Beyond the paradox of progress

Recent scientific advances in biology and genomics have amplified the call to identify targets for anticancer therapies. Meanwhile, the cost of developing oncology drugs has increased, while the number of molecules that survive the arduous path to market has declined.

In the development of molecularly targeted therapies, the need to become efficient through the use of new biomarkers becomes blatantly obvious. Time, cost, and effectiveness, the ever present, unattainable trinity, are seemingly in competition as scientists attempt to validate biomarkers throughout the clinical research process.

The paradox of progress is a cliché that is nonetheless true: the more we know, the more we still have to discover. Even with the giant leap of bringing targeted therapies from concept to reality, using biomarkers successfully in clinical practice remains very challenging. Identifying biomarkers is only the first hurdle. What follows is a drastically difficult and time consuming series of steps to prove them clinically relevant.

The challenges are related in part to the multitude of methods used in assessing biomarkers: immunohistochemistry (IHC), fluorescent in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH), detection of circulating tumor cells (CTC), and microarray analysis. Other complications surround the availability and accessibility of adequate tissue samples and reference laboratories, as well as the ability to reproduce and validate assays.

Demonstrating that the biomarker is, indeed, a surrogate for the clinical benefit, whether or not the two have a guaranteed relationship, is a major undertaking. This type of validation is done through random, controlled clinical trials that measure both the candidate surrogate and the clinical benefit.

Prognostic and predictive biomarkers

With a few notable exceptions, including Imatinib for the treatment of chronic myeloid leukemia and Rituximab for the management of CD20-positive B-cell non-Hodgkin’s lymphoma, the therapies currently available for targeting the majority of biomarkers are not breakthroughs in the “cure of cancer.” Rather, they represent incremental progress.

While prospective clinical trials are the gold standard in validating a predictive biomarker, they can be time consuming, costly, and not even optimally informative. In such situations, an optional approach is to perform retrospective biomarker testing from previous randomised trials comparing therapies for which the marker is conjectured to be predictive. Some essential requirements for a retrospective validation include: data from a well designed and well conducted randomised trial, the availability of an adequate patient population and samples, a prospectively-stated hypothesis, analytical techniques, and a predefined and standardised assay.

Two current examples of prospective-retrospective validations of predictive biomarkers are:

• EGFR inhibitor in metastatic colorectal cancer and Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), received US FDA and European Medicines Agency (EMA) approval in 2004 for the treatment of EGFR-expressing metastatic colorectal patients.

A small benefit has been observed when adding Cetuximab to chemotherapy over chemotherapy alone for metastatic colorectal cancer patients. A growing understanding of the EGFR pathway and retrospective investigations of patients treated with Cetuximab led to extended biomarker testing to better identify patients who may benefit from Cetuximab.

The most extensive research indicates that the mutation of KRAS may explain resistance to Cetuximab. Retrospective analysis of randomised controlled trials has shown that Cetuximab treatment may only benefit patients with wild-type KRAS. This finding has led to the modification of labels by the FDA and EMA to include information about KRAS mutations.

• HER2 expression in breast cancer and Trastuzumab The human epidermal growth factor, receptor 2 (HER2) is over-expressed, or positive, in approximately 25 percent of breast cancer patients. Trastuzumab, a monoclonal antibody, has been developed to target the HER2 positive breast cancer patients. Several randomised, controlled trials for metastatic breast cancer as well as adjuvant therapy situations have demonstrated a strong benefit of Trastuzumab therapy for this subgroup of patients.

The design of such trials is based on a paradigm in which not all patients will benefit from the study drug and that the benefit will be restricted to a subgroup of patients who over-express the HER2 marker. The test for this biomarker is now established and validated using the IHC, FISH, or CISH method. Before any treatment, breast cancer patients are screened for HER2 status.

Biomarkers in early clinical development

Because metabolic pathways in the tumor cells are highly complex, no consistent scientific process has emerged for identifying and validating biomarkers. Key dilemmas in moving forward have been: how does the R&D system best balance the need for compounds that are not too generalised (and toxic) or too specific (and prone to resistance and relapse)? How does the industry justify the costs of clinical trials for such small populations? Could the cost of development actually decrease if eventually much more information can be gained from far fewer patients?

