September 14, 2018 by Dale Yuzuki
In a plenary talk at the Advances in Genome Biology and Technology – Precision Health, the Vertex Pharmaceuticals EVP and CSO shares on the topic of humanizing drug discovery
It isn’t very common to hear a drug development scientist give a talk at a genomics conference, and at the recent Advances in Genome Biology and Technology, the keynote speaker Dr. David Altshuler (Executive VP of Research and Chief Scientific Officer of Vertex Pharmaceuticals) did not disappoint. Before moving to Vertex about three years ago, he was a founding member of the Broad Institute; more about Dr. Altshuler’s background can be found here.
His sub-title, ‘Humanizing Drug Discovery’, he pointed out that human genetics and genomics is ‘unmatched at getting at human biology’, and that in the world of pharmaceutical drug development scientists’ dedication is ‘on-par with academia, but no one knows who they are’ since their work is not public.
The disease is Cystic Fibrosis (CF), and Dr. Altshuler began with President Obama’s 2015 State of the Union speech, where a cystic fibrosis patient and advocate Bill Elder a 27-year old medical student was highlighted for progress in the promise of precision medicine. Bill is expected to live a long and full life, thanks to a breakthrough drug called Ivacaftor, developed by Vertex.
Background of the CFTR gene
In 1989 the causative gene for CF was identified (Cystic Fibrosis Transmembrane conductance Regulator, or CFTR); in the 1990’s its function elucidated. He pointed out in 1992 a paper observed a small thermodynamic shift in getting the CFTR protein to the surface, thus suggesting a small molecule approach to therapy, and in 1999 Aurora Pharmaceuticals / Vertex (located a few blocks away from the conference venue in Torrey Pines / La Jolla California) started work on small molecule drug discovery. In 2004, Ivacaftor was synthesized, and in 2009 Lumacaftor was designated for further development. Ivacaftor was first approved for a specific G551D mutation in the CFTR gene in 2012, affecting about 4% of those with CF.
Ivacaftor and Lumacaftor received FDA approval in 2015 as a combination therapy (the combination of Ivacaftor and Lumacaftor is called Orkambi). The specific mutation, a homozygous F508del in the CFTR gene, accounts for about 50% of all CF cases, and recently the indications have been expanded in 2016 to ages 6-11, and in 2018 to children ages 2-5.
Dr. Altshuler pointed out that Mendelian diseases (since 1986) and other genetic disease (since 2007) set the stage for precision medicine; at times the genetic and genomic approaches suggest avenues for repurposing medicines. However in ‘most cases the biology will be new’ and thus there is the need for discovery and development of innovative medicines. He said ‘human genetics is the foundation but it is only the first step’ in drug development.
The challenge of drug development
He then lays out the challenge of the drug development pipeline: after discovery of 13-15 clinical candidates, and a sharp attrition of 75% from Phase II to Phase III clinical trials, mainly due to lack of efficacy. And this is due to lack of understanding of the human biology. (For those unaware, Phase I is to show safety and lack of toxicity in humans.) The rate of failure is 52% from Phase I to Phase II.
At this point in his talk, almost as an aside, he pointed to this paper in Nature Reviews Drug Discovery titled “Validating therapeutic targets through human genetics”, and his own movement to industry (along with Dr. Plenge who went to Celgene) to accelerate drug discovery efforts. He said ‘when you have done something for 15 or 20 years, go off and do something different but related’.
Remarkable benefits of a breakthrough drug
Cystic Fibrosis (CF) was first identified in 1938; CF has a median age of death in the mid-20’s, with 75,000 affected by CF in North America, Europe and Australia. Sweat chloride was identified as the biomarker; carriers have 80% function, and intermediate function of the CFTR gene leads to related or delayed disease. It was thought that the chloride channel defect could not be overcome by a small molecule approach, and that gene therapy would be needed instead. One G511D mutation in the CFTR gene is in the channel gating activity, and Ivacaftor opens up this gate.
He showed data from a 2012 database of lung function with n=27,804 CF patients, documenting a 2% annual decline in lung function. This 2015 study with Ivacaftor alone the rate of declining lung function was reduced by 47%. The overall, long-term effect of Ivacaftor was a 59% reduction in death, 85% less transplantation, and 35% less hospitalization. The problem however, is that only 10% of CF patients could receive this benefit (those with the specific G511D mutation or another one similar in function to it).
The F508del mutation is a protein-processing defect, where the protein gate does not reach the cell surface. 90% of CFTR patients have at least one F508del allele. One compound developed at Aurora / Vertex VX-809 (Lumacaftor) was shown in 2011 to correct this F508del processing defect. Two other compounds, VX-661 and VX-770 (Tezacaftor and Ivacaftor) were shown to be effective in 2017 in a Phase III study for homozygous F508del mutations and this combination (Tezacaftor and Ivacaftor) was approved in 2018.
These three novel mechanism-of-action (MOAs) were developed to boost function, two of which are called VX-445 and VX659; it was decided over 3 years ago to try the combination of all three, with the potential to benefit 90% of all CF patients. (These clinical trials are now underway.)
Do you currently assay for the CFTR gene in your laboratory? Access our recent poster on the development of a CFTR assay using SLIMamp technology, or contact us regarding obtaining a trial kit to run in your lab.