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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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) + 10.9 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 + 10.9 day delay 83 £24,269 4 ERG exploratory analysis (max. duration 100 days +2 weeks) 89.3 £26,518 5 ERG exploratory analysis (max. duration 100 days +6 weeks) 101.9 £31,016 Source: table 2 ERG comments on company response to ACD

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

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

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?