Case Study Option 4

A large pharmaceutical company has shown in late-stage clinical trials that only 20% of
the target population of melanoma patients respond to a new kinase inhibitor. However,
these patients appear to contain a novel gene expression profile that can be distinguished
from the other 80% of patients. Discuss the transition of this observation into a clinically
viable test.

Student Name: Avril Coyle

Srudent Number: 06525920

1. Executive Summary

Although there is a lot of research and investment being put into new drugs and disease research,
the rate of release of new drugs has remained stagnant, with 90% of novel drugs failing to reach
the market. With regards to discovering toxicity or ineffectivity of a drug, the later the problem
found, the more it will cost a company. Therefore it is vital that companies take all precautions
necessary to prevent toxicity and to try to discover problems early on in clinical trials. This
company found in late-stage clinical trials that only 20% of target patients responded to their
kinase inhibitor drug. Therefore, this would result in a severe financial loss. However, there is an
opportunity for the company to benefit from their observation. They observed that this 20% had
a novel gene expression profile. This suggests that there is a novel biomarker for melanoma on
the verge of discovery. This paper discusses how this company can utilise omic technologies
including proteomics, transcriptomics, and metabolimics to investigate this biomarker and to
develop a viable clinical trial for this.
2. Technology Description

Protein kinases are key regulators of cell processes, with a functional role in regulating the activity,
localisation, and function of many proteins. They also regulate DNA damage repair, cell motility, and cell
survival or apoptosis. They are enzymes which chemically modify other proteins by adding phosphate
groups to them.

Melanoma is a type of skin cancer which is caused by the uncontrolled growth of melanocytes. Malignant
tumours of melanocytes are responsible for the most skin cancer-related deaths. Becuase protein kinases
have such a significant role in the regulation of cellular processes, research into the use of kinase
inhibitors for the treatment of many types of cancer has increased in the past decade since the human
genome was sequenced in 2002. Kinase inhibitors are specific and block the action of one or more protein
kinases.

In this particular case study, the pharmaceutical company found that the kinase inhibitor was only
effective on 20% of the target population of melanoma patients, and they observed that this is due to a
novel gene expression profile which distinguishes them from the other 80%. Therefore, a way in which to
sequence all patients’ genomes needs to be utilised in order to subsequently identify specific genes which
result in the production of specific proteins or phenotypes which may determine whether the kinase
inhibitor would be effective or not.

Gene expression profiling and protein expression profiling should therefore be carried out to further
understand the progression of the disease, to develop new diagnostics, and to develop therapeutics based
on this. Omics techniques including transcriptomics, proteomics, and metabolomics should be
implemented in order to do so.

The Sanger method of genome sequencing, also known as dideoxy sequencing or chain termination has
dominated industry for the past two decades and was used for monumental accomplishments including
the sequencing of the human genome. This method is based on the use of ddNTPs in addition to the
nucleotides found in DNA. However due to the limitations of this technique, there has been a demand for
new technologies; next-generational sequencing. There are three main stages to sequencing; template
preparation, sequencing and imaging, and data analysis. Single templates will not be detected with many
fluorescent imaging techniques, and therefore amplified templates are required. Two methods of
amplifying templates are 1) emulsion PCR (emPCR), which amplifies templates in an oil/water emulsion
and can be done in cell-free systems which has the additional benefit of avoiding loss of genomic
sequences, and 2) solid-phase amplification which can produce 100-200 million spatially separated
clusters which then have free ends to which a primer can bind.

Some protocols which do not require a large amount of DNA material would be best suited to sinlge-
molecule templates, which are more straightforward to prepare. In this case, sequencing of multiple
genomic material simultaneously would be more beneficial, and therefore emPCR should be used.
Microarrays should also be used in order to sequence large amounts of genetic material simultaneously
and efficiently (Metzker, 2010).
3. Market Analysis

The development of next-generational sequencing techniques has broadened opportunities to learn more
about the genetics behind disease development and progression. Through understanding a disease more,
this can facilitate the development of new and improved diagnostics and the development of more
effective therapeutics.

While there is ongoing investment put into research and the development of novel therapeutics for many
diseases, including melanoma, the number of new drugs entering the market has in fact stagnated
(Gallagher et al., 2009). The difficulty that prevails with new drugs not reaching the market is with drug
safety assessments and toxicology of drugs in humans. 90% of drugs that undergo pre-clinical trials
currently fail to reach the market (3), and this is because of many factors. Firstly, there are limited
breakthrough toxicology tests available, and new models for toxicology studies are still undergoing
research. Secondly, for a pharmaceutical company to discover toxicity at such a late stage in clinical
trials, as in this case study, this results in extremely high costs. Typically, for a new drug to reach the
market it takes ten years and costs approximately $1400 million (2). Therefore, it can already be
estimated that the pharmaceutical company that produced this kinase inhibitor will already suffer a
substantial loss as it was found to be ineffective in 20% of melanoma patients. It also suffers because this
was only discovered at such a late stage in clinical trials. It is therefore vital for companies to go to all
lengths possible to prevent such discoveries at such late-stages, as the earlier the stage a problem is noted,
the lower the costs will be for the company.

The current preclinical toxicology methods used to determine the potential risk that a drug might pose to
humans, are well established, fully developed, and therefore new methods will take years to be used.
There is also a risk involved for any company that invests in these new methods, as they will be costly to
research and set up, and even more so if they fail. There are however problems with current toxicology
methods. Many of them use animals and tissue culture, however even if these in vitro studies appear to
deem the drug clinically safe, the effects that a drug may have on an animal may be extremely different to
the effects it could have on humans. Differences in absorption, distribution, metabolism and elimination
may cause problems as they may be different for humans than these animal models, therefore the choice
of which animal model to use for testing of which drug is highly disputed (Gallagher et al., 2009).
Sometimes it is difficult to predict the exact mechanism of action a drug will have, even after it has
passed clinical trials and been released onto the market, the side affects cannot always be predicted.

