Response to Comments: Voretigene Neparvovec-rzyl (Luxturna™)

We write today to strongly urge you to not restrict access to voretigene neparvovecrzyl (brand name LUXTURNA) for those with biallelic RPE65 mutation-associated retinal dystrophy.

Sofia Sees Hope is a nonprofit advocacy organization that works on behalf of those with rare inherited retinal diseases (IRDs). We are dedicated to patient advocacy and education to advance research to cure blindness caused by rare inherited retinal disease. We represent families across the United States. We fully support the principle that all FDA-approved treatments should be made available to all those who will benefit from such treatments.

Access to a full range of options is essential for people with IRDs to effectively manage their own disease course, and for their physicians to make the most optimal treatment decisions.

SSH asks Palmetto to ensure that eligibility for treatment should be limited only to guidelines outlined by the FDA, which were developed throughout the extensive clinical and trial phases of testing and included in the final FDA approval of LUXTURNA.

Thank you for your comment. Coverage decisions are made on the basis of publically available evidence. We agree that Luxturna^TM should be made available to those for whom there is evidentiary support and have written the LCD accordingly.

I have several concerns regarding the proposed LCD determining coverage for Voretigene Neparvovec-rzyl (Luxturna) and strongly feel the LCD, as proposed, will unfairly limit access to patients desperately in need of this vision-saving/vision-restoring therapy. Please find below the areas of concerns with associated commentary (all addressing points made in the “Documentation Requirements” of the proposed LCD):

1. Best corrected visual acuity worse than 20/60 or visual field < 20° in any meridian of each eye (pretreatment baseline).

The goal of replacing the loss of function of the RPE65 gene product is to prevent further degenerative retinal cell loss. This level of impairment, VA worse than 20/60 and/or visual field worse than 20 degrees, is SEVERE. Earlier intervention should be able to prevent permanent damage and are certainly in the best interest of the disease. It is well established that the natural history of biallelic RPE65-related retinal dystrophy leads inexorably to blindness, thus “waiting” to assure appropriate symptomatology seems inappropriate.

It appears the authors of the LCD based this visual acuity/visual field requirement on study inclusion/exclusion criteria, however, the use of such criteria is justifiable in a clinical trial given that the experimental therapy has yet to prove its positive benefit/risk ratio and it would be unethical to expose patients to treatment without a significant visual impairment. Once a definite therapeutic benefit and adequate safety has been demonstrated in a clinical trial, those same criteria become over-restrictive.

2. Clinical documentation confirming diagnosis of Leber congenital amaurosis or retinitis pigmentosa including clinical features, funduscopic appearance, and results of testing such as dark-adapted thresholds, Ganzfeld-flash ERG, and when appropriate, perimetry. When performed, documentation of baseline (pre-treatment) white light FST per eye and baseline (pre-treatment) MLMT score should also be included

Voretigene Neparvovec-rzyl (Luxturna) was FDA-approved for “biallelic RPE65 mutation-related retinal dystrophy.” It is essentially a genetic diagnosis with 100% penetrance (meaning that confirmation of a biallelic mutations confirms eventual development of clinical disease). Confirmation of the appropriate genetic diagnosis and retinal cell viability should serve as the only required treatment eligibility criteria; any additional tests used to determine treatment eligibility should be optional based on physician discretion.

Moreover, the specific tests mentioned including dark-adapted thresholds, Ganzfeld-flash ERG, and perimetry may be useful for the evaluating physician, however, determination of specific testing should be left to the discretion of the evaluating physician and not pre-specified in the medical policy.The requirement for a baseline MLMT is also unreasonable. MLMT is not available outside of the clinical research setting and thus CANNOT be utilized outside of highly specialized centers, which severely restricts access to this critical therapy.

