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Feature Articles : May 1, 2007 ( )
BioSimilars Market Ripe for Expansion
Can Innovation in Drug Design Stem the Rising Tide?
Therapeutic proteins are a $60-billion industry. However, since 40% have lost their patent protection and more are soon to follow, producing biosimilars is now arousing great interest from generic manufacturers everywhere, warned Beatrice Muzard, equity analyst for pharmaceuticals at Ixis Corporate Solutions (www.cdcixis-cm.com), during the recent “BioSquare” conference held in Lyon, France.
“The age of biosimilars is upon us. A Chinese company already claims to have a biosimilar version of Enbrel, which is licensed for use in China,” noted Michael Goettler, vp, new business development, biopharma unit at Wyeth (www.wyeth.com). “Depending on legislation, by the time many protein- and antibody-based drugs come off patent in a few years, companies in India and China will have their own versions ready to go to market, and the prices of these products could be as much as 30 percent lower than the original biologicals.”
“In India, we have an agenda to bring any effective biologicals developed before 1995 to market as we have a huge population that can benefit from having affordable versions available,” confirmed Villoo Morawala-Patell Ph.D., vice chairperson and managing director of Avesthagen (www.avesthagen.com), which is based in Bangalore. “Many Indian scientists are returning from Europe and the U.S. fully trained, so there exists now a capacity and capability to do this type of work. It is not an easy game, but since India has the largest number of FDA-approved GMP facilities outside the U.S., there is no going back.
“At Avesthagen we intend to manufacture the top 11 biological drugs and market them in a joint venture partnership with Cipla (www.cipla.com) to the BRIC markets (Brazil, India, China, and Russia) first and may then develop co-marketing agreements in Europe and the U.S.,” Dr. Morawala-Patell added. “Using the revenue stream from these biosimilars, we will, in the next decade, develop our own innovative biologicals.” The company is serious—it just began construction of new facilities, including GMP pilot and commercial-scale biomanufacturing as well as pilot-scale plant extraction capabilities.
The Case Against Biosimilars
Delegates and speakers at “BioSquare” differed in their opinions about the increase in numbers of biosimilars and how it would affect the global pharma market. According to Thomas Bols, director of government affairs, Europe, at Amgen (www.amgen.com), “Biosimilars will play a limited role in patient care because in many cases newer innovative biotechnology medicines are available that offer advantages. Also biosimilar companies may not have the ability to develop and manufacture complex biological molecules.”
Dr. Morawala-Patell agreed, “Scale-up of protein therapeutics is not easy and even major Indian pharmas like Ranbaxy (www.ranbaxy.com) are manufacturing bacterial-based proteins and only Avesthagen and Biocon (www.biocon.com) are using mammalian cell culture.”
“Biosimilars will be copies of older biological products, and since their introduction, in many cases, newer biotechnology medicines are available that offer benefits over the ones that biosimilars attempt to imitate,” Bols reiterated. “We believe patients and medical professionals have the right to access the most appropriate medicines and should not be forced to use biosimilars based purely on economic grounds as newer innovations may offer better care. Also biosimilars may not even offer the same price discounts as generics due to the complexity and costs of manufacturing.”
The main strategies suggested to combat the rise in biosimilars were: bolstering pipelines with new innovations; adding new technologies to decrease manufacturing costs; and providing more effective or palatable drug delivery.
“The way to protect against generic competition is to continually innovate, and we have done this by taking on board technologies for our portfolio of drugs through such activities as our acquisition of Glycart and partnership with Halozyme,” explained Nigel Sheail, global head of licensing pharma partnering at Roche (www.roche.com). “The technology from Glycart has the potential to improve the efficacy of antibodies and increase production yields. At the other end of the chain, Halozyme’s technology may allow for subcutaneous delivery of biologics currently administered by infusion.”
At “BioSquare”, there was no shortage of biotech companies with novel ideas, all of which were up for grabs to discerning pharma partners. For example, Kiadis Pharma (www.kiadis.com) presented a method of activating drug toxicity using light. “We use a platform known as Theralux™, which is based upon a photosensitive compound (TH9402) that can be selectively retained in actively growing cells such as cancer cells and activated T cells,” Maarten Frijlink, director of business development, noted.
“On exposure to light, cells that retain the drug die, leaving other cells unharmed.” Kiadis has used its Theralux technology to create drug candidates. Kiadis Pharma’s lead product, ATIR, helps remove alloreactive cells that can attack patients’ tissues and organs (graft versus host disease). Treatment with ATIR allows the use of mismatched donors for life-saving stem cells transplants given to end-stage patients with blood cancers, according to Frijlink.
“In a Phase II trial of ATIR, none of the nine patients treated with ATIR who received donor lymphocyte infusions after a mismatched stem cell transplant experienced host versus graft rejection,” Frijlink commented. “This is good, as patients often die from the complications of a transplant, such as an infection, rather than the cancer. If we can prevent this, we can make life-saving stem cell transplants to much larger patient groups, including those that would not even be considered for a transplant because of their age, fitness, or lack of a suitable donor.”
