The current standard of pharmacotherapy is corticosteroids for all patients regardless of genetic mutation. Treatment is initiated once patients reach a plateau of motor skill development, generally at ages 4 to 6 years, but prior to onset of motor decline. The goal of corticosteroid therapy is to preserve ambulation and minimize respiratory, cardiac, and orthopedic complications.¹

There are three drugs approved by the U.S. Food and Drug Administration to treat patients with DMD: Eteplirsen (Exondys 51), Golodirsen (Vyondys 53), and Viltolarsen (Viltepso). Eteplirsen (Exondys 51) was FDA approved in September 2016, Golodirsen (Vyondys 53) was FDA approved in December 2019 and Viltolarsen (Viltepso) was FDA approved in August 2020. Eteplirsen (Exondys 51) is approved to treat roughly 13% of patients with disease caused by an error in the DNA sequence known as exon 51. Golodirsen (Vyondys 53) and Viltolarsen (Viltepso) are approved to treat roughly 8% of patients whose Duchenne is caused by an error in the DNA sequent known as exon 53.

Eteplirsen (Exondys 51) is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) class that induces skipping of exon 51 and thereby repairing the mutated reading frame. PMO are stable RNA analogues that selectively binds to exon 51 of the dystrophin premessenger RNA. This causes the exon to be skipped and prevents that part of the code from being read during mRNA processing, thereby repairing the mutated reading frame in the mRNA coding sequence in patients with a deletion in exons 45-50, 47-50, 48-50, 49-50, 50, 52, or 52-63 of this gene. As a result, eteplirsen (Exondys 51) enables the production of an internally truncated, yet functional, dystrophin protein.

Golodirsen (Vyondys 53) is a phosphordiamidate morpholino oligomer engineered to treat those individuals with Duchenne muscular dystrophy (DMD) who have genetic mutations subject to skipping exon 53 of the dystrophin gene.

Viltolarsen (Viltepso) is the third DMD antisense oligonucleotide to be approved and the second specific for DMD patients amenable to exon 53 skipping.

Populations	Interventions	Comparators	Outcomes
Individuals: · With confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping · With confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 53 skipping	Interventions of interest are: · Eteplirsen (Exondys 51) · Golodirsen (Vyondys 53) · Viltolarsen (Viltepso)	Comparators of interest are: · Continued medical management (eg, glucocorticoids)	Relevant outcomes include: · Disease-specific survival · Change in disease status · Morbid events · Functional outcomes · Health status measures · Quality of life · Treatment-related mortality · Treatment-related morbidity

REGULATORY STATUS
In September 2016, eteplirsen (Exondys 51™; Sarepta Therapeutics) was approved by the U.S. Food and Drug Administration through the orphan drug status process for use in Duchenne muscular dystrophy (DMD) patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication was approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen.

In December 2019, golodirsen (Vyondys 53^TM, Sarepta Therapeutics) was approved by the U.S. Food and Drug Administration through the orphan drug status process for use in Duchenne muscular dystrophy (DMD) patients who have confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with golodirsen. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

In August 2020, viltolarsen (Viltepso, NS Pharma) was approved by the U.S. Food and Drug Administration through the orphan drug status process for use in Duchenne muscular dystrophy (DMD) patients who have confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with viltolarsen. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Eteplirsen (Exondys 51), golodirsen (Vyondys 53), and viltolarsen (Viltepso) were approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (i.e., how patients feel or function or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of both drugs was based on the surrogate endpoint of an increase in dystrophin production in the skeletal muscle observed in some patients treated with the drugs. The FDA has concluded that the data submitted demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 or 53 skipping. A clinical benefit of the drug, including improved motor function, has not been established.

Policy:

(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)

The use of eteplirsen (Exondys 51), golodirsen (Vyondys 53), or viltolarsen (Viltepso) is considered investigational for all indications including treatment of Duchenne muscular dystrophy.


[RATIONALE: This policy was originally created in December 2016 based on a search of the MEDLINE database. The most recent literature search was conducted through August 2020.

