A Paradox of the Field's Own Success: Unintended Challenges in Bringing Cutting-Edge Science from the Bench to the Market

Abstract

INTRODUCTION

Gene therapy, once a highly experimental field fraught with unknowns, has firmly established itself within the apparatus of biological therapies to combat some of the most elusive of human diseases. Since that pivotal day on September 14, 1990, when a 4-year-old girl with adenosine deaminase deficiency severe combined immunodeficiency (ADA SCID) received the first infusion of autologous T cells, into which a normal ADA gene had been inserted,¹ researchers have diligently filled critical knowledge gaps, propelling gene therapy from speculation to reality.

The market for gene therapy is on a steady ascent, poised to reach a global market size of $42.56 billion by 2030.² According to the most recent Gene, Cell, & RNA Therapy Landscape Quarterly Data Report, 27 gene therapies have been approved globally for clinical use, with an additional 2082 therapies in various stages of development.³ In the United States alone, 16 gene therapies have been approved,⁴ and projections from the U.S. Food and Drug Administration (FDA) suggest that between 10 and 20 cell and gene therapy products will be approved annually by 2025,⁵ with an estimated 1.09 million patients in the United States receiving gene therapy between January 2020 and December 2034.⁶

To support this growth, FDA initiatives like the Office of Therapeutic Products⁷ and the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program⁸ strive to usher gene therapy from the realm of research to approved therapeutics.

Despite these promising medical and economic prospects, challenges persist. Commercially, concerns loom over the affordability of gene therapy.⁶ An analysis by the Institute for Clinical and Economic Review suggests that the average cost of a gene therapy is between $1 million and $2 million per dose.⁹ This financial barrier, coupled with the threats of uninsurance¹⁰ and underinsurance,¹¹ poses a risk of limiting access to gene therapy for some patients.

Although a segment of eligible patients in the United States receive coverage from Medicaid, a study published in JAMA Pediatrics estimated that if a $1.85 million sickle cell gene therapy were to be administered to only 7% of qualifying patients annually, the average 1-year budget impact per state Medicaid program would be ∼$30 million, causing a considerable strain on yearly Medicaid budgets.¹²

UNRAVELING THE “GREAT ABANDONMENT”: INDUSTRY SHIFTS IN RARE DISEASE THERAPIES

More recently, a newer challenge has surfaced. In what has been coined the “Great Abandonment,”¹³ since 2021, drugmakers have shelved, abandoned, or rolled back development in >50 rare disease programs (Table 1), based on a review of public filings and news reports conducted from August 2023 to November 2023. One must also note that this review is limited by what companies choose to disclose.

Table 1.

Summary of Dropped Gene Therapy Programs

Sponsor	Program	Citation
Taysha	SCL6A1 epilepsy	^19,20,52,53
	Fragile X
	Prader-Willi
	KCNQ2 epilepsy
	FoxG1 epilepsy
	CLN1
	CLN7
	SURF1 deficiency
	GM2 gangliosidosis
	Giant axonal neuropathy
Homology	Phenylketonuria	⁵⁴
	Hunters syndrome
	Metachromatic leukodystrophy
AvroBio	Fabry disease	^55 –57
	Gaucher disease
	Hunter disease
	Pompe disease
Neurogene	Aspartylglucosaminuria	⁴⁶
Novartis	Rett syndrome	^24,25,58
	Sickle cell disease
Pfizer	All preclinical gene therapy R&D^*	⁵⁹
Selecta	Methylmalonic acidemia	⁶⁰
Graphite Bio	Sickle cell disease	²⁶
Astellas	Duchenne muscular dystrophy	⁶¹
Takeda	All preclinical gene therapy R&D^*	^62,63
Freeline Therapeutics	Hemophilia A	⁶⁴
	Hemophilia B
	Fabry disease
PTC Therapeutics	Friedreich ataxia	⁶⁵
	Angelman syndrome
	Programs targeting rare CNS disease^*
	Programs targeting rare ophthalmological disease^*
Roche	Hemophilia A	⁶⁶
GlaxoSmithKline	All investment in gene therapy^*	⁶⁷
Sangamo	Sickle cell disease	²⁸
Orchard Therapeutics	ADA-SCID	^68 –70
	Wiskott-Aldrich
	X-linked chronic granulomatous disease
Passage Bio	Krabbe disease	⁷¹
	Metachromatic leukodystrophy
Editas Medicine	Cutting two ophthalmological diseases^*	⁴⁰
	Cutting NK cell cancer therapies^*
Bluebird Bio	Zynteglo^**	^41,72
	Skysona^**
Amicus	CLN6	^73 –76
	CLN3
Intergalactic	Company has since closed	⁷⁷

Discontinued program is unspecified.

