How A Hematologist Can Use IVF To Treat And Prevent Disease, Lower Costs And Make CRISPR Irrelevant

As the annual meeting of the American Society of Hematology takes place this week in San Diego, I humbly offer a plan to treat current patients with hemophilia, sickle cell anemia, thalassemia and other genetic hematologic diseases AND prevent future cases AND lower healthcare costs AND remove the incentives to alter the DNA inside embryos with CRISPR.



Some background:

Over the past few weeks 1) Novartis floated the idea of a four million dollar price tag for a curative gene therapy fora one-shot cure gene therapy for spinal muscular atrophy (SMA), 2) a researcher claimed to have used CRISPR (clustered regularly interspaced short palindromic repeats) to genetically alter embryos that were subsequently transferred and resulted in the birth of two baby girlsand 3) the United States held midterm elections in which the most important factor in races where seats flipped from one party to another was healthcare spending.

Three conclusions:

• Gene therapy, when finally approved, is going to be really expensive.
• “Fixing” embryos, and the still undefined risks of doing so, is a now issue and a now problem, and not an issue and problem for the future.
• Healthcare costs too much and people want solutions now.

In an ideal world, every couple at risk for having a baby (or, any many cases, another baby) with an inherited disease could take steps to eliminate that risk without exposing that child to unknown “off-target” effects (and bypass the ethical issues surrounding germline modification) and be able to afford to do so.

In this same ideal world, we should have incentives for biopharma entrepreneurs to develop treatments for those who already have these diseases, suffer pain and other symptoms, face a decreased life expectancy, and for whom only long-term, continuous and chronic treatments exist presently – treatments like gene therapy. But these treatments are expensive as hell to develop and, in a best-case scenario, would need to recoup their costs from a necessarily expensive single shot or infusion.

So how do we develop a system that results in effective treatment AND prevention AND continuous cost reduction? And does so in a way that makes the genetic modification of embryos and germ cells (sperm and eggs) less relevant?

My modest plan:

• Continue to let free market incentives (and free market capital) guide and fund gene therapy development
• Accept Novartis’ four million dollar proposed price tag for a gene therapy for SMA, or any other monogenic disease, and add in a provision that Novartis only gets paid if the treatment works PLUS…
• Fifty thousand of the four million dollars is set aside for reproductive medicine procedures (egg retrieval and freezing or in vitro fertilization with embryo freezing with preimplantation genetic analysis for disease carrier status), relieving affected families of the burdens of seeing their future children suffer, paying for their chronic care and/or prematurely limiting the size of their families.

This plan merges treatment of existing disease with prevention of future disease, an equilibrium that results in lower aggregate costs over time per disease.

Further, since this disease reduction through prevention and these cost savings rely on techniques that already work, that are relatively inexpensive ($25,000 or so for a single IVF/PGD cycle or $50,000 at most for 2-3 healthy pregnancies,) and avoid the ethical and philosophical aspects of germ line or embryo modification. PGD is purely diagnostic -- it allows us to choose between embryos (and in some cases now and more in the future choose eggs and sperm pre-fertilization) without the need for (and undefined risks of) modifying embryonic or germ cell DNA. While we work through these complex issues, our treat and prevent strategy makes them less urgent.

There are practical aspects of this type of plan of course. For one, there is no existing efficient patient supply chain that directs families with or at risk for genetic disease to IVF clinics. Second, the shifting foundation of risk sharing between Medicaid, private insurers, biopharma companies and the capital markets would be disruptive to existing research and development funding models. And finally, at least half of the pregnancies in the United States are unplanned, and therefore out of reach of a proactive process like this.

But each of these potential problems has solutions. Building a patient pipeline from rare disease centers, patient advocacy organizations, hematology departments and Children’s Hospitals to IVF centers (or perhaps the building of specific disease prevention IVF clinics) can start with a few provocative journal article and a grand rounds series. Our capital markets react to changes in the incentives within the healthcare system with a no tears, free markets efficiency that could digest this modest shift in incentives rather easily. And while half of pregnancies in the US are unplanned, those conceived by families at risk are already under the care of hematologists and others who can counsel and put these stakes in perspective.

Offer every family with a child or family member with a at risk for conceiving a child with one of these diseases an in vitro fertilization (IVF) cycle with preimplantation genetic diagnosis (PGD). Freeze and store the eggs or embryos created, and bring the risk for having another affected baby down to zero. Pay for it all with a small percentage of the sky-high gross margins of the gene therapy treatments in development, and make that a condition for FDA approval.

A crazy plan? Perhaps. I’m open to suggestions for others that treat existing patients, prevent future disease, distribute risk more equitably between every group that stands to benefit (and minimizes the burden on patients and their families) and by default leads to lower costs over time.

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