An guest-post from Noor Siddiqui and Nikki Teran of Orchid

Rare diseases cost Americans around 8 trillion dollars a year. About half of that is direct medical costs. If families are lucky, they may go bankrupt paying for treatment of often questionable effectiveness. The unlucky families may go bankrupt just trying to find a cure; unfortunately less relevant as only about 5% of rare diseases have treatments. 

What can we do to reduce this burden? 

Two options are: 

1. Incentivize the development of more treatments

or

2. Reduce the incidence in future generations by screening as early as possible

Towards option one, the FDA created a “golden ticket” to encourage the development of treatments for rare diseases. Their transferable golden ticket (technically a “priority review voucher”) allows its owner to shave four months off the FDA’s review process. Previous vouchers have sold for as high as $350 million. But the program is set to sunset this fall, raising the question of whether the problem of rare diseases will be dealt with at the federal level.

Towards option two, preimplantation genetic testing may provide its own “golden ticket” for preventing rare diseases. Preimplantation genetic testing in concert with in vitro fertilization has already been shown to be cost effective for inherited rare diseases like sickle cell and Huntington’s disease, with cost savings in the millions per individual (not to mention the priceless improvement in quality of life). Advances in whole genome sequencing open up this technology to potentially prevent all rare genetic diseases.

Rare Diseases Aren’t Actually Rare – 10% of Americans are affected 

In the United States, a rare disease is defined as one that affects fewer than 200,000 Americans. Despite each disease affecting no more than .06% of the population, there are about 7,000 different rare diseases, meaning roughly 10% of the U.S. population has a rare disease. 

These numbers may seem large, but it makes sense if you consider the complexity of human genetics and development. Humans have around 20,000 genes. Mutations in some genes are lethal. Mutations in some genes lead to normal human variation; you may not even know the person has a mutation. And mutations in others lead to rare diseases; not lethal at or before birth, but often quite deleterious. Around 80% of rare diseases are genetic and many of these diseases are discovered in children – the mutations are severe enough to be noticed early.

30% of children with rare diseases do not live past the age of 10 

The devastation of rare diseases stems from their chronic, progressive nature and the fact that many involve multi-organ system failure or neurological impairments. For families, this can be unimaginably cruel. Children may be robbed of normal development or, even more brutally for families, regression. In Sanfillipo syndrome, children may develop normally until age four before showing any behavioral changes. They then progressively develop dementia and lose motor function. Most do not make it to adulthood.

The emotional toll is compounded by a profound sense of isolation as healthcare providers often lack expertise with the particular rare condition. Making matters worse, the few treatments that do exist frequently carry price tags in the millions, straining families to the breaking point financially as well as emotionally and physically through caretaking demands.

Just last December a gene therapy treatment was approved for sickle cell disease, which affects around 100,000 Americans and as many as one in every 365 African-Americans. Unfortunately, gene therapy is not a perfect cure. For sickle cell disease, the chemotherapy administered as part of the treatment leads to infertility.

But many rare diseases are too complex for over-the-counter solutions and affect too few people a year to interest drug companies. The market just isn’t there.

The FDA Priority Review Voucher Program Incentivises Orphan Drug Development

The priority review voucher program turns the inefficiencies in the FDA’s approvals process from a bug into a feature. The government created the priority review voucher program to incentivize the development of treatments of certain tropical diseases, rare pediatric diseases, and medical countermeasures against biological, chemical, radiological, or nuclear threats. These are known as “orphan” indications as they otherwise lack the financial incentive needed for a pharmaceutical company to invest in research.

The voucher allows for fast-tracked new drug application approval. Time is money for pharmaceutical companies. Being able to jump the approval line and get a drug approved in six months instead of ten can be huge for pharma company’s bottom lines.

The first priority review voucher sale was used by Regerneron Pharmaceuticals to get their PCSK9 inhibitor to market a month ahead of Amgen’s cholesterol lowering drug targeting the same pathway. 

Pharmaceutical patents last 20 years, but that clock starts when the patent is filed, not when the drug is approved. Patents are typically filed during preclinical trials, which can take upwards of two to five years. These are followed by clinical trials (when the drug is actually tested in people). Clinical trials can take upwards of three to ten years. By the time a drug is ready for FDA evaluation, there may only be a handful of years left on the patent.

Some drugs can make billions of dollars per year, meaning it may make financial sense to spend hundreds of millions of dollars on an extra four months of sales.

https://www.gao.gov/assets/gao-20-251.pdf

Vouchers are sold in more ways than one. Some larger pharma companies will acquire smaller biotechs, or their assets, when the smaller company is going after “voucherable” targets. These acquisitions can help bring to market drugs for orphaned diseases that may not otherwise have had the resources from venture capital to survive.

A friend of mine worked for small drug companies that were pursuing treatments for Ebola primarily because of the priority review voucher program. They weren’t targeting the financial incentive of the antiviral’s sale; they were targeting the voucher itself. 

