Important Points Highlighted by Individual Speakers
- Gaining access to compounds and their data, having a willingness to explore other indications, and forming collaborative partnerships are key components of a successful repurposing program.
- Establishing internal, dedicated teams to repurposing and improving the efficiency of the process by which drug data are organized and updated may encourage more of those in industry to explore drug repurposing as part of their business models.
- Industry–academia collaborations can provide both valuable access to drugs and information to use for finding therapies for patients in need.
- The use of animal models can be useful for elucidating mechanisms of disease, such as in Marfan syndrome, and these insights can guide therapeutic development for the initial disease of study as well as for additional disorders.
Academia, industry, and government stakeholders each have a distinct set of concerns regarding the state of the science for drug repurposing, but workshop speakers emphasized that because each of those groups has its own strengths, if they work together it can increase the likelihood of the successful translation of a repurposed drug. Many of the examples cited by individual speakers in this session—and throughout the workshop—involved rare diseases, which have been a focus of re-
purposing efforts to date. For example, Marfan syndrome was discussed as an example of the potential of repurposing in a broad range of Mendelian disorders.
Three strategic elements are key to drug repositioning, said Don Frail, vice president of science at AstraZeneca. The first is having access to compounds, which typically involves access not just to the compound itself but to all of the information associated with that compound, such as safety data and clinical study reports.
The second element is exploring the indication space—whether broad or narrow—to include both core areas and opportunistic indications. Within pharmaceutical companies, project teams can be focused on therapeutic areas, or groups can be dedicated to repurposing across therapeutic areas. Biotechnology companies often take the latter approach because they are interested in maximizing the value of their compounds and will often explore opportunities in broader treatment areas.
The third key element is maximizing the generation of ideas, in part through partnerships with others. It is increasingly more common for some nonprofit organizations to support repositioning or repurposing efforts, Frail said. For example, the nonprofit organization Cures Within Reach1 uses a model of providing small grants to repurpose drugs and devices already on the market to quickly deliver safe and affordable treatments and cures for both common and rare disorders for which no effective treatments currently exist.
AstraZeneca is working on all three elements through a partnership with the Medical Research Council (MRC) in the United Kingdom. The objective of the partnership is to provide MRC investigators with access to well-characterized compounds for the discovery of new indications, Frail said. (Chapter 5 covers this program in greater detail.) Data on 22 compounds attracted more than 100 clinical and preclinical proposals from 37 UK institutions, and in 2012, 8 preclinical and 7 clinical projects were selected for funding by the MRC at a level of about $10 million, Frail said. This partnership has been recognized internationally and serves as a model for future collaborations in translational research.
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1For more information about Cures Within Reach, see http://cureswithinreach.org (accessed January 21, 2014).
AstraZeneca also has developed open innovation partnerships with the eye care company Alcon and the dermatology company Galderma, Frail said. These companies have access to AstraZeneca’s compound collections and are developing therapies in two areas where AstraZeneca is not active, allowing the company to maximize the value of its compounds.
Potential Barriers
There are several barriers to drug repurposing, Frail said. Companies are typically focused on certain disease areas, so they sometimes miss opportunities to follow the biology of a compound into different areas. Repositioning can also be a distraction to current project teams and organizations that are focused on specific disease areas. A discontinued compound does not have a project team, and an active project team typically is dedicated to getting a drug to work on its current indication rather than exploring different indications. Furthermore, individuals in a company may view drug repositioning as less innovative than developing an entirely new drug.
Companies have a limited number of compounds with which to work, and they may have limited capital to invest in projects, Frail said. The response to limited resources is to focus one’s efforts, which can work against repositioning. Other reasons that a project might not proceed include a company not having an appropriate compound, a project having a low probability of success, reimbursement by payers posing challenges, the market being too small, or regulatory approval endpoints having not been defined, Frail said.
Repositioning can also raise complex issues about regulatory filings, pricing, and other considerations, all of which can serve as deterrents to project teams. For example, in collaborations an investigator will often request updated clinical regulatory documents, such as an investigational new drug application, and it can be time-consuming to collect all of the updated information and make the changes to the existing document, Frail said. A clinical study may have closed before all the data were in, or a new set of pharmacokinetic data or chemistry, manufacturing, and control sections may need to be generated. Safety reporting and pharmacovigilence also can be complicated for such projects, Frail said.