Age > 3 years

The clinical trial required patient to participate in and understand instructions for the MLMT, thus the requirement for patients to be >3 years of age. Based on the data the FDA reviewed and their benefit-risk assessment, the FDA granted approval of Voretigene Neparvovec-rzyl (Luxturna) for pediatric use in children 12 months or older. By the age of 12 months, active retinal cell proliferation should be completed, thereby avoiding any potential dilution or loss of the gene product. A lower age limit should allow intervention earlier in disease course at a time when more extant retinal tissue is present.

In terms of general comments, Luxturna represents a sea change in treatment of inherited retinal dystrophies, a set of conditions for which no previous vision-saving/vision-restoring therapies were previously available. To deprive this (very small) group of patients of a therapy for which they have desperately been hoping seems very unjust. The proposed LCD, as currently written, is notably more restrictive than the FDA-approved label.

Thanks for your consideration of my comments.

After careful consideration of this comment, we agree with the commenter’s first point and as such, will remove the requirement for best-corrected visual acuity worse than 20/60 and/or visual field worse than 20 degrees from the policy coverage requirements.

Regarding the commenter’s second point, we disagree that a clinical diagnosis is not relevant. It is the constellation of clinical findings that allow for more accurate interpretation of genetic testing results as to the causative genetic mutation(s) given the genetic heterogeneity of the heritable retinal diseases of interest and high degree of normal, non-pathogenic, variation in the human genome. We will therefore keep the requirement for clinical test results and phenotypic information that are supportive of the clinical diagnosis of Leber congenital amaurosis or retinitis pigmentosa, though acknowledge the phenotypic heterogeneity of these conditions.

We agree with the commenter that certain types of testing, such as perimetry, may not be appropriate given the age and/or functional limitations of the patient. Additionally, we realize the MLMT will likely not be available to patients outside of participation in a clinical trial. As such, the LCD does not include results of these tests as a condition for coverage; however, when performed, it is expected that the results of pre-treatment testing, including perimetry and MLMT, will be included in the clinical documentation records submitted for review.

As to the commenter’s third point, we disagree. Coverage decisions are made on the basis of publically available evidence. At the present time, there exists no peer-reviewed, published evidence for safety and efficacy of Luxturna^TM in children < 3 years of age. Moreover, evidence to the contrary is found on the transcript of the FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting during which the decision to approve Luxturna^TM was made, which indicates that members of the committee and individuals speaking on behalf of the sponsor raised concern for the safety of the procedure in those < 3 years of age given the challenges inherent in anatomically small eyes of patients in this age group. Should evidence become available supportive of Luxturna^TM in individuals < 3 years of age, the LCD may be reconsidered.

HCA is a major hospital provider in multiple states within Palmetto’s Jurisdictions J and M. Because we are focused on consistent and accurate coding and compliant billing practices, we are submitting the following comment regarding Palmetto’s Draft Local Coverage Determinations (LCD) DL37863 - Voretigene neparvovec-rzyl (Luxturna^TM).

The FDA Approval Letter states Voretigene Neparvovec-rzyl (Luxturna™) is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. ICD-10 Diagnosis Code H35.54 (Dystrophies primarily involving the retinal pigment epithelium) would fall under this indication, however it is not included as a covered diagnosis code in the Draft LCD.

We request that ICD-10 Diagnosis Code H35.54 be included as a covered diagnosis in the Proposed LCD for Voretigene Neparvovec-rzyl (Luxturna™).

We appreciate the opportunity to comment and your thoughtful consideration our request.

Thank you for the comment. At this time, there is supportive evidence for Luxturna^TM treatment in a subset of patients with clinical findings consistent with either retinitis pigmentosa or Leber congenital amaurosis for whom the biallelic RPE65 mutation is pathogenic. The ICD-10-CM index classifies retinitis pigmentosa as H35.52 and Leber congenital amaurosis as H35.50. As vitrectomy surgery is required to inject Luxturna^TM into the subretinal space, NCD 80.11, Vitrectomy, has been updated by CMS to accommodate H35.50 and H35.52 as indications; H35.54 is not among the indications supportive for vitrectomy in NCD 80.11. Should evidence become available supportive of Luxturna^TM in the treatment of other RPE65 mutation associated conditions, changes to this LCD can be reconsidered.