Eteplirsen (Exondys 51)

STUDY 201/202 (PIVOTAL TRIAL)
In single-center, double-blind, placebo-controlled trial, 12 boys ages 7 to 13 years with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping and on stable corticosteroid dose for last 6 months were randomized to eteplirsen (30 or 50 mg/kg/wk) or placebo (4 patients per group). Treatment was continued to 24 weeks and then placebo patients switched to eteplirsen 30 or 50 mg/kg (n=2 per group) at week 25. All treatment subsequently became open-label and patients were followed for additional 24 weeks (48 weeks in total). The primary end point was dystrophin expression. Clinical end points such as 6-minute walk distance (6MWD) were also assessed. 6MWD measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. Patients had a mean age of 9.4 years and a mean 6MWD at baseline of 363 meters.^4,5

Dystrophin Levels
The primary trial end point was a surrogate measure of change in dystrophin-positive fibers as measured in muscle biopsy tissue using immunohistochemistry.⁶ Serial biopsies were performed at 12, 24, and 48 weeks, although biopsies were performed on only half the treated patients at each of the 12- (only for eteplirsen 50-mg/kg group) and 24-week periods (only for eteplirsen 30-mg/kg group); all 12 patients were receiving drug treatment by week 48. The results published in 2013 reported substantial increase (range, 23%-52%) in the percentage of dystrophin-containing fibers in the biopsy specimens at week 24 and 48 in the eteplirsen-treated groups.⁵ However, immunohistochemistry analysis is not a quantitative measure of dystrophin. This analysis evaluates thin slices of muscle biopsies to asses if dystrophin is present or absent. Each muscle fiber that shows any amount of dystrophin is counted as positive, regardless of the actual quantity of dystrophin present. On the other hand, Western blot analyzes how much dystrophin is present in a sample. Results reported in the prescribing label show the average dystrophin protein level after 180 weeks of treatment with eteplirsen measured by Western blot analysis of biopsy was 0.93% of the dystrophin level in healthy subjects.⁴ Further, a more rigorous and fully blinded reanalysis by 3 investigators of the immunohistochemical assay by the Food and Drug Administration (FDA) cast further doubt about the consistency of immunohistochemical analysis as there was little difference in positive fibers between original baseline samples and week 180.⁷

6-Minute Walking Test
The prespecified clinical end points on 6MWT of study 201 (week 24) and study 202 (week 48) were negative.⁷ The published article reported a 67.3-meter benefit in 6MWT at week 48 in ambulation- evaluable eteplirsen-treated patients compared to placebo/delayed patients (p<0.005).⁵ However, this was a post hoc analysis as it excluded 2 eteplirsen-treated patients who deteriorated quickly while receiving therapy and lost ambulation at or beyond week 24. FDA has recommended retraction of the published study due to concerns related to interpretation of its findings.⁸ Further, in an exploratory analysis, FDA found no correlation between dystrophin levels and 6MWT.⁷ For example, among 4 patients with most preserved 6MWT, 2 had the lowest levels and 2 had the highest dystrophin levels as per Western blot. As per the prescribing label, there was no significant difference in change in 6MWD between patients treated with eteplirsen and placebo. While 6MWT may seemingly be an objective test, the results can also be influenced by expectation bias, motivation, and coaching especially in the context that patients in the pivotal 201/202 trial were aware of treatment assignment for majority of the investigation period.

Sarepta also claimed a gain of 162 meters in 6MWD at 4 years after treatment with eteplirsen in 12 patients in study 202 compared to data of 13 patients from an external control at the FDA peripheral and central nervous system drugs advisory committee.⁶ Results were subsequently published in a peer- reviewed journal.⁹ The data for external control was extracted from pooled data from an Italian and Belgium registry by matching corticosteroid use at baseline, availability of longitudinal data for 6MWT, age and genotype amenable to exon 51 skipping therapy. However, FDA¹⁰ and others¹¹ have identified several issues related to the use of an external control such as differences in the use of steroids and physical therapy between the 2 groups. Most importantly, the impact of unknown prognostic factors cannot be ascertained in an externally controlled study.

FDA was unable to draw conclusions from the data of pivotal trials about whether eteplirsen increased dystrophin production as quantitative estimates of pretreatment dystrophin levels were not available. In June 2016, FDA requested Sarepta to submit additional data for review of eteplirsen.¹² Sarepta complied with this request by submitting data of 13 patients from the ongoing PROMOVI trial for whom quantitative estimates of dystrophin at baseline and at week 48 were available. PROMOVI is a 96-week, open-label, multicenter, phase 3 study with a planned enrollment of 160 genotypically confirmed DMD patients; 80 patients amenable to exon 51 skipping will be treated with eteplirsen (30 mg/kg) and compared to 80 untreated group who are not amenable to exon 51 skipping.¹³ Male ambulatory patients aged between 7 to 16 years who are on stable dose of corticosteroids for at least 6 months and have intact right and left bicep muscles (the preferred biopsy site) or 2 alternative upper arm muscle groups will be included in the trial. The estimated completion date of this trial is January 2019. Subsequent FDA’s approval was based on data of these 13 patients with a mean age of 8.9 years.⁴ In the 12 patients with evaluable results, the pretreatment dystrophin level was 0.16%±0.12% of the dystrophin level in a healthy subject and 0.44%±0.43% after 48 weeks of treatment with eteplirsen (p<0.05). Median increase after 48 weeks was 0.1%. The clinical benefit of this increase in eteplirsen is unknown.