Investigator-initiated studies or out-licensing may require a support infrastructure and legal agreements. Patent exclusivity or remaining patent life can be major considerations, as can data exclusivity, which is another way—in addition to patenting a product—of obtaining market
exclusivity. In Frail’s view, the U.S. data exclusivity regulations are some of the least accommodating in the world, and he suggested that the waiting period for data exclusivity for small molecules (currently 5 years) should be the same as the waiting period for biologics (12 years) (Goldman et al., 2011; see also Chapter 5 for more discussion on patents).
According to the NIH Office of Rare Diseases Research, about 6,800 diseases with limited therapeutic options affect between an estimated 25 and 30 million Americans. Most of them affect fewer than 200,000 people in the United States and most are single-gene diseases. Since the passage of the Orphan Drug Act in 1983, about 250 pharmaceuticals have been developed to treat an estimated 13 million Americans (FDA, 2012). Orphan diseases are definitely of interest to the pharmaceutical industry, especially as more specialty care markets develop. Overall, 11 percent of pharmaceutical companies’ total revenues are from drugs used for orphan diseases, Frail said. Sometimes working on orphan diseases has been profitable for companies, despite the fact that drugs for these diseases are needed by a relatively small number of patients. One benefit of repurposing drugs for orphan diseases is that they have data exclusivity for a longer period than other drugs, Frail said.
Indeed, more than 30 percent of the drugs approved by the U.S. Food and Drug Administration (FDA) in each of the past 6 years have been for rare diseases, said Weida Tong, director of the Division of Bioinformatics and Biostatistics at the National Center for Toxicological Research at FDA. For example, in 2013, 9 of 27 drugs approved by the FDA Center for Drug Evaluation and Research were for the treatment of rare diseases (FDA, 2013a). Tong and his group use computational means to determine drug similarity as one way of meeting the agency’s goal of identifying new indications of marketed drugs for rare and neglected diseases, for diseases for which safer or less expensive drugs are needed, and for diseases for which drug shortages exist (Liu et al., 2013). The fundamental principle behind drug repositioning is straightforward, Tong said: If two drugs are similar, both drugs could treat the same disease, and if two diseases are similar, a drug that treats one disease could be equally effective for the other disease. The challenge, he said, is how to define or determine “similarity.”
The FDA’s Office of Orphan Products Development aims to advance the evaluation and development of products that demonstrate promise for the diagnosis or treatment of rare diseases or conditions, said Tong. For example, the office has established a Rare Disease Repurposing Database containing drugs that have received orphan status designation (that is, they have been found promising for treating a rare disease) or that have been approved for the treatment of another disease (FDA, 2013b).
Drug Repositioning in Cystic Fibrosis
Tong cited his group’s work on cystic fibrosis (CF) as an example of how a genomic approach can be used for drug repositioning. CF is a Mendelian disease that affects the lung and digestive systems. In the United States about 30,000 patients have been diagnosed with CF, and every year about 1,000 new cases are reported. The predicted median age to which a patient with CF will survive is the early 40s (Cystic Fibrosis Foundation, 2014).
Kalydeco™ was developed with the help of $75 million from the Cystic Fibrosis Foundation and was approved by FDA in 2012, Tong said. However, it is only for patients above age 6 who have a particular CF mutation (G551D) in the CF transmembrane conductance regulator gene (CFTR). Kalydeco also costs about $5,700 per week, which has generated reluctance among insurance companies to cover such drugs (O’Sullivan et al., 2013).
The hypothesis being evaluated is that CFTR, a protein channel involved in transport, is regulated by a set of feed-forward loops and that drugs that interfere with these loops can serve as treatments, Tong explained. His group is using a genomic approach in combination with bioinformatics to delineate feed-forward loops, and drugs have been tested to determine which may have the potential to treat the disease. So far, this research has identified about 15 feed-forward loops and about 40 drugs that could be effective, safe, and affordable, he said.