I wanted to comment upon Palmetto MAC’s proposed Luxturna policy with physician input. Generally speaking, I believe the policy should be in line with the product labeling, which was reviewed and approved by the FDA based upon clinical trial outcomes.

1) Regarding establishment of the diagnosis of biallelic RPE65-mediated LCA or RP, I agree there needs to be an established clinical diagnosis to indicate reduced vision or visual performance, although funduscopic evidence may not be present in the youngest patients, even if the patient is symptomatic.

2) Further follow-up of clinical trial patients and real-world experience is demonstrating that patients treated at the youngest ages typically have the greatest visual preservation (that effect is anticipated to be lifelong), and therefore those patients would benefit most from early treatment. Establishing an arbitrary age beyond the guidance of the FDA may result in reduced function lifetime for your members if they don’t receive the Luxturna treatment. As a pediatric retinal surgeon, I can state that there is not a significant technical challenge difference in treating a 1 year old versus a 3 year old, as the posterior hyaloid face elevates more easily than normal eyes based on their age.

3) To that end, requiring visual acuity and visual field minimum scores would preclude treatment of patients age 3 or younger who cannot adequately perform those tests. Instead, a pattern of disease demonstrated by full field electroretinography is sufficient to demonstrate disease and candidacy for treatment with Luxturna. This requirement would delay treatment in patients who would potentially benefit the most from early treatment.

Thank you for your comment. We agree with the commenter that a clinical diagnosis is relevant. It is the constellation of clinical findings that allow for more accurate interpretation of genetic testing results as to the causative genetic mutation(s) given the genetic heterogeneity of the heritable retinal diseases of interest and high degree of normal, non-pathogenic, variation in the human genome. We will therefore keep the requirement for clinical test results and phenotypic information that are supportive of the clinical diagnosis of Leber congenital amaurosis or retinitis pigmentosa, though acknowledge the phenotypic heterogeneity of these conditions.

Limiting coverage for treatment to individuals > 3 years of age was not arbitrary. Coverage decisions are made on the basis of publically available evidence. At the present time, there exists no peer-reviewed, published evidence for safety and efficacy of Luxturna^TM in children < 3 years of age. Moreover, evidence to the contrary is found on the transcript of the FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting during which the decision to approve Luxturna^TM was made which indicates that members of the committee and individuals speaking on behalf of the sponsor raised concern for the safety of the procedure in those < 3 years of age given the challenges inherent in anatomically small eyes of patients in this age group. Should evidence become available supportive of Luxturna^TM in individuals < 3 years of age, the LCD may be reconsidered.

We agree with the commenter that certain types of testing, such as perimetry, may not be appropriate given the age and/or functional limitations of the patient. As such, the LCD does not include results of these tests as a condition for coverage; however, when performed, it is expected that the results of pre-treatment testing, such as perimetry, will be included in the clinical documentation records submitted for review.

After careful consideration, we will remove the requirement for best-corrected visual acuity worse than 20/60 and/or visual field worse than 20 degrees from the policy coverage requirements.

Spark Therapeutics, Inc. (Spark) has reviewed Palmetto’s proposed local coverage determination (LCD) policy for LUXTURNA® (voretigene neparvovec-rzyl), and has proposed revisions in Appendix A. As described in more detail below, we believe that certain criteria in the proposed LCD may inadvertently disqualify patients who in fact may benefit from treatment. We respectfully provide this letter to supply additional medical, clinical and scientific support so that Palmetto may revise the proposed LCD policy to be consistent with the FDA prescribing information, which we believe is reasonable and necessary to allow appropriate patients to have access to LUXTURNA.

1. Policy Bullet Point 1: It is not reasonable or necessary to request clinical documentation to confirm diagnosis of Leber’s Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) because a clinical diagnosis is not required per the Food and Drug Administration (FDA)-approved prescribing information.

