The Ups and Downs of Clinical Translation of New Technologies: Déjà Vu All Over Again
Authors: Paul A Burke
Journal: Molecular Therapy (2015)

Drug development is a risk-laden enterprise, and new technologies will always experience periods of boom and bust. Although attrition experienced by new technology platforms can tarnish them unfairly, history shows these setbacks can be overcome. This is demonstrated by the field of gene therapy, which suffered seemingly catastrophic setbacks with deaths in phase I trials in 1999 and 2007 but is once again a hot area in biotechnology. RNAi provides another illustration of a technology coming in and out of fashion only to return again, in this case within a 10-year period. The twenty-fifth anniversary of the original publication of SELEX (aka in vitro evolution) provides a unique opportunity for reflection on the impact of aptamer technology on the therapeutic landscape. Although the record shows significant achievements, areas where impact has fallen short of early aspirations provide translational lessons for this and other novel compound classes. Aptamers were recognized early on as potential therapeutics because of the rapidity with which compounds with high binding affinity and specificity could be identified. Produced chemically via readily scalable processes, aptamers benefit from mature manufacturing and analytical capabilities developed for related nucleic acid therapies. Further assets include the lack of a significant adaptive immune response and amenability to various conjugation chemistries. Limitations, including short circulating half-lives and metabolic instability, can in many cases be addressed by established approaches. The aptamer field counts more than two dozen clinical trials in the United States alone, including treatments for bleeding disorders, hematological malignancies, and renal disease. In an important milestone, 2004 saw the approval of the "first-in-class" therapy pegaptanib (Macugen), a PEG-aptamer binding the VEGF-165 isoform, for treatment of neovascular (wet) age-related macular de­generation. Despite this advance, the track record of aptamer technology as a broad source of pharma­ceutical products provides a less sanguine view. By the metric of product approvals, aptamer technology has not lived up to the promise envisioned in 2006, the year in which Macugen sales peaked. A closer look at the clinical arena shows significant attrition of both product candidates and companies. Over the past 10 years, aptamer clinical trial activity has concentrated in the ophthalmic space, despite the original prospects for a technology-based product engine supporting a wide range of therapeutic areas, including those requiring systemic administration. Most recently, the rapid and unexpected failure of Regado Biosciences' REG1 (Revolixys) in a phase III clinical trial threatens to cast a shadow over the remaining and future potential players. REG1 is a two-component aptamer anticoagulation therapy consisting of pegnivacogin, with specific binding affinity for factor IXa, and anivamersen, which binds pegnivacogin, thereby inactivating it. In a phase II trial, three patients had allergic-like reactions shortly after pegnivacogin administration; two of these reactions were reported as serious. A subsequent phase III trial was terminated in the summer of 2014 after enrollment of 3,250 patients (about 25% of the initial target) because of the frequency and severity of serious allergic adverse events. What factors contributed to the failure of REG1? Oligonucleic acid–based therapies are known to be potentially immunostimulatory, as are PEG (a component of pegnivacogin) and double-stranded RNA such as the pegnivacogin–anivamersen duplex. However, these are merely speculative causes that cast little light on what actually happened in the clinic in the absence of supporting data. The unanswered questions regarding REG1 pose a potential obstacle for others aspiring to develop related therapies, in that safety risks applying to aptamers as a class can jeopardize future investment. The product development history of aptamers, including REG1, affords several lessons regarding steps that can be taken at discovery and early preclinical development stages to maximize the chance for success. Some of these lessons apply to oligonucleotides in general. For example, control assays for immunostimulatory effects and preclinical animal safety models should always be included in early research aspiring to clinical impact. Although these cannot guarantee safety in the clinic (and with REG1 they did not), their inclusion early in the discovery process serves as an important milestone and ensures that research efforts focus on molecules least likely to hit safety roadblocks down the road. When setbacks in development occur, especially in matters pertaining to safety, it is important to understand their causes whenever possible. There are many potential causes of allergic reactions. Understanding them could require years of basic research—and future advances in the field are not necessarily contingent on elucidating them. Unfortunately, when small companies experience big setbacks, they often do not survive long enough to conduct rigorous post hoc investigations. Even if they do survive, the relative lack of predictive animal models poses a particular challenge when investigating immunoreactivity. Characterization of serious adverse events with low incidence—often detected only in large clinical studies or after product launch—is impractical even when animal models are available. It is not presently feasible for early researchers to anticipate or prevent them. The hurdles in clinical translation of new science are often of a commercial nature. Some of these—such as the need to articulate how a proposed new technology compares with established competing approaches—should be addressed in early work when feasible. Aptamers share product attributes with monoclonal antibodies, a more mature technology platform with a vast development infrastructure. Clarifying a technology's unique strengths can help investigators outside the immediate field appreciate its value in addition to giving focus to future research. Setbacks—whether pertaining to safety issues or perceived lack of progress compared to inflated expectations—as well as anniversaries provide opportunities for reflection and, in some cases, course correction. For aptamer research with a therapeutic goal, in addition to addressing toxicity early and demonstrating why the approach is a compelling one, reminders of the high-stakes nature of the endeavor are also important. Sometimes the biggest asset a new technology can have is the dogged determination of the investigators developing it.