19 minute read
Gene Therapy
Changing Market Landscape and Pipeline
As more gene therapies for larger patient populations enter the pipeline, payers must meet the immense challenge of how to fund the coverage.
Natalie A. Tate, PharmD, MBA, BCPS Vice President, Pharmacy BlueCross BlueShield of Tennessee
Once just a pipe dream, gene therapy has become a reality. Several groundbreaking gene therapies have received FDA approval since 2017, 1 offering significant treatment advancements and, in some cases, even cure. While gene therapy has been a long time coming, there will certainly be a learning curve for patients, payers, and providers as these innovative therapies are incorporated into clinical practice.
Gene Therapy: 101
To best understand the complexities of gene therapy in clinical development and, ultimately, in clinical practice, it is critical to understand how gene therapy works. Gene therapy is essentially the use of genetic material to manipulate a patient’s cells in order to treat an inherited or acquired genetic disease. 2-4 The genetic material that is inserted directly into the cell is typically nonfunctional and may include nucleic acids, viruses, or genetically engineered microorganisms. This genetically engineered vector is used to deliver the gene to the desired location. Viruses, one of the most efficient vectors utilized, insert genetic material into the cell by infecting the cell, but modifications prevent that virus from causing disease in the human host. 2-4 Commonly utilized viruses include retroviruses, which integrate their genetic material into chromosomes in the human cell, and adenoviruses, which introduce deoxyribonucleic acid (DNA) into the nucleus of the cell but not into the chromosome. 2-4
Currently Available Gene Therapies
Luxturna ® (voretigene neparvovec-rzyl)
Luxturna ® received FDA approval in December 2017, making it the first directly administered gene therapy approved in the U.S. that targets disease caused by mutations in a specific gene. 5 Leading up to the approval, the FDA granted Luxturna ® the Priority Review, Breakthrough Therapy, and
Orphan Drug designations, and, following approval, the manufacturer, Spark Therapeutics, received a Rare Pediatric Disease Priority Review Voucher. 6 Specifically, Luxturna ® was approved for the treatment of children and adult patients with confirmed biallelic retinal pigment epithelium (RPE65) mutation-associated retinal dystrophy — an inherited form of vision loss that may cause complete blindness in certain patients. 5, 6 The RPE65 gene encodes an enzyme that is essential for normal vision; mutations in the RPE65 gene result in reduced or absent RPE65 activity, inhibiting the visual cycle and resulting in visual impairment. For individuals with biallelic RPE65 mutation-associated retinal dystrophy, progressive deterioration of vision occurs over time, typically during childhood or adolescence, and progresses to complete blindness. Biallelic RPE65 mutation-associated retinal dystrophy affects somewhere between 1,000 and 2,000 individuals in the U.S. 5, 6
Luxturna ® utilizes an adeno-associated viral (AAV) vector to deliver a normal copy of the human RPE65 gene to the retinal cells in order to restore vision. 6 These retinal cells are then able to produce normal protein that converts light to an electrical signal within the retina. 6, 7 As such, Luxturna ® should only be given to patients who have viable retinal cells. Luxturna ® is administered via subretinal injection into each eye separately, with a minimum of six days between injections. Patients are also given a course of oral prednisone to mitigate any potential immune reactions. 6, 7
The safety and efficacy of Luxturna ® was evaluated in a clinical program that included 41 patients between the ages of 4 and 44 years. 8 In the phase three trial (n=31), 20 patients were randomly assigned to treatment with Luxturna ® . 8 At baseline, patients had best corrected visual acuity of 20/60 or worse in each eye or visual field less than 20 degrees in any meridian, or both, with sufficient viable retina and the ability to perform standardized multiluminance mobility testing (MLMT) within the luminance range evaluated. 8 The MLMT is a test that evaluates a patient’s ability to maneuver through an obstacle course at various light levels. One year after treatment, the mean bilateral MLMT change score was 1.8 light levels in the intervention group, compared to 0.2 light levels in the control group (difference 1.6; 95% confidence interval 0.72 to 2.41; p=0.0013). Of the patients treated with Luxturna ® , 65% successfully passed the MLMT at the lowest luminance level tested (one lux, equivalent to a moonless night), demonstrating the maximum possible improvement. 8
Zolgensma ® (onasemnogene abeparvovec-xioi)
In May 2019, the FDA approved the second gene therapy, Zolgensma ® , for the treatment of spinal muscular atrophy (SMA) in children less than two years of age, who get the most severe form of SMA. 9 As with Luxturna ® , the FDA granted Zolgensma ® the Fast Track, Breakthrough Therapy, and Priority Review designations leading up to approval, and awarded the manufacturer, Novartis, a Rare Pediatric Disease Priority Review Voucher. 10