POTENTIAL OPPORTUNITIES FOR DRUG DISCOVERY
Mendelian disorders represent a great opportunity in drug discovery, said Harry Dietz, the Victor A. McKusick professor of pediatrics, medicine, and molecular biology and genetics at the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. While individually
rare, Mendelian disorders are collectively common and personally burdensome, he said. Patients with these disorders have disproportionately fueled progress in human genetics and molecular therapeutics, often at personal cost to themselves despite little chance of personal advantage. Mendelian disorders facilitate the identification of genetic modifiers in people and in experimental models, which can lead to surprising and appealing treatment strategies. Genetically defined animal models of rare diseases allow for genetic or pharmacologic perturbations that allow mechanisms to be refined. In addition, animal models aid in the development of assays and biomarkers for use in small molecule screens. Finally, Mendelian disorders offer the potential to explore the mechanisms and treatments in more common presentations of component phenotypes.
Marfan Syndrome
Marfan syndrome provides an example of all these opportunities. A systemic disorder of connective tissue with dominant inheritance and a prevalence of about 1 in 5,000, Marfan syndrome is characterized by effects in the ocular, skeletal, and cardiovascular systems, including lens dislocation, overgrowth of the long bones, and progressive dilatation of the root of the aorta (Dietz, 2011). If left untreated, early death can result from aortic rupture (Judge and Dietz, 2005).
In 1991 Dietz and his colleagues demonstrated that mutations in the gene encoding the connective tissue protein fibrillin 1 cause Marfan syndrome (Dietz et al., 1991). “Fibrillin 1 monomers [normally] aggregate to form complex extracellular structures called microfibrils that cluster around the maturing ends of elastic fibers during embryonic growth,” Dietz said. Without these microfibrils, those with Marfan syndrome have a structural predisposition for tissues to fail as they age.
Animal models showed that these microfibrils also serve a separate important regulatory function, Dietz said. They bind the large inactive complex of the multi-potential growth factor TGF (transforming growth factor)-beta and suppress TGF-beta release or activation. In the presence of insufficient microfibrils, matrix sequestration of latent TGF-beta is not sufficient. Free TGF-beta then interacts with its cell surface receptor and activates an intracellular signaling cascade that mediates transcriptional responses and can lead to stretching of the aorta (Holm et al., 2011).
Repositioning a Blood Pressure Medication
Aortic aneurysm, emphysema, mitral valve prolapse, and skeletal muscle myopathy were greatly attenuated or even prevented in mouse models of Marfan syndrome after treatment with TGF-beta neutralizing antibody, Dietz said (see Cohn et al., 2007; Habashi et al., 2006). This led to the question of whether there was an FDA-approved drug that would mimic these protective effects. Losartan, which is an angiotensin II, type 1 receptor blocker that lowers blood pressure and has been approved for the treatment of hypertension, had been shown to attenuate TGF-beta signaling in rodent models of chronic kidney disease. Treatment of Marfan mice with losartan led to attenuation of disease phenotypes, making them indistinguishable from wild-type littermates. Losartan also induced a dramatic rescue in aortic root growth that correlated with weakened TGF-beta signaling (Habashi et al., 2006).
Remarkably, losartan also addressed manifestations outside of the cardiovascular system. In mouse models, it caused improvement in distal alveolar septation, a process by which surface area for gas exchange is increased in the lung, and it prevented developmental emphysema, Dietz said. It also improved skeletal muscle architecture and function in mouse models of Marfan syndrome that show a distinct skeletal muscle myopathy.
Nine clinical trials of losartan in Marfan syndrome are ongoing, and the two whose outcomes have been reported have produced promising results, Dietz said. He and his colleagues have focused on treating a subset of children with the most severe and rapidly progressive form of Marfan syndrome; these children normally exhibit unrelenting aortic root growth despite maximal treatment with beta blockers and/or angiotensin-converting enzyme (ACE) inhibitors. After two treatments with losartan, the children exhibited no further aortic root growth (Brooke et al., 2008; Lacro et al., 2013).
Access to information from pharmaceutical companies about the effects of angiotensin receptor blockers on the TGF-beta signaling cascade has been a tremendous advantage in this research, Dietz said. Dietz’s group has also gained access to a selective and potent extracellular-signal-regulated kinase (ERK) antagonist in collaboration with the Therapeutics for Rare and Neglected Disorders program at NIH; this drug has been as effective as losartan in preventing abnormal aortic growth in Marfan syndrome (Holm et al., 2011). Indeed, mice treated with this therapy show a slight but statistically significant decrease in aortic size over time.
