PATIENT-CENTERED OUTCOMES RESEARCH INSTITUTE WWW.PCORI.ORG | [email protected] | FOLLOW US @PCORI 1828 L STREET NW, SUITE 900 | WASHINGTON, DC 20036 | 202.827.7700 ISSUE BRIEF Gene Therapy in 2019: Milestones and Challenges or as long as medical researchers have been able to identify the genes responsible for particular KEY POINTS Fdiseases, they have set their sights on using that knowledge to devise gene therapies—ways to repair or Gene therapy research has yielded 10 circumvent the abnormal gene expression—to prevent approved treatments so far, and dozens or treat those diseases. What is the state of the science more are on the horizon. These therapies of gene therapy in 2019? What can we expect in the target both rare genetic diseases and more near future? And what gaps and challenges stand in the common diseases like some cancers. way of realizing our goals? Both research and clinical care face To address those questions, we reviewed the findings technological, ethical, and especially from completed trials of gene therapies and those financial challenges. ongoing trials that have completed recruitment. We also interviewed a diverse group of stakeholders, including Experts and stakeholders are exploring clinicians, pharmaceutical industry representatives, ways to tackle some of the most patients and patient advocates, government and private challenging issues, such as modifying insurers, and policy makers on the challenges and the approval process and how to pay important issues as well as their hopes for gene therapy. for treatment. This brief summarizes the findings of the report for policy makers. Gene Therapy Explained administered to patients directly (to modify cells in the body) or they may be transferred to a patient’s cells in the We define gene therapies as products that replace or lab with the modified cells then being transferred back to circumvent defective genes by a variety of mechanisms: the patient. Since 2013, 10 therapies have successfully navigated f Replacing a disease-causing gene with a healthy the multi-phase Food and Drug Administration (FDA) copy of the gene, approval process, for the treatment of 11 different f Repairing, inactivating, or modulating a disease- diseases (Table 1). Only a few of the therapies are causing gene that is not functioning properly, or expected to cure the targeted disease with one f Introducing a new or modified gene into the treatment, while most other therapies require body to help treat a disease repeated—possibly lifelong—treatments. However, whether or not potentially curative treatments live up to Gene therapy products that replace defective genes that potential has yet to be seen. Treated patients have or introduce new genes comprise the gene itself and not yet been followed long enough to see if benefits a vector (delivery vehicle) that consists of a tiny piece persist, compared to the 10 or more years needed to see of viral or bacterial DNA. These products may be if cures have been realized and harms are avoided. RESEARCH DONE DIFFERENTLY® Table 1. Approved Gene Therapies as of 2019 Treatment Repeated Treatment Disease Mechanism of Gene Therapy (Generic names, Year approved) Required? Metabolic and Other Multi-Organ Diseases Homozygous familial Kynamro Antisense Yes hypercholesterolemia (Mipomersen sodium, 2013) Vision and Neuromuscular Diseases Biallelic RPE65 mutation- Luxturna Adeno-associated viral vector No associated retinal dystrophy (Voretigene neparvovec, 2017) serotype 2 (AAV2) Duchenne muscular dystrophy Eteplirsen Antisense Yes (Exondys 51, 2016) Spinal muscular atrophy Spinraza Antisense Yes (Nusinersen, 2016) Polyneuropathy of hereditary Tegsedi Antisense Yes transthyretin amyloidosis (Inotersen, 2018) Hereditary transthyretin Patisiran RNA interference (RNAi) Yes amyloidosis with (Onpattro, ALN-TTR02, 2018) polyneuropathy Spinal muscular atrophy Zolgensma1 Adeno-associated virus (AAV 9) No (Onasemnogene abeparvovec-xioi, 2019) Cancer Melanoma (inoperable lesions Imlygic Genetically modified oncolytic Yes such as those in organs) (Talimogene laherparepvec, 2015) viral therapy–replication- competent, attenuated derivative of herpes simplex virus type 1 Relapsed or refractory large Yescarta Chimeric antigen receptor No B-cell lymphoma (Axicabtagene ciloleucel, 2017) (CAR)-T CD19-targeted cell immunotherapy Adult relapsed or refractory Kymriah Chimeric antigen receptor No large B-cell lymphoma (Tisagenlecleucel, 2018) (CAR)-T CD19-targeted cell immunotherapy Pediatric refractory B-cell Kymriah Chimeric antigen receptor No precursor acute lymphoblastic (Tisagenlecleucel, 2017) (CAR)-T CD19-targeted cell leukemia immunotherapy 1 Zolgensma was approved by the FDA after completion of the report on which this brief is based. 