Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1

Figures & data

Table 1. Treatment effect covariates identified A Priori.

Mean CHOP INTEND score at baseline Percentage with nutritional support at baseline Percentage with ventilator support at baseline Age at symptom onset Age at study start (first dose) Baseline weight SMN2 copy number Sex

Expert consensus identified this list of treatment effect covariates for adjustment. All covariates were used and tested in the model.

Table 2. Summary of study characteristics and patient eligibility of the included trials.

Trial	Publication	SMA type	Treatment group	Dose	Frequency	Eligibility
						Age	SMN gene	Gestational age	Age at symptom onset	Body weight
SHINE^a [37,40,53]	NICE 2018	Infantile- and later-onset (type 1, 2, and 3)	Nusinersen	12 mg (scaled^b)	D1, D15, D29, D64, D183^c, D302^c	≤210 d	Two copies of SMN2	37–42 weeks	NR	≥3rd percentile for age
START [18]	Mendell 2017	Type 1; two copies of SMN2 gene	Onasemnogene abeparvovec (low dose)	6.7 × 10^13 vg per kg body weight	D1	≤6 months	Proven mutations of the SMN1 gene with exactly two copies of SMN2	NR	0–6 months	>5th percentile for age
			Onasemnogene abeparvovec (therapeutic dose)	2.0 × 10^14 vg per kg body weight^d	D1
STR1VE-US [33]	Novartis Gene Therapies, Inc., data on file	Type 1; two copies of SMN2 gene^e	Onasemnogene abeparvovec	1.1 × 10^14 vg per kg body weight	D1	≤6 months	Proven mutations of the SMN1 gene with one or two copies of SMN2	≥35 weeks	0–6 months	≥3rd percentile for age

Abbreviations. D. day; NICE. National Institute for Health and Care Excellence; NR. not reported; SMN: survival motor neuron.

^aSHINE (CS11) [37,40,53] is the extension trial for multiple nusinersen trials (CS3A [38], ENDEAR [CS3B] [39], EMBRACE [58], CHERISH [CS4] [32], or CS12 [59]); only data from patients who were enrolled in ENDEAR [39] (active treatment arm) and enrolled in SHINE [37,40,53] were used in the MAIC analysis presented.

^bDosage adjusted based on age; 12-mg scaled equivalent dose was given based on projected cerebrospinal fluid (CSF) volume. Each infant received the estimated dose that is proportional to the estimated CSF volume for age, such that dose volume will be equivalent to 5 mL for a 2-year-old child to adult.

^cMaintenance dosages.

^dDirect testing of the actual lot of investigational products used in START [18] by an improved and more fully qualified analytical method (droplet digital PCR) has determined the actual dose received by Cohort 2 (therapeutic dose) to be 1.1 × 10¹⁴ vg/kg (the same method has been used to establish an equivalent dose for the investigational medicinal product in all Phase III trials).

^eSTR1VE-US [33] allowed patients with one or two copies of SMN2. However, only patients with two copies were ultimately enrolled.

Table 3. Patient baseline characteristics of the included trials.

Trial name	Publication	Treatment	N	Mean age at study start (first dose), days (range)	Mean age at onset of symptoms, days (range)	Mean age at genetic diagnosis, days (range)	Female, n (%)	Mean weight, kg (range)	Mean CHOP INTEND score (range)	Mean HINE-2 score (range)	Nutritional support, n (%)	Ventilator support, n (%)
SHINE [37,40,53]	NICE 2018	Nusinersen	81^a	164.3 (60.8–456.3)	48.7 (0–121.7)	NR	44 (54%)	NR	26.7 (8.1)^b	1.3 (1.1) ^b	NR	NR
START [18]	Mendell 2017	Onasemnogene abeparvovec (therapeutic dose)	12	103.4 (27.4–240.3)	42.6 (0–91.3)	60 (0–136)	7 (58%)	5.7 (3.6–8.4)	28 (12–50)	NR	5 (42)	2 (17)
STR1VE-US [33]	Novartis Gene Therapies, Inc., data on file	Onasemnogene abeparvovec	22	112.5 (15.2–179.5)	57.8 (0–121.7)	63.9 (15.2–121.7)	12 (55%)	5.8 (3.9–7.5)	32 (18–52)	NR	0	0
STR1VE-US [33] and START [18] pooled	Novartis Gene Therapies, Inc., data on file	Onasemnogene abeparvovec	34	108.6 (15.2–240.3)	52.5 (0–120)	62.5 (0–136)	19 (56%)	5.8 (3.6–8.4)	30.8 (12–52)	NR	5 (15)	2 (6)

