• 9 May 2011
  • News
  • By Nayantara Som

Biotech Drugs: The Wave Arrives

Indian companies ride the wave with about 50 biotech drug brands, already in the market, and 72 in pipeline. A special report from BioSpectrum

Biotech Drugs: What is rDNA?
Recombinant DNA (rDNA) molecules are nucleic acid sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms. Recombinant DNA is made possible because DNA molecules from all organisms share the same chemical structure; they differ only in the sequence of nucleotides within that identical overall structure. Therefore, when DNA from a foreign source is hooked up to host sequences that can drive DNA replication and then introduced into a host organism, the foreign DNA is replicated along with the host DNA.

The DNA sequences used in the construction of recombinant DNA molecules can originate from any species. For example, plant DNA may be joined to bacterial DNA, or human DNA may be joined with fungal DNA. In addition, DNA sequences that do not occur anywhere in nature may be created by the chemical synthesis of DNA, and incorporated into recombinant molecules. Using recombinant DNA technology and synthetic DNA, literally any DNA sequence may be created and introduced into any of a very wide range of living organisms.

The recombinant DNA differs from genetic recombination in that the former results from artificial methods in the test tube, while the latter is a normal biological process that results in the remixing of existing DNA sequences in essentially all organisms. Proteins that result from the expression of recombinant DNA within living cells are termed recombinant proteins.
Wikipedia

Recombinant pharmaceutical / therapeutic products in clinical trials
 
YEAR 2011YEAR 2007
Pegylated GCSFHuman G-CSF
Humanized Monoclonal antibody Bmab 200 (Trastuzumab)Somatropin
YEAR 2010Pegylated recombinant methionyl human Granulocyte Colony Stimulating Factor (PEG-r-met hu G-CSF)
Bmab100 monoclonal antibody rh-Tissue Plasminogen Activator (tPA)
Pegylated recombinant human erythropoietin (PEGEPO)Polysialated Erythropoietin
Polysialylated erythropoietinDarbopoetin
Anthrax vaccineNesiritide
Peg-Interferon alfa-2bInsulin Glargine
Follitropin alfa (Follicle Stimulating Hormone)IN-105 (Oral insulin)
rh-GCSF (Filgrastim)YEAR 2006
BVX20 monoclonal antibodyHuman tissue Plasminogen Activator (rh-TPA)
Insulin-Aspart R and Insulin-Aspart 30/70Pegylated r-h-erythropoietin
Rituximab-monoclonal antibodyPentavalent vaccine (Diphtheria, Tetanus, Pertusis, recombinant Hepatitis B and Haemophilus influenzae type B conjugate vaccine)
Chimeric monoclonal antibody (IgG1k) AbciximabRituximab (monoclonal antibody)
Palivizumab“BIOMAb EGFR” Humanized Anti-EGFR monoclonal antibody: Generic name Nimotuzumab injection) and Nimotuzumab-Bulk BIOMAb EGFR-Bulk.
Pandemic H1N1 and seasonal trivalent influenza VLP vaccines.Monoclonal Tetanus Immunoglobulin
Human Granulocyte Colony Stimulating Factor (rh G-CSF)Human MAB RM1 IgGI.k
Anti Rho (D) immunoglobulin Human Granulocyte Colony Stimulating Factor (rh-G-CSF)
Human Insulin API (r-DNA origin)Hepatitis B antigen
Salmonella typhi strain expressing HPV18 L1 and HPV16 L1 VLPs for Oral VaccineClinical evaluation of Relivax-DC for immunotherapy of prostate cancer
Human Chorionic Gonadotropin (rHCG)Tetravalent combination vaccine (DPT-r-Hepatitis B) and pantavalent combination vaccine (DPT-r-Hepatitis B + HIB)
Human B-type Natriuretic peptide (rhBNP, VB17) Human Interferon alpha 2b (rh-IFNá2b)
BioChaperone 1 (PDGF-BB+DMCTrp)Human Erythropoietin (rh-EPO)
YEAR 2009YEAR 2005
Human Interferon gamma-1b (IFNg)Pegylated Granulocyte Colony Stimulating Factor (r-h-peg-G-CSF)
Human Parathyroid Hormone (rHu PTH)Lysostaphin gel
Combination Malaria Vaccine Composed of Recombinant Granulocyte Colony Stimulating Factor (r-h-G-CSF)
PfMSP-119 and PfF2 streptokinase
Darbepoetin-alphaHuman Granulocyte-Macrophase Colony Stimulating Factor (r-hu-GM-CSF)
Etanercept (TNFr-antibody fusion protein)Pegylated Human Interferon Alfa 2b
Teriparatide (rDNA origin) Injection (750 mcg/vial)Pentavalent combination vaccine consisting of Diphtheria, Tetanus, whole cell Pertussis, r-Hepatitis B & Hemophilus Influenzae type B (DTwPH-Hib)
Human Follicle Stimulating Hormone (rFSH)TNK-t-PA
Human Platelet Derived Growth Factor-BB (PDGF-BB)Human Follicle Stimulating Hormone (rh-FSH)
Human Interleukin 2 (r-hu-IL-2)Interferon a2a
YEAR 2008pegylated Interferon a2a
BevacizumabInterferon a2b
TrastuzumabPegylated Interferon a2b
Human Parathyroid Hormone (rhPTH1-34) Human interferon alpha 2b (rh-IFN  2b)
THR-100 (recombinant staphylokinase)Erythropoietin
Hepatitis B antigen in novel formulationList of Recombinant pharmaceutical/therapeutic products recommended by RCGM for clinical trials to be conducted with the permission of Drug Controller General of India.
Source: Indian GMO Research Information System
Tetravalent vaccines (DPT+HEP-B)
Pegylated Human IFN alpha- 2b [PegIFN alpha2b]
Urate Oxidase (VB 37)
Anti Rabies Human Monoclonal Antibody (SII RMab)

