Julianna LeMieux Ph.D. Senior Science Writer GEN

Lessons from Vertex’s Small Molecule Drug Development Program for Cystic Fibrosis

To kick off the Advances in Genome Biology and Technology (AGBT) precision health meeting held in La Jolla, California early this September, David Altshuler, M.D., Ph.D., executive vice president of global research and CSO at Vertex Pharmaceuticals, shared his perspective on “humanizing drug discovery.”

In 1999, 10 years after the discovery of the gene associated with cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR), Paul Negulescu, Ph.D., senior vice president and site head of San Diego research at Vertex, made a bold proposal. He wanted to study small molecules that could restore function to the mutated CFTR protein.

The idea of using small molecules for a genetic disease was not embraced by all. Harvey Lodish, Ph.D., professor of biology and biomedical engineering at Massachusetts Institute of Technology, told Vertex at that time that it was extremely unlikely that small molecules would correct the underlying mutations in the CFTR protein. Similarly, Francis Collins M.D., Ph.D., NIH director (who co-discovered the CFTR gene along with Lap-Chee Tsui, Ph.D., and John Riordan, Ph.D.), said that gene therapy would be the solution for CF and thought that inserting a good copy of the CFTR gene would be relatively straightforward—something that has not been achieved to this day.

From there, the AGBT meeting audience was taken on a 20-year journey of CF drug design: from the FDA approval of Vertex’s first small-molecule drug to a clinical trial that became fully enrolled just days before the meeting. It was the lessons from this journey that were the theme of Dr. Altshuler’s opening address. Humanizing the drug discovery going on in the CF field was a prescient way to kick off three days of in-depth discussion about the technicalities of genomics and precision medicine.

Looking through the lens of ongoing research at Vertex, Dr. Altshuler reflected on the challenges and triumphs that have accompanied drug development for CF. Ironically, and despite the long road of ups and downs, all of the work that he talked about had been done at the Vertex facility located just two blocks from the conference location.

Despite being a pioneer in the field of human genetics, long-standing academic at Harvard Medical School, and a founding member of the Broad Institute, Dr. Altshuler was quick to point out that he himself had done none of the science that he was presenting, giving credit where credit was due. He also emphasized the important role of the patients that motivate the scientists at Vertex to do what they do best.

In spite of doubters, using small molecules to target the CFTR gene has proven an effective strategy. Kalydeco® (ivacaftor), which the FDA approved in 2012 and recently received wider approval for use in children one year or older, has been referred to as the “most important new drug of 2012” and “a triumph of genetics and drug development” (Matthew Herper, 2012, Forbes). And, not unexpectedly, two other CF drugs have followed in ivacaftor’s wake: Orkambi® (lumacaftor/ivacaftor) was FDA-approved in 2015 and Vertex’s third drug, Symdeko® (tezacaftor/ivacaftor and ivacaftor) was approved earlier this year. Each of these drugs is approved for subsets of patients with one or more mutations in the CFTR gene.

Dr. Altshuler raised the point that “there is much discussion about why so much time and money goes into developing therapeutics and how relatively few therapeutics come out the other end.”

The common misconceptions that surround precision medicine, Dr. Altshuler says, can be explained using a phase well known to fans of the TV show Seinfeld. He said that people think that a genetic discovery is made, “yadda yadda yadda,” then a patient receives a benefit. But, this could not be farther from the reality of the challenges faced when developing new therapeutics.

Coming up with a clinical candidate, the first step in the process, can involve hundreds of compounds and many years. The compound need not only be potent, but must also be selective, metabolically stable, soluble, and cause no side effects, while still being manufacturable and deliverable—a tall order indeed. Only when all of these boxes are checked can a clinical trial be started.

It routinely takes 13–15 clinical candidates to obtain one approved medicine. Where does the attrition occur? Dr. Altshuler explained that 75% of molecules fall Phase II testing and, although some may think that this high failure rate is due to a lack of safety, it is mostly a lack of efficacy. The low rates of success, according to Dr. Altshuler, is because we don’t understand human biology well enough and that “human genomics is an unmatched approach to getting to that discovery.”

Because there are many different mutations in the CFTR gene that cause CF, therapeutic design is not one size fits all. Indeed, ivacaftor is useful for less than 10% of patients. The CF field is instead turning to the development of small molecules that could have the same beneficial effect for the other 90% of patients with the ultimate goal of a single combination therapy. Because, if it is the same underlying cellular defect, even if arrived at by different mutational mechanisms, then the same therapeutic may be appropriate for different genotypes. This approach is distinct from the more traditional view of precision medicine that fragments different genotypes, but could be applicable to the treatment of other diseases with a unified biology underlying the disease.

The goal of precision medicine, according to Dr. Altshuler, is to address the underlying cause of a serious disease, not just symptoms. “It is only through the dogged pursuit of new therapeutics that patient benefit will come,” he adds. Even further, Dr. Altshuler aims to go beyond treating patients, toward prevention of the disease before it occurs.

To answer critics who note that years pass with no new drugs coming to light, Dr. Altshuler offers that three Nobel Prizes were awarded in the field of cholesterol over the last century before the appearance of the first approved drug. Although he notes that “this may seem like a long road,” Dr. Altshuler makes clear that “it is the only road.” And, with their recent successes in treating CF, Vertex’s journey to the next drug that helps patients may not take nearly as long.

Dr. David Altshuler speaking at the Advances in Genome Biology and Technology meeting. [AGBT]

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