An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the Institute for Clinical and Effectiveness Review (ICER)

Figures & data

Figure 1. Model health states – previous model vs ICER model

Note: in this updated model, no patients enter ‘A’ state.

Table 1. Comparison between old model, new model, and ICER model

Model Element	Previous model	ICER model	Updated model
Updated elements that are aligned with the ICER model
Comparators	Nusinersen	BSC (base case) Nusinersen (scenario analysis	BSC Nusinersen
Onasemnogene abeparvovec price	Range of placeholder values ($2.5 M-$5 M)	Placeholder price of $2 M	List price of $2.125 M
Long-term clinical outcomes	Nusinersen-treated patients: projected additional milestones based on CHOP INTEND data published from ENDEAR Onasemnogene abeparvovec: no projected additional milestones	Nusinersen: Milestones based on SHINE extension study. No projected additional milestones. Onasemnogene abeparvovec: no projected additional milestones	Nusinersen: Milestones based on SHINE extension study. No projected additional milestones. Onasemnogene abeparvovec: no projected additional milestones
Nusinersen stopping rules	No stopping rules	Patients in not sitting health states (D and E) assumed to stop nusinersen after 24 months of treatment	Patients in not sitting health states (D and E) assumed to stop nusinersen after 24 months of treatment
Nusinersen drug cost	60% markup applied to wholesale acquisition cost for hospital inpatient administration based on expert opinion	Estimated net cost per package of $127,500 (Average Wholesale Price – 15% discount).	Estimated net cost per package of $127,500 (Average Wholesale Price – 15% discount).
Utility sources	CHERISH – caregiver-proxy EQ-5D utility scores ranging from 0.73 to 0.878 (with scenario analyses of alternate scores with greater range between low and improved health states)	Derived from multiple sources – utility scores ranging from 0.19 to 0.92	Same as ICER utility scores
Elements in the updated model that differ from the ICER model
Onasemnogene abeparvovec milestones per observed patient development	Incorporated 11/12 patients achieved independent sitting and 2/12 patients achieved independent walking as observed during clinical trial	Assumed that one-third of onasemnogene abeparvovec patients received nusinersen at the end of the short term model and that 50% of those would lose a milestone in the absence of nusinersen	No change to previous model as there is no evidence to suggest that subsequent nusinersen therapy was required or would be beneficial for onasemnogene abeparvovec patients
Comparison with Nusinersen	Compared onasemnogene abeparvovec-treated patients to nusinersen-treated patients using a naïve comparison with no adjustments	Compared onasemnogene abeparvovec-treated patients to nusinersen-treated patients using a naïve comparison with no adjustments, but assumed one-third of onasemnogene abeparvovec patients would receive payer-funded sequential nusinersen treatment	No change to previous model
Survival source in Permanent Ventilation state	Used pooled data from observational trial for patients in Noninvasive Ventilation group and Tracheostomy group	Used data from same observational trial for patients in Noninvasive Ventilation group only	No change to previous model
Additional ventilator assistance costs (beyond claims analysis data for SMA)	Cost of Ventilatory devices used at home factored in via microcosting of Durable Medical Equipment	Additional cost of ventilator estimated from a UK study[^21], converted to US dollars using 2002 exchange rates and then inflated to 2017 dollars, applied to PAV state and all patients before death	Additional cost of ventilator estimated from a UK study[^21], converted to US dollars using 2002 exchange rates and then inflated to 2017 dollars, applied to PAV state only (as it is assumed that costs for other states are included in the claims analysis source)
Model cycles	6-monthly for first 3 years then annually	Monthly cycles	No change to previous model
Presymptomatic analysis	No presymptomatic analysis	Exploratory analysis of ‘Drug X’ assuming equal efficacy to nusinersen	Exploratory analysis of ‘Drug X’ assuming efficacy equal to that of 6 onasemnogene abeparvovec patients treated before age 3 months

