulin, this has prompted the engineering of the insulin molecule leading to insulin analogues with altered amino acid sequences. Several insulin analogs are commercially available today, either with an accelerated or prolonged duration of action.

The fast-acting insulin analogues were obtained by altering those amino acid residues of insulin where side chains contribute to oligomerization. Insulin Lispro (Lilly), insulin Aspart (Novo Nordisk) and insulin Glulisine (Sanofi-Aventis) are commercially available short-acting insulin analogs. Engineered long-acting insulin analogs support an once-daily dosage regimen and are an alternative to appropriately formulated rhu insulins. Insulin Glargine (Sanofi-Aventis) and insulin Detemir (Novo Nordisk) are engineered insulins with a duration of action of up to 24 hours.

Worldwide sales of the major brands of insulin and insulin analogues in the year 2005 exceeded US$ 7.2 bln . Insulin, therefore, represents one of the single most important biopharmaceutical product classes both in terms of medical impact and market size.

The worldwide demand for insulin is steadily increasing. According to the WHO about 171 mln. people suffer from diabetes mellitus. This figure is expected to double by 2030. Furthermore, the introduction of drug delivery systems for insulin will further contribute to the growing need for insulin supply as dosing efficiency, e.g. by inhalation, is reduced. Patents for major first generation insulin products have already expired, and the major insulin players have successfully launched insulin analogues which boosted the sales of their insulin franchises.

Biogeneric recombinant insulin is already available in unregulated markets and manufactured in countries such as Poland and India . Although the EMEA paved the regulatory path for development and registration of biosimilar insulin, this protein is not listed in the pipeline of European biogenerics companies. In contrast, major Indian biogeneric companies such as Bangalore-based Biocon are using biogeneric insulin for development of needle-free delivery of insulin. After acquisition of Nobex' assets for oral insulin, Biocon is conducting large scale process optimization studies for production of insulin which serves for preparation of its oral insulin IN-105. Biocon is on track to file an IND for clinical evaluation of IN- 105 in 2006. Biocon already has conducted European trials in European subjects with its biogeneric insulin. This indicates that biogeneric supply of insulin will be used to develop and commercialize needle-free delivery insulin products. Another Indian company also succeeded in developing an oral presentation form of insulin to be administered in liquid form as oral drops. The company is in negotiation with one of the Big Pharma companies. Indian companies are also in the business of manufacturing and developing insulin analogs. The first Indian launch of an insulin glargine is scheduled for 2006.

The recent FDA-approval of inhaled insulin Exubera from Pfizer, using technology from Nektar Therapeutics, marks the beginning of the new era of needle-free insulin administration. It also means the entry of a fourth Big Pharma player into the lucrative insulin market. Pfizer used the opportunity of the Sanofi-Aventis merger with an “change-of-ownership clause” to skip Aventis out of the joint development which leaves Sanofi-Aventis as the only one of the insulin oligopoly without an inhaled insulin. Eli Lilly and Novo Nordisk both are in phase III clinical development with an inhaled insulin. It remains to be seen which next generation of needle-free insulin Sanofi-Aventis will elect to stay competitive with its peers. Among the choices are nasal, oral/buccal and transdermal apart from other clinical phase inhaled insulin projects.

Thrombolytics

Thrombolytics were among the first recombinant protein products to be introduced into the market and as such their patents have expired or are expiring. Combined sales of branded recombinant plasminogen activators in the year 2005 were about US$ 300 mln and include first generation alteplase as well as second generation modified recombinant plasminogen Read more about Thrombolytics Competitor Analysis activators such as tenecteplase, monteplase, pamiteplase and reteplase. Plasminogen activators are primarily used for treatment of acute myocardial infarction, but compete with mechanical recanalization of occluded coronary arteries by interventional cardiologists. In addition, as thrombolytic therapy is associated with the risk of intracerebral hemorrhage and the costs of recombinant thrombolytics are higher than those of cell-culture derived streptokinase, recombinant plasminogen activators never gained a large market share and the sales are low compared to other block buster classes of therapeutic proteins.

Thus, there is no ongoing biogeneric development in the EU and the US , but numerous recombinant thrombolytic products are manufactured, sold and used in unregulated markets where a luxurious 24-hour cardiovascular catheter laboratory service for emergency PTCA is not available. Recombinant streptokinase is the preferred thrombolytic, but biogeneric recombinant tissue type plasminogen activator, tenecteplase and reteplase are now being developed in India and China .

Research and development of new thrombolytics regained impetus by molecules directly lysing fibrin, the thrombus stabilizing mesh, in clinical indications different from acute myocardial infarction. Nuvelo and partner Bayer lead the field with their thrombolytic alfimeprase which is in clinical phase III evaluation for treatment of acute peripheral arterial occlusive disease and central venous catheter occlusion.

Search in our News Channels

Search in our Online Store