1. Public observer slides – redacted
Letermovir for the prophylaxis of cytomegalovirus (CMV) reactivation or disease in people with seropositive-CMV who have had an allogeneic haematopoietic stem cell transplant
2nd Appraisal Committee meeting
Committee D, 16 April 2019
Lead team: Malcolm Oswald, Bernard Khoo, Paula Parvulescu
Company: Merck, Sharp & Dohme
Chair: Gary McVeigh
Evidence review group: CRD and CHE Technology Assessment Group
NICE team: Thomas Paling, Nicola Hay, Linda Landells

2. Recap: ID1153 First appraisal committee meeting (ACM): 12 June 2018
Not recommended
ACD consultation closes: 25 July 2018
Consultation comments received
ACM2 (August 2018) delayed
“The company (Merck Sharp & Dohme) requested that NICE suspend this appraisal because it is considering its commercial arrangement for this product. Therefore, the basis for the decision making is likely to change and the appraisal committee meeting (previously scheduled for 8 August 2018) will be rescheduled”
ACM2 (April 2019)
Updated ACD response from the company
Changes to the commercial arrangement

3. Recap: The nature of the condition Cytomegalovirus
Cytomegalovirus (CMV) is a common viral pathogen of the Herpesviridae family
Approx. 50% to 60% of adults in the UK are infected with CMV
Higher prevalence with increasing age
In healthy people, CMV is usually dormant and asymptomatic
For people undergoing haematopoietic stem cell transplant (HSCT) the virus can become active again (80% of cases) because of a weakened immune system, causing serious complications and increased mortality
Risk factors for CMV infection post-HSCT include the use of high dose corticosteroids, T-cell depletion, graft versus host disease (GvHD) and use of mismatched or unrelated donors

4. Letermovir (Prevymis)
Marketing authorisation (MA)
Letermovir is indicated for the prophylaxis of CMV reactivation and disease in adult CMV-seropositive [R+] recipients of an allogeneic HSCT
Mechanism of action
Inhibits viral replication by targeting the pUL56 subunit of the CMV viral terminase complex
Administration & dosage
Oral tablets or intravenously (IV)*, 480 mg once daily, decreased to 240 mg once daily if co-administered with cyclosporin A (CsA)
Duration of treatment
Up to 100 days post-transplant
Cost (PAS price)
XXXX per 240mg x 28 tablets (XXX per tablet)
XXXX per 480mg x 28 tables (XXX per tablet)
XXX, 240mg IV*
XXX, 480mg IV*
A confidential patient access scheme has been agreed
*IV letermovir formulation not currently available in England

5. Clinical evidence: PN001 Trial
Study type
Phase III, International, multicentre, randomised, double-blind, placebo-controlled trial
Population
Adult CMV-seropositive recipients of an allogeneic HSCT (n=570)
Intervention
Oral or IV letermovir 480 mg once-daily (OD, n=376), adjusted to 240 mg OD if co-administered with CsA)
Comparator
Placebo (mimicking pre-emptive therapy; current SoC)
Outcomes
(outcomes in bold are incorporated in the model)
Clinically-significant CMV infection*
Time to onset of clinically-significant CMV infection
Initiation of PET for documented CMV viraemia
Time to initiation of PET for documented CMV viraemia
All-cause mortality
Reduction of hospital in-patient days
Adverse events
Health-related quality of life
Time points
Efficacy data: week 14 (end of therapy) and 24 post-transplant
Safety data: week 14, 24 and 48 post-transplant
Source: table 5 (page 27-29) of the company submission; * Clinically-significant CMV infection is defined as the initiation of PET based on documented CMV viraemia (~151 copies/ml) or onset of CMV end-organ disease

6. Treatment pathway – CMV in allogeneic HSCT
Determine risk of CMV infection
Transplant
Current
Proposed
Surveillance monitoring (PCR testing weekly+) and/or Prophylaxis with high dose aciclovir.* Gancicolvor/valgancicolvir used rarely (toxicity)
IF Recipient Seropositive (R+): receive Letermovir from day of transplant up to 100 days
Centre-specific threshold reached for initiation of PET?
Prophylaxis successful  continue monitor by PCR (if necessary)
CMV reactivation  STOP prophylaxis & follow PET pathway
PET - (IV) ganciclovir, oral valganciclovir or foscarnet used
Cidofovir reserved for 2nd line
* Clinical experts stated that aciclovir used in NHS but has poor effectiveness
Abbreviations: PET = pre-emptive therapy

7. ACD preliminary recommendation
Letermovir is not recommended, within its marketing authorisation, for preventing cytomegalovirus (CMV) reactivation and disease after an allogeneic haematopoietic stem cell transplant (HSCT) in adults who are seropositive for CMV.