Discontinued only in European markets. (Zynteglo is treatment for Beta-thalassemia; Skysona is treatment for Cerebral adrenoleukodystrophy).

ADA-SCID, adenosine deaminase deficiency-severe combined immunodeficiency.

Although this retreat of biotech companies has largely coincided with a broader pharmaceutical industry downturn,^14,15 the issue draws parallels to the challenges that vaccine developers have faced when introducing their products to the market. For years, pharmaceutical companies refrained from pursuing vaccines because, like gene therapy, the process of researching, developing, testing, and producing vaccines is costly, intricate, and carries significant risks.¹⁶ Furthermore, most vaccines are only administered a handful of times over the course of a patient's life, akin to the promise of one-time dosage gene therapy, thus resulting in a much smaller market than other drug products.^16,17

The observed shift may signify a natural evolution of the field. Gene therapy development is inherently expensive, necessitating companies to make calculated choices around manufacturing. This often leads companies to strategically pivot from less viable products to products with a higher likelihood of market success.¹⁸ For example, Taysha, a Dallas-based company that once listed 18 programs in its pipeline¹⁹ with plans to launch a new product every 2 to 3 years, has since shelved all but one program for Rett Syndrome (NCT06152237).^20,21

Another potential factor could be intercompany competition, prompting companies to divest from a program when a similar product progresses further along with competitors. In 2022, Astellas discontinued its three gene therapy programs for Duchenne muscular dystrophy (DMD),²² whereas Sarepta's DMD drug, Elevidys, secured FDA approval in June of 2023.²³ Similarly, Novartis,^24,25 Graphite Bio,^26,27 and Sangamo Therapeutics²⁸ withdrew their respective sickle cell gene therapy programs. In contrast, Bluebird Bio and Vertex Therapeutics both received FDA approval for their sickle cell therapies this year.²⁹

Vertex has also received approval for their CRISPR gene editing sickle cell therapy in the United Kingdom.³⁰ Although such practice reduces redundancy in the field, it is important to highlight that there is no evidence suggesting that having various brand-name drugs within the same category reduces the listed prices of those drugs.³¹

This trend might also hint at a degree of skepticism within the pharmaceutical industry regarding the profit potential of gene therapies, prompting reflection on the balance between scientific progress and the commercial viability of groundbreaking medical treatments. One highly publicized example^13,32 was the abandonment of OTL-101 for ADA SCID by Orchard Therapeutics, despite excellent data published in the New England Journal of Medicine.³³ Comparably, after unsuccessful negotiations with European payers regarding reimbursement costs, Orchard opted to divest from Strimvelis, a stem cell gene therapy for SCID. Before Orchard's involvement, Strimvelis had been discontinued by GlaskoSmithKlein³⁴ after being available in the EU since 2016.¹³

GLOBAL DISPARITIES: CHALLENGES AND ADVOCACY

Disruptions to the gene therapy market may further exacerbate regional disparities between high and low- and middle-income countries (LMICs). The American Society of Gene and Cell Therapy's call to “level the playing field” for equitable access to gene therapies globally³⁵ and the World Health Organization's advocacy for an equity-driven gene therapy agenda³⁶ demonstrates an international consensus regarding more widespread access to therapies. Despite this, among the previously mentioned 27 approved gene therapies worldwide, 8 have received approval in middle-income countries, while 0 has been approved in low-income countries,^3,37 underscoring a stark imbalance.

Furthermore, patients with rare diseases in LMICs often encounter diagnostic delays, intensifying inequities in access.³⁸ Verónica de Pablo personally experienced this struggle with her son and Lautaro was diagnosed with metachromatic leukodystrophy (MLD) at 10 years of age. In 2011, after years of consultations and misdiagnoses, Verónica reached out to researchers in Milan conducting a gene therapy trial for MLD. They explained to her that the trial only admitted patients up to 6 years old. After her experiences with her son, Verónica founded the Fundación Lautaro te Necesita,³⁹ a nonprofit organization in Argentina whose mission is to contribute to improving the quality of life of people affected by leukodystrophies.