Unfortunately, the priority review voucher program for neglected tropical diseases has already sunset. Despite (or more realistically due to) the recent pandemic, Congress was unable to reauthorize the Pandemic and All Hazards Preparedness Act this past fall. The neglected tropical disease and medical countermeasure priority review programs are casualties of congressional dysfunction. Without the financial incentives created by this program, many of these drug pipelines will dry up.

The pediatric rare disease program has a little more time — it’s set to sunset this fall — and its fate will likely be the same. Although the program has successfully contributed to 19 new treatments for rare pediatric diseases, even its continuation wouldn’t be enough. What about the other 6,981 rare diseases? For genetic disorders, prevention may be worth five thousand pounds of cure.

https://www.gao.gov/assets/gao-20-251.pdf

Preimplantation Genetic Testing (PGT) Can Prevent Many Rare Diseases

During typical in vitro fertilization (IVF), multiple embryos are created and the “highest quality” embryo is implanted. Historically, the “highest quality” embryo was determined subjectively based on appearance (“morphology”). This appearance often correlated with genetic issues and, inversely, later pregnancy success. Today, success can be increased by looking for the genetic issues directly: preimplantation genetic testing (PGT) has been shown to reduce the miscarriage rate from 9.1% to 2.6%. As genetic issues are more common with age, this particularly increases success in older mothers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8984775/figure/jld220010f2/

Cutting-edge preimplantation genetic testing can read 99.6% of an embryo’s genome, allowing for the identification of mutations that can cause rare diseases. This process works both for mutations that parents may pass on to their children (inherited mutations) and formutations that spontaneously occur (de novo mutations). Orchid performs this cutting-edge version of preimplantation genetic testing. The whole-genome sequencing has provided parents with information on these rare diseases, enabling improved decisions on which embryo to implant. 

Doctors already recommend screening procedures that are similarly priced and arguably less impactful. The chances of a 35 year-old woman having a child with Down syndrome is just under 0.3%. The life expectancy of someone with Down syndrome is 60 years and they generally report living happy, fulfilling lives. In contrast, the combined prevalence of the monogenic disorders Orchid screens for is 3-4%, more than 10 times as likely, and many are fatal at birth. Whole genome screening is able to detect these mutations whether they are inherited from the parents or de novo mutations that are unique to the embryo. Additionally, preimplantation genetic screening also provides information on chromosomal abnormalities like Down syndrome or others that are incompatible with life. Amniocentesis typically costs $4,100 per fetus while Orchid’s whole-genome testing is $2,500 per embryo.

Many of the disorders detectable by whole-genome preimplantation genetic testing carry additional cost beyond just reduced lifespan. 40% of infants in the NICU have a detectable single-gene mutation, meaning many of these babies require intensive care due to their detectable genetic disease. A single day in the NICU costs upwards of $3,500.

Even just alternative forms of diagnosis are comparable to whole-genome preimplantation genetic testing. A 2014 study that looked at neurodevelopmental disorders, which affect more than 3% of children, found the average family spent $19,100 on inconclusive diagnostics alone. That means the families spent nearly $20,000 each on diagnostics, not treatments or other care, before the cost of the test that ultimately provided a diagnosis.

Parents and Patients Should Have As Many Options as Possible

Ideally, biotech companies would have access to priority review vouchers and parents would have access to whole-genome preimplantation genetic testing. The federal government should create policies to maximize the public welfare. The priority review voucher program has encouraged the development of treatments that will change millions of lives. Systematic incentives like the voucher program can only be executed by this sort of top-down approach.

Practically, parents want to provide the best lives possible for their children. Preimplantation genetic testing can prevent monogenic genetic diseases and mitigate risk for chronic diseases like schizophrenia, bipolar disorder, and diabetes. However, the cost of IVF is an impediment to universal access, as the US does not have as extensive coverage as other countries. The federal government could require insurance to cover both IVF and genetic screening of embryos created through IVF. Parents would then have the necessary information to make their own choices about their children.

The voucher program will not be able to create treatments for all rare diseases and genetic tests may never be able to prevent all rare diseases. But the voucher program may be able to make many conditions minor inconveniences and genetic testing may provide families the opportunity to make informed decisions, making both social and financial sense. 

Authors 

Dr. Nikki Teran has worked in biotech at Pfizer, AncestryDNA, and startups. She earned her bachelor’s degree in Molecular Biophysics and Biochemistry from Yale, and her PhD in Genetics from Stanford, focusing on rare disease diagnostics. 

Noor Siddiqui is the CEO of Orchid, a reproductive technology company that built the world’s first whole genome embryo reports. She taught Frontiers in Reproductive Technology at Stanford, where she was an AI and genomics researcher and earned her Master’s and Bachelor’s degrees in Computer Science.