The path breaking monoclonal antibody, BIOMAb-EGFR is a product from the Indian biotech major Biocon Limited and was granted regulatory marketing and manufacturing approval in India in September 2006. The product is a therapeutic monoclonal antibody-based drug for treating solid tumors of epithelial origin, such as head and neck cancers. This novel drug is engineered to specifically target and block the epidermal growth factor receptor (EGFR) responsible for the proliferation of cancer cells.
The drug is the first of its kind to be clinically developed in India and is the first anti-EGFR humanized monoclonal antibody for cancer to be made available commercially, anywhere in the world. The product has shown consistent response in clinical trials initiated both in India and globally, and being extended to other indications. BIOMAb-EGFR is produced at Biocon’s state-of-the-art manufacturing facility Biocon Park in Bangalore, India and is available as a unit carton of four 10 ml vials each containing 50 mg.
Dr Kiran Mazumdar-Shaw, CMD, Biocon Limited says, "This product spearheads Biocon’s foray into proprietary immunotherapeutics and today we join the exclusive league of monoclonal antibody developers worldwide. While therapeutic monoclonal antibodies have been introduced in the country, they are beyond the reach of a majority of cancer patients because of their prohibitive cost. BIOMAb—EGFR is competitively priced, making cancer treatment more affordable. We aspire to become a key player in this segment."
Mechanism of Action
BIOMAb-EGFR targets the human Epidermal Growth Factor Receptor (EGFR), a type of protein found on the surface of both normal and cancer cells. Small proteins circulating in the blood, called Epidermal Growth Factors (EGF), bind with the EGFR. The binding action stimulates certain biological processes within the cell to promote cell growth in a controlled manner. However, in many cancer cells EGFR is overproduced, leading to their uncontrolled and abnormal growth. This pivotal role of EGFR in malignant cell formation has prompted the development of biological agents, such as BIOMAb-EGFR that disrupts and inhibits the EGFR signaling process.
BIOMAb-EGFR is indicated for use in combination with radiation therapy/chemotherapy in patients with positive expression of EGFR in squamous cell carcinoma of head and neck cancer. In clinical trials BIOMAb-EGFR showed extensive proliferation inhibition activity in non-small cell lung cancer, breast cancer, colorectal cancer, pancreatic cancer, and glioblastoma (brain tumours).
The Genesis
Development of BIOMAb was a joint venture between Biocon and the Center of Molecular Immunology (CIM), Cuba. CIM has done the molecule research for the drug and also provided the initial human data. "Antibodies are a new class of therapies and Cuba was doing R&D and innovation in this area. Since we needed to be innovative, we took the risk of partnering with CIM as we believed in the cutting edge work being done there and they also had human data. We joined hands for developing the product, invested in the clinical development and technology for antibody production, and finally brought it to the Indian market at a very affordable price," shares Dr Shaw.
She further adds, "It was interesting to bring the first true proprietary immuno-therapeutics to the Indian market. It has the potential to be a billion-dollar product. Importantly, in terms of affordability and quality we score much higher than the multinationals, and our mission is to bring an innovative drug at an affordable price."
Biocon has made an investment of more than $30 million on BIOMAb-EGFR including the clinical development programs and the manufacturing facility. The investment in the clinical development program is still in progress for other cancers and each clinical trial is costing around $3—$4 million. BIOMAb-EGFR is indicated for use in combination with radiation therapy or chemotherapy.
Market Opportunity
Immuno-therapeutics is a new class of drugs that effectively address unmet needs, particularly in oncology and autoimmune diseases such as rheumatoid arthritis, psoriasis, and lupus. Immuno-therapy is the most recent form of treating such diseases wherein use of antibodies and vaccines play a key role in disease management.
Globally, there are very few monoclonal antibodies that have been approved and a majority of those are from companies in the US. The last few years have witnessed the approval of few chemo-therapeutics and immuno-therapeutics including various antibody-based products for the clinical management of diverse cancers. The first MAb approved for cancer was rituximab, a chimaeric IgG1 kappa MAb, indicated for the treatment of low-grade or follicular CD20+ non-Hodgkin’s lymphoma (NHL) and is sold as MabThera/Rituxan by Biogen Idec and Genentech in the US, and Roche in the European and other markets. The other monoclonal antibody from the same class is cituximab from Merck which is also being widely prescribed for cancer patients in India and other regions. In the absence of too many similar class of drugs in the market, the company expects BIOMAb to gain a good market share by this
year end.