In order to overcome the hurdle of understanding diseases further, and in order to develop appropriate,
safe, cost-effective novel therapeutics, the study of the use of omic technologies in drug safety
assessments is currently being researched. While omic technologies are currently prevalent in the non-
clinical phases of drug development (Gallagher et al., 2009), transcriptomics, proteomics, and
metabolomics among others have potential uses in clinical trials. In this case, gene expression profiling
via the use of transcriptomics would provide a deeper understanding of melanoma disease mechanisms,
and thus a deeper understanding of drug treatments and their effects also. Micro-arrays would be the
technique to do this. In drug safety assessments, omics techniques can be used to firstly research the mode
of action (MOA) of toxic compounds of melanoma, and also to carry out predictive studies to identify
biomarkers in the gene expression profiles of melanoma patients. This enables the correct treatment to be
allocated to the correct patient, and biomarkers also enable for early detection or even potentially
prevention of melanoma. The issue with omics is that the collection of the data and processing of it
requires high investments. In this current economy, companies will not take risks very easily. In recent
years however, public-private partnership models have emerged to highlight the benefits, uses, and
reliability of omics technologies. Industrial, academic, and other non-profit associations have collaborated
to promote the viability of omics. This will help potential investors to feel more comfortable putting a lot
of money into the research of the use of such omics technologies.
4. Value Proposition

While the pharmaceutical company in this case study will potentially suffer dramatic financial
losses due to the lack of response to the kinase inhibitor experienced by many patients, and at
such a late-stage in clinical trials, there is still an opportunity for this company to benefit from
their discovery. The fact that only 20% of patients responded to this kinase inhibitor, and that
these patients appeared to have a novel gene expression profile in comparison to the other 80%,
suggests that there is a possibility of a new biomarker being on the verge of discovery. It is
important that the company carry out research to further understand the reason behind this
observation.

In the past, gene expression profiling in breast cancer has improved scientists understanding of
the molecular basis of Histolic Grades, therefore improving prognosis. Microarrays were
performed to carry out a gene expression analysis, and Sotiriou et al. (2006) found that higher
expression patterns correlated with grade and they found that Grade 2 tumours were at a higher
risk of recurrence than a low gene expression grade index. This information is invaluable for
improved prognosis, and the pharmaceutical company in this case study could benefit in the
same way.

The company should use omic technologies to investigate this observation further. Although the
clinical trials for the effectiveness of the kinase inhibitor will be put to a hault for the time being,
the company still has an opportunity to carry out gene expression profiling to potentially disover
a new biomarker for melanoma. Microarrays should be used to carry out this gene expression
profiling in order to better understand the mechanisms of disease of melanoma, to learn more
about the various stages of melanoma (early to late), to better understand how drugs such as
kinase inhibitors interact with the disease in humans, and to ultimately produce novel drugs to
treat or prevent the disease.

The use of omics could potentially offer an improved prognosis of melanoma and even possibly
prevent it. Improved therapeutics for melanoma produced by the company, and identification of
a biomarker for this disease would therefore result in massive financial gain for this
pharmaceutical company, and also have a major impact on human medicine and health.
5. Route-to-Market

There are five main stages to developing a biomarker:

1) Target selection- this stage involves the discovery of the biomarker, which in this case
can be identified through the use of omics technologies. Proteomics, genomics,
metabolomics, and imaging technologies are all important for this process.

2) Lead identification- this step involves the integration of omics technologies and multi-
analysis assays to confirm the biomarker and develop viable assays at an early stage to
prevent substantial financial losses in later clinical trials.

3) Pre-clinical validation- this stage involves further clinical trials via high-throughput
assays, and the development and efficient planning of clinically viable assays before they
are carried out.

4) Regulatory Clinical Trial Phases 1, 2, and 3- this stage involves the regulatory approval
of clinical trials to ensure that they are safe to the human body and to ensure that they
comply with regulatory affairs.

5) Product Launch/Marketing- the final stage of the development of a biomarker is the

product launch and of course marketing. Once regulatory approval has been achieved, the
biomarker can be released onto the market as a diagnostic product. Investments need to
be made in advertising, packaging, and training of staff to promote the products success.
References

1. Gallagher, W.M., Tweats, D., Koenig, J. (2009). Omic Profiling for Drug Safety Assessment:
Current Trends and Public-Private Partnerships. Drug Discovery Today. Vol. 14, No’s 7/8.

2. DiMasi, J.A and Grabowski, H.G. (2007) The cost of biopharmaceutical R&D: is biotech
different? Manage. Decis. Econ. 28, 469-497.

3. European Federation of Pharmaceutical Industries and Associations, (2008). The

Pharmaceutical Industry in Figures ((2008 edn)), EFPIA.

4. Metzker, L.M. (2010). Sequencing technologies-the next generation. Nature reviews. Vol. 11
pp31- 45.

5. Sotiriou, C., Wirapati, P., Loi, S., Harris, A., Fox, S., Smeds, J., Nordgren, H., Farmer, P.,
Praz, V., Haibe-Kains, B., Desmedt, C., Larsimont, D., Cardoso, F., Peterse, H., Nuyten, D.,
Buyse, M., Van de Vijver, M.J., Bergh, J., Piccart, M., Delorenzi, M. (2006) Gene Expression
Profiling in Breast Cancer: Understanding the Molecular Basis of Histologic Grade To Improve
Prognosis. Journal of the National Cancer Institute. Vol. 98. No. 4.