The dynamics of the India biotech market is undergoing a paradigm shift with Indian companies establishing a firm footing in the recombinant DNA therapeutics market space. Pre-1997, the technology that enables individual genes and DNA sequences to be manipulated was the sole forte of the multinational companies, such as Eli Lilly and Novo Nordisk. In fact, Danish company Novo Nordisk was the first company to introduce recombinant human insulin in India - way back in 1991. This was followed by Eli Lilly & Company launching human insulin under the brand name Huminsulin. At that time, most of the recombinant products, except hepatitis-B were being imported. According to a report, in 1996-97 the total import of these products clocked a little over $50 million (237 crore).

The turning point came in 1997, when Hyderabad-based, Shantha Biotechnics introduced the first indigenously produced hepatitis-B vaccine, Shanvac-B. Since then, there has been no looking back. Today, most of the top Indian biotech companies are bullish about the rDNA therapeutics space. The list includes companies such as Biocon, Bharat Biotech International, Reliance Life Sciences, Virchow Biotech, Transgene Biotech, Intas Biopharmaceutcials, Wockhardt, Serum Institute of India, Panacea Biotec, Zenotech Laboratories, Dr Reddys Laboratories, Cadila Pharmaceutical, Shreya Life Sciences and of course, Shantha Biotechnics – the first mover in the space. These companies have bolstered manufacturing capabilities for recombinant DNA products and have maintained a healthy pipeline of products. Not just that, they are also looking at exporting these products, mainly to the emerging markets, globally.

The recombinant DNA products are part of biopharma segment that comprises conventional and rDNA vaccines, statins and diagnosic kits.

Today, there are 20 recombinant therapeutic products approved for marketing in the India market. And, Indian companies have established capabilities to manufacture about 15 of these recombinant therapeutic products (see table on page 30). Out of these, the products that have a large share in the market include Human insulin Erythropoietin Hepatitis-B vaccine (recombinant surface antigen-based), Human Growth Hormone, Granulocyte Colony Stimulating Factor (GCS-F) and Streptokinase. Close to 50 brands are being marketed in India by Biocon, Shantha Biotechnics, Bharat Serums and Vaccines, Virchow Biotech, Zenotech, Reliance Life Sciences, Bharat Biotech International, Wockhardt, Shreya Life Sciences, Intas Biopharmceutcials and Shreya Life Sciences-manufacturing an average of five brands in India.