Additionally, the number of cancer cases is alarmingly high in India, about 100 per lakh, and the highest rates of head and neck cancers are reported in South Asian countries. The Indian sub-continent accounts for one-third of the world burden of head and neck cancers thus offering a good market opportunity to BIOMAb-EGFR.
Commenting on the product’s market success, Mr Rakesh Bamzai, Head-Marketing, Biocon, said, " BIOMAb-EGFR is the largest selling monoclonal antibody in the country and we aim to be the leader in cancer care. The product has already been launched in Pakistan and Sri Lanka."
Biocon’s manufacturing rights are more as compared to its marketing rights. Currently, the company has marketing rights for almost 25 countries and will be marketing the product based on the regulatory approvals through alliance partners and distribution channels.
Patient response and comparison
Data from the BEST trial in India, that compared BIOMAb-EGFR in combination with chemo-radiotherapy versus chemo-radiotherapy alone in patients with SCCHN indicates a superior median overall survival benefit for patients treated with BIOMAb-EGFR (mOS not reached at 30 months, vs 21.3 months), with no serious safety concerns. Significant benefits were also observed in progression free survival in the BIOMAb-EGFR treated patients as compared to those treated with chemo-radiotherapy alone (mPFS – 10.1 months vs 6.9 months). No other EGFR targeting agent has been studied in conjunction with chemo-radiotherapy in such a setting.
Two other arms in the BEST trial also evaluated BIOMAb-EGFR in combination with radiotherapy vs radiotherapy alone; and the results indicate a trend towards a superior survival benefit for BIOMAb-EGFR (14.37 months vs 12.79 months).
Comparative data for EGFR-targeted therapy in conjunction with radiotherapy indicates a superior survival benefit for patients treated with Cetuximab+RT as compared to RT alone (mOS 49 months vs 29.3 months). However, there are differences in both the trials with respect to the radiation therapy provided (BEST—external beam conventional radiotherapy; Bonner et al—Hyperfractionated radiotherapy), as well as the patient population selected, the effects of both of which can greatly influence the different survival rates observed in the control arms for both
the trials.
A dramatic absence of skin toxicity (rash) has been noted when patients are treated with BIOMAb-EGFR as compared to any other EGFR targeting therapies. In particular, grade 1/2 skin rash (no grade 3/4) has only been reported in about six percent patients, compared to the high frequency often seen with both cetuximab and panitumumab. Furthermore, no significant hypomagnesemia occurred in patients treated with nimotuzumab.
A phase II/III trial in India that seeks to evaluate BIOMAb-EGFR in combination with chemotherapy and brachytherapy in chemotherapy naive cervical cancer patients is in development and will likely see a 2009 start.
The next level: Ongoing clinical trials
The total number of registered patients for BIOMAb is almost 1500 in India, which is much higher than any other similar product from the multinational companies. The drug indicated for head and neck cancer is also being tried as first line combination therapy in late phase trials in NSCLC (in combination with carboplatin and docetaxel) and glioma (in combination with temozolomide and radiation therapy) currently in India. Recruitment for the NSCLC trial is on-going, while accrual for the glioma trial has reached its target accrual. Multiple other clinical trials led by the global consortium of partners for the development of BIOMAb-EGFR are either planned, ongoing or completed. These include trials in head and neck cancers, cervical cancer, esophageal cancer, diffuse intrinsic pontine glioma, pediatric glioma, pancreatic cancer and colorectal cancer.
A number of strategies aimed at the functional inhibition of EGFR, such as the use of tyrosine kinase inhibitors (TKI), toxin-linked monoclonal antibodies, antisense oligonucleotides against the EGFR mRNA, vaccines, and monoclonal antibodies (MAb) specific for the extracellular domain of the receptor or its ligands are in development. Within this repertoire of alternatives, anti-EGFR MAbs such as nimotuzumab (BIOMAb-EGFR) and cetuximab, together with TKI such as gefitinib and erlotinib are among the most widely studied drugs, and have been approved for the treatment of multiple cancers.
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