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European Biopharmaceutical Review

Oncology Drugs

Purposeful Reprofiling

A burgeoning trend in oncology clinical development is the treatment of patients with drugs that have been approved for, or are no longer in, clinical development in therapeutic areas other than oncology. At its forefront are investigators who are evaluating these drugs as both single agents and in combination with standard chemotherapies for the treatment and prevention of cancer

While the repurposing of drugs has yet to become the standard-of-care in oncology, the use of repurposed drugs is not new. History provides us with three examples that show different pathways for incorporation into cancer treatment. Valproic acid or Valproate – an analogue of valeric acid found in the plant Valerian – was first synthesised in 1882 by BS Burton, and it was first approved in France in 1967 as an antiepileptic drug (1,2). This gamma-aminobutyric acid (GABA) transaminase inhibitor and voltage-gated sodium channel blocker has also been approved for the treatment of bipolar disorder and migraines and, more recently, it was discovered to function as a histone deacetylase (HDAC) inhibitor (3).

According to PubMed, it was first used in the treatment of breast cancer patients in 1989 to regulate prolactin levels, and it is has been evaluated in over 80 oncology trials (4).

Bisphosphonates, inhibitors of bone osteoclastic resorption, provide another example. First synthesised in 1865 in Germany, they had only been used in various industrial processes until about 40 years ago, when etidronate was used to treat myositis ossificans (5,6). Since then, bisphosphonates have been used to treat osteoporosis and Paget’s disease of the bone. They are now widely used to treat breast and prostate cancer patients with bone metastases and multiple myeloma patients.

Finally, mifepristone, or RU-38486, was originally investigated as a glucocorticoid receptor antagonist for the treatment of Cushing’s syndrome.

However, clinical development shifted to take advantage of its function as progesterone receptor antagonist when preclinical studies identifi ed it as an abortifacient. It was approved by the Food and Drug Administration (FDA) for this unintended use as an abortifacient in 2000, but 12 more years passed before the FDA approved it for the original purpose of controlling hyperglycemia in adults with Cushing’s syndrome (7,8). Currently, mifepristone is in its third chapter of clinical development for the treatment of patients with breast cancer, depression in Parkinson’s disease, memory function in alcoholics and post-traumatic stress disorder (4).

Since the safety and toxicity profiles are already known for most repurposed drugs, reprofiling has been touted as a more efficient method of clinical development. In theory, providers should also be more comfortable in prescribing approved drugs to their patients for off-label use. This analysis describes the current state of drug reprofi ling in oncology clinical trials.

Methodology of the Analysis

Repurposed drugs in oncology were fi rst identifi ed from a list of clinical trials, excluding supportive care, in which the primary drug did not belong to a therapeutic class related to oncology as of 19th April 2013 (4). From this list of trials, the top five drug types were identified as Cyclooxygenase (COX) inhibitors, antidepressants, antivirals (excluding interferons), metformin and HMG-CoA reductase inhibitors or ‘statins’ (see Figure 1). A detailed analysis was then undertaken of clinical trials which were evaluating repurposed drugs belonging to these top five drug types that had already been approved or launched in at least one market.

Data Trends

Sponsorship not surprisingly, investigators affiliated with non-industry sponsors, such as academic and medical institutions, cooperative groups and government entities, have conducted the vast majority of trials with these five types of repurposed drugs. Industry was most likely to join with non-industry investigators in trials with antidepressants and COX inhibitors, and only in trials of COX inhibitors where industry sponsorship was above five per cent of the total (see Figure 2). Furthermore, according to start year, industry-only sponsorship has been relatively flat since 1993, while non-industry sponsorship of trials has climbed, albeit haphazardly, since 2000, the first year in which more than 10 trials started with repurposed drugs. Unfortunately, joint sponsorship of trials appears to have peaked in 2003.

Location
More trials with repurposed drugs were conducted in the US than in all other countries combined, with 328 trials. Italy was a distant second with 43 trials, followed by Germany, China, Netherlands, Canada, UK, Japan, France and South Korea.

Trial Design
Consistently, trials of these five drugs types were more likely to evaluate these drugs in combination with other chemotherapeutic drugs or regimens, rather than as a single agent. One notable exception was trials with COX inhibitors in which almost 30 per cent of the trials evaluated COX inhibitors as single agents (see Figure 3). These trials were also more likely to include second-line patients rather than first-line, neoadjuvant and adjuvant patients. However, trials with metformin were almost equally split between first-line, second-line and neoadjuvant patients.

Trial Phase The majority of trials for all five drug types were Phase 2, ranging from 33 per cent of the total for antiviral trials, to 66 per cent of the total for metformin trials. Next were Phase 1 trials, followed by Phase 1/2 trials for all five types. Phase 3 trials accounted for 3-4 per cent of the total with metformin, antiviral and antidepressant drugs, and 10-11 per cent of the total with statins or COX inhibitors (see Figure 4, page 27). Very few of these repurposed drugs seem to have advanced into the later stages of clinical development – perhaps because the safety and efficacy of the repurposed drug could not be validated in combination with chemotherapeutic drugs.