Section Summary: Study 201/202 (Pivotal Trial)
The clinical benefit of treatment for DMD with eteplirsen, including improved motor function, has not been demonstrated. Establishment of a clinical benefit is warranted in ongoing clinical trials.

HARMS
The most frequently reported adverse events across clinical trials were balance disorder, vomiting, and contact dermatitis.⁴

SUMMARY OF EVIDENCE
For individuals with confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping who are treated with eteplirsen, the evidence includes 1 randomized controlled trial (RCT) and its open-labelled follow-up study, and interim data from an ongoing RCT. Relevant outcomes are disease-specific survival, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. As per Food and Drug Administration analysis, the pivotal RCT and its open-labelled follow-up study failed to provide evidence of a clinical benefit in terms of 6-minute walk distance. Evidence regarding impact of eteplirsen treatment on dystrophin levels was inconclusive. Interim results from an ongoing study provided evidence that eteplirsen increased dystrophin levels in skeletal muscle in some patients by a median of 0.1% after 48 weeks of treatment. In summary, the clinical benefit of treatment for Duchenne muscular dystrophy with eteplirsen, including improved motor function, has not been demonstrated. Establishment of a clinical benefit is warranted in ongoing clinical trials. The most frequently reported adverse events across clinical trials were balance disorder, vomiting and contact dermatitis. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

PRACTICE GUIDELINES AND POSITION STATEMENTS
The U.S. Centers for Disease Control and Prevention has developed care recommendations.^1,14 These recommendations focus on the overall perspective on care, pharmacological treatment, psychosocial management, rehabilitation, orthopedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, in addition to general surgical and emergency room precautions. They recommend the use of corticosteroids to slow the decline in muscle strength and function in Duchenne muscular dystrophy (DMD). Eteplirsen is mentioned as being available, however, the guidelines do not provide strong evidence for this drug to be used. When the newer therapies demonstrate and prove safety and efficacy, future considerations should be taken in regards to the overall management of DMD.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in April 2020 did not identify any ongoing or unpublished trials that would likely influence this review.

The Food and Drug Administration, under the accelerated approval regulations, 21 CFR 314.510, requires that Sarepta conduct a 2-year randomized, double-blind, controlled trial of eteplirsen in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Patients should be randomized to the approved dosage of eteplirsen (30 mg/kg/wk) or to a dosage that provides significantly higher exposure (eg, 30 mg/kg daily). The primary end point will be the North Star Ambulatory Assessment.¹⁵

Golodirsen (Vyondys 53)

STUDY 1 (PIVOTAL TRIAL – NCT02310906)
Vyondys 53 was evaluated in a two-part clinical study.Study 1 Part 1 was a double-blind, placebo-controlled, dose-titration study in 12 DMD patients. Patients were randomized 2:1 to receive Vyondys 53 or matching placebo so 8 patients received Vyondys 53 and 4 received placebo. Vyondys 53-treated patients received four escalating dose levels, ranging from 4 mg/kg/week (less than the recommended dosage) to 30 mg/kg/week by intravenous infusion for 2 weeks at each dose level.

Study 1 Part 2 was a 168-week, open-label study assessing the efficacy and safety of Vyondys 53 at a dose of 30 mg/kg/week in the 12 patients enrolled in Part 1, plus 13 additional treatment-naive patients with DMD amenable to exon 53 skipping. At study entry (either in Part 1 or Part 2), patients had a median age of 8 years and were on a stable dose of corticosteroids for at least 6 months. Efficacy was assessed based on change from baseline in the dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 48 of Part 2.

Dystrophin Levels
The primary trial end point was a surrogate measure of change in dystrophin-positive fibers as measured in muscle biopsy tissue using immunohistochemistry. Muscle biopsies were obtained at baseline prior to treatment and at Week 48 of Part 2 in all Vyondys 53-treated patients (n=25) and were analyzed for dystrophin protein level by Western blot. Mean dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal by Week 48 of Study 1 Part 2, with a mean change in dystrophin of 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%

Section Summary: Study 1 (Pivotal Trial)
The clinical benefit of treatment for DMD with golodirsen, including improved motor function, has not been demonstrated. Establishment of a clinical benefit is warranted in ongoing clinical trials.