A specific clinical diagnosis of LCA or RP is not required per the FDA-approved prescribing information for LUXTURNA. Genetic testing is the only confirmatory test for biallelic RPE65- mutation associated retinal dystrophy, which is specified in the LUXTURNA prescribing information. Specifically, as stated in the prescribing information, LUXTURNA is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy in patients who have viable retinal cells as determined by the treating physician(s). It is not reasonable or necessary to request a confirmation of a clinical diagnosis of LCA or RP as long as the patient’s phenotype is consistent with biallelic RPE65 mutation associated disease as described in the scientific literature.

Prior to the advances in molecular genetics, patients with biallelic RPE65 mutation-associated retinal dystrophy may have received clinical diagnoses including but not limited to: Leber congenital amaurosis type 2 (LCA2), retinitis pigmentosa type 20 (RP20), early onset retinal dystrophy (EORD), early onset severe retinal dystrophy (EOSRD), severe early childhood onset retinal dystrophy (SECORD), or early childhood-onset retinitis pigmentosa (ECRP). Clinical nomenclature may have varied according to physicians’ preferences and patients may have been misdiagnosed based solely on clinical symptoms. Considering that LUXTURNA is indicated for patients with confirmed genetic mutations in a specific gene (RPE65), which is confirmed by a genetic test for such mutation, a clinical diagnosis is no longer relevant.

Although a diagnostic workup is required to evaluate patient eligibility for viability of retinal cells, including funduscopic evaluation and optical coherence tomography, it is not necessary to mandate a list of multiple tests such as dark-adapted thresholds, Ganzfeld-flash ERG, and perimetry be performed because some of these tests are invasive and not necessary when a less invasive test is appropriate and can accomplish the same diagnostic result. Also, some tests, such as the Ganzfeld-flash ERG requires sedation for young children, so such a test is usually not an appropriate test to determine treatment in children. Overall, the physician should have the ability to prescribe the appropriate test(s) to be completed according to his or her discretion in order to determine retinal viability and eligibility for patients to receive LUXTURNA.

Perhaps even more importantly, the multi-luminance mobility test (MLMT) from the LUXTURNA clinical trials is not available for use outside of clinical research setting and therefore cannot be utilized as a diagnostic or monitoring tool outside of Spark Therapeutics’ clinical trials. The MLMT was developed in response to discussions with the FDA for the need for a relevant, reliable and clinically meaningful measure of functional vision in patients who were participating in the clinical trials.10 This mobility course, with 12 standardized configurations having the same number of turns and obstacles, was designed to be navigable by children as young as age 3.11 Since the MLMT is not used outside of a clinical research setting, it is not feasible or reasonable to include it in the LCD as a required test for determining treatment eligibility with LUXTURNA.

Therefore, we believe policy bullet point 1 is not required in the LCD because genetic testing will confirm diagnosis and appropriate treatment eligibility for patients with RPE65 biallelic gene mutations, and some of the suggested documentation, such as the MLMT, would be impossible to obtain. As noted above, confirmation of the appropriate genetic diagnosis for RPE65, combined with confirmation of retinal cell viability based on a determination by the treating physician, should serve as the only necessary treatment eligibility criteria for LUXTURNA; the specific tests used to determine eligibility should be left to the physician’s discretion.

2. Policy Bullet Point 2: Segregation analysis to confirm biallelic involvement is not necessary for diagnosis.

We recommend removing the requirement for segregation analysis because it may not always be possible to obtain, such as when the patient is adopted or if one or both parents are deceased. In these situations, the two identified RPE65 variants can be determined to be disease causing if the inherited retinal disease specialist at the treatment center confirms that the phenotype in the patient matches the genetic sequencing test results with a high degree of specificity. This recommendation is based upon the fact that monoallelic RPE65 mutations (cis configuration, which means two mutations involve only one copy (allele) of the RPE65 gene) are expected to be extremely rare and have not been described in the scientific literature in association with a RPE65 biallelic retinal dystrophy phenotype.

