Repositioning drugs for systemic lupus erythematosus

Why try to repurpose/reposition drugs for SLE patients?

The term drug repurposing refers to using or testing a drug that has been approved by the regulatory authorities for one disease indication in another disease, in this case systemic lupus erythematosus (SLE). Drug repurposing has a number of other names including repositioning, rescue, reprofiling, retooling, and retasking. Because only five medications have been approved by the United States Food and Drug Administration (FDA) for treatment of SLE, lupus patients are routinely treated with drugs that have been “repurposed”. Methotrexate (MTX), cyclophosphamide (CTX), mycophenolate mofetil (MMF), and rituximab are frequently used for lupus, but were originally approved for other indications, such as cancer (MTX, CTX), transplant rejection (MMF), and lymphoma (rituximab), respectively ( Table 67.1 ). However, the concept of repurposing is not unique to SLE; numerous drugs in a variety of conditions have been successfully repurposed for new indications, often quite disparate from the original focus of their development or approval.

Drug repositioning emerged as a scientific field relatively recently. Initially, biotech/pharma took a traditional approach by examining chemical libraries for compounds with shared structures or side effects with drugs of known activity. Often, compounds were rescreened against targets with a similar molecular composition (e.g., kinases, receptors, signaling molecules). Subsequently, the concept of using genome-wide association studies (GWAS) and bioinformatics to facilitate drug repositioning was developed. This advance led to a tenfold increase in the number of publications in drug repositioning to around 50 per year in 2009. By 2016 interest accelerated further resulting in over 500 published papers per year. More than half of all of the papers in PubMed discussing drug repositioning have been published between 2016 and 2018. These recent papers discuss a variety of specific methodologies used for disease-specific drug repurposing, but the approaches have yielded mixed results.

There are a variety of reasons for the interest in drug repurposing. One driving force seems to be the developmental cost to bring a compound to market, currently estimated to be approximately $1.4–2.9 billion for a successful compound. This extreme cost is coupled with the perceived “innovation deficit”— the widening gap between productivity and research and development budgets over the last 10 years. This has generated an intense interest in attempts to rescue products that have failed for one indication or have been shelved for various reasons. There are many benefits to repurposing/repositioning, when successful. Drug repositioning can quickly bring new treatments to patients because early preclinical work as well as dosing, formulation, drug metabolism/interaction, and pharmacokinetic/dynamic issues have already been characterized. Moreover, the side effect profile has frequently been examined. This only leaves the matter of efficacy to be established, thereby foreshortening the pathway to possible acceptance and/or regulatory approval. Perceived limitation on drug repurposing include patent life and the expectation of the availability of generic formulations. Although potentially beneficial to the consumer population, these features can be negative factors for pharmaceutical companies and sometimes limit interest in repurposing/repositioning.

Physicians treating patients with diseases such as SLE are interested in drug repositioning because biotech/pharma has not been very successful in bringing new drugs to market. In addition, commonly used SLE treatments have serious side effects, poorly address symptoms, and often fail to normalize the core mechanisms driving the disease, making remission rare. Compared to other autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis (RA), which have numerous FDA-approved drugs, there are only five drugs specifically approved for SLE, and four [aspirin, corticotropin, glucocorticoids, and hydroxychloroquine (HCQ)] were approved in the 1940s and 50s ( Table 67.1 ). Many of the current standard of care (SOC) drugs were developed outside of the traditional pharmaceutical model and all were “repurposed/repositioned” after positive experiences in lupus patients or other conditions thought to be mediated by similar immunologic processes ( Table 67.1 ). After a gap of 56 years, belimumab, an antibody directed against B-cell activating factor or B Lymphocyte Stimulator (BAFF/BLyS, TNFSF13B ), became the first and only targeted therapy approved for generalized lupus in 2011. However, the commercial success of belimumab has been modest, as treatment is expensive relative to other available immunomodulatory agents, the comparative efficacy has not been shown to be great, the agent does not appear to be effective in subjects of African ancestry, and there are questions surrounding benefit of continuous, long-term treatment. Among other routinely used drugs, those that fall under the corticosteroid label (hydrocortisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone) are frequently used in addition to or in place of prednisone; chloroquine is used off-label as a replacement for hydroxychloroquine; sirolimus has been used, although not approved for lupus; and tacrolimus is SOC in Japan. Thalidomide has also been used off-label, particularly for cutaneous lupus, but is difficult to obtain because of concerns about teratogenicity.