In recent years, the discovery of new anticancer drugs has involved an increasingly targeted approach, taking into consideration the specific receptor, enzyme, ligand, pathway, or gene. The identification and use of biomarkers in early development is now fully incorporated into clinical research, particularly in helping to make an early decision for further development of a drug candidate. However, many “targeted therapy” phase one trials have not been able to evaluate “target” inhibition, mainly due to the lack of appropriate methods to detect such effects.

Pharmacodynamic assessment using sequential tumor biopsy is a promising method to evaluate molecularly targeted therapies. However, validated assays to measure the inhibition of the targets are still not available in many cases. In addition to pharmacodynamic assessment, serum marker levels and specific tissue toxicity may be used for surrogate endpoints of biological effect.

In developing preclinical models, it is mandatory that researchers carefully define predictive and prognostic biomarkers as well as their modulation and validation requirements. It is also critical to establish and validate biologic, radiological, pharmacokinetic, and pharmacodynamic endpoints in early clinical development.

Imaging biomarkers

The entire trajectory for the development of imaging biomarkers (IB) has accelerated enormously in the last few years. The most significant and numerous advances in recent years relate to molecular imaging. Among these has been the ability to determine tumor volumes using computed tomography (CT) scans for cancer trials rather than the sum of the maximum diameter of the target lesions.

Dynamic, contrast-enhanced magnetic resonance imaging (DCE-MRI) has become almost routine in the early development of cancer agents that inhibit tyrosine kinases, especially antivascular endothelial growth factor (anti-VEGF) agents. DCE-MRI permits the measurement of tumor vasculature permeability, which is increased in tumors and decreases in response to an active anti-VEGF agent.

Position emission tomography (PET) using 18F-labeled 2-deoxyglucose (FDG) to measure tumor metabolism is used routinely for detection, diagnosis, treatment selection, and treatment monitoring in clinical practice and clinical trials. This is an impressive evolution since Warburg hypothesized nearly a century ago that tumors metabolise glucose at a significantly higher rate than most normal tissues (brain excluded).

Many new molecular probes have been developed using these imaging techniques, often involving two or more capabilities in a given situation. In the pre-clinical arena, optical imaging is making very rapid progress in interrogating model systems in interesting ways. One example is that the firefly’s luciferase gene can be inserted into animal models and the signal used to answer questions about the systems involved.

One of the most important impacts of IB is that it permits one to actually visualise the pharmacodynamic effect of the drug and the response to treatment in the patient. The use of IB has permitted the acceleration of drug development in cancer studies by not requiring that death be the clinical endpoint. Most solid tumor studies today rely on assessing progression free survival (PFS) as a surrogate for survival, which dramatically decreases the time and cost of development.

In early development phases, IB are used frequently to assess activity of the agent. Many years ago the concept of the “quick kill” was proposed for compound candidates that did not measure up in advanced trials, especially in companies with extensive portfolios. Such determinations were not surprising considering that 50 percent of drugs failed in phase three after many millions of dollars had been spent.

Some companies have adopted this approach, but very likely, more companies are using assessment techniques to increase their confidence in moving drug candidates to the next level. There remains some level of reluctance to trust the pharmacodynamic results to abandon compounds early.

The potential of the entire field of molecular imaging (MI) and IB is only beginning to unfold. This provides the opportunity to assess in research animals and people not just physiology and metabolism, but also gene expression, protein trafficking, and receptor distributions in the brain and throughout the healthy and diseased body.

Unlike CT and nuclear medicine techniques, ultrasound (US), optical imaging, and MRI do not involve ionizing radiation and hence are much more acceptable to regulatory groups and in studying special patient groups such as children and pregnant women. MRI can be used to study structure, metabolism, blood flow, permeability, water diffusion, nerve fiber tracts, and much more.

New drug targets will be revealed with the use of new contrast agents such as targeted US microbubbles. All of the imaging techniques are being used in more dramatic ways to reveal physiological functions and not just structural information. Novel techniques are now employed in studying the potential of stem cell therapies when it is important to know where the cells go, whether they remain viable, and if they can repair the injury or disease state.

Advancing discoveries from bench to bedside is the ultimate goal of clinical and translational research. Developing a novel drug is driven by scientific, clinical, statistical, and ethical considerations. Simultaneous development of appropriate biomarkers could save time and costs during the course of drug development, and analytical validation is a critical starting point. Current inefficiencies and challenges can be overcome in the design of clinical trials that will unleash the full potential of a new technology.