Abbreviations. CHOP INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2 ,  Hammersmith Infant Neurological Examination Section-2; NR: not reported.

^a One infant randomized to receive nusinersen in ENDEAR [39] was not dosed but was dosed in SHINE [37,40,53].

^b Standard deviation.

Table 4. Summary of covariates matching nusinersen pooled average before and after weighting, individual and pooled onasemnogene abeparvovec trials.

Trial	Scenario	Treatment	CHOP INTEND score at baseline	Nutritional support at baseline	Effective sample size
1 (START [18] and STR1VE-US [33] data pooled)	SHINE [37,40,53]	Nusinersen	26.7	9%	24.6
	STR1VE-US and START pooled – after matching	Onasemnogene abeparvovec	26.7	9%
	STR1VE-US and START pooled – before matching		30.6	15%
2 (START only) [18]	SHINE [37,40,53]	Nusinersen	26.7	Did not converge	11.8
	STR1VE-US and START pooled – after matching	Onasemnogene abeparvovec	26.7
	STR1VE-US and START pooled – before matching		28.2
3 (STR1VE-US only) [33]	SHINE [37, 40, 53]	Nusinersen	26.7	Did not converge	16.4
	STR1VE-US and START pooled – after matching	Onasemnogene abeparvovec	26.7
	STR1VE-US and START pooled – before matching		32.0

Figure 1. Matching-adjusted indirect comparison of event-free survival and overall survival for onasemnogene abeparvovec (START [18] and STR1VE-US [33]. Because STR1VE-US [33] only followed patients until 18 months of age, patients from this trial are censored at their last date of follow-up.) compared with nusinersen. (A) Event-free survival (B) Overall survival. Dashed lines represent 95% confidence intervals. The Kaplan Meier curves for ENDEAR [39]/SHINE [37, 40, 53] were digitized and reconstructed using the Guyot algorithm [64], which uses the published number at risk at each time point to account for censoring over the course of the study. The Kaplan Meier curves from STR1VE-US [33] and START [18] were constructed directly from patient-level data.

Table 5. Matching-adjusted indirect comparison of event-free survival and overall survival for onasemnogene abeparvovec (START [18] and STR1VE-US [33]) compared with nusinersen.

Trials	Comparison	Event-free survival HR (95% CI) (99% CI)	Overall survival HR (95% CI) (99% CI)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	Onasemnogene abeparvovec vs. nusinersen	0.19	0.35
		(0.07–0.54)^a	(0.09–1.32)
		(0.05–0.74)^a	(0.06–2.01)
	Nusinersen vs. onasemnogene abeparvovec	5.13	2.87
		(1.87–14.10)^a	(0.76–10.83)
		(1.36–19.42)^a	(0.50–16.50)

Abbreviations. CI, confidence interval; HR, hazard ratio; MAIC, matching-adjusted indirect comparison.

^a Treatment effect estimate is statistically significant.

