Gene therapy

50 years after it was first proposed, gene therapy - the modification of DNA to treat disease - has gone from science fiction to clinical reality. Where traditional drugs manage the metabolic effects of a disease, gene therapy cures disease at its DNA source. However, as prices for gene therapies are released, widespread sticker-shock is raising questions about affordability and fair pricing. As a result, there is no guarantee that these potentially curative treatments will actually get to the patients who need them.

In order to safeguard gene therapy’s vast promise, scientists and biotech leaders need to establish a win-win social contract with the public. Gene therapies should be provided at low-cost to patients, market incentives for research and development must be preserved, and governments should foot the bill.

Initially proposed at the time of the first Moon landing, the idea of gene therapy is elegant in its simplicity: cure genetic disease with a one-time repair of the faulty DNA¹. However, for therapies to get to patients, the benefits to patients must outweigh the risks: gene therapy has to be proven to be both safe and effective. This proved to be a significant challenge. In the 1990s and early 2000s, the first wave of gene therapy trials presented little clinical benefit, or were too toxic. After some sobering setbacks, including a high profile and widely criticised patient death, gene therapy itself was left for dead by many academics and investors, written off as impractical and fraught with risks²,³.

Fast forward 15 years to today. Against all odds, and after much fine-tuning, gene therapy is mounting a comeback, with several gene therapies approved and many close behind ⁴,⁵. For the first time, humanity is effectively challenging the inevitability of genetic disease. Spark Therapeutics’ Luxturna is emblematic of this paradigm shift in medicine.

In December 2017, the United States (U.S.) Food and Drug Administration (FDA) approved Luxturna (voretigene neparvovec-rzyl) as the first gene therapy in the U.S. for an inherited disease ⁶. Luxturna treats patients with inherited vision loss caused by mutations in the RPE65 gene. How does the therapy work in practice? In short, 150 trillion copies of the functional RPE65 gene, each carried by a viral vector, are injected into the eye, just underneath the retina. The functional gene makes its way into the retinal cells, which then acquire healthy function, and vision is restored. At the 1 year follow-up, children who underwent the treatment in the phase 3 trial were able to see rain for the first time, and observe stingrays at the aquarium⁷.

Gene therapies are expensive

Children successfully treated with Luxturna and other curative treatments like it will no longer have a disability limiting their future career or life prospects, allowing them to better contribute to and engage with society for many years ⁷. Yet, how do you price something as unquantifiable as sight?

According to Spark Therapeutics, the answer is $850,000, or $425,000 per eye, for the one-time curative treatment. That’s the equivalent of buying two Lamborghini Aventadors! The swift media reaction re-sparked the debate about drug pricing, and in the process, eclipsed discussion about the inherent value of such treatments. The Financial Times wrote: “Luxturna is the most expensive treatment on the market”; while STAT, a prominent life-science website, wrote: “Spark prices its gene therapy as the most expensive U.S. medicine”; and FiercePharma wrote: “There's a new medicine atop of pharma's global pricing charts”⁸,⁹,¹⁰.

High drug prices have long been the target of public frustration in both North America and Europe. As gene therapies finally arrive on the market, they are setting record high prices, further fueling the debate of what’s too high a price to pay for a cure. $850,000 dollars for Luxturna, but also $1,000,000 for Glybera (from UniQure), which treats a rare lipid disorder. Kymriah (from Novartis) which, as a chimeric antigen receptor T-cell (CAR-T) therapy, programs immune T cells to target cancers, costs $475,000. Similarly, Yescarta (from Kite Pharma/Gilead), another CAR-T therapy, lists at $373,000¹¹. Underpinning the concern surrounding the high prices is the fear that patients and institutions, including hospitals, would not be able to afford these life-changing therapies. Additionally, gene therapies are expected to be curative, however, the data on long-term outcomes does not yet exist. Companies like Spark Therapeutics have responded by offering outcome-based rebates, and exploring payment instalments.

In order to be widely available to patients, new gene therapies must be commercially viable. For instance, despite a $1,000,000 price tag, UniQure’s pioneering Glybera, the first gene therapy approved in Europe, was pulled from the market after failing commercially ¹². Uniqure’s target disease - familial lipoprotein lipase deficiency - was very rare, and only one patient ended up being treated during Glybera’s five years on the market. That patient’s physician had to submit a large binder of paperwork and follow-up with a personal call to the insurance company’s CEO ¹³. The physician had to expend a lot of time to advocate for his patient, time that many physicians do not have. Today, hundreds of patients with lipoprotein lipase deficiency are left with no available gene therapy option, suffering from pain and undergoing hospitalizations, despite the fact that curative technology exists.

Looking forward, the questions we must ask ourselves are: what is the value of a cure for a genetic disease to society, even if that disease is rare and relatively few patients are cured? The answer is not a simple one, but to get there we can start by exploring how gene therapies differ from traditional drugs.