Indications
The indications explored with these five drug types reflect the disease prevalence in the general population. All but head/ neck, glioblastoma and liver cancers are included in the National Cancer Institute’s list of cancer types that are diagnosed in the US with the greatest frequency (9). For most of the top 10 indications, trials with COX inhibitors represented about 50 per cent of each disease's total. Notable exceptions to this average were found in colorectal and non-small cell lung cancer trials where COX inhibitors were included in 76 per cent and 67 per cent of the totals, respectively. Breast cancer was notable with the highest proportion of metformin trials at 30 per cent, while liver cancer was almost evenly divided between trials that included a COX inhibitor, antiviral or statin. Finally, acute myelogenous leukemia (AML) was the only indication in which greater than 20 per cent of the trials included an antidepressant at 75 per cent (see Figure 5).

Primary Endpoints

A logical use for repurposed drugs in oncology is for supportive care, given that common drugs used to relieve the side effects of chemotherapy regimens are generally approved for use in other therapeutic areas. Since this analysis excluded supportive care trials, it was important to determine what types of primary endpoints were being evaluated. For ease of presentation, trials that assessed one or more survival-related endpoints (for example, overall survival, progression-free survival, time-to- progression, disease-free survival, eventfree survival, recurrence-free survival) were designated as ‘Survival’. Likewise, any primary endpoint related to safety or toxicity was designated as ‘Safety/ Toxicity’, and any primary endpoint that was related to response (such as response rate or PSA response) or vaguely to efficacy was designated as ‘Response/ Efficacy’. ‘Prevention’ and ‘Other’ were the other primary endpoint designations. The category ‘Other’ encompassed those trials assessing bio- or genomic markers, pharmacokinetics/dynamics, bioavailability, metabolic changes or quality-of-life as primary endpoints.

Almost 30 per cent of these trials included primary endpoints designated as Other. Response/Efficacy and Survival trials were next at 22 per cent and 21 per cent, followed by Safety/Toxicity trials at 19 per cent, Prevention trials at 10 per cent and trials with both Response/Efficacy and Safety/Toxicity at seven per cent (see Figure 6 on page 28). All five drug types were represented in trials with these primary endpoints. However, just two Safety/Toxicity trials included statins, while for Prevention trials, only one included antidepressants and two involved antiviral drugs.

Phase 1 trials accounted for approximately two thirds of the Safety/ Toxicity trials; no Phase 3 trials had endpoints related solely to this area. The other four categories were represented across all phases. As expected, the majority of Phase 3 trials had survivalrelated endpoints, but interestingly, 20 per cent of the Phase 3 trials were Prevention trials.

The top 10 diseases were represented in trials with all of the primary endpoints with the exception of Prevention. Glioblastoma, AML and liver trials did not include any prevention-related primary endpoints.

Biomarkers and Pharmacogenomics

Almost 70 per cent of Prevention trials included endpoints/objectives related to biomarkers or pharmacogenomics (PGX); 50 per cent of Other trials included these types of endpoints/ objectives. The high percentage of biomarker/PGX use in Prevention trials was expected since the measurement of change in proliferation markers, for example Ki-67, was a commonly used clinical indicator for prevention. Approximately 35-40 per cent of the other three categories included such endpoints/objectives. When biomarker/ PGX use was assessed by drug type, about 60 per cent of trials with either metformin or statins, 40 per cent of trials with either COX inhibitors or antidepressants, and 30 per cent of the trials with antivirals included these endpoints/objectives (see Figure 7).

Next Steps

The above describes in detail the current state of purposeful reprofiling of drugs in oncology trials. As for what the future holds, we can expect the following:

 ●● More oncology trials with antidepressants, antivirals, COX inhibitors and metformin. Trials are planned with all of these drug types. Additionally, if historical start-year trends remain true, oncology trials with metformin should continue as it was the last of these five drug types to be incorporated into oncology trials, starting in 2008 (see Figure 8).

 ●● Increasing use of repurposed drug pair combinations in oncology trials. Open trials are evaluating COX inhibitors paired with antihypertensive, antiparasitic, antihyperlipidemic, antigout or antithrombotic drugs and antifungal/retinoid and Metformin/ statin pair combinations. Planned trials will evaluate the pair combinations of COX inhibitor/antihypertensive, antidepressant/retinoid and antidepressant/metformin.

●● Enhanced support for the clinical development of repurposed drugs in the US by the National Institutes of Health’s (NIH) National Center for Advancing Translational Sciences (NCATS). In May 2012, NCATS launched the collaborative initiative, Discovering New Therapeutic Uses for Existing Molecules, to match NIH-funded researchers with existing pharmaceutical compounds provided by various pharmaceutical companies (10). Already in existence is NCATS’ Pharmaceutical Collection, a publicly accessible database of small molecules already approved in the US, Canada, Europe and Japan, and all compounds that have been registered in clinical trials (11).

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Rachel Meighan-Mantha has been involved in supporting drug development for 20 years. She is currently a Principal Analyst in Oncology at Citeline Inc, a comprehensive provider of realtime clinical research and development intelligence. She is responsible for enhancing Citeline’s products and assisting clients with their competitive intelligence needs. Previously, she worked as a scientist in basic research and for a contract research organisation. She holds a BA in Biology from Taylor University, and a PhD in Cell and Molecular Biology from Boston University. She is currently following several trends in the development of oncology drugs.

Email: rachel.meighan-mantha@citeline.com

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