Open-Label Evaluation of Etelpirsen in Patients With Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial

BACKGROUND

Table 1. Primary Efficacy Set: Untreated Group

FVC%p: PROMOVI Consistent With Study 201/202 in Slowing Pulmonary Annual Decline

• •Duchenne muscular dystrophy (DMD) is a fatal, X-linkedneuromuscular disease caused by mutations in the dystrophin gene1,2

• •Eteplirsen binds to exon 51 of dystrophin pre-mRNA to allow skipping of exon 51, restore the mRNA reading frame, and allow translation of a truncated dystrophin protein1,3,4

  • •Compared with the untreated CINRG exon 51 cohort, eteplirsen-treated patients experienced a significant, clinically meaningful attenuation in pulmonary function decline (P<0.001) (Figure 4)

• •Clinical trials of eteplirsen have confirmed the mechanism of action and demonstrated a significant increase in dystrophin protein accumulation, and indicate that eteplirsen may slow muscle deterioration, prolong ambulation, and preserve pulmonary function in patients with DMD with eligible genetic mutations3-6

  • -In PROMOVI, the annual rate of decline in FVC%p was -3.3 based on the use of ulnar calculated height and -3.1 based on standingheight

  • •Baseline characteristics are shown inSupplementary Table 3

  Figure 4. FVC%p in Eteplirsen-Treated Patients From PROMOVI vs Study 201/202 and Untreated CINRG Exon 51 Cohort (Age 10-18 Years)

• •Accumulation of natural history studies demonstrates disparate disease trajectories for patients with different mutations; nonmutation-matched comparisons may be inappropriate7

• •PROMOVI included a flawed comparison of eteplirsen-treated patients (Table 2) to a control arm consisting entirely of patients with mutations not amenable to exon 51 skipping

  CINRG DNHS Exon 51

  (untreated)PROMOVI (2-year analysis)Study 201/20210(4-year analysis)

  (n=20)

  (n=52)

  (n=12)

  • -Emerging natural history data demonstrate patients with different mutations have different disease trajectories7-9

    OBJECTIVE

  • -The untreated arm does not provide a relevant comparator group because patient mutations were not equivalent

    • •To report results from the Phase 3 PROMOVI study of eteplirsen efficacy/safety in boys with DMD amenable to exon 51 skipping

  • -Inadequate choice of control group became clear only after study initiation

METHODS

FVC%pAnnualRateofChange,%(SE)

Study Population

0 -1 -2 -3 -4 -5 -6 -7

-6.0

• •Confirmed DMD, amenable to exon 51 skipping

• •7-16 years of age, inclusive

  Safety: PROMOVI Consistent With Study 201/202

• •Stable oral corticosteroids ≥24 weeks before study

• •Stable pulmonary function: forced vital capacity (FVC) ≥50%

• •6-minute walk test (6MWT) distance: ≥300 m

• •Adverse events (AEs) reported in PROMOVI reflected those observed in other PMO studies, with no major differences; overall, once-weekly eteplirsen IV appeared to be well tolerated

  Study Design/Treatment

• •The majority of the treatment-emergent AEs (TEAEs) reported were mild or moderate in severity

  • •The PROMOVI study design is shown inFigure 1; treated patientsreceived eteplirsen IV 30 mg/kg/wk for 96 weeks

  • •Post hoc, matched comparisons were performed

• •No treatment-related discontinuations due to TEAEs

  • -For 6MWT, PROMOVI patients were matched to study 201/202 baseline criteria

  • -PROMOVI FVC%p data were compared to study 201/202 and the Cooperative International Neuromuscular Research Group (CINRG) exon 51 cohort

• •AEs observed among patients who received eteplirsen and those in the untreated control group were generally consistent with AEsobserved in a younger population with DMD and in patients withDMD receiving chronic corticosteroid treatment

  Exon 51 Skipping and Dystrophin: PROMOVI Consistent With Study 201/202 and Shows Accumulation Over Time

  • •Exon 51 skipping and increases in dystrophin were observed following eteplirsen treatment (Figure 2)

    • -One treatment-related serious AE of urticaria was observed approximately 15-20 minutes after infusion and resolved approximately 1 hour after an IV steroid and antihistamine were administered; although the patient continued on eteplirsen without subsequent events and without pretreatment with corticosteroids, the event may have been related to drug hypersensitivity