Companies ride rDNA drugs wave
According to IMS Health, in 2010, the total biologics market in India stood at over $330 million (1,480 crore), human insulin and analogues stood at over $120 million (539 crore), Erythropoietin stood at $8 million (80 crore). While addressing the issue of hepatitis B remains a big challenge in India, it also opens up doors of opportunities for homegrown companies and will likely see a sharp rise in the rDNA segment growth curve.

From just six top Indian companies with manufacturing capabilities in recombinant therapeutic products in 2005, the number has more than doubled to about 15 companies in 2011.

The indigenous production of recombinant therapeutic products in 1997 led to the reduction in price of the imported vaccine from about $10 (487) per dose (in 1996) by SmithKIine Beecham to an average of  $3 (150) per dose. This also resulted in increased consumption of homegrown products, providing an incentive to more companies to get into indigenous production. The Indian products have now come to acquire a substantially higher market share.

Globally, the market for recombinant DNA has made impressive strides. Rise of chronic diseases is attributed to be the primary reason for the rise of this market space. Moreover, production of therapeutic products by the rDNA technology has several advantages such as provision of drugs that could not be produced by conventional methods, manufacture of sufficient quantities of drugs and provision for manufacture of safe drugs. It has been estimated that in 2006, the annual global market for human recombinant protein drugs was around $60 billion. Ten blockbuster drugs constituted a large share of sales in the global market. Rituximab, alone clocked $4 billion in sales. Since most of the blockbuster drugs will lose patents between 2012-2019, reports suggest that this market could witness a skyrocketing boom in the coming years. According to estimates, the global biologics market is valued at an estimated $149 billion in 2010 and is expected to reach $239 billion by 2015, at a compound annual growth rate (CAGR) of 9.9 percent from 2010-2015. Hepatitis B Vaccine: The GameChanger
India entered the recombinant therapeutic space with the launch of Shantha Biotechnics hepatitis-B vaccine, Shanvac-B. With the development of Shanvac-B, India became the fifth country in the world to develop this technology, indigenously. By 2003, Shanvac-B commanded more than 40 percent market share in the hepatitis-B market. Industry observers point out that the introduction of India's first recombinant DNA product was but a stimulus for vaccine companies to manufacture other low-cost vaccines.
Indian companies looking at recombinant DNA therapeutic products have excellent manufacturing capabilities, the best expertise specializing in the technology and are the best in quality control. However, the hiccup lies in scaling up for global markets. Getting approval for the global market will be difficult for Indian companies. Presently, the US framework lacks a set of guidelines for these products. Plus we need to conduct separate trials for each of the matured markets, which is an expensive proposition. This is when partnering and alliances come as a good option. Indian companies have good capabilities when it comes to entering RoW markets of the world.

- Dr Arumugam Muruganandam
Senior scientific manager, preclinical-
research and development, Biocon


According to estimates by Frost and Sullivan, the hep-B market in India is estimated at about $6.7 million (30 crore) in 2009. “Due to a large number of players and intense competition, the market is growing faster by volume, than by value. Exports constitute a major part of hep-B revenues for Indian companies, with contracts towards PAHO, UNICEF, GAVI and so on. The major players include GSK, Shantha (Sanofi-Pasteur), Bharat Biotech, Wockhardt and Serum Institute of India. The market share of all the companies is almost equal, with around 13 marketers in India with their own brands for plain hep-B vaccines.

Combination vaccines are the new trend, as launched by Panacea Biotec, Shantha and Serum Institute, and may be the way ahead to increase the market share of these companies for hep-B vaccines,” says Ms Dipta Chaudhury, senior consultant-South Asia and Middle East; Pharma and Biotech Practice.