The public’s social contract with biopharma

The established social contract between the public and the biopharmaceutical industry is premised on traditional drugs. Prices are high whilst the branded drug is under patent protection for a limited number of years, but once the patent expires, competition from generic alternatives drives down the cost of the drug for the future. The result is that companies are encouraged to innovate and develop new drugs, while patients benefit from a growing abundance of inexpensive, life-saving drugs. This vast bank of useful drugs, termed armamentarium in physician-speak, includes cholesterol-lowering statins, blood pressure medications, beta-blockers, antibiotics, and many more drug classes that, combined, save millions of lives every year worldwide, improve quality of life, and extend life expectancy. The inevitable expiration of patent protection and attendant introduction of inexpensive generic versions, a process termed “genericization”, leads to lower prices that benefit many patients in the future. Indeed, genericization is the cornerstone of this implicit contract¹⁴.

Even if this social contract is violated legally, society perceives injustice. Indeed, in 2015, when Martin Shkreli’s biotech company, Turing Pharmaceuticals, suddenly raised the price of an old, off-patent traditional drug - Daraprim - from $13.50 to $750 a tablet, a massive public outcry followed¹⁵. Since Turing Pharmaceuticals was the only Daraprim seller in the U.S., patients with HIV/AIDS or cancer, who needed Daraprim to fight off infections, found themselves facing prohibitive bills. This widely-reported incident highlighted that in exchange for paying for expensive new drugs, the public expects access to inexpensive generics. After all, the point of developing new drugs is to prolong and increase quality of life, with financial incentives for companies and researchers to continue to innovate and develop new drugs. The current system overall arguably balances these two aspects fairly well, but that may not be the case for gene and cell therapies because they are markedly different.

Gene therapies are different

Gene therapies are different from traditional drugs. Instead of being taken for months or years, gene therapies are designed to be one-off curative treatments. However, the one-time treatment gives gene therapy companies only one opportunity to recover their costs. An insulin manufacturer, on the other hand, has several such opportunities per day, per patient, over the course of their lifetime. Furthermore, the nature and complexity of gene therapies makes genericization unlikely. While Luxturna is an example of an “in vivo” therapy where the therapy is directly injected into the patient, many other gene therapies require a cell handling step outside the body: “ex vivo.”

For instance, a gene therapy cure for hemophilia entails removing blood stem cells and introducing the functional gene with a viral vector, before re-infusing the modified blood stem cells back into the patient. In another example, CAR-T cell therapies require collecting a patient’s own immune T cells and adding new DNA “ex vivo” using a viral vector. The new DNA rewires T cell-killing activity against a B-cell marker, CD19, therefore allowing for the targeting of B-cell acute lymphoblastic leukemia (Kymriah) or large B-cell lymphoma (Kymriah and Yescarta). The T cells are then infused back into the patient to attack the tumor. The virus production and cell handling procedures require rigorous manufacturing, tightly controlled conditions, and quality control in highly specialized clinical-grade Good Manufacturing Practices (GMP) facilities.

In summary, while gene therapies are usually given only once, with hopefully life-long effects, they are inherently complex and expensive to manufacture. This is beyond the resources and expertise of a typical generics drug manufacturer. Additionally, small differences in the generic gene therapy could lead to far worse clinical results. So, if gene therapies will remain expensive for the indefinite future, we need to devise a different social contract that will allow for these life-saving therapies to get to the patients that need them.

We need more gene therapies

Although individual genetic diseases are rare, when combined, rare diseases affect 1 in 10 individuals, and about half of those affected are children¹⁶. Of the more than 7,000 rare diseases, 95% don’t have any approved therapy. Because gene therapy fixes the faulty DNA that causes a disease in the first place, expanding gene therapies is our best hope for curing inherited diseases.

There is a clear moral case for curing those who suffer from debilitating or painful disease. However, even from a pure financial perspective, it makes sense to pursue gene therapy as a cost-effective approach¹⁷. Existing therapies which only manage the downstream metabolic consequences of the faulty DNA, and have to be taken regularly, are already vastly expensive, with varying clinical results. Patients with sickle cell disease have to endure agonizing pain their whole lives with frequent emergency visits to the hospital. Lifetime costs reach into the millions. Current therapies for “bubble boy” X-linked severe combined immunodeficiency (X-SCID) can cost $500,000 a year, and life expectancy remains low. Hemophilia management is overall more successful in terms of clinical outcomes, but still costs approximately $160,000 per year for hemophilia A and $130,000 per year for hemophilia B.

In addition to the direct costs of current non-curative treatments, there are many other indirect and less quantifiable costs of continued disease. Since children bear a disproportionate disease burden, gene therapies will allow for a healthier workforce and economic participation. In addition to affecting patients’ lives and work prospects, genetic diseases incur significant opportunity costs for caregivers, who often compromise their careers to care for their loved ones.