  • •Positive correlation was observed between exon 51 skipping vsdystrophin (Pearson coefficient = 0.710 [P<0.001]; Spearman coefficient = 0.692 [P<0.001])

  • -Overall, 8 eteplirsen-treated patients (10.1%) experienced renal TEAEs; each as proteinuria, which resolved in all but one individual

  • -One infected venous port serious AE was reported as severe and unrelated to treatment

Figure 2. Exon 51 Skipping and Dystrophin Accumulation in Eteplirsen-Treated Patients

CONCLUSIONS

1.6

Study Endpoints

• •Primary: change from baseline to Week 96 in 6MWT distance

• •Additional endpoints, measured from baseline to Week 96:

  • -Change in dystrophin protein levels

    • •Western blot, immunohistochemistry

  • -Exon 51 skipping

    MeanExon51%Skipping(SE)

    1.4

    1.047†

    1.091†

    1.2

    1

    0.724†

    0.8

    0.588†

    0.6

    0.4

    0.186

    0.2

    Mean%NormalDystrophin(SE)

    0.9

    0.630†

    • •PROMOVI, a large, US-based, multi-center study, contributes to the growing body of evidence for eteplirsen and confirms evidence oftreatment effect and safety profile seen in study 201/202

      0.8

      0.532*

      0.578†

      0.7

      0.6

    • •PROMOVI control arm did not retain sufficient patients, precluding statistically and clinically meaningful comparisons

      0.5

      0.303*

      0.4

      0.244

      0.3

      0.2

      0.1

      0

      0

      • •A quantitative digital droplet PCR assay was used, providing precise and accurate measurements

      Baseline Week 24 Week 48 Week 72 Week 96

      Baseline Week 24 Week 48 Week 72 Week 96

      Time (weeks)

      Time (weeks)

    • •PROMOVI included a flawed comparison of eteplirsen-treated patients to a mismatched control arm that consisted entirely of patients with mutations not amenable to exon 51 skipping-Inadequate choice of control group became clear only after study initiation, as emerging natural history data demonstrate patients with different mutations have different disease trajectories

  • -Percent predicted FVC (FVC%p) annual rate of change

• •Safety and tolerability

• •Exon skipping increases post treatment demonstrating target engagement, and dystrophin protein accumulated over time

  RESULTS

  *P-value <0.05; † P-value <0.001. SE=standard erroraCalculated from scatter plot (not shown) of change from baseline dystrophin level vs change from baseline in percent exon 51 skipping.bPvalue is based on one-sample permutation t-test.

• •Matched comparison with previous eteplirsen study 201/202 and natural history data suggest eteplirsen treatment slowed disease progression

  Patient Characteristics

  • •Patients were enrolled over a 2.5-year period starting October 2014

  • •A total of 79 patients were enrolled in the eteplirsen-treated group and 30 in the untreated group

    6MWT at Week 96: PROMOVI Consistent With Study 201/202 in Slowing Disease Progression

• •Long-term eteplirsen treatment was shown to have a favorable safety profile, with generally mild-to-moderate AEs and no discontinuations due to safety

• -Baseline characteristics of the eteplirsen-treated group are shown inSupplementary Table 1

• -78 patients received eteplirsen and completed 96 weeks of treatment

  • •Mean change from baseline in 6MWT in eteplirsen-treated patients was -68.9 m in PROMOVI compared with -67.3 m in patients from study 201/202 (Figure 3); baseline characteristics are shown inSupplementary Table 2

  REFERENCES

• -13 patients in the untreated group completed the study; only 9patients completed in the primary efficacy set

Figure 3. Mean Change From Baseline to Week 96 in 6MWT in Eteplirsen-Treated Patients From Study 201/202 and PROMOVI

• •The untreated control arm did not retain sufficient patients; statistically and clinically meaningful comparisons were precluded-50% of patients in the untreated arm withdrew from the study; as their mutations were not amenable to exon 51 skipping, they could not cross over into the treatment arm (Table 1)

450

Mean6MWTDistance(m[SE])

