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Luxturna: FDA Documents Reveal the Value of a Costly Gene Therapy

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Luxturna: FDA Documents Reveal the Value of a Costly Gene Therapy Drug Discovery Today Volume 24, Number 4 April 2019 PERSPECTIVE feature Luxturna: FDA documents reveal the value of a costly gene therapy Jonathan J. Darrow In 2017, the US Food and Drug Administration (FDA) approved voretigene neparvovec-rzyl (Luxturna), a gene therapy used to treat a rare form of inherited blindness. Widely described by the media as a curative treatment that ‘restores vision’, it was priced at US$850 000. Although voretigene neparvovec-rzyl represents a substantial therapeutic advance, most reports have failed to adequately describe study outcomes as documented by FDA reviewers. These documents reveal that the drug is not expected to restore normal vision, that only about half of treated patients met the FDA’s threshold for minimally meaningful improvement, that improvements might not persist long-term, that the most common PERSPECTIVE measure of visual function was rejected as a primary endpoint after yielding mixed results, and that two patients experienced permanent vision loss. Over US$100 million of additional publicly-funded costs are not evident from the US$850 000 figure. Features Introduction that targets a disease caused by mutations in a while looking through a tunnel. Other patients Voretigene neparvovec-rzyl (Luxturna) was ap- specific gene [1]. or their family members reported improvements proved by the FDA in December 2017 for the The transformative nature of voretigene such as the ability to read large print rather than treatment of biallelic retinal pigment epitheli- neparvovec-rzyl has been widely lauded by Braille, eat at dimly lit restaurants, use iPhone um-specific 65 kilodalton (RPE65) mutation-as- regulators, patients, and the media. The FDA accessibility features, and see the ‘faces of family sociated retinal dystrophy, an inherited enzyme granted the drug a breakthrough therapy des- and . some letters on the eye chart’. Parents deficiency that generally progresses to total ignation and provided priority regulatory re- emphasized the life-altering impact the treat- blindness. The treatment relies on a viral vector view; in addition, the agency’s Commissioner ment had in normalizing social interaction and to deliver a normal copy of a gene that encodes hailed the approval of the drug as a ‘milestone’ enhancing academic achievement. a human retinal protein, the absence or dys- reflecting the ‘culmination of decades of re- Media outlets reacted with similar enthusi- function of which interrupts the visual cycle search’ [1]. At a meeting of the advisory com- asm. Boston’s National Public Radio news station involved in the conversion of a photon of light mittee of the FDA, which unanimously described voretigene neparvovec-rzyl as a into an electrical signal by the eye. It is ad- recommended approval, one patient described ‘miracle treatment’ and the ‘kind of therapeutic ministered as a one-time treatment to each eye how he could now see ‘things that I’ve never home run scientists have dreamed about for no fewer than 6 days apart. According to the been able to see before, like stars, snow falling, decades’ [3]. STAT reported a claim by the maker FDA, the treatment was the first directly ad- fireworks, but most importantly, the moon’ [2]. of the treatment that it ‘restores vision’, and ministered gene therapy approved in the USA Another explained that the postsurgical world noted that one-time gene therapies, such as was bright and colorful, whereas she previously voretigene neparvovec-rzyl, are ‘meant to be ’ E-mail address: [email protected]. saw as though she had sunglasses over her eyes curative [4]. A Wall Street Journal article noted 1359-6446/ã 2019 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2019.01.019 www.drugdiscoverytoday.com 949 PERSPECTIVE Drug Discovery Today Volume 24, Number 4 April 2019 that, in the pivotal trial, 13 of 20 participants nally inherited (‘biallelic’) mutant copies of the randomized to the treatment arm and ten who received voretigene neparvovec-rzyl ex- RPE65 gene, the label of the drug indicates that patients to the control arm. To assess outcomes, perienced the ‘maximum possible improve- patients must have viable retinal cells remaining. patients were asked to navigate a course (Fig. 1) ment’ [5]. Multiple sources stated or implied that Researchers have distinguished between two under increasing illumination, progressing from the drug was ‘curative’ [6–9]. pathological mechanisms of RPE65-associated 1 lux (equivalent to a moonless night) through 4, Despite the clear advance represented by the conditions: visual dysfunction, which relates to 10, 50, 125, 250, and 400 lux (equivalent to an therapy, these characterizations fail to fully de- the biochemical pathway in which the RPE65 office environment). A custom-designed as- scribe the reported benefits of the treatment, enzyme serves as a catalyst; and photoreceptor sessment, termed multi-luminance