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Everyone loves to talk about how precision medicine is changing the face of oncology research, and with good reason. Over the past few years, the use of genomics to target specific patient populations has changed cancer care positively, transforming many diagnoses into manageable diseases. It’s also enabled drug developers to bring new drugs to market that previously might have been abandoned because individuals participating in clinical trials happened to be genetically predisposed not to respond.

But oncology isn’t the only field that can benefit from this targeted approach. Developers pursuing any disease category with a genetic etiology stand to benefit from making genomics part of their research and screening process, especially in categories that have few treatment options, such as certain rare diseases. As many as 10 percent of the world’s population have some degree of chronic kidney disease (CKD), and millions of people progress to requiring dialysis or die each year because they do not have access to effective treatments. Yet CKD generally gets far less attention and financial support than many other prominent areas of research, including cancer, diabetes without associated nephropathy, and cardiovascular disease. The rare diseases that are associated with CKD have received even less attention and support. 

Part of the problem is high rates of inconclusive Phase III trials for CKD. Several have been terminated early due to safety issues, some have been determined not feasible to conduct, and others that do get completed show a less than favorable benefit/risk profile. Adding genomic testing to relevant trials could potentiate higher rates of success in demonstrating benefit by identifying which patient groups are likely to respond to the treatment. Such strategies of “predictive enrichment” can prevent useful treatments from being abandoned for not working in all patient populations, and can help developers speed the trial delivery process and get these products to market sooner.

The nephrology and medical genetics community recently witnessed the benefits of genomic screening for CKD trials with migalastat, trade name Galafold™, a novel oral agent for Fabry Disease developed by Amicus Therapeutics and employing precision medicine for success.

Amenable mutations hold the key

Fabry is a genetic disease that results in an enzyme deficiency and abnormal deposits of the fatty substances GL-3 and lyso-Gb3 in blood vessels and organs of the body. As a result, the fatty substances impair circulation and organ function across body systems. Fabry patients face an array of symptoms that are progressive over time, from neuropathic pain in early adolescence, to rashes and abdominal pains by the fourth decade of life. Other manifestations include cardiovascular morbidity (atypical at relatively young ages), strokes, cardiac disease (heart failure, coronary artery disease, valve dysfunction and arrhythmias), and renal dysfunction that may require dialysis or transplant…all by the mere ages of 30-40 years old.  Fabry Disease is a rare disease, found in roughly one in 100,000 individuals, and often the diagnosis is delayed, despite patients suffering over decades.  Unfortunately, this delay prolongs proper treatment to potentially avoid serious complications. 

Migalastat works by facilitating proper folding and cellular trafficking of certain dysfunctional forms of the enzyme α-Gal A produced by abnormal variants of the related genes.  This ultimately enables the proper breakdown of the fatty molecules, so the culprit deposition of unwanted material in blood vessels and organs decreases, and organ damage is minimized. The benefits of this oral drug are comparable to enzyme replacement therapies (ERTs), which are the only other treatment for Fabry but require bi-weekly infusions for life.

However, only Fabry patients with ‘amenable mutations’ respond to this treatment, which Amicus estimates comprises 30-50% of the Fabry patient population. These patients are identified using a cell-based amenability laboratory test as a follow up to a Fabry diagnosis initially being established with a blood test.

This is a perfect example of why precision medicine is so important in drug development. Without genetic testing to identify the amenable mutations as part of the study’s inclusion criteria, the clinical trial likely would have recruited a large number of patients without that genetic marker, causing clinical results to reflect unacceptably high rates of failure. By linking the treatment to the genetic marker, Amicus was able to demonstrate to regulators and physicians that the drug works for an identifiable subset of patients.

Migalastat has already been approved for use in Europe by the European Medicines Agency (EMA) and recommended by NICE. In the United States migalastat is currently only available to people who are the in the Amicus studies. However, in November 2016 Amicus announced a planned regulatory pathway to collect additional data to support full approval by the US Food and Drug Administration (FDA).

Not only is this good news for a significant proportion of Fabry patients, but it also exemplifies models for the application of precision medicine in disease categories beyond oncology. It is true that defining study populations using specific predictive biomarkers will target more narrow end-user groups, but developing an effective drug that can help some people is a lot more beneficial — and potentially profitable — than investing millions of dollars and years of research in trials that ultimately fail across study populations that are too broad.

Moreover, when developers proceed in this manner, it can help them shift their focus toward research paths that produce the most good in the shortest amount of time. If you can clearly define a population who will benefit from a treatment early on in development, you are better positioned to achieve regulatory approval for products that improve lives and positively impact your own bottom line.

Topics in this blog post: Precision Medicine, Biopharma, R&D, Nephrology