Therefore, we recommend the proposed policy bullet 2 to be re-written as follows (noted as 1b in Appendix A):

“Documentation of a positive genetic test result confirming two pathogenic or likely pathogenic RPE65 mutations by a MolDX-approved mutational test. When possible, segregation analysis may be conducted to confirm the presence of RPE65 mutations on both alleles, and patients with two mutations involving only one copy of the RPE65 gene (confirmed as not biallelic via segregation analysis) are excluded from coverage. If segregation analysis is not possible, the treating physician must determine that the genetic sequencing test results match the patient’s phenotype with a high degree of specificity based on the scientific literature related to RPE65.”

3. Policy Bullet Point 3: The age limit for patients to be prescribed LUXTURNA should align with  the FDA-approved prescribing information.

The FDA granted approved of LUXTURNA for pediatric use in children 12 months or older. This age limit allows physicians and caregivers to intervene as early as possible in the natural history of the disease, aiming to treat a larger number of retinal cells that are still viable. Use in infants under 12 months of age is not recommended because of potential dilution or loss of LUXTURNA after administration due to the active retinal cells proliferation occurring in infant patients.

The age of onset of biallelic RPE65 mutation-associated retinal dystrophy is variable and can range from infancy to young adulthood. It is important to note that over time, most untreated patients with biallelic RPE65 mutation–associated retinal dystrophy lose the ability to detect light of any intensity, and eventually progress to total blindness. A retrospective chart review of 70 patients with confirmed mutations in the RPE65 gene showed a significant correlation in progression of visual function loss with increasing age over a mean observation time of 7.3 years (P<0.001 ).

It is not necessary to restrict the age limit of patients based on the clinical trial program for LUXTURNA, which enrolled patients who were 4 years of age and above (protocol allowed participants as young as 3 years old to enter the trial). An age limit of 3 years was set in the clinical trial because the LUXTURNA Phase 3 trial required patients to undergo the Multi-Luminance Mobility Test (MLMT), which required participants to understand and follow test instructions to ensure the integrity of the results. It is unlikely that patients under 3 years old would have the required level of maturity to follow the instructions that were provided to trial participants for the test completion without assistance. However, since the MLMT is not used in clinical practice, only in the clinical trial setting, an age limit over 3 years to receive LUXTURNA is unnecessary. Instead, it would be more appropriate to align the age limit in the LCD with the FDA-approved prescribing information for patients older than 12 months.

4. Policy Bullet Point 4: Limiting or delaying treatment based on certain narrow inclusion/exclusion criteria used in the LUXTURNA clinical trial program, such as visual acuity or visual field, will unnecessarily deny a patient who may potentially benefit from the treatment.

The current draft LCD policy includes a requirement that, “Best corrected visual acuity worse than 20/60 or visual field < 20° in any meridian of each eye (pretreatment baseline).” While payers sometimes rely on the Phase 3 clinical trial inclusion/exclusion criteria when drafting medical policies, it is not always an appropriate way to determine medical necessity. Particularly in the case of a progressive, genetic disease like RPE65 mutations, relying on these inclusion/exclusion criteria may inadvertently exclude eligible candidates when it comes to real-world patient selection.

The general purpose of a clinical trial’s inclusion/exclusion criteria is to help ensure patient safety and to demonstrate a statistical and clinically meaningful difference in effect (primary, secondary and/or safety endpoints) between a treatment and a control group. The inclusion/exclusion criteria also aim to remove the influence of specific confounding variables to help ensure that a treatment effect is more clearly defined.

The LUXTURNA Phase 3 program utilized a prespecified range for the visual acuity (VA) and visual field (VF) measures as part of inclusion/exclusion criteria, determining that a minimum level of visual impairment was necessary to incur the risks of study participation. This level of impairment, VA worse than 20/60 and/or visual field worse than 20 degrees, is significant. The use of such criteria is justifiable in a clinical trial given that the experimental therapy has yet to prove its positive benefit/risk ratio and it would be unethical to expose patients to treatment without a significant visual impairment. In addition, participants had to have sufficient vision loss at baseline in order to be able to demonstrate measurable improvement in functional vision (MLMT) and visual function (FST, VF) in the trial.