At the policy level, there is growing realization of the societal value that gene therapy provides. For example, in January 2018, the U.K.’s National Institute for Health and Care Excellence (NICE) commission approved Strimvelis (from GlaxoSmithKline), a gene therapy for adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID), a life-threatening metabolic disorder that results in a non-functioning immune system¹⁸. Children with ADA-SCID suffer from developmental delay and chronic infections. In recommending the €594,000 ($736,000) gene therapy, NICE applied a new limit for the treatment of rare diseases, based on cost-effectiveness. Strimvelis was subsequently acquired by Orchard Therapeutics in April 2018. Similarly, in the U.S., an insurance company named Harvard Pilgrim decided to cover Luxturna soon after FDA approval. A move towards annuity-based payments and pay-for-performance, as spearheaded by Spark Therapeutics, is designed to demonstrate the value of gene therapy over time.

Nevertheless, the public remains deeply wary of new expensive therapies. High prices on brand-name drugs feed corporate profits, while many patients struggle to pay their share of rising healthcare costs. In the U.S., insured patients have been asked to pay more for medications, a process known euphemistically as “cost-sharing”. New non-curative medications can cost more than $100,000 per year, and many insurance plans, including Medicare, require patients to contribute thousands of dollars per year¹⁹. The resulting phenomenon, termed financial toxicity, results in a quarter of all cancer patients not filling a prescription due to cost, with many more skipping doses or cutting pills²⁰,²¹. Frustrated physicians have raised the alarm in medical journals and on social media²²,²³,²⁵,²⁶. Financial toxicity has become a common, severe side-effect of costs being shifted disproportionately onto patients.

Although they dominate headlines, high prices for a cure for an inherited form of blindness or sickle cell disease are not the true problem. Because of the curative value of these therapies, high prices are necessary to attract talent and investment to the field. Uniqure’s experience with Glybera, and gene therapy’s recent history, is a reminder that gene therapy progress is not inevitable. If gene therapies are not commercially viable, they will not get to patients. However, it is imperative that the burden of the cost of treatment is not unfairly placed on the shoulders of the sick and the dying. Already, 50% of people with genetic disease are in medical bankruptcy. If we do not act now, financial strain could prevent patient access to gene therapies, as experienced currently in the U.S. healthcare system for cancer drugs²⁰.

A new social contract

As a society, we have yet to discuss how gene therapies deliver vast social value and thus should be a funding priority along the lines of critical infrastructure. We expect a major bridge or tunnel to cost billions of dollars and accept that cost for the widespread and diffuse benefits that good infrastructure provides. The same applies to clean water and sanitation. Gene therapies are a new, different type of ‘public good’, distinct from traditional drugs, therefore governments and societies should pay for them.

Even in societies without universal health care coverage, there is precedent for comprehensive coverage for certain indications. In the U.S., since 1972, Medicare covers dialysis for any patient with end-stage renal disease²⁷. The cost to Medicare alone is $34 billion dollars a year for about 500,000 patients, with additional costs covered by other payers. The 5-year survival rate of patients on dialysis is 35%²⁸. In comparison, gene therapy would be far more cost-effective with far higher quality of life and productivity benefits.

Only dedicated government support can drive the necessary progress for gene therapy. Recent gene therapy clinical trial data for beta-thalassemia, a devastating inherited blood disease that causes severe anemia that affects more than 300,000 people, is very encouraging⁵. However in some countries where beta-thalassemia is relatively widespread, the necessary facilities do not exist. Countries and governments must work together with biotech to build global gene therapy infrastructure. Let’s consider the human and economic benefit of expanded access to gene therapy beyond the originator countries.

For patients, gene therapy must be affordable, and free of toxic financial side-effects. Indeed, as in building a bridge or highway, governments need to invest in gene therapy infrastructure and treatments. Scientists, physicians, biotech leaders, and policymakers need to engage directly with the public and establish this gene therapy social contract. It’s only by working together towards the common goal of delivering cures for genetic diseases that we can realize the full potential of this new dawn for medicine.

Gene therapy’s new phase

The development of gene therapy occurred in three stages, each stage defined by its own unique challenge. In the first stage (1965-1990), human gene therapy had to clear initial conceptual and technical obstacles. Namely: can foreign DNA, when introduced, correct a genetic disease? The second stage (1990-2015) was one of initial technical and clinical implementation, characterized by challenges in the clinical application of human gene therapy and attendant technical and process improvements. We have now entered a third stage, one of commercial and affordability challenges. For those who have worked hard to fine-tune the science behind gene therapy, it’s only the latest installment of a long saga. Yet, perhaps, it’s also the most crucial in terms of delivering on gene therapy’s promise to patients. After all, to quote Doug Olson, one of the first CAR-T cell patients, “a cure that is not accessible to all patients is not a cure at all”²⁶.

The views expressed in this article are my own and may not reflect those of institutions or individuals with whom I am affiliated with. I do not have any financial conflicts to disclose.

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