Today, apart from Shantha Biotechnics, other major manufacturers of hepatitis-B vaccines include, Serum Institute of India, Bharat Biotech International, Wockhardt and Panacea Biotec. In early 2000, these were amongst the first companies to indigenously manufacture hepatitis-B vaccines while other rDNA products were imported into the market. Inclusion of the hepatitis-B vaccine into India's Universal Immunization Program has also led to the rise in production of these vaccines supplied at affordable prices, confirm market observers.

Serum Institute of India's hepatitis-B vaccine, GeneVac-B is manufactured with the latest German recombinant technology using a superior yeast vector, Hansenula Polymorpha at the Serum Institute's state-of-the-art facility at Pune. After the launch of the vaccine, the company subsequently announced a 40 percent drop in the price of the vaccine. The 10 ml vial, which was priced at $15 (668), became available at about $6 (255.94).

Bharat Biotech International's product, Revac B (launched in 1998) is sold in more than 30 countries worldwide with manufacturing and quality standards on par with USFDA, EMEA and WHO guidelines. Ten years after its launch, the company announced that it had crossed the production and delivery of more than 150 million doses of REVAC-B. The company has the largest manufacturing capacity for making hepatitis-B (10 crore doses). After the thumping success of Revac-B, Bharat Biotech announced the launch of its thimerosal-free hepatitis B vaccine, REVAC-Bmcf in 2007. Until then, globally, there were only seven MNCs manufacturing thimerosal-free vaccines.

Panacea Biotec's hepatitis B vaccine-Enivac HB, is currently manufactured in collaboration with CIGB (Center for Genetic Engineering and Biotechnology), Havana, Cuba – a world leader in biotechnology. Similarly, Wockhardt's Biovac-B, (launched during March 2000 in joint venture with Rhine Biotech Gmbh) showed an impressive performance and achieved a market share of 15 percent within the first year of its launch. Biovac-B is also offered through few NGOs, which will not only create awareness but also improve the reach. The company is working on a new facility with JV partner Rhein Biotech for hepatitis-B, which will be commissioned in the middle of next year. This will have a capacity of 50 million adult doses.

Human Insulin: Blockbuster Potential
The sky rocketing rise of the diabetic market in India has led to the rise in demand of human insulin products. The large market size is reflective of India emerging as the diabetes capital of the world. Between 1995 and 2005 the number of diabetic patients doubled from 20 million to 40 million and this is projected to grow to 70 million patients by 2025. Analogs which currently, contribute 27 percent in value (8 percent in volume) are the fastest growing segment (with 2007-09 CAGR of 32 percent) in value. Within insulin market, novel delivery devices would be the growth drivers in the coming years. However, MNCs continue to dominate this market segment. In Insulin (including Analog) segment, Novo Nordisk is the market leader with over 50 percent market share while Eli Lilly has 22 percent market share. This has not stopped Indian companies from entering the market. Amongst home grown companies, the market today is dominated by majors such as Biocon, Wockhardt and Shreya Life Sciences. As such there has been no new entrant in the market who has captured a major share. Biocon today, has a 12 percent market share in insulin, in India.

Biocon manufactures four insulin products-Human Insulin, Insulin Glargine, Insulin Lispro and Insulin Aspart. These insulin products have been manufactured using the recombinant DNA technology using the yeast, Pichia Pastoris.

Wockhardt was the first company in Asia to launch its recombinant human insulin product, Wosulin back in 2003. At the time of its launch, worldwide there were only three MNC manufacturers of recombinant human insulin products. Prior to this launch, many companies produced insulin from pigs and cows. Wockhardt achieved a milestone by manufacturing this product using yeast-based technology. Subsequently, 18 months later, the company manufactured and commercialized Wosulin in a cartridge format. The company also made a breakthrough with the launch of its recombinant insulin product Glargine in 2009. The price band for this product was $3 (129) per unit.