mobility the risks and uncertainties of the procedure, or degeneration, relating to deterioration of the testing (MLMT) [17], was administered and the technical challenges that remain. They also cells (rods and cones) in the retina in which the points were assigned (Table 1) both before omit important details about the approval biochemical processes underlying vision occurs injection and at 1-year follow-up, according to process and the outcomes that study patients [12]. Voretigene neparvovec-rzyl appears to the lowest light level at which a patient could actually experienced, as described by the FDA address dysfunction, but it is unclear whether, or accurately and with reasonable speed navigate reviewers who evaluated the voretigene to what extent, it mitigates degeneration the 5 ft  10 ft course, which was reconfigured neparvovec-rzyl submission package. A bal- [13,14,15]. Given that the disease is progressive, at each attempt. The course comprised large anced picture of the benefits, limitations, and older patients may therefore be less likely to black arrows on the floor and required patients costs of voretigene neparvovec-rzyl is important respond as well as younger patients, or at all to avoid obstacles. For a given patient, a change to patients seeking to become informed re- [14]. In addition, if photoreceptor degeneration in score of two points, from baseline to year 1, garding eligibility for treatment and probable continues to progress despite treatment, loss of was considered by the FDA as the minimum outcomes, and payors attempting to appropri- visual function could eventually follow for most change needed to demonstrate clinically ately assess the value of the treatment and or all patients, thus qualifying descriptions of the meaningful benefit [15]. The mean improve- negotiate a fair price. drug as a ‘one-time’ therapy [16] that restores ment for all treated subjects was 1.9 points, vision. compared with 0.2 points in the control arm. Eligibility for treatment The changes in score for each of the 20 The RPE65 gene is only one of more than 220 Efficacy measurement for voretigene treated patients and nine untreated patients genes that, if mutated, can lead to inherited neparvovec-rzyl (one patient in each arm withdrew consent retinal dystrophies [10], accounting for an esti- For those patients who respond, the treatment before beginning the baseline assessment) are mated 2% of cases [11]. As a result, most patients cannot be expected to be curative or to restore summarized in Fig. 2, with right-facing arrows with inherited blinding conditions will not fall normal vision, even temporarily. The single indicating improvement in assessment score. In Features within the indication of voretigene neparvovec- Phase III trial supporting approval was an open- the control arm, 11% of patients improved by rzyl. For those with both maternally and pater- label (unmasked) trial in which 21 patients were two or more points, compared with 55% in the PERSPECTIVE Foam Raised Door Grass Hole Cone Hole Foam Stop Waste Step Grass Cone Raised Hole Start Drug Discovery Today FIG. 1 Example of a navigation course used as an efficacy assessment for voretigene neparvovec-rzyl. Patients were assessed according to their ability to quickly and accurately navigate a 5 ft  10 ft course under increasing illumination. The custom-designed assessment was reconfigured before each run and standardized for each of 12 different configurations with a fixed number of turns and obstacles. The assessment was validated for correlation with visual acuity and for inter-rater agreement of successful completion. Adapted from [17]. 950 www.drugdiscoverytoday.com Drug Discovery Today Volume 24, Number 4 April 2019 PERSPECTIVE TABLE 1 a Points assigned on successful completion of course at lowest possible lux level Lux 1 4 10 50 125 250 400 Does not pass 400 Points 6 5 4 3 2 1 0 –1 a Points were assigned according to the lowest illumination level at which a patient could accurately and with reasonable speed complete the course. A score of –1 indicated the patient failed the test at the brightest illumination level. A score of 6 indicated a patient passed the test at the lowest illumination level [17]. treatment arm, including 30% who improved by Notably, the trial sponsor decided not to use among other treatment-related ocular adverse three or more points. Given that 13 patients in as a primary endpoint a more traditional mea- events. Overall, 27 (66%) treated patients ex- the treatment arm achieved the maximum sure of vision function [logarithm of the mini- perienced one or more ocular adverse events, possible score, there might have been a ‘ceiling mum angle of resolution (logMAR) which were primarily attributed to the surgical effect’ to the efficacy outcomes, suggesting that improvement of 0.3 or more] after an earlier trial procedure rather than to the drug itself. Most the improvement could have been even greater yielded mixed results: a 5-year follow-up of were mild or moderate and resolved, or were than the assessment was able to measure.
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