HARMS
The most common side effects reported by participants receiving Vyondys 53 in clinical studies were headache, fever (pyrexia), cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. Hypersensitivity reactions, including rash, fever, itching, hives, skin irritation (dermatitis) and skin peeling (exfoliation), have occurred in patients who were treated with Vyondys 53. Additionally, renal toxicity was observed in animals who received golodirsen. Although renal toxicity was not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in patients taking Vyondys 53.

SUMMARY OF EVIDENCE
For individuals with a confirmed variant of the DMD gene that is amenable to exon 53 skipping who receive golodirsen, the evidence includes a 2-part multicenter study which consists of a part 1 randomized, double-blind safety and tolerability study and a part 2 open-label efficacy and safety study. Although the study has been completed, results have not been published and only interim analysis of selective outcomes (change from baseline in dystrophin protein levels) has been reported. The interim analysis was based on 25 patients who received a weekly intravenous infusion of golodirsen 30 mg/kg. At week 48, the mean change in dystrophin protein levels was 0.924% increase from the baseline (1.019% vs 0.095%; P <0.001). While treatment with golodirsen may increase dystrophin levels detected in muscle fibers and exon 53 skipping, its impact on clinically meaningful outcomes is unclear. Other safety and efficacy outcomes of the 2-part study as well as 2, phase 3 clinical trial results are not currently published.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
NCT02500381: Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE) – currently a phase 3 study in children and adults aged 7 to 23 years old. ESSENCE is Sarepta’s placebo-controlled, post-marketing confirmatory trial for Vyondys 53. It is currently enrolling and expected to be complete by May 2023.

Viltolarsen (Viltepso)

STUDY 1 (PIVOTAL TRIAL – NCT02740972)
The effect of Viltepso on dystrophin production was evaluated in one study in DMD patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Study 1 was a multicenter, 2-period, dose-finding study conducted in the United States and Canada. During the initial period (first 4 weeks) of Study 1, patients were randomized (double blind) to Viltepso or placebo. All patients then received 20 weeks of open-label Viltepso 40 mg/kg once weekly (0.5 times the recommended dosage) (N=8) or 80 mg/kg once weekly (N=8). Study 1 enrolled ambulatory male patients 4 years to less than 10 years of age (median age 7 years) on a stable corticosteroid regimen for at least 3 months.

Dystrophin Levels
Efficacy was assessed based on change from baseline in dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 25. Muscle biopsies (left or right biceps brachii) were collected from patients at baseline and following 24 weeks of Viltepso treatment, and analyzed for dystrophin protein level by Western blot normalized to myosin heavy chain (primary endpoint) and mass spectrometry (secondary endpoint)

In patients who received Viltepso 80 mg/kg once weekly, mean dystrophin levels increased from 0.6% (SD 0.8) of normal at baseline to 5.9% (SD 4.5) of normal by Week 25, with a mean change in dystrophin of 5.3% (SD 4.5) of normal levels (p=0.01) as assessed by validated Western blot (normalized to myosin heavy chain); the median change from baseline was 3.8%. All patients demonstrated an increase in dystrophin levels over their baseline values. As assessed by mass spectrometry (normalized to filamin C), mean dystrophin levels increased from 0.6% (SD 0.2) of normal at baseline to 4.2% (SD 3.7) of normal by Week 25, with a mean change in dystrophin of 3.7% (SD 3.8) of normal levels (nominal p=0.03, not adjusted for multiple comparisons); the median change from baseline was 1.9%.

Section Summary: Study 1 (Pivotal Trial)
The clinical benefit of treatment for DMD with viltolarsen, including improved motor function, has not been demonstrated. Establishment of a clinical benefit is warranted in ongoing clinical trials.

HARMS
The most common side effects reported by participants receiving Viltepso in clinical studies were upper respiratory tract infections, injection site reactions, cough, and pyrexia. Renal toxicity was observed in animals who received viltolarsen. Although renal toxicity was not observed in the clinical studies with Viltepso, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in patients taking Viltepso.

SUMMARY OF EVIDENCE
For individuals with a confirmed variant of the DMD gene that is amenable to exon 53 skipping who receive viltolarsen, the evidence includes a phase 2 multicenter study in which 100% of patients showed an increase in dystrophin levels and 88% of patients showed dystrophin levels ≥3% than normal. Overall, patients showed an increase in dystrophin expression to an average of 5.9% of normal after 24 weeks of treatment versus 0.6% at baseline. The trial included 16 patients with a median age of 7 years. Patients were on a stable dose of corticosteroid for at least 3 months. Efficacy was assessed based on change from baseline in dystrophin protein level at week 25.