1.Cirak S, et al.Lancet.2011;378:595-605.2.Emery AE, et al.Duchenne Muscular Dystrophy. 4th ed. Oxford, UK: Oxford University Press; 2015.3.Mendell JR, et al.Ann Neurol.2016;79:257-71.4.Mendell JR, et al.Ann Neurol.2013;74:637-47.5.Kinane TB, et al.J Neuromuscul Dis.2018;5:47-588.6.Alfano LN, et al.Medicine.2019;98:26(e15858).7.Brogna C, et al. PLoS ONE.2019;14:e0218683.8.Bello L, et al.Neurology.2016; 87:401-9.9.Ricotti V, et al.J Neurol Neurosurg Psychiatry.2016;87:149-55.10. Khan N, et al. J Neuromuscular Dis 2019;6:213-225.

400

ACKNOWLEDGMENTS & DISCLOSURES

350

300

250

PROMOVI (n=42a)Study 201/202 (n=12)

200

0

12

24

36

48

60

72

84

96

Time (weeks)

aAt 12, 72, and 96 weeks, n=41 patients. One patient did not have a 6MWT value at Week 12, but did at later visits. Another patient withdrew after Week 48. SE=standard error

The authors and Sarepta Therapeutics, Inc, thank the patients, families, and the dedicated CINRG DNHS researchers. Editorial support was provided by Eloquent Scientific Solutions and was funded by Sarepta Therapeutics, Inc.Disclosures: CM: Consulting (Astellas/Mitobridge, Bristol Myers Squib, Capricor, Cardero Therapeutics, Catabasis Pharmaceuticals, Eli Lilly, Gilead, Halo Therapeutics, Italfarmaco, Novartis, Pfizer, Prosensa, PTC Pharmaceuticals, Santhera Pharmaceuticals, Sarepta Therapeutics); research funding, principal investigator, and speaking fees (Sarepta Therapeutics).PS: Consultant/independent contractor (AveXis, Biogen, Cytokinetics, Sarepta Therapeutics); grants/research support (AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Sanofi Genzyme, Sarepta Therapeutics).HZA-H: Advisory board participation (Avexis, Audentes, Biogen, and Sarepta).AMC: Advisory board participation (Acceleron, Avexis, Genentech, and Sarepta), DMSB participation (Catabasis).NK, EK, DS, JM, WZ, and BH: employees of Sarepta Therapeutics, Inc.EC: Advisory board participation (Avexis, Biogen, Sarepta).

Craig McDonald,1Perry Shieh,2Hoda Z. Abdel-Hamid,3Anne M. Connolly,4Navid Khan,5Erica Koenig,5Deb Steiner,5Jyoti Malhotra,5Wenfei Zhang,5Baoguang Han,5Emma Ciafaloni6; on behalf of the PROMOVI Clinical Investigators

1University of California Davis Health System and School of Medicine, Sacramento, CA;2David Geffen School of Medicine at UCLA, Los Angeles, CA;3UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA;

4St.Louis Children'sHospital, Washington University School of Medicine, St. Louis, MO;5Sarepta Therapeutics, Inc., Cambridge, MA;6University of Rochester Medical Center, Rochester, NY

Endpoints	Baseline (n=20)	96 Weeks (n=9)
6MWT distance, m
Mean (SD)	382.63 (45.69)	252.17 (133.08)
Min, max	301.5, 448.0	0.0, 453.5
FVC%p
Mean (SD)	96.85 (17.71)	91.90 (14.17)
Min, max	67.54, 125.79	70.50, 113.83

Endpoints	Baseline(n=67)	96 Weeks (n=66)
6MWT distance, m
Mean (SD)	374.64 (44.06)	256.18 (148.71)a
Min, max	303.0, 449.5	0.0, 496.0
FVC%p
Mean (SD)	90.44 (15.95)	87.27 (16.32)
Min, max	50.00, 125.99	56.04, 128.43

Exon 51 Skipping

n= Absolute Difference of Means 78 16 32 (Week 96 vs baseline)	1F4old Changea	P-Valueb 16
0.956	18.74	<0.001

Dystrophin

n= Absolute Difference of Means 77 16 (Week 96 vs baseline)31	Fold14 Changea	16 P-Valueb
0.516	7.02	<0.001