It has become standard practice for pharmaceutical companies to investigate alternative uses for their compounds based upon similar disease category and expected pathophysiology. However, historically, drug repurposing/repositioning for lupus began in academia and the clinical care community. Aside from antimalarial agents, which were investigated for lupus by Winthrop Chemical Laboratories after Page reported that quinacrine treatment induced responses in 17 of 18 SLE patients, most repurposing/repositioning efforts came from early experiences or trials in academic centers or clinical practice. The investigation of glucocorticoids in SLE and other rheumatic diseases was conducted soon after positive results were reported in RA at the Mayo Clinic. Trials of antineoplastic agents, such as CTX and AZA, were primarily conducted by the National Institutes of Health before their adoption as SOC. From 1969 to 1981, the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases completed trials comparing the efficacy of CTX and AZA for lupus nephritis (LN), ultimately concluding that CTX had superior benefit. Other trials with AZA and prednisone for either SLE or LN were conducted at the University of California Los Angeles, the State University of New York, and the Mayo Clinic. Repurposing/repositioning for MTX occurred in various academic centers in mostly observational trials with few patients, the first of which was completed in 1965 by Miescher and Riethmüller and demonstrated improvements in skin rash and arthralgia in ten patients. In 1988 MTX was evaluated in another small cohort of patients by Rothenberg and coworkers from the Middleton Memorial Veterans Administration Hospital, again with demonstrated improvements in arthritis and skin rash in the majority of patients. There are only a few randomized controlled trials for MTX. In 1999 the Universidade Federal de São Paulo, Brazil conducted a study with 40 participants, and in the early 2000s the University Health Network in Toronto, Canada conducted a study with 86 participants (NCT00470522). Both controlled trials reported steroid-sparing effects and some improvements to disease activity with MTX use.

The shift from academia/clinical care-based repurposing to pharmaceutical company involvement occurred in the last two decades, as MMF, which was first approved in 1995 for transplant rejection, relied on both academia and industry for evaluation. Small-scale early trials of MMF were conducted across various academic centers, but one large-scale trial in academia was coordinated by the State University of New York at 19 study centers. Large trials were subsequently sponsored by pharma (NCT00377637, NCT00425438), but failed to meet primary endpoints. Similarly, following approval of rituximab for lymphoma and RA, two controlled trials in generalized SLE and LN carried out by pharma (NCT00137969, NCT00282347) failed to meet their primary endpoints, whereas numerous experiential and uncontrolled studies carried out in academia claimed benefit. In these circumstances, the academic community believed the agents were beneficial, even though the pharma-sponsored trials did not meet their primary endpoints. These agents have become part of the standard treatment for SLE, demonstrating the essential role of the opinion of the clinical community in prioritizing treatment options.

More recently, however, because of regulatory requirements, reimbursement, and cost of drug and clinical trials, a corporate platform is increasingly required for successful drug repurposing/repositioning and marketing. Compounds tested in small, academic trials, unless supported by pharma, are unlikely to obtain regulatory approval or gain acceptance by third party payors to become used widely in clinical practice. Indeed, several companies, including AMPEL BioSolutions, Axaonomics, Biovista, Excelra, Sistemic Inc., Healx, NuMedii, Recursion Pharmaceuticals, and SOM Biotech, have been founded on the principles of drug repurposing/repositioning. Most companies focus on drug repositioning for any disease indication using their specialized pipelines, whereas others specialize in identifying existing drugs that could treat a rare disease (Healx) or SLE (AMPEL BioSolutions). SLE is one of many diseases in which drugs have been repurposed/repositioned after success in a similar or widely differing condition. Some repurposing efforts have resulted from pure serendipity or clinical observation, whereas others have resulted from an evolving knowledge of underlying pathophysiologic pathways. It should be pointed out, however, that despite the decreased risk of repurposing/repositioning, many efforts testing previously FDA-approved drugs or other repurposed compounds in SLE have still failed in clinical trials as shown in Table 67.2 . Some failures are related to the complexity of lupus clinical trials. Among the difficulties, lupus clinical trials often employ endpoints that are poorly responsive to change. A newly developed outcome measure, Lupus Multivariate Outcome Score (LuMOS) , shows promise of being more responsive to change than standard outcome measures. For example, in reanalysis of the pivotal lupus trials for belimumab, LuMOS was able to distinguish a difference in the impact of active therapy as compared to placebo when standard outcome measures could not. Utilizing novel outcome measures, such as LuMOS, in repurposing trials for lupus may make them less risky.