Shreya Life Sciences' Recosulin is based on technology from Shreya's collaborator, Biotechnology General Corporation (BTGC), now known as Savient Inc., US. Recosulin was developed using advanced technology in second-generation rDNA human insulin. It initially launched Recosulin by importing the finished product from Bioton, Poland (manufactured using BTGC technology). In the second phase, crystals were imported and formulated at the Shreya manufacturing facility at Aurangabad.  Shreya has already ventured into backward integration and the group company, Shreya Biotech was in the process of setting up a $13.5 million (60 crore) facility in Pune for the manufacture of insulin crystals.

The entry of Indian companies in the r-DNA insulin market led to an instant drop of prices in insulin products. Wockhardt's entry into this market led to a 40 percent drop in the price of insulin products, which has led to a 20 percent increase in usage of insulin by diabetic patients in India. Around 2004, when three insulin brands were launched by home grown companies in the market, multinational companies had cut their insulin prices in India by 35-40 percent in January 2003 and the price points ranged from $3-$3.5 (145-262) per unit.

Niche Opportunities
While human insulin and hepatitis-B vaccine continue to dominate the recombinant DNA market, other growth segments forecasted to change the dynamics of the market include EPO, GCS-F, interferon and streptokinase. According to estimates, in India, EPO has clocked a sales of about $22 million (102 crore), c-GSF has sales of about $11 million (51 crore), interferon has a sales of about $22 million, (102 crore), streptokinase has sales of about  $16 million (75 crore). These class of products are predicted to be the next cash cow for India.

Globally, gradual expiry of patents will create significant market opportunities for developers through to 2016. Between 2012-19, the market will see a patent expiry of a whopping $60 billion (about 3 lakh crore) of biotech drugs. This will have a ripple affect on Indian companies. Currently, Dr Reddy's Labs, Ranbaxy, Biocon, Shantha Biotechnics, Intas Biopharmaceuticals, Bharat Serums and Vaccines, Reliance Life Sciences, Zenotech and Transgene Biotek are active players in the market.Reliance Life Sciences launched five biosimilars in the Indian market – ReliFeron (Recombinant Interferon α), ReliPoietin (Recombinant Erythropoietin), ReliGrast (Recombinant Granulocyte colony stimulating factor), MIRel (Recombinant plasminogen activator (Reteplase) and FostiRel (Recombinant follicle stimulating hormone). While these products are targeting the Indian market, Rest of the World (RoW) markets are also
being explored.

Dr Reddy's Labs created a niche in the oncology segment with the launch of its affordable biosimilar product, Reditux, in 2003. Biocon has four products developed in India; viz EPO, insulin, GCSF and streptokinase with its human insulin product being sold in the market at a discount of almost up to 80-85 percent. Other major companies include Wockhardt manufacturing and selling its EPO product, Wepox; Intas Biopharmaceutical with Erythropoietin (Erykene), Interferon Alpha 2b(Intalfa), G- CSF (Neukine and Pegylated G-CSF (NEUPEG). Bharat Serums and Vaccines manufactures and markets Recombinant-Human Follicle Stimulating Hormone For Injection (FOLIGRAF), Human Chorionic Gonadotrophin (HuCoG), Human Menopausal Gonadotrophin (HuMoG), Follicle Stimulating Hormone (Foliculin ). Bharat Biotech currently manufactures and markets its indigenously developed and India's first Recombinant Human Epidermal Growth Factor−Regen-D.

Recombinant therapeutics approved for marketing in India
Molecules Therapeutic applications
Human insulin Diabetes
Erythropoietin Treatment of anaemia
Hepatitis B vaccine (recombinant surface antigen based) Immunization against Hepatitis B
Human growth hormone Deficiency of growth hormone in children
Interleukin 2 Renal cell carcinoma
Interleukin 11 Thrombocytopenia
Granulocyte Colony Stimulating Factor Chemotherapy induced neutropenia
Granulocyte Macrophage Colony Stimulating Factor Chemotherapy induced neutropenia
Interferon 2Alpha Chronic myeloid leukemia
Interferon 2Beta Chronic myeloid leukemia, Hepatitis B and Hepatitis C
Interferons Gamma Chronic granulomatous disease and Severe malignant osteopetrosis
Streptokinase Acute myocardial infarction
Tissue Plasminogen Activator Acute myocardial infarction
Blood factor VIII Haemophilia type A
Follicle stimulating hormone Reproductive disorders
Teriparatide (Forteo) Osteoporosis
Drerecogin (Xigris) alpha Severe sepsis
Platelet Derived Growth Factor (PDGF) Bone marrow induction and osteoblasts proliferation
Epidermal Growth factor (EGF) Mitogenesis and organ morphogenesis
Eptacogalpha (r-F VIIa) r-coagulation factor Haemorrhages, congenital or acquired hemophilia
Source: Indian GMO Research Information System