Table 6. Onasemnogene abeparvovec (START [18] and STR1VE-US [33]) compared with nusinersen: independent sitting–time on study.^a

Comparison^b	Time point	Onasemnogene abeparvovec n/N (%)	Nusinersen n/N (%)	Relative risk^c (95% CI) (99% CI)	Risk difference^c (95% CI) (99% CI)
Scenario A (≥30 s definition for STR1VE-US [33] and START[18])
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	6 months	0.8/24.6	3/65	0.72	–0.01
		(3.3%)	(4.6%)	(0.07–7.95)	(–0.10–0.07)
				(0.03–16.89)	(–0.13–0.10)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	12 months	6.4/24.6	7/48	1.79	0.12
		(26.2%)	(14.6%)	(0.69–4.66)	(–0.08–0.32)
				(0.51–6.28)	(–0.15–0.38)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	18 months	13.3/24.6	9/31	1.86	0.25
		(54.1%)	(29%)	(0.96–3.60)	(–0.00–0.50)
				(0.78–4.43)	(–0.08–0.58)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	24 months^d	15.1/24.6	4/17	2.60	0.38
		(61.3%)	(23.5%)	(1.05–6.49)^c	(0.10–0.66)^c
				(0.78–8.64)	(0.01–0.74)^c
Scenario B (≥30 s definition for STR1VE-US [33], ≥5 s for START [18])
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	6 months	0.8/24.6	3/65	0.72	–0.01
		(3.3%)	(4.6%)	(0.07–7.95)	(–0.10–0.07)
				(0.03–16.89)	(–0.13–0.10)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	12 months	6.4/24.6	7/48	1.79	0.12
		(26.2%)	(14.6%)	(0.69–4.66)	(–0.08–0.32)
				(0.51–6.28)	(–0.15–0.38)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	18 months	13.5/24.6	9/31	1.90	0.26
		(55%)	(29%)	(0.98–3.65)	(0.01–0.51)
				(0.80–4.49)	(–0.07–0.59)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	24 months^d	16.1/24.6	4/17	2.79	0.42
		(65.7%)	(23.5%)	(1.13–6.89)^c	(0.15–0.70)^c
				(0.85–9.15)	(0.06–0.78)^c

Abbreviations. CI, confidence interval; n, number.

^a START [18] and STR1VE-US [33] used the Bayley Scales Gross Motor Subtest to define independent sitting (sits alone for ≥5 s in START [18] and ≥30 s in STR1VE-US [33]). Two scenarios were used to define independent sitting from the onasemnogene abeparvovec trials: Scenario A used the ≥30 s threshold for both STR1VE-US [33] and START [18]; Scenario B used the ≥30 s threshold for STR1VE-US [33] and the ≥5 s threshold for START [18]. In ENDEAR [39] and SHINE [37,40,53], independent sitting was defined as stable sitting and pivoting as per the Hammersmith Infant Neurological Examination Section 2.

^b Odds ratios are not presented because of unstable estimates.

^c Relative treatment effect estimate is statistically significant. Relative treatment effect estimates presented in bold are statistically significant.

^d 18-month results for STR1VE-US [33] were carried forward to the 24-month time point.

Table 7. Onasemnogene abeparvovec (START [18] and STR1VE-US [33]) compared with nusinersen: independent walking–time on study.^a

Comparison^b	Time point	Onasemnogene abeparvovec n/N (%)	Nusinersen n/N (%)	Relative risk (95% CI) (99% CI)	Risk difference (95% CI) (99% CI)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	6 months	0/24.6	0/65
		(0%)	(0%)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	12 months	0/24.6	0/48
		(0%)	(0%)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	18 months	0.2/24.6	0/31^c	1.40	1.39
		(0.7%)	(0%)	(0.04–54.50)	(0.04–50.16)
				(0.01–172.35)	(0.01–154.90)
START [18] + STR1VE-US [33] vs. SHINE [37,40,53]	24 months^d	0.6/24.6	0/17^c	2.08	2.03
		(2.5%)	(0%)	(0.06–76.33)	(0.06–67.02)
				(0.02–236.73)	(0.02–201.04)

Abbreviation. CI, confidence interval.

^a To assess independent walking, START [18] and STR1VE-US [33] used walking alone as per the Bayley Scales Gross Motor Subtest and ENDEAR [39] and SHINE [37,40,53] used walking as stable without assistance per the HINE-2 score scale.

^b Odds ratios are not presented because of unstable estimates.

^c Continuity correction was used.

^d 18-month results for STR1VE-US [33] were carried forward to the 24-month time point.

Italics denote the 99% CI.

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