What does precision medicine mean for biotechnology? It means a future where every inherited genetic disease is curable.
What does precision medicine mean for assisted reproduction? It means a present where these same diseases are preventable. And the prevention is cheaper, and safer, and prevents pain and suffering and restores a normal life expectancy.
As a life sciences investor and advocate for entrepreneurship in the sciences, I have boundless admiration for what has been achieved in biotechnology and with gene therapy. But I cannot help but contrast the current enthusiasm for (and the billions of dollars invested in) our slow but steady progress in developing gene therapy to treat heritable disease with our progress in preventing these diseases in the in vitro fertilization (IVF) lab. For most of this century we have been preventing the very same diseases in the same populations, for a small fraction of the cost of treatment and at much lower risk for side effects using IVF and preimplantation genetics (PGD.)
What’s IVF with PGD? It’s an assisted reproductive technology where we combine a couple’s egg and sperm in the laboratory (ie in vitro) to form embryos. After several days of cell division we biopsy each of the embryos and test the cells’ DNA. In the earliest days of preimplantation genetic diagnosis we removed a single cell and used fluorescent dye to stain for the 13, 18, 21, X and Y chromosomes. Over time the technique has become more sophisticated, and we can do much more complex gene sequencing on a much greater number of cells, without damaging the embryo.
PGD was first used to test for abnormal chromosome counts (aneuploidy) in cases of repeated IVF failure and in women with multiple unexplained early pregnancy losses. In the early 2000’s we started testing embryos for specific genetic mutations that caused disease. Cystic fibrosis was one of the first we encountered. Rather than face a one-in-four chance of conceiving a child with CF (the genetic math when one copy of an abnormal gene from each parent causes the disease), couples where each member is a carrier of a cystic fibrosis mutation create multiple embryos in an IVF cycle, biopsy and test them all, then hopefully have a number of normal embryos. One or two (now the standard is one) embryos are transferred to achieve a pregnancy right away, and the remaining normal embryos are then cryopreserved (frozen) and saved for future pregnancy attempts.
IVF isn’t perfect, but it is highly effective in eliminating risk for inherited disease in known at-risk couples. Unfortunately, it is little used for this purpose. According to the U.S. Center for Disease Control (CDC), approximately 150,000 babies are born per year in the U.S. with birth defects (the CDC term), of which 20%, or 30,000, are congenital, i.e., could be prevented with IVF and PGD. That equates to between 60,000 and 120,000 pregnancies conceived at risk (60,000 if all were dominant genetics and 120,000 if all were recessive.) In 2015, again according to the CDC, we performed 242,000 cycles of IVF in the U.S., the overwhelming percentage of those for the treatment of infertility. Genetic screening, if it was used at all, was used to detect missing or extra chromosomes, to improve the probability of the IVF cycles resulting in a pregnancy.
Having defined how we can advance precision medicine for inherited disease using the IVF version of gene therapy, let’s look at the alternatives. The first is doing better and better versions of what we have always done: develop drugs to treat symptoms. Let’s use Vertex Pharmaceuticals as an example.
In 2009, Vertex Pharmaceuticals sold 13 million shares of common stock, raising 500 million dollars, in part to develop ivacaftor (Kalydeco), the foundation of its cystic fibrosis (CF) franchise.
Vertex is a great company (disc: no position) and ivacaftor is an effective drug, improving lung function in a large sub-population of patients with cystic fibrosis. Combination therapy with other drugs expands these benefits to other subgroups of CF patients.
Vertex Pharmaceuticals’ drugs for cystic fibrosis cost approximately $300,000 per year. The drugs treat the disease and decrease the risk for its complications but do not cure it. Side effects include liver function problems and cataracts. Based on industry statistics, ivacaftor likely cost $1–2 billion to develop.
Since cystic fibrosis is caused by specific gene mutations, couples where both the mother and father-to-be carry a cystic fibrosis associated mutation have a one in four risk of conceiving a child with CF.
Approximately 1,100 babies are born in the United States per year with CF. That means that 4,400 pregnancies were conceived at risk.
Let’s make the very conservative assumption that the medical cost of care for patients with CF is $200,000, which assumes that the true cost of the drugs is substantially lower than the “sticker” price and that there are no costs for hospitalization or physical therapy or supplemental oxygen or drugs to prevent or treat the persistent lung infections that people suffering from CF are prone to.
Under this scenario, the 1100 CF children born per year would incur $2.2 billion of treatment expense per decade of life. The reality is likely a much higher number.
And these children would still suffer from the respiratory, gastrointestinal and other manifestations of disease, and this pain and suffering would continue into adulthood; indeed it would be life-long. Ivacaftor and similar drugs could greatly improve both the quality of life and the expected lifespan of CF patients, as long as the drugs were available and affordable and did not prove to have unexpected side effects or toxicities.
How does IVF / PGD compare to treatment with ivacaftor or drugs like it?
Let’s look at costs first. Imagine that the 500 million dollars raised by Vertex in 2009 was matched by a research grant. Assume that all couples at risk were identified by pre-conceptual screening and underwent in vitro fertilization (IVF) and preimplantation genetic diagnosis of their embryos for CF mutations. Assume each cycle cost $25,000.
Assuming a 33% take-home baby rate (I hate the term but it is the most common description) per cycle, the 4,400 couples would undergo 26,400 IVF cycles, with an aggregate one-time cost of approximately $220 million.
Subtracting the $220 million for IVF from the $500 million Vertex matching grant leaves $280 million, enough to prevent the next year’s CF cases and a good part of the year after that.
After the costs of the IVF cycles are absorbed, neither the families nor the healthcare system faces any costs at all.
And as for quality of life? The 2,500 children would suffer *zero* CF symptoms and have a normal life expectancy.
Having compared IVF and PGD with traditional symptom-directed therapeutics, let’s move on to capital G/ capital T Gene Therapy; in other words, treating existing patients with agents that replace the abnormal genes, swapping an abnormal gene for a normal version.
Having followed the progress in gene therapy over the past fifteen years, I am as excited and impressed as anyone with the progress made over the past few years, with the accrual of real efficacy data resulting in very significant clinical benefits for suffering patients that have had no good options. I am confident that this progress will continue. For many people, development of these therapies represents the difference between their current symptoms and a disease-free future.
But Gene Therapy still has a long way to go, and each entity is another billion+ dollar hill to climb. Plus, clinical experience with Gene Therapy is still relatively sparse — our aggregate safety database is pretty small and the picks and shovels of gene therapy, particularly the delivery systems and the viral vectors that carry the new genetic material into the nucleus, have not been optimized.
Then there is the pricing debate. Gene Therapy is very expensive to develop and not trivial to manufacture; the debate in 2018 over how these treatments should be priced comes down to “a little more than a million dollars per dose or a little less?”
Finally, one has to suffer from a disease to be cured of a disease. Preventing CF, or sickle cell anemia, or beta thalassemia, or polycystic kidney disease means thousands, or tens of thousands, or millions of days of pain, feelings of helplessness, anxiety and depression are replaced by normal life. Curing those same cases adds the days of suffering back.
Ultimately we do not need to compare IVF and PGD to Gene Therapy. The techniques are complementary. They solve two different but related problems and affect different but related patient groups. IVF and PGD prevent genetic disease for couples at risk for conceiving a child with disease. Gene Therapy cures (or at least treats) disease that affects a patient now. Both are relatively young technologies with processes that are far from optimized, and both hold tremendous promise for the future.
Of course only one of these is attracting billions of dollars for research and business development. And it’s not the one that already works.