Study	Change From Baseline to Week 96
PROMOVI	-68.9
201/202	-67.3

Craig McDonald,1Perry Shieh,2Hoda Z. Abdel-Hamid,3Anne M. Connolly,4Navid Khan,5Erica Koenig,5Deb Steiner,5Jyoti Malhotra,5Wenfei Zhang,5Baoguang Han,5Emma Ciafaloni6; on behalf of the PROMOVI Clinical Investigators

1University of California Davis Health System and School of Medicine, Sacramento, CA;2David Geffen School of Medicine at UCLA, Los Angeles, CA;3UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA;

4St.Louis Children'sHospital, Washington University School of Medicine, St. Louis, MO;5Sarepta Therapeutics, Inc., Cambridge, MA;6University of Rochester Medical Center, Rochester, NY

ADDITIONAL BASELINE CHARACTERISTICS

Supplementary Table 1. Baseline Characteristics: Treated Group (Efficacy Set)

Characteristic	Eteplirsen IV 30 mg/kg/wk (N=79)
Age (years), mean ± SD (min, max)	9.1±2.0 (7.0, 16.0)
Standing height (cm), mean ± SD (min, max)	125.5±9.0 (106.0, 148.5)
Time since DMD diagnosis at baseline (months), mean ± SD (min, max)	53.3±33.3 (5.5, 147.1)
Corticosteroid treatment, n (%) Deflazacort Prednisone	22 (27.8) 57 (72.2)
Corticosteroid schedule, n (%) Continuous Intermittent	65 (82.3) 14 (17.7)

Supplementary Table 3. Baseline Characteristics for FVC%p Matched Comparator Analysis: PROMOVI vs CINRG DNHS vs Study 201/202 (10 to <18 Age Group)a

Characteristic, mean±SD (min, max)	PROMOVI (n=42)a	Study 201/202 (n=12)
Age, years	9.0 ± 2.1 (7.0, 13.0)	9.5 ± 1.2 (7.4, 11.0)
6MWT distance, m	389.3 ± 41.9 (301.0, 450.0)	363.2 ± 42.2 (256.0, 416.0)
NSAA total score	25.0 ± 4.2 (17.0, 31.0)	24.9 ± 4.9 (17.0, 31.0)
10-m run, s	5.2 ± 0.8 (3.8, 7.2)	6.2 ± 1.5 (3.9, 8.7)
Age at start of corticosteroid use, years	5.8 ± 1.9(1.9, 10.0)	5.1 ± 1.1(3.4, 6.6)
Duration of corticosteroid use, months	43.0 ± 28.4 (5.7, 120.4)	52.1 ± 24.1 (15.5, 91.7)
Time since DMD diagnosis, months	59.4 ± 33.0 (5.5, 131.2)	58.3 ± 26.0 (18.0, 112.0)
NSAA=North Star Ambulatory Assessment. aPrimaryefficacy subset for comparison to study 201/202: consists of all treated patients with ≥1postbaseline assessment who have a baseline 6MWT distance of 300-450 m, inclusive, baseline NSAA score 17-31, and age 7-13 years, inclusive.

Characteristic, mean±SD (min, max)	CINRG DNHS Exon 51 (n=20)	PROMOVI (n=52)a	Study 201/202 (n=12)
Age at baseline, years	11.8 ± 2.2 (10.0, 17.9)	11.0 ± 1.4 (10.0, 16.3)	10.3 ± 0.3 (10.0, 11.0)
Height at baseline,bcm	140.8 ± 12.1 (124.0, 178.1)	138.3 ± 7.7c(122.4, 155.2)	126.1 ± 7.6 (116.0, 140.5)
FVC%p at baseline,b%	79.6 ± 13.3 (50.0, 106.0)	78.5 ± 14.5c(52.6, 127.0)	96.9 ± 14.0 (84.0, 121.0)

aThe analysis set included all treated patients with assessments in age group 10 to <18 years.bPROMOVI and CINRG DNHS used ulnar length calculated height, Study 201/202 used actual standing height.cn=51.

Presented 2020 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, Virtual Poster Session

Corresponding author: Craig McDonald; email:[e-mail]

REFERENCES

1.Shieh PB, et al. Poster at the 2nd Symposium of the Latin American Society of Neuromuscular Diseases (SOLANE). June 7-9, 2018. Rio de Janeiro, Brazil.