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Meeting a pressing need

Given the supportive legislative and political environments, Asia is set to dominate the stem cell research industry.

Santhosh Kumar Ramaraj, analyst GBI Research

Similar to other path breaking technologies that have transformed healthcare, stem cell research is now firmly on the path to being fully developed and commercialised. Currently, the technology is in its early stages of development which implies that barriers to entry in this market are relatively low and that is where Asia has an advantage. Asia dominated this industry over the last few years and will continue to retain its position.

Most of the stem cell research that is conducted in Asia is expected to gratify the unmet needs that are associated with treatment of certain chronic diseases. Limited availability of treatments for chronic diseases will increase the market opportunity for stem cell products across the globe.

There are very few treatment options available in the market to cure certain cardiovascular disorders, cancers, autoimmune and inflammatory disorders, spinal cord injury and others. It is expected that stem cell therapies that are under development in the Asian countries will bridge this gap of unmet need through its novel therapeutic approach.

The cost of R&D on stem cells is expensive for Asian companies. The development phases are expensive to operate. Most of the companies seek out partners to receive funds to run the trials or collaborate to carry out clinical trials. Failure to do so results in substantial increase in cash requirements for a company, rendering it financially incapable to operate. This would result in delay in development and commercialisation of products which would adversely affect the business.

General public acceptance of stem cell therapy is significant for Asian stem cell research companies. Stem cell research has been subjected to national and international debate regarding ethical, legal and social issues. Some people agree and support the use of stem cells while others oppose embryo destruction to harvest stem cells.

There still exists negative public perception regarding stem cell therapy. This might dissuade the public from using the derived products and also hinder companies’ research due to controversies. The challenge is to commercialise new stem cell therapy by substantiating and solving the existing concerns, and gaining support from the government and public.

Supportive environment

The legislation in most developing countries of Asia is supportive. The major difference in countries is their capability and the initiative to spend on research. Few countries have increased their funding on stem cell research whereas others haven’t concentrated much on investments, but they promote stem cell research. The legislation network is improving and will continue to contribute to the success of the industry. At present, the legislation framework in developing countries is generally supportive.

The political scenario is supportive of conducting stem cell research. But there are uncertainties in few areas of research. It would take time for the government to adjust to the needs of the stem cell research companies. Current research is in a critical path breaking phase and needs urgent funding. The political establishment had realised the importance of stem cell research and is supporting the demands of the industry globally.

Although the political environment is supportive, economically viable companies find it difficult to continue their research. Resources to conduct R&D are very expensive and the cost of therapies to be launched is also expected to be priced high in order to recover the R&D costs. In this case, the adoption rate of these therapies is still under debate.

Stem cell tourism is a buzz word in Asian countries. Patients who do not respond to chemotherapy prefer alternative treatment options such as stem cell therapies. Since the nonavailability of stem cell therapies in western countries, patients seek them from Asia. China, India, Thailand, Israel and Malaysia are some of the countries which promote stem cell tourism.

It has become a potential business opportunity for these countries to provide stem cell therapies. Though the scenario is criticised by western countries regarding issues on regulatory compliance with international standards, and also the possibility of wrong treatment, stem cell tourism continues to grow and holds strong promise for the future. Government support that ensures safety related issues are necessary to simplify the prevailing perplexity among the patients.

Moreover, centralising the process will be encouraging; collaboration between countries to support the issues pertaining to the treatment of several diseases will be crucial. Stem cell tourism in Asia is expected to increase in the future. Countries that are prepared to improve their regulatory standards to international standards, pioneer in stem cell research, provide proof-of-treatments, and provide low cost therapies will be set as a benchmark in this industry. A new task force to provide a vigil on these activities will aid this process. China, Israel, Singapore and India will focus strongly on stem cell R&D. Other countries that are opening up their doors and provide the right investment and infrastructure mix for research include Japan, Malaysia, Thailand, Taiwan and Turkey.

Looking ahead

Increasing entry of pharmaceutical companies will boost stem cell R&D. In the present scenario, one of the critical issues most pharmaceutical companies face is the drying up of drug pipelines coupled with increasing R&D cost. There has been a spur in investments from pharmaceutical companies in stem cell research through strategic partnerships with stem cell research companies.