2 Issue Brief The approval process was designed to ensure, to the “cure” that has been a prime goal of gene therapy), and it extent possible, that a medical intervention is effective, has the potential to cause severe liver damage. that all potential safety issues are considered, and that Another gene therapy, LuxturnaTM (Voretigene the benefit-to-risk ratio is acceptable. Gene therapy neparvovec), approved in 2017 for the treatment of a interventions may also be subject to ethical and social rare eye disease, was the first approved to make use of scrutiny, as well, to gain approval. a—theoretically—benign viral vector to transport genetic Our review identified dozens of seemingly promising material into human cells. Localized side effects are therapies that have undergone testing in controlled trials, observed in about two-thirds of recipients. although at least one treatment has been approved Gene therapies have also been approved for five without a placebo-controlled trial, because such trials neuromuscular disorders. While SpinrazaTM (nusinersen) are not always feasible for gene therapies targeted to has been approved to treat a rare condition called extremely rare or devastating diseases. And even though spinal muscular atrophy with repeated administration, some gene therapies appear promising and have been ZolgensmaTM (Onasemnogene abeparvovec-xioi) has approved or are near approval, the evidence to support just been approved to treat this condition with a single clear clinical effectiveness may be lacking. administration, which may cost over $2 million. Conditions for which Gene Therapies Though much of the initial promise of gene therapies lay in their potential to treat rare, incurable conditions, Have Been Approved science is discovering that these therapies can The interventions approved by the FDA thus far target successfully treat much more common diseases such as a variety of diseases, ranging from metabolic disorders cancer and blood disorders. to neuromuscular disorders to cancer. The first gene therapy to be approved, KynamroTM (Mipomersen sodium), Therapies on the Horizon treats familial (inherited) hypercholesterolemia; this More than 75 additional gene therapies have shown condition results in significant suffering and decreases life promise in clinical trials and may be close to approval to expectancy by causing dangerously high blood cholesterol treat patients. These therapies are being tested for their levels. The disease can be caused by a variety of defects in ability to treat multiple disease types, from the exceedingly any of several genes that encode the proteins involved in rare (like cerebral adrenoleukodystrophy, commonly forming and transporting cholesterol throughout the body. known as Lorenzo’s Oil disease) to the far more common The approved therapy appears to work in many but diseases like mesothelioma and Parkinson’s (a sample of not all patients, highlighting the vital importance of conditions is shown in Table 2). As Table 2 shows, some knowing the precise genetic cause of a patient’s disease. diseases are the targets of multiple therapeutic efforts, In addition, this treatment must be administered via partly because of the many different mutations that can repeated injection (contrary to the single-treatment have the same clinical presentation. Table 2. Examples of Diseases for which Gene Therapies Are in Clinical Trials (Number of Unique Therapies) Metabolic and Other Multi-Organ Diseases Cancer f Amyloidoses (5) f Adult solid tumors (16) f Familial amyloidotic neuropathies (1) f Pediatric neuroblastoma (1) f Cerebral adrenoleukodystrophy or Lorenzo’s Oil f Leukemia and lymphoma (20) disease (1) f Mucopolysaccharidosis I, II, IIIa, b (1) Immune Disorders Vision Diseases f HIV (2) f X-linked retinitis pigmentosa (2) Blood Diseases Neuromuscular Diseases f Hemophilia A and B (5) f Alzheimer’s disease (1) f Huntington’s disease (1) f Limb-Girdle muscular dystrophy, type 2B, 2D, 2E (4) Gene Therapy in 2019: Milestones and Challenges 3 Realizing the Promise of Gene Therapy: PAYMENT Challenges and Opportunities One of the greatest challenges may be how to pay for treatment—both for single-administration therapies with The potential promise gene therapy holds for treating a large upfront costs and for those that require repeated, broad variety of heretofore untreatable diseases must be often lifelong, administration—and how equitable access tempered by the many challenges moving forward. We to treatment will be assured. Prices can range from present here some of the unknowns for which answers the thousands to the millions and per person lifetime will be most useful for policy makers. costs for some approved therapies can reach well over $1 million, with the prevalence of the conditions varying LONG-TERM