8. Recap: ACD considerations
Nature of the condition
Cytomegalovirus (CMV) reactivation has a psychological effect on patients and their families
There is an unmet need for an effective and well tolerated treatment
Clinical
The evidence shows letermovir is effective in reducing CMV infection, reduces the need for toxic pre-emptive therapy and improves quality of life
Letermovir has a better side effect profile than current treatments
The effect of letermovir on reducing mortality from CMV disease was unclear
Concern about the generalisability of the trial data to NHS clinical practice
Cost
The most plausible ICER was above £20,000/QALY and higher than £30,000/QALY in some scenarios
ICER driven by changes in letermovir’s mortality benefit which was uncertain

9. ACD consultation responses
Consultee comments from:
Merck Sharp & Dohme
Clinical and patient experts and professional organisations:
University College Hospital
Anthony Nolan
Royal College of Physicians (RCP)
Web comments
None
No comment responses from

10. ACD consultation comments Clinical expert and professional groups
Duration of therapy
Treatment duration is likely to be between 72 and 83 days
The PN001 trial results are generalisable to UK populations
Committee incorrectly concluded that a maximum treatment duration of 100 days was inappropriate in clinical practice
No evidence to suggest patients may or may not benefit from longer prophylaxis
Committee incorrectly concluded that PN001 overestimates CMV rate and use of pre-emptive therapy by using the wrong threshold level of viraemia
CMV rate is determined by detectable DNA not the threshold level of viraemia
Mortality
The mortality data from Wingard et al (2011) is not relevant
CMV reactivation is only linked to mortality if it progresses to CMV disease
Pre-emptive therapies mostly stop this → letermovir is unlikely to reduce mortality
Quality of life (QoL)
QoL benefits from reduced CMV reactivation were not adequately accounted for

11. ACD consultation comments Patient experts group: Anthony Nolan
Mortality
Too much emphasis has been placed on mortality
Mortality was only an exploratory end point in the trial
Because pre-emptive therapies mostly prevent progression to CMV disease, letermovir is unlikely to reduce mortality
Quality of life
Quality of life benefits could not be demonstrated in PN001 because it focused on pre-emptive therapy quality of life utility decrements
It did not capture the psychological benefits from reduced CMV reactivation
Adverse effects
Some pre-emptive therapies can cause neutropenia which increases the risk of potentially fatal infections
Letermovir reduces the need for pre-emptive therapy and subsequently reduces the risk of potentially fatal infections

12. ACD consultation comments: Company Treatment duration
“the mean duration of treatment was assumed to be 83 days… (72.1 days) plus an additional 10.9 days from the delayed start of prophylaxis”
“… the ERG’s assumption for the treatment duration [83 days] was more plausible than the company’s [69.4 days].”
ACD
Company ACD response:
The mean duration of treatment from PN001 (72.1 days) includes patients who delayed initiating prophylaxis → including extra days risks double counting
The model does not account for delays in starting letermovir prophylaxis, people enter at treatment initiation → adding a delay would not reflect clinical practice
Accept that duration of treatment is likely to be longer than 69.4 days (base-case) → 72.1 days is used in the updated base-case
ERG comment:
Delay between HSCT and initiation of prophylaxis in PN001 was because of safety concerns which have now been addressed → delays unlikely to occur in practice
A treatment duration > 100 days (per the licence) is plausible for some people
ERG base-case: the 83 day average treatment duration from PN001 is realistic