SMA is a rare genetic disease that represents the leading genetic cause of infant mortality. 11 SMA is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the survival motor neuron (SMN) protein essential for the maintenance and function of motor neurons in the brain and spinal cord that control muscle movement throughout the body. 10, 11 When functional SMN protein is lacking, motor neurons die, resulting in debilitating and potentially fatal muscle weakness. Zolgensma ® is approved for infantile-onset SMA. Infants with this form of SMA typically display symptoms between birth and six months of age; these may include problems holding their head up, swallowing, and breathing. Unfortunately, affected children are not expected to survive past early childhood. 10, 11
Zolgensma ® is an AAV vector-based gene therapy that works by delivering a fully functional copy of the human SMN gene into the target motor neuron cells. 10, 12 A single intravenous administration promotes the expression of the SMN protein in the patient’s motor neurons, improving both muscle function and the patient’s survival. 10
The efficacy and safety of Zolgensma ® was evaluated in an ongoing clinical trial as well as a completed clinical trial that included 36 pediatric patients with infantile-onset SMA between the ages of two weeks and eight months at study entry. 10, 12 All patients had genetically-confirmed biallelic SMN1 gene deletions, two copies
of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of the SMN2 gene, which predicts a milder phenotype. 12 The primary efficacy data included in the package insert was based on data from 21 patients enrolled in the ongoing clinical trial. The efficacy of Zolgensma ® was established on the basis of survival and achievement of developmental motor milestones such as sitting without support. 12 As of the March 2019 data cutoff, 19 of 21 patients enrolled in the trial were alive without permanent ventilation, which was considered event-free survival. Of the two patients no longer enrolled, one patient died at age 7.8 months due to disease progression and one patient withdrew from the study at age 11.9 months. 12 By the data cutoff, 13 of the 19 patients continuing in the trial had reached 14 months of age without permanent ventilation. Furthermore, 10 of the 21 patients initially enrolled (47.6%) were able to sit without support for 30 seconds or more between 9.2 and 16.9 months of age (mean, 12.1 months). 12 Comparatively, based on the natural history of disease in SMA, only 25% of these patients would be expected to survive without permanent ventilation beyond 14 months of age. It is important to note that Zolgensma ® does have a boxed warning for acute serious liver injury and elevated aminotransferases. 12
Current Market Landscape
With the advancement of gene therapy technology, there has been an explosion of activity within the gene therapy pipeline. According to the Alliance for Regenerative Medicine’s first-quarter report for 2019, there were 372 clinical trials for gene therapy in progress, 58% of which were phase two and 9% of which were phase three. 14 Notably, the number of clinical trials increased 17% yearover-year from the 319 trials that were ongoing in the first three months of 2018. 14 Following the approval of the first gene therapy, Luxturna ® , former FDA Commissioner Scott Gottlieb stated that “we’re at a turning point when it comes to this novel form of therapy,” and that he believes “gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable diseases.” 6 With excitement around gene therapy and the robustness of the pipeline, the FDA anticipates approving 10 to 20 cell and gene therapies per year starting in 2025. 9
Gene Therapy Pipeline
Valoctocogene Roxaparvovec
There are hundreds of gene therapies currently in early-stage development, and a few that may receive FDA approval within the next year. 14 One such product, valoctocogene roxaparvovec by BioMarin, is an investigational AAV-based gene therapy currently being studied for adults with hemophilia A. 15 Hemophilia A, also known as Factor VIII deficiency, is an X-linked genetic disorder caused by missing or defective Factor VIII, which is an essential clotting protein. Individuals with the most severe form — which approximately 60% of those with hemophilia A have — may experience spontaneous, painful bleeds into the muscle tissue or joints. 16 The current standard of care for hemophilia A includes a prophylactic regimen of replacement Factor VIII infusions administered intravenously two to three times per week. Unfortunately, affected individuals may continue to experience bleeds and progressive, debilitating joint damage. 15
Zolgensma ® appears to offer a transformative approach to the treatment of a form of SMA that impacts 450 to 500 infants born each year. It quickly became the most expensive drug in the world, at a staggering $2,125,000 per patient. 9 Novartis does offer a payment plan that divides the total cost of the one-time treatment into five yearly installments of $425,000. 9 Although the cost seems extreme, the existing SMA competitor product, Spinraza ® (nusinersen), costs $750,000 for the first year and $375,000 annually thereafter for the patient’s lifetime. 9, 13 After five years, Spinraza ® , which offers a temporary fix to the genetic mutations in SMA, costs $2,175,000, which is similar in cost to the potentially curative gene therapy. 9, 13