As with most genetic diseases, earlier intervention may prevent permanent damage to the body, which is in the best interest of the patient. Waiting to provide LUXTURNA treatment to eligible patients in a real-world setting until a patient reaches such a level of profound visual impairment would be inappropriate because the natural history of this genetic disease demonstrates a clear progression to complete blindness. Administering LUXTURNA as soon as an eligible patient is identified will allow he or she to benefit from the treatment earlier in the disease’s progression. The overall treatment focus in patients with this genetic disease should be on vision and retinal cell preservation rather than waiting for vision worsening to be considered for treatment.

Therefore, limiting or delaying treatment with LUXTURNA based on the narrow inclusion/exclusion criteria used in the clinical trial program will unnecessarily deny or delay a patient who may potentially benefit from the treatment for this progressive disease that leads to total blindness in nearly all patients.

To conclude, we emphasize that LUXTURNA has demonstrated both statistical significance and a clinically meaningful improvement in functional vision in the majority of Phase 3 trial participants and our recommendations for Palmetto’s draft LCD policy are in line with the FDA-approved prescribing information and current clinical practice. We respectfully request that you review this letter and we urge you to re-evaluate the draft policy to more appropriately allow eligible patients in need of therapy to have timely access to it.

Please let us know if we can provide any further information as you assess the policy.

Regarding point 1, we disagree with the commenter that a clinical diagnosis is not relevant. It is the constellation of clinical findings that allow for more accurate interpretation of genetic testing results as to the causative genetic mutation(s) given the genetic heterogeneity of the heritable retinal diseases of interest and high degree of normal, non-pathogenic, variation in the human genome. We will therefore keep the requirement for clinical test results and phenotypic information that are supportive of the clinical diagnosis of Leber congenital amaurosis or retinitis pigmentosa.

Regarding point 2, we disagree with the recommendation from the commenter to remove the requirement for segregation analysis in cases where more than one RPE65 mutation is detected. Segregation analysis is the only means by which these cases can be confirmed as trans or biallelic. Given the genetic heterogeneity of Leber congenital amaurosis and retinitis pigmentosa, and evidence of a treatment benefit only in those with biallelic RPE65 mutations, confirmation of a trans configuration in the case of heterozygous RPE65 mutations is key to identifying patients most likely to benefit from treatment while protecting those unlikely to benefit from treatment from potential harm that could result from undergoing an unnecessary invasive surgical procedure. However, changes in the policy have been made to accommodate cases in which segregation analysis is not possible (e.g. adoption).

Regarding point 3, we disagree with the recommendation to remove the restriction for coverage for treatment in those > 3 years of age. Coverage decisions are made on the basis of publically available evidence. At the present time, there exists no published evidence for safety and efficacy of Luxturna^TM in children < 3 years of age. Moreover, evidence to the contrary is found on the transcript of the FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting during which the decision to approve Luxturna^TM was made which indicates that members of the committee and individuals speaking on behalf of the sponsor raised concern for the safety of the procedure in those < 3 years of age given the challenges inherent in anatomically small eyes of patients in this age group. Should evidence become available supportive of Luxturna^TM in individuals < 3 years of age, the LCD may be updated

We agree with the commenter that certain types of testing, such as perimetry may not be appropriate given the age and/or functional limitations of the patient. Additionally, we realize the MLMT will likely not be available to patients outside of participation in a clinical trial. As such, the LCD does not include results of these tests as a condition for coverage; however, when performed, it is expected that the results of pre-treatment testing, including perimetry and MLMT, will be included in the clinical documentation records submitted for review.

As to the commenter’s 4^th point, we agree, and as such will remove the requirement for best-corrected visual acuity worse than 20/60 and/or visual field worse than 20 degrees from the policy coverage requirements.