Verónica, now a full-time advocate working to increase awareness for leukodystrophies, explained that her son's story is not an uncommon one. “The problem is that all clinical trials have requirements to apply, and age is one of them. If these diseases are not detected at birth, then we will have treatments available without patients who can be treated, because, when they are diagnosed, it is too late. I know babies who have not been able to access gene therapy due to their age.”

Even if LMICs approve gene therapies, their cost will exert a severe strain on their health care systems. For example, when Zolengasma was approved in Brazil for the treatment of children with spinal muscular atrophy (SMA), the Brazilian drug pricing authority set a maximum provisional price that was 77% less than what was intended by the manufacturer, Novartis, citing concerns with the long-term efficacy of the drug. Consequently, Novartis ceased commercialization in Brazil.⁴⁰ Court mandates and a constitutionally protected right to health have obligated the Brazilian Ministry of Health to finance the therapy, and the government has now agreed to cover treatment in certain cases, however, there is continued debate regarding its cost and its staggering impact on the Brazilian health system.⁴¹

A PATH FORWARD: NAVIGATING COMPLEXITIES IN ACCESS AND EFFICIENCY

These ongoing dynamics prompt contemplation about the future landscape of gene therapy development and ways to optimize both approval and delivery of lifesaving treatments. The FDA's recent reiteration of support for novel drugs targeting rare diseases through the START Pilot Program, whose objective is to provide resources to researchers and accelerate the clinical trial process for rare disease therapies, signifies another step toward a more efficient development standard.⁸ However, the complexities within chemistry, manufacturing, and controls present significant hurdles in terms of time and cost, often stretching into years and millions of dollars. Beyond this, auxiliary tasks such as shipping and equipment logistics add to the overall expenses of bringing therapies to market.

Introducing a streamlined process under a quality by design paradigm, with input from both the FDA and academic circles, could modernize the developmental phase. Such an approach would not only aim to mitigate manufacturing risks but also ensure product quality, aligning with the FDA's mandate of ensuring safe and effective pharmaceuticals. Nevertheless, achieving this objective demands a strategic emphasis on organizational efficiency and early-stage risk mitigation strategies. These considerations are crucial to safeguard and build upon the successes already achieved in the field. Further collaboration between academic institutions and the FDA is warranted to ensure that approved therapies not only reach the market but also have a sustainable impact.

In Europe, initiatives such as the Access to Gene Therapies for Rare Disease (AGORA) have embarked on this journey with plans to serve as a central body of support for academic medical centers and not-for-profit organizations, seeking regulatory approval. Ultimately, AGORA aims to explore the establishment of an independent sustainable not-for-profit entity to support marketing authorization, delivery, and access to therapies that may not be commercially sustainable, consequently ensuring availability to patients in need.⁴²

CONCLUSION

Although classified as “rare,” there are >7000 diseases, each impacting fewer than 200,000 Americans and collectively affecting ∼30 million people in the United States.⁴³ A considerable number of these conditions pose life-threatening risks and lack approved treatments. The prospect of curing these devastating diseases remains an exhilarating challenge. Beyond the excitement lies the profound hope for patients and families to live fulfilling and productive lives free from the burdens of continued clinical management. However, without robust and sustained investment in the field, we risk thwarting crucial developments. In the realm of patient care, these considerations bear tangible real-life consequences.

Orchard's OTL-101 has since been returned to researchers at UCLA who have begun working to enroll patients under a compassionate care protocol and ensure this lifesaving medicine reaches those who need it.⁴⁴ Alongside this, the Fondazione Telethon in Milan, Italy, has taken up the license to produce and distribute Strimvelis in Europe and plans to take up the helm for other gene therapies as well.⁴⁵ Several not-for-profit organizations such as the Rare Trait Hope Fund,^46,47 Cure SMA,⁴⁸ the Muscular Dystrophy Association,⁴⁹ and Fundación Lautaro te Necesita³⁹ have made meaningful strides, collaborating with industry, funding clinical trials, and offering support to patients and families facing challenges associated with rare conditions.

Similarly, for-profit companies such as Elpida Therapeutics have emerged with plans to advance programs that other biotech companies have paused or have found difficult to bring through to completion.^50,51 Although these efforts are commendable, a sustainable unifying solution within the field remains imperative for gene therapy to fulfill its potential in transforming the lives of those affected by rare diseases.

AUTHOR DISCLOSURE

No competing financial interests exist.

FUNDING INFORMATION

No funding was received for this article.

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