Valoctocogene roxaparvovec works by delivering a functional copy of the B-domain-deleted Factor VIII gene, and it is given as a single dose. 16 Three-year follow-up data from an ongoing phase one/two study was presented at the 2019 Congress of the International Society on Thrombosis and Haemostasis. 17 The phase one/two study was an open-label, dose-escalation study that enrolled 13 men. Patients were included in the study if they had severe hemophilia A with residual Factor VIII levels ≤1 IU/dL and were exposed to Factor VIII concentrates or cryoprecipitate for at least 150 days. 17 All study subjects received a single dose of valoctocogene roxaparvovec, at 6 x 1013 v/kg (n=6) or 4 x 1013 vg/kg (n=6). After three years of follow-up, subjects in both dose groups required fewer infusions
of Factor VIII per year, with reductions from baseline of 96% in the 6 x 1013 v/kg dose group and 97% in the 4 x 1013 v/kg dose group. 17 Of note, the Factor VIII expression reached a plateau at approximately 20% at year three, and the study investigators noted that Factor VIII expression levels were expected to decline over time. 17 The investigators noted that current projections conservatively estimate the persistence of bleeding control for at least eight years post-administration, and longer if the Factor VIII expression plateaus are maintained. 17
In addition to improvements in Factor VIII expression, study subjects in both groups experienced significant reductions in the annualized bleeding rate. 17 In the year prior to treatment, subjects in the 6 x 1013 v/kg dose group experienced a mean of 16.3 bleeds, compared to 0.9 bleeds in the first year post-treatment, 0.2 bleeds in the second year, and 0.7 in the third year (p-value not reported). 17 This represents a 96% reduction in mean annualized bleeding rates. Similar reductions in annualized bleeding rate were observed in the 4 x 1013 v/kg dose group. 17
Valoctocogene roxaparvovec has been awarded the Breakthrough Therapy and Orphan Drug designations by the FDA, and in December 2019, BioMarin announced the submission of a Biologics License Application to the FDA, initially seeking accelerated approval based on phase one/two data. 15 While valoctocogene roxaparvovec is likely to be the first gene therapy for hemophilia A to reach the market, there are a handful of competitors in latestage development in what has become one of the most competitive therapeutic areas in the emerging field of gene therapy. 18 Additional gene therapies in development for hemophilia A include SPK-8011 from Spark Therapeutics and SB-525 from Sangamo and Pfizer. While SB-525 is the furthest out, Sangamo and Pfizer announced promising phase one/two data that demonstrated that patients who received the highest dose of SB-525 were sustaining normal levels of Factor VIII clotting protein at the interim analysis. 18 As excitement for new gene therapies in hemophilia builds, a survey of 25 doctors who treated approximately 3,000 patients with hemophilia in the U.S. and Europe found that 28% intend to prescribe valoctocogene roxaparvovec to eligible patients within two years of launch, and 39% would prescribe within five years. 18 While the cost is not yet known, it will likely be substantial — some studies have estimated that the average cost of managing a patient with hemophilia in the U.S. is approximately $140,000 to $155,000 annually. 19-22 For patients who develop inhibitors and require more Factor VIII concentrate, the cost of management can jump to $697,000 to $1 million per year. 19-22 It is important to note that these estimates are based on current treatment and management of hemophilia and are likely much lower than the cost of managing hemophilia with emerging gene therapies. In an interview, the CEO of BioMarin drew comparisons between valoctocogene roxaparvovec and Zolgensma ® , with each product competing against a current standard of care. 23 He stated that it may “be difficult for payers to pay more” for the gene therapy than the equivalent cost of five years of hemophilia care, which may suggest that there are plans to utilize a similar five-year payment strategy for valoctocogene roxaparvovec. 23
Zynteglo ® (formerly known as LentiGlobin ® )
Zynteglo ® is an investigational gene therapy from Bluebird Bio being studied for the treatment of transfusion-dependent β thalassemia (TDT). 24 β thalassemia, an inherited genetic disease, results in defective red blood cells that are unable to carry oxygen appropriately. Severe cases require frequent blood transfusions, which may be associated with a toxic accumulation of iron in the blood. 24
Zynteglo ® works by delivering functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells (HSC). 25 Once a patient has the functional gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that eliminate or drastically reduce the need for transfusions of donor HSC. 25
The efficacy and safety of Zynteglo ® were evaluated in a completed phase one/two study, as well as two ongoing phase three studies. 25