Magic Bullets Ride Again
There were several methods of targeting toxic molecules to sites showcased at “BioSquare”, among them were Protox Therapeutics’ (www.protoxtherapeutics.com) Trojan horse approach. “Our lead molecule, PRX321, is an anti-interleukin-4 antibody fused to a Pseudomonas toxin. The drug works by attaching to the interleukin-4 receptor found on many cancer cells; the molecule is then internalized where the toxin is released. This toxin then prevents protein synthesis, which induces cell death, and is so potent that just one molecule is enough to kill a cell,” Fahar Merchant Ph.D., president and CEO, explained.
Dr. Merchant presented the results of Phase I and I/IIa clinical trials conducted in a total of 76 brain cancer patients. In these trials, patients treated with PRX321 in combination with the chemotherapy drug Temodar had 80% increased survival and survival was improved by 12–24 months, he said. In one Phase I/IIa trial, 31 patients with recurrent brain cancer who had previously failed surgery, radiation, and/or chemotherapy were infused with a single dose of PRX321 as a monotherapy.
Compared to historical survival of approximately six months in this patient population, PRX321 reportedly extended survival by as much as 80% to almost 11 months. “We have orphan drug and fast-track status from the FDA to develop PRX321 for brain cancer, and we hope to have enough data to commence a Phase IIb program by the end of 2007, in order to optimize the protocol in preparation for a pivotal Phase III study,” Dr. Merchant concluded.
New Mouse Models of Human Cancer
Something completely different was presented by OncoStem Pharma (www.oncosp.com), a new company based in Salamanca, Spain. The firm has developed novel animal models based on current understanding of cancer as a disease driven by cancer stem cells. These animal models are based on introduction of human oncogenes in the stem cell compartment of mice, to give rise to human-like disease. “As an example, we have created an accurate model of chronic myeloid leukemia (CML) by introducing the BCR/ABL p210 gene, implicated in human disease, into the mouse stem cell compartment. The resulting mice show similar disease pathology and response to treatment as human CML,” Arcadio Garcia de Castro, Ph.D., business development director, explained.
Cancer stem cells are now being associated with all common disease recurrence after standard treatment, and OncoStem is aiming to use its human mouse models of cancer to identify therapeutic targets and drugs against cancer stem cells and also diagnostics and imaging procedures capable of identifying this cell type.
The Golden Egg
Manufacturing is also an important part of keeping the cost of biological drugs competitive and Karen Jervis, vp and managing director of Viragen (www.viragen.com), showed that her company managed to express VG101, its humanized anti-GD3 antibody for the treatment of patients with Stage IV melanoma, in its transgenic chickens’ egg OVA™ System.
“This is an easily scalable technology, which has shown proof of concept with alpha interferon and now one of our own protein therapeutics. Using OVA, we could have large-scale manufacturing capabilities for producing low cost biologicals but without the massive capital expense of setting up a typical steel biomanufacturing facility.”
An array of different formulation and drug delivery technologies was also presented at “BioSquare” and among these Sonus Pharmaceuticals (www.sonuspharma.com) offered an interesting concept. Sonus uses its Tocosol® technology platform of vitamin E oil (a-tocopherol) and tocopherol derivatives to solubilize, stabilize, and formulate poorly soluble cancer drugs.
The company’s lead product candidate is a combination of Paclitaxel and Tocosol. According to Neile Grayson, Ph.D., vp of strategic planning and corporate development, in Phase II trials, Tocosol Paclitaxel has shown promising antitumor activity in breast, non-small cell lung, bladder, and ovarian cancers.
Compared to currently marketed taxane products, Tocosol Paclitaxel has a shorter infusion time (15 minutes), and because Tocosol formulation produces a neutrally charged droplet of 40–80 nm, it may allow passive diffusion into targeting of tumors and therefore a sustained release of Paclitaxel.
“We do need improved taxane-based drugs because we believe that this class of drugs will continue to be the backbone of cancer treatment,” Dr. Grayson concluded. “Tocosol Paclitaxel is currently in Phase III testing for metastatic breast cancer. Based on preclinical and Phase II clinical results to date, Tocosol Paclitaxel may offer a more effective alternative to Paclitaxel therapy as well as a better side-effect profile with potentially reduced peripheral neuropathy, so we have high hopes for its approval.”
What's in Store for Biologicals
There was certainly plenty of innovation showcased at “BioSquare”, and with the threat of increasing numbers of biosimilars coming onto the market, delegates at the conference agreed that biotechs are going to have to come up with some clever drug delivery or manufacturing ideas to attract big pharma to their wares as this is increasingly what big pharma will be looking to license.
“We are just seeing not only competition in biological manufacturing increase but also competence, so we have to think laterally with future drug discovery,” Giampiero De Luca, senior executive vp, licensing and intellectual property at Merck Serono (www.merckserono.net), noted.
“Life-cycle management of biologicals is going to become critical in keeping ahead, and big pharmas that continue to perform drug research and development in traditional ways and do not implement new manufacturing and drug delivery technologies are likely to lose their competitive edge.”
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