In October 2019, the manufacturer begun its Phase 3 confirmatory trial (RACER53 trial) which will enroll 74 patients treated with Viltepso or placebo for 48 weeks. The primary endpoint is time to stand test (TTSTAND) after 48 weeks. Secondary endpoints include: time to run/walk test (TTRW), 6-minute walk test (6MWT), North Star Ambulatory Assessment (NSAA), time to climb 4 steps test (TTCLIMB), hand-held dynamometer.


ONGOING AND UNPUBLISHED CLINICAL TRIALS
NCT04060199 (RACER53): NS Pharma's placebo-controlled, phase 3, post-marketing confirmatory trial for Viltepso. It is currently enrolling and expected to read out in 2024.]

Medicare Coverage

There is no National Coverage Determination (NCD or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage will follow the Horizon Policy.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy
Exondys 51 (Eteplirsen) for Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy, Eteplirsen (Exondys 51) for
Muscular Dystrophy, Duchenne, Eteplirsen (Exondys 51) for
Golodirsen (Vyondys 53) for Duchenne Muscular Dystrophy
Vyondys 53 (Golodirsen) for Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy, Golodirsen (Vyondys 53) for
Muscular Dystrophy, Duchenne, Golodirsen (Vyondys 53) for
Viltolarsen (Viltepso) for Duchenne Muscular Dystrophy
Viltepso (Viltolarsen) for Duchenne Muscular Dystrophy

References:
1. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. Jan 2010;9(1):77-93. PMID 19945913

2. Center for Disease Control and Prevention: MD STARnet Data and Statistics. http://www.cdc.gov/ncbddd/musculardystrophy/data.html. Accessed November, 2016

3. Falzarano MS, Scotton C, Passarelli C, et al. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. Oct 07 2015;20(10):18168-18184. PMID 26457695

4. Prescribing Label: EXONDYS 51 (eteplirsen) injection, for intravenous use. Sarepta Therapeutics, Inc. Cambridge, MA. February 2018.

5. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. Nov 2013;74(5):637-647. PMID 23907995

6. Sarepta Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee FDA. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNe rvousSystemDrugsAdvisoryCommittee/UCM500822.pdf. Accessed November 2016.

7. FDA Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNe rvousSystemDrugsAdvisoryCommittee/UCM500821.pdf. Accessed November, 2016

8. Center For Drug Evaluation And Research. Application Number: 206488orig1s000 (Summary Review). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206488_summary%20review_Redacted.pdf. Accessed November 2016.

9. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. Feb 2016;79(2):257-271. PMID 26573217

10. FDA Briefing Information for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNe rvousSystemDrugsAdvisoryCommittee/UCM497063.pdf. Accessed November 2016.

11. Kesselheim AS, Avorn J. Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy. JAMA. Oct 24 2016. PMID 27775756

12. Sarepta Therapeutics Announces FDA Request for Dystrophin Data Prior to Making a Decision on Eteplirsen NDA. http://investorrelations.sarepta.com/phoenix.zhtml?c=64231&p=irol-newsArticle&ID=2175522. Accessed November, 2016.

13. Confirmatory Study of Eteplirsen in DMD Patients (PROMOVI). https://www.clinicaltrials.gov/ct2/show/NCT02255552?term=NCT02255552&rank=1. Accessed November, 2016.

14. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. Feb 2010;9(2):177-189. PMID 19945914

15. Approval Letter: NDA 206488. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/206488Orig1s000ltr.pdf. Accessed November, 2016.

16. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. The Lancet Neurology. 2018;17(3):251-267. doi:10.1016/S1474-4422(18)30024-3.

17. ClinicalTrials.gov Exondys. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=exondys&cntry=&state=&city=&dist=

18. Vyondys 53 (golodirsen). [Package Insert] Sarepta Therapeutics, Inc. Cambridge, MA. December 2019.

19. https://www.statnews.com/2019/12/12/fda-changes-course-approves-sarepta-once-rejected-muscular-dystrophy-drug/

20. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation

21. Clinicaltrials.gov. Phase I/II Study of SRP-4053 in DMD Patients. NCT02310906. https://clinicaltrials.gov/ct2/show/NCT02310906?term=NCT02310906&rank=1.

22. Clinicaltrials.gov. Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE). NCT02500381. https://clinicaltrials.gov/ct2/show/NCT02500381

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