The phase one/two study enrolled 18 patients, including 10 who did not have a β0/β0 genotype and eight who did have a β0/β0 genotype. After completion of the two-year study, all 18 patients enrolled in a long-term follow-up study. 25 Of the 10 patients who did not have a β0/β0 genotype, eight achieved transfusion independence (no transfusion for at least 12 months and maintenance of weighted hemoglobin ≥9 g/dL). 25 Of the patients with a β0/β0 genotype, three of the eight achieved transfusion independence and maintained a median weighted average hemoglobin ranging from 9.5 to 10.1 g/dL for a median duration of 16.4 months. 25
In March 2019, Zynteglo ® received regulatory approval in the EU and set a price of $1.8 million USD. 26 Bluebird Bio has told their investors to expect a regulatory submission to the FDA by the end of 2019. Although they haven’t announced their intentions with pricing in the U.S., they did suggest that the product has an “intrinsic value” of $2.1 million. 26
Managed Care Implications
Undoubtedly, gene therapy has and will continue to make waves in the managed care world. With each new therapy that is approved, the question of how much the market is willing to pay for innovation arises. It seems obvious that curative therapies for devastating, deadly diseases would be covered; however, with upfront costs exceeding $2 million per patient, funding this coverage becomes a major challenge. While many gene therapies may actually save money in the long term, the initial payer may never accrue those savings due to the rate at which patients change health insurer. This could disincline payers from providing coverage from such costly therapies, thus limiting access for patients. A payer survey showed that four out of five national payers and nine out of 16 regional payers reported “very high” concern with regard to managing the potential financial risk and impact of gene therapies. 27 In the same survey, nearly one-third of small-employer third-party administrators and managed Medicaid plans indicated they were likely to exclude coverage for gene therapies due to the associated financial challenges. 27 Naturally, this could lead to a disparity in access for patients based on their specific payer, resulting in patients shopping for payers with more favorable criteria for these emerging therapies.
tions around the efficacy and the durability of effect remain. Manufacturers of gene therapy products justify their hefty price tags by arguing that these therapies offer potentially curative effects; however, many are concerned about those patients who fail to respond and, for those that do respond, whether those effects will truly last 10 years and beyond. For those patients who lose effect after several years, will it be possible to treat them again, and will it be financially feasible?
With all these challenges and unanswered questions facing payers, it will be imperative to take a proactive approach, staying abreast of the gene therapy pipeline and the data supporting these products. Many gene therapies target patients with specific characteristics such as mutations. Given the cost and the fact that gene therapies may only work for patients with certain characteristics, access to patient screening is essential to ensure that only the appropriate patients receive treatment. In light of the questions around efficacy and durability, value-based contracting will likely gain new traction in the gene therapy arena, as payers seek contracts that reimburse for gene therapy that does not maintain its effect or does not work at all. As we have already seen to some degree, manufacturers are also getting creative in the pricing of their gene therapies, offering payment plans in lieu of larger, upfront payments. Despite these efforts, payers and manufacturers will need to continue working together to identify solutions that can bring these innovative therapies to the patients who need them.
Furthermore, in the not-so-distant past, payers only had to worry about the one or two patients in their plan with a rare disease who may be candidates for gene therapy. Now, as the gene therapy pipeline expands to a greater number of therapeutic areas, including genetic diseases that impact more people, the potential pool of patients is ever-increasing. In addition to the growing treatment pool, there are several other challenges with gene therapy. Ques
References
“Approved Cellular and Gene Therapy Products.” U.S. Food and Drug Administration, March 29, 2019, https://www.fda.gov/vaccinesblood-biologics/cellular-gene-therapy-products/approved-cellularand-gene-therapy-products.
“Gene therapy vs. cell therapy.” American Society of Gene & Cell Therapy, https://annualmeeting.asgct.org/about_gene_therapy/ genevscell.php.
“Guidance for Industry: Gene Therapy Clinical Trials — Observing Subjects for Delayed Adverse Events.” U.S. Food and Drug Administration, Nov. 4, 2015, https://www.fda.gov/media/72225/ download.
“How does gene therapy work?” Genetics Home Reference, Aug. 15, 2017, http://ghr.nlm.nih.gov/primer/therapy/procedures
Darrow, J.J. “Luxturna: FDA documents reveal the value of a costly gene therapy.” Drug Discovery Today, April 2019, https://www.ncbi. nlm.nih.gov/pubmed/30711576.
“FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss.” U.S. Food and Drug Administration, Dec. 18, 2017, https://www.fda.gov/news-events/press-announcements/ fda-approves-novel-gene-therapy-treat-patients-rare-forminherited-vision-loss.
Luxturna ® [package insert], Philadelphia, PA, Spark Therapeutics, 2017.