Treating Marfan Syndrome in Pregnant Women
There is a high risk of aortic dissection in women with Marfan syndrome if they become pregnant, Dietz said. This risk had been attributed to high stress from circulating blood, but the majority of dissections occur within the weeks after delivery; the risk was not affected by C-section or antihypertensive agents. Because the oxytocin receptor is up-regulated in the aorta in response to estrogen in pregnancy, Dietz’s group hypothesized that oxytocin, which stimulates uterine contraction and milk release, might play a role in these pathogenic events. The oxytocin receptor is up-regulated in the aorta in response to estrogen in pregnancy, and oxytocin mediates its effects on peripheral tissues.
With mice that have 95 percent death due to aortic dissection within 3 weeks after delivery, the removal of the pups immediately after birth prevented lactation-induced oxytocin release and improved survival from 5 percent to 74 percent (Habashi et al., 2012). When oxytocin is delivered to non-pregnant Marfan mice, aortic growth and death due to aortic dissection are dramatically increased, Dietz said.
Most recently, Dietz and his colleagues studied a selective oxytocin antagonist that has 150 times greater potency for the oxytocin receptor than for the vasopressant receptor. When mice were treated 2 weeks into pregnancy and through delivery with this agent, survival transitioned from 0 percent to 100 percent. “These data suggest that oxytocin antagonists such as atosiban, which is approved for use in pre-term labor in other countries, may find utility in the treatment of aortic aneurysm and aortic tear,” Dietz said.
Genetic Modifiers
In five exceptional families that showed discrete intrafamilial variation in phenotypic severity, where half of the mutation carriers died because of aortic dissection by the age of 15 and the other half had no vascular manifestation of Marfan syndrome at the age of 60, linkage analysis revealed a protective locus on human chromosome 6 with a logarithm-of-odds (LOD)2 score of greater than 4. All 20 individuals with the protective locus shared a four-megabase haplotype between selected markers on chromo-
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2The LOD score is a statistic that provides information about whether two genes are located near each other on a chromosome and whether they are likely to be inherited together. A score of greater than or equal to 3 typically means two genes are located near each other.
some 6, while only 2 of 19 affected individuals without the protective locus carried this haplotype, Dietz explained.
Of the 32 genes in this critical interval, attention is being focused on MAS1, which encodes the receptor for angiotensin-(1-7) as the most likely candidate to be involved with this protective effect. Mouse models also demonstrated a comparable modification of the Marfan phenotype on certain genetic backgrounds, which led to the discovery of a single locus on mouse chromosome 9 with a LOD score of more than 9 at a map position coincident with the gene encoding the type 2 subunit of the TGF-beta receptor, Dietz said. This finding also provides a target for therapeutic intervention, he said.
Implications Beyond Marfan Syndrome
The relevance of these drug repurposing findings extends well beyond Marfan syndrome, Dietz said. For example, compounds related to those effective in Marfan syndrome have been shown to attenuate vascular disease in multiple TGF-beta vasculopathies, including common conditions such as bicuspid aortic valve with aneurysm, which affects 1 percent of the general population, he said. TGF-beta-induced suppression of muscle regeneration also contributes to both rare and common myopathic states, and the angiotensin receptor blockers are protective in mouse models of Duchenne muscular dystrophy or immobility associated with muscle atrophy and weakness (Ennen et al., 2013). Finally, losartan improves total lung capacity in patients with chronic obstructive pulmonary disease and also reduces lung damage associated with cigarette exposure in mice (Podowski et al., 2012).
Lessons Learned
Rare disease studies highlight the fact that diseases can be treated without necessarily correcting the original defect, Dietz said. Correcting the integrity of the connective tissues throughout the body would be challenging if not impossible, but focusing on disease pathogenesis led to an understanding of downstream effects of matrix deficiency that were easier to address with therapeutics. The use of mouse models may not necessarily be the best way to test drugs, but it can reveal details of mechanisms of pathogenesis that create new therapeutic opportunities. “Virtually every hypothesis that we test in the lab derives from a clinical encounter,” Dietz said. Finally, the study of a single rare disorder can lead to many therapeutic insights, and these experiences could be repeated with other disorders.