Table 2. Inputs used in model

Variable	Source
Health state transitions: proportion of patients sitting or walking.	onasemnogene abeparvovec: AVXS-101-CL-101 [NCT02122952][8,28] nusinersen: ENDEAR [NCT02193074][17] and SHINE [NCT02594124][16] BSC: No sitting/walking patients.
Health state transitions: Probability of death or permanent ventilation (D state only)	Permanent Ventilation (E state) – onasemnogene abeparvovec/nusinersen/BSC: Based on a retrospective chart review of SMA patients with tracheotomy or non-invasive ventilation, projected using parametric estimation[^13] Not sitting (D state) – onasemnogene abeparvovec: Short term model: AVXS-101-CL-101 [NCT02122952][8] Long term: Projected overall and event-free survival using curve fitted to ENDEAR/SHINE (sham control arm) [NCT02193074, NCT02594124][16,17] nusinersen: Short term model: ENDEAR [NCT02193074][17] and SHINE [NCT02594124][16] Long term: Projected overall and event-free survival using curve fitted to ENDEAR/SHINE (sham control arm) [NCT02193074, NCT02594124][16,17] BSC: ENDEAR (sham control arm)[17] Sitting (C state) – onasemnogene abeparvovec/nusinersen: Parametric curve fitted to overall survival curve for SMA type 2[11] Walking (B state) – onasemnogene abeparvovec/nusinersen: Assume general population mortality in US[29]
Utility Scores	Equivalent to weightings used in the ICER analysis[^14], derived from multiple sources Permanent Ventilation: 0.19 Not sitting: 0.19 (BSC) 0.29 (Treatment arms) Sitting: 0.60 (BSC) 0.65 (Treatment arms) Walking: US general population utility
Cost inputs	Price of onasemnogene abeparvovec: $2.125 M one-time dose All other costs were equal to costs used in the ICER analysis[^14]
Caregiver disutility (Modified societal perspective)	Equivalent to values used in the ICER analysis[^14], derived from The Lewin Group report[^30]: Permanent Ventilation: −0.394 Not sitting: −0.2955 Sitting: −0.197 Walking: 0
Lost Household income (Modified societal perspective)	Equivalent to values used in the ICER analysis (estimate 1)[^14], derived from The Lewin Group report[^30]: SMA early onset: predicted loss $19,833 SMA other: predicted loss $14,800
Non-Medical costs (Modified societal perspective)	Equivalent to values used in the ICER analysis (estimate 1)[^14], derived from The Lewin Group report[^30]: Permanent ventilation, Not sitting, Sitting: $964 per month
Patient productivity gains	Equivalent to values used in the ICER analysis (estimate 1)[^14], derived from The Lewin Group report[^30]: Sitting, Walking: potential monthly income $4,540, estimated from age 30–65 years.

Table 3. Comparison of results from old model, new model and ICER model

Variable	Treatment arm	Previous model	ICER model	Updated model
Life-Years (undiscounted)	Onasemnogene abeparvovec	37.20	33.13	37.60
	BSC	N/A	2.68	7.27
	Nusinersen	9.68	10.28	12.10
Life-Years (discounted)	Onasemnogene abeparvovec	19.81	18.17 (19.76 in scenario vs nusinersen)	20.09
	BSC	N/A	2.40	5.91
	Nusinersen	7.11	7.64	9.06
QALYs (discounted)	Onasemnogene abeparvovec	15.65	12.23 (13.46 in scenario vs nusinersen)	13.33
	BSC	N/A	0.46	1.15
	Nusinersen	5.29	3.24	2.85
Costs (discounted)	Onasemnogene abeparvovec	$3,735,826*	$3,657,000*	$3,930,879**
	BSC	N/A	$789,000	$1,961,710
	Nusinersen	$6,316,711	$3,884,000	$4,602,692
Cost/QALY gained	Onasemnogene abeparvovec vs BSC	N/A	$243,000	$161,648
	Onasemnogene abeparvovec vs Nusinersen***	Dominant at $2 M placeholder price	$139,000	-$64,121) onasemnogene abeparvovec dominant

*Assuming a $2 M placeholder price ** Incorporating list price of $2.125 M ***Scenario analysis