13. ACD consultation comments: Company Pre-emptive therapy and IV letermovir usage
“The committee concluded that foscarnet use in the model should be between 15 and 25%.”
“The committee considered that concomitant use of ciclosporin A would be closer to 90%”
“.. committee took into account its preferred assumptions that … intravenous letermovir to be used for 5% of patients ”
ACD
Company ACD response:
Updated model assumptions to align with committee preferences
20% use of foscarnet as a pre-emptive therapy (PET)
Concomitant ciclosporin A use reduced from 95% to 90%
IV letermovir used in 5% of patients (reduced from 27% in ERG model)
Additional analyses: no IV letermovir (0%) explored
ERG comment:
Incorporated the committee preferred assumptions in the ERG’s updated base case

14. ACD consultation comments: Company Mortality
“Mortality data from the haematological malignancy research network (HMRN) is more relevant to clinical practice”
“The all-cause mortality benefit of letermovir compared with placebo is not statistically significant at 48 weeks”
ACD
Company ACD response:
Both the data sources Wingard et al 2011 (original) and HMRN are valid but with limitations
There is a plausible mortality benefit of letermovir due to prevention of CMV reactivation
• PN001 was not designed to demonstrate letermovir mortality benefit, however;
CMV reactivation is associated with increased mortality for people receiving standard of care (SoC) (HR = XXXXXXXXXXXXXXXXXXXX), but not associated with increased mortality in the letermovir group (HR = XXXXXXXXXXXXXXXXXXXX)
• CMV viraemia is an appropriate surrogate for mortality post-HSCT
When risk factors are controlled for, CMV viraemia (post-HSCT) is associated with overall and non-relapse mortality
Post stem cell transplant only around 5% progress to CMV disease after pre-emptive therapy → large sample sizes would be required to show a changes in CMV disease
ERG comment:
A case for a causal relationship between CMV reactivation and mortality was not made

15. ACD consultation comments: Company Clinical data used in the model (24 weeks vs. 48 weeks)
“[The company’s base-case was] not appropriate for decision making because of concerns about […] The use of 24-week data over 48-week data because this may overestimate the mortality benefit of letermovir”
ACD
Company ACD response:
The 48 week data endpoints should not be used for decision making
Committee accepted that in PN001 letermovir met its primary endpoint [reduced rate of clinically significantly CMV reactivation] at week 24 compared with placebo
Without data it’s challenging to predict the rate of clinically significantly CMV reactivation at week 48 → however, it is expected to fall as the immune system strengthens
The trial follow-up phase (to week 48) was agreed to investigate letermovir safety
Letermovir prophylaxis stops at week 14 → inappropriate to assess the effect of prophylaxis at week 48
ERG comment:
Benefits driven by improvements in mortality not CMV reactivation → company’s concerns about inferring CMV reactivation rates at 48 weeks are of little importance to model results
Company ignores mortality events between weeks 24 and 48, assuming an additional 1.9% of people stay alive and accrue QALYs beyond week 48 → increasing mortality benefit

16. ACD consultation comments: Company Health-related quality of life
“The committee agreed there could plausibly be a health-related quality-of-life benefit associated with preventing CMV reactivation but concluded that the trial did not show this”
“The committee agreed that the disutility associated with graft versus host disease should have been included in the model”
ACD
Company ACD response:
Health-related quality of life (HRQoL) was an exploratory endpoint → not powered to detect statistically significant differences in HRQoL between treatment groups
HRQoL assessment was made prior to pre-emptive therapy initiation → expected disutility associated with the toxicity of pre-emptive therapies were not captured
The disutility associated with graft versus host disease (GvHD) should only apply to chronic-GvHD (occurring after the first 100 days) → discounting (3.5%) applied to the GvHD disutility after the first year

17. ACD consultation comments: Company Company updated base-case (with updated PAS)
Company’s updated base-case
Changes to the ERG original base-case
Committee preference
HMRN data used to model long-term mortality
Yes ✓
Discounting (3.5%) the disutility associated with graft-versus-host-disease (GvHD) and disease relapse beyond the first year
Treatment duration of 72.1 days
No ✖
Use of 24 week data end points to inform the analyses
20% use of foscarnet as a pre-emptive therapy (PET)
Concomitant ciclosporin use reduced from 95% to 90%
IV letermovir used in 5% of patients
Model correction: apply admin costs to valganciclovir (oral) not ganciclovir (IV)
N/A
Technologies
Total
Incremental
Costs (£)
QALYs
ICER (£/QALY)
Standard of care
£38,665
6.02 -
Letermovir
£45,655
6.41
£7,000
0.40
£17,713
Source: adapted from table 3 company ACD response updated