Russell, S. et al. “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised controlled, open-label, phase 3 trial.” The Lancet, Aug. 2017, https://www.ncbi.nlm.nih.gov/ pubmed/28712537.
Cross, Ryan. “FDA approves second gene therapy, Zolgensma, to treat spinal muscular atrophy in infants.” Chemical & Engineering News, May 30, 2019, https://cen.acs.org/business/FDA-approvessecond-gene-therapy/97/i22.
“FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality.” U.S. Food and Drug Administration, May 24, 2019, https://www.fda.gov/news-events/press-announcements/ fda-approves-innovative-gene-therapy-treat-pediatric-patientsspinal-muscular-atrophy-rare-disease.
“About SMA.” Cure SMA, 2019, https://www.curesma.org/aboutsma/
Zolgensma ® [package insert], Bannockburn, IL, AveXis, Inc, 2019.
Spinraza ® [package insert], Cambridge, MA, Biogen, 2019.
Philippidis, Alex. “25 Up-and-Coming Gene Therapies of 2019.” Genetic Engineering & Biotechnology News, May 20, 2019, https:// www.genengnews.com/a-lists/25-up-and-coming-gene-therapiesof-2019/. “BioMarin Submits Biologics License Application to U.S. Food and Drug Administration for Valoctocogene Roxaparvovec to Treat Hemophilia A.” BioSpace, Dec. 23, 2019, https://investors.biomarin. com/2019-12-23-BioMarin-Submits-Biologics-License-Applicationto-U-S-Food-and-Drug-Administration-for-ValoctocogeneRoxaparvovec-to-Treat-Hemophilia-A. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27. “Hemophilia A.” National Hemophilia Foundation, 2020, https:// www.hemophilia.org/Bleeding-Disorders/Types-of-BleedingDisorders/Hemophilia-A.
“Valoctocogene Roxaparvovec Continues to Improve Bleeding Outcomes in Patients With Hemophilia A.” ASH Clinical News, Sept. 1, 2019, https://www.ashclinicalnews.org/on-location/ other-meetings/valoctocogene-roxaparvovec-continues-improvebleeding-outcomes-patients-hemophilia/.
Bell, Jacob. “BioMarin confirms timeline for hemophilia gene therapy, putting pressure on rivals.” BioPharma Dive, July 8, 2019, https://www.biopharmadive.com/news/biomarin-confirmstimeline-for-hemophilia-gene-therapy-putting-pressureon/558279/.
Chen, S. L. “Economic costs of hemophilia and the impact of prophylactic treatment on patient management.” American Journal of Managed Care, April 2016, https://www.ncbi.nlm.nih. gov/pubmed/27266809.
Escobar, M. “Health economics in haemophilia: a review from the clinician’s perspective.” Haemophilia, May 2010, https://www. ncbi.nlm.nih.gov/pubmed/20586799.
Guh, S. et al. “Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, 2008.’ Haemophilia, March 2012, https://www.ncbi.nlm.nih.gov/ pubmed/22151000.
Chen, S. L. “Economic costs of hemophilia and the impact of prophylactic treatment on patient management.” American Journal of Managed Care, April 2016, https://www.ncbi.nlm.nih. gov/pubmed/27266809.
Lash, Alex. “With Sliver of Data, BioMarin to Seek OK for Hemophilia Gene Therapy.” Xconomy, May 28, 2019, https:// xconomy.com/san-francisco/2019/05/28/with-sliver-of-databiomarin-to-seek-ok-for-hemophilia-gene-therapy/.
Terry, Mark. “BlueBird Bio presents more data on its $1.8 million gene therapy Zynteglo.” BioSpace, June 14, 2019, https://www. biospace.com/article/bluebird-bio-presents-more-data-on-its-1- 8-million-gene-therapy-zynteglo/.
“bluebird bio presents long-term efficacy and safety data from clinical studies of LentiGlobin ® gene therapy for transfusiondependent β-thalassemia (TDT) at 24th European Hematology Association (EHA) Congress.” BusinessWire, June 14, 2019, https:// www.businesswire.com/news/home/20190614005119/en/ bluebird-bio-Presents-Long-Term-Efficacy-Safety-Data.
Weintraub, Arlene. “bluebird tees up its first gene therapy approval with Zynteglo thumbs-up in EU.” FiercePharma, March 29, 2019, https://www.fiercepharma.com/pharma/europe-setsup-first-bluebird-gene-therapy-approval-thumbs-up-thalassemiatreatment. Ciarametaro, Michael et al. “Are Payers Ready to Address the Financial Challenges Associated With Gene Therapy?” HealthAffairs, June 28, 2018, https://www.healthaffairs.org/ do/10.1377/hblog20180626.330036/full/.