Major pharmaceutical companies have planned and aligned their objectives in the stem cells space for the next five years. They are exploring various methods where stem cells could be utilised in the drug discovery process to accelerate the discovery of novel drug molecules. Many top companies have already begun work along with leading academic and stem cell research companies in Asia. These companies ensure that the research projects meet ethical standards.

Stem cell research in Asia needs more structure in place. Since research is in its nascent stages in some of the Asian countries, it becomes cumbersome for an investor to fund. Asian companies should perform an analysis on the length of commercialisation timelines along with their long term commitment to R&D. More importantly companies should follow hybrid business models and try to mitigate risks. Commercial models with factors such as ROI, profits, reimbursements, commercial support, market access, and government support play a crucial role in invest/no-invest decisions for an investor.

Also cell source, manufacturing and scaling up issues have to be answered with clarity. Venture capitalists are risk averse in investing in stem cell research. Only by projecting a long term viability of the project, a company or a country in Asia can gain its trust in this industry. For Asia, it’s not a long way; only a thoughtful restructuring.

China

Stem cell research in China has made great progress as compared to other countries and will be one of the leading countries in stem cell research in the future. The overall support is strong. The primary support is from the Ministry of Science and Technology and the Ministry of Health. The authority published ethical guiding principles for research on human embryonic cells and from there onwards, China has pioneered embryonic stem cell research globally.

Furthering the nation’s development, Beike Biotechnology, opened a stem cell storage and processing facility. The company receives support from the Jiangsu government-backed China Medical City. This leap is significant for China where industry partnerships are part of it.

Singapore

Singapore is one of the most important destinations for outsourcing by pharmaceutical companies. The policies are highly flexible for conducting stem cell research.

The primary supporting authority such as the Bioethics Advisory Committee has made Singapore one of the prime locations for conducting stem cell research. An annual fund of US$25m to US$29m is provided to conduct R&D of stem cell therapies. There are more than 40 groups performing stem cell research. Singapore has also become one of the prominent destinations to conduct research with its dynamic mix of robust legislative framework, government support, state-of-the-art research infrastructure and the excellent human talent pool.

South Korea

South Korea is catching up in the stem cell research field. The spending on stem cell research will be very high in the next few years. The bioethics and biosafety law of the government has provided supporting legislations for stem cell research. It is expected that billions of dollars will be spent on stem cell research in the next few years. The overall support for conducting stem cell research remains strong. In 2009, the nation lifted a ban on stem cell research using human eggs and the national committee on bioethics approved the first research proposal since the national scandal.

Israel

Israel’s overall support for stem cell research is very strong. Research clusters and government support are fuelling the growth of stem cell research. The Israeli parliament and supporting networks such as the Bioethics Advisory Committee of the Israel Academy of Sciences and Humanities are the back bone. Israeli stem cell consortium provides sufficient funds to perform research.

Tel Aviv University, the Hebrew University of Jerusalem, Technion- Israel Institute of Technology and Ben Gurion University are some of the stem cell research clusters in Israel. Israel companies are capitalising on the discoveries and innovations that are emanating from its stem cell research. The researchers’ pool in Israel is the strongest support for their nation in stem cell research.

India

The Indian Council of Medical Research is the authority that regulates medical research. The Department Of Biotechnology and the council together announced the guidelines for stem cell research and therapy in 2007. This directed a fundamental framework setup to understand the areas where stem cell research could be performed and also norms for conducting clinical trials that could help to estimate the effectiveness of the therapies. Moreover, in a verge to follow the footsteps of prominent Asian countries that dominate the stem cell research arena, the government allocated funds to conduct basic and applied research in the stem cell arena.

The government is implementing aggressive investment programmes to expand stem cell research. With increasing support from the government, Stempeutics Research, promised to launch the country’s first ever adult stem cell therapy to treat heart attack. The launch is expected in the next two years. Preclinical studies that demonstrate safety profile of human bone marrow-derived ex-vivo cultured adult mesenchymal stem cells in allogenic settings were completed and the initiation of phases one and two was done.

This product will be manufactured based on Indian FDA guidelines and GMP compliance. On the launch of the product, it will be the first Indian stem cell product in the market. The company has planned to establish strategic alliance with one of India’s largest pharmaceutical company, Cipla, to fund its R&D and also support its product and marketing activities. This trend is an important driver for stem cell research.