18. ACD consultation comments: Company Sensitivity analysis: mortality
“the ICER was very sensitive to the estimate of all-cause mortality and a small change could result in substantial changes to the ICER”
ACD
Company ACD response:
Presented a 2-way sensitivity analysis varying the all-cause mortality rates of letermovir and no letermovir at 24 weeks in 0.5% increments
Inappropriate to suggest that the ICERs are sensitive to a “small change” (3.8% to 4.8%) in mortality rate
1% change in absolute mortality is approx. a 20% change in relative mortality
ERG comment:
Letermovir must reduce all-cause mortality by 3% to bring the ICER < £20k /QALY
If assuming no difference in all-cause mortality the ICER is around £200k /QALY
In PN001 the 95% CI for change in mortality rate was (-15.3% to +7.7%)
Company stated referring to a 1% change as small was inappropriate, however a 1% change is well within this interval

19. ERG updated base case (with PAS)
ERG’s updated base case incorporates the following committee preferences:
Discounting (3.5%) the disutility associated with graft-versus-host-disease (GvHD)
20% use of foscarnet as a PET
Concomitant ciclosporin use reduced from 95% to 90%
IV letermovir used in 5% of patients (reduced from 27% in ERG model)
Use of 48 week data end points to inform the analyses
Treatment duration of 83 days
The ERG also corrected for the company’s misinterpretation of the ERG model settings for some utility value inputs
Technologies
Total
Incremental
Costs (£)
QALYs
ICER (£/QALY)
Standard of care
29,646
5.36 -
Letermovir
37,090
5.66
7,444
0.307
£24,269
Source: table 3 ERG comments on company response to ACD

20. ERG exploratory analysis: Treatment duration
Exploring the effect of treatment duration on the ERG base case: scenarios
PN001 all subjects as treated (ASaT): company original base case
PN001 full analysis set (FAS): company updated base case
PN001 full analysis set (FAS) day delay: ERG updated base case
Assumes 45% of people still on letermovir at 100 days continue for 2 weeks more
Assumes 45% of people still on letermovir at 100 days continue for 6 weeks more
Scenario
Source
Treatment duration (days)
ICER
(£/QALY) 1
PN001 ASaT
69.4
£19,414 2
PN001 FAS
72.1
£20,378 3
PN001 FAS day delay 83
£24,269 4
ERG exploratory analysis (max. duration days +2 weeks)
89.3
£26,518 5
ERG exploratory analysis (max. duration days +6 weeks)
101.9
£31,016
Source: table 2 ERG comments on company response to ACD

21. Differences in key assumptions between model iterations
Parameter
Company original base case
ERG original base case
Committee’s preferred assumptions
Company updated base case
ERG updated base case
Trial endpoints
24-week
48-week
Treatment duration
69.4 days
83 days
72.1 days
Foscarnet use
25%
15%
15-25%
20%
IV letermovir use 5%
27%
Ciclosporin A use
95%
90%
ICER
£10,904
£27,536
£23,124 to >30,000
£16,982*
£24,269
Source: table 1 ERG comments on company response to ACD
Notes: CS = company submission (ACM1)
*Corrected for the company’s misinterpretation of the ERG model settings for some utility value inputs

22. Additional analyses No IV letermovir (100% oral letermovir)
Additional analyses provided to reflect the current availability of letermovir formulations in England → no IV letermovir
Scenarios incorporating 100% oral letermovir usage
All other assumptions unchanged
Scenario
ICER (£/QALY)
Company updated base case
£17,352
Company updated base case (ERG corrected)
£16,636
ERG updated base case (48-week end points)
£23,822
ERG updated base case (24-week end points)
£19,544

23. Key issues for consideration
What is the expected treatment duration of letermovir?
Is letermovir expected to have an effect on mortality? Has this been adequately reflected in the economic model?
Which clinical data points (24 or 48 weeks) should be used in the economic model?
Do the utility values sufficiently capture the benefits of letermovir?
Is letermovir innovative?
What is the committee’s preferred ICER?
Are there any potential equality issues?