The Pipeline
Considering the huge market potential, Indian companies entered the recombinant therapeutic products development arena in 1997, with the launch of hep-B vaccine. However, it was only in 2005 that the segment witnessed the influx of companies. Until then, only six companies had established capabilities to produce recombinant DNA drugs. With biologics losing patents, starting 2011, the biotech industry, on an average, expects to see the launch of at least one-two recombinant DNA products from each company, per year, in India. Between 2005-2011, a total of 72 recombinant pharmaceutical/therapeutic products were recommended by RCGM for clinical trials to be conducted with the permission of Drug Controller General of India. Reliance Life Sciences (RLS) by far has the largest pipeline of r-DNA products. Says Mr KV Subramaniam, President, RLS, “RLS' biosimilar product pipeline includes 24 products and five of these products are in phase III clinical development. RLS plans to launch two biosimilars in 2011. These biosimilars will be launched for the first time in India and perhaps, in the world.” Market opportunity for both these products is quite significant.

Having launched its EPO product, ErepoXen, last year, Serum Institute of India has in its pipeline, two rDNA products–GCS-F and interferons. Says Dr SD Ravetkar, senior director, Serum, Institute of India, Pune “We are looking at launching the GCS-F product by the end of 2011. The interferon product is still in its initial stages of clinical trials.”

Panacea Biotec, currently, has two products containing recombinant antigens in phase III trial and these are likely to be approved for launch in FY 2011-12. “Panacea Biotec is working not only in recombinant therapeutic space, but also in prophylactic area where in we have a penta and hexavalent vaccine containing recombinant antigens in phase III trial. In addition, Panacea Biotec is working on a dengue vaccine and some of the much awaited biosimilars in the field of rheumatoid arthritis, oncology and immunotherapeutics,” says Mr R K Suri, chief executive-Biologicals, Panacea Biotec.

Bharat Biotech has developed BBT-055, a novel formulation containing Recombinant Human Epidermal Growth Factor for treating first and second degree burns, which is currently in advanced stages of commercialization. Bharat Biotech also has two novel therapeutic products in the pipeline i.e., BBT-079 and BBT-059. BBT-079, a novel thrombolytic agent designed for the treatment of AMI (a.k.a. acute myocardial infarction or heart attack) and other vascular diseases, based on its ability to dissolve blood clots. BBT-079 is currently undergoing phase III clinical trials. BBT-059, a recombinant protein, to treat MRSA (Methicillin-resistant Staphylococcus Aureus) infections is currently under clinical development.

In addition to the above companies, which have already established their presence, in developing and manufacturing rDNA drugs, there are other companies also working on establishing a foothold in this space. Bangalore based-Avesthagen started making two of its eight biosimilars last year. Four products from its pipeline of biosimilars are in an advanced stage of development. The company's biosimilar product Avdesp, to check anaemia, has completed pre-clinicals and will be produced in small quantities for conducting clinical trials in India. The biosimilar for auto-immune disorders, Avent, is produced by its Malaysian partner Inno Biologics.

Then, there are small and medium-sized companies such as Navya Biologicals and Inbiopro that are also developing biotech products. With such developments in view, it won't be long before India emerges as a major producer of rDNA drugs.

Nayantara Som in Mumbai
(Inputs from Rahul Koul & Suchitra Pillai)

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