Table 4. Results of key scenario analyses in the updated model – Onasemnogene abeparvovec vs Nusinersen

Variable		Base case	Presymptomatic Analysis	Pessimistic scenario: waning of effect of onasemnogene abeparvovec after 25 years	Pessimistic scenario: waning of effect of onasemnogene abeparvovec after 15 years	Pessimistic scenario: waning of effect of onasemnogene abeparvovec after 10 years	Conservative milestone scenario (2 walkers removed from onasemnogene abeparvovec arm)	Scenario with 95% overall survival for onasemnogene abeparvovec arm	Optimistic survival scenario: improved survival for gene therapy patients who sit	Modified societal perspective
Life years (discounted)	Onasemnogene abeparvovec	20.09	22.83	16.16	12.46	9.86	18.15	18.96	27.77	20.09
	Nusinersen	9.06	21.57	9.06	9.06	9.06	9.06	8.82	9.06	9.06
QALYs (discounted)	Onasemnogene abeparvovec	13.33	16.47	10.25	7.54	5.66	10.85	12.74	18.32	10.02
	Nusinersen	2.85	14.87	2.85	2.85	2.85	2.85	2.81	2.85	−0.13
Costs (discounted)	Onasemnogene abeparvovec	$3,930,879	$3,803,120	$3,788,187	$3,589,189	$3,442,147	$4,038,734	$3,742,991	$4,516,175	$4,328,330
	Nusinersen	$4,602,692	$10,589,128	$4,602,692	$4,602,692	$4,602,692	$4,602,692	$4,336,457	$4,602,692	$4,874,280
Cost/QALY gained	Nusinersen	-$64,121 onasemnogene abeparvovec dominant	-$4,244,823 onasemnogene abeparvovec dominant	-$110,102 onasemnogene abeparvovec dominant	-$216,181	-$413,140	-$70,515 onasemnogene abeparvovec dominant	-$59,757 onasemnogene abeparvovec dominant	-$5,592 onasemnogene abeparvovec dominant	-$53,815 onasemnogene abeparvovec dominant

Noyes J, Godfrey C, Beecham J. Resource use and service costs for ventilator-dependent children and young people in the UK. Health Soc Care Community. 2006;14(6):508–522.

 Web of Science ®Google Scholar

Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713–1722.

 PubMed Web of Science ®Google Scholar

Mendell JR, Al-Zaidy S, Shell R, et al. AVXS-101 Phase 1 gene replacement therapy clinical trial in SMA type 1: continued event-free survival and achievement of developmental milestones. 22nd Annual SMA Researcher Meeting; June 14–16, 2018, 2018; Dallas, TX.

 Google Scholar

Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–1732.

 PubMed Web of Science ®Google Scholar

Castro D, Farrar M, Finkel R, et al. Longer-term assessment of the safety and efficacy of nusinersen for the treatment of infantile-onset Spinal Muscular Atrophy (SMA): an interim analysis of the SHINE study. American academy of neurology. Los Angeles, CA;2018. April 21–27.

 Google Scholar

Gregoretti C, Ottonello G, Chiarini Testa MB, et al. Survival of patients with spinal muscular atrophy type 1. Pediatrics. 2013;131(5):e1509–1514.

 PubMed Web of Science ®Google Scholar

Zerres K, Rudnik-Schöneborn S, Forrest E, et al. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J Neurol Sci. 1997;146(1):67–72.

 PubMed Web of Science ®Google Scholar

Database USM. Human mortality database. 2017; https://usa.mortality.org/

 Google Scholar

(ICER) IfCaER. Spinraza and Zolgensma for Spinal Muscular Atrophy: Effectiveness and Value. Final Evidence Report. April 3, 2019 (Updated May 24, 2019) 2019.

 Google Scholar

The Lewis Group Inc. Cost of amyotrophic lateral sclerosis, muscular dystrophy, and spinal muscular atrophy in the USA. 2012; https://www.mda.org/sites/default/files/Cost_Illness_Report_0.pdf

 Google Scholar