Maribavir for treating refractory or resistant cytomegalovirus infection after transplant

There are limited treatment options for CMV and an oral treatment given at home would be beneficial

3.1 Cytomegalovirus (CMV) is present in approximately 60% to 70% of the population. Although it is generally mild and treatable, CMV can become active again when a person's immunity is weakened, such as by immunosuppressive chemotherapy or after a transplant. Latent CMV can also be transferred from a transplant donor to the recipient. Currently, there are few treatments for CMV after a transplant, and treatment resistance can be an issue. Several antiviral therapies, including valganciclovir, ganciclovir, foscarnet and cidofovir, are used off-label. But there are no licensed medicines in the UK for treating CMV infection after a solid organ transplant (SOT) or allogeneic haematopoietic stem cell transplant (HSCT) if the infection is refractory or resistant to treatment. The patient experts explained that CMV reactivation can substantially negatively affect mental health and wellbeing in people and their families. Hospital admissions to treat CMV reactivation can be stressful, especially after the heavy burden of transplant procedures. Refractory or resistant CMV infections can have serious effects on quality of life. Intravenous treatments are needed several times a day, which can result in extended hospitalisation. Other comorbidities and further infections can develop during treatment for CMV. All of this can delay recovery. The clinical experts explained that foscarnet can be associated with kidney damage, making it less suitable for people who have had a kidney transplant or who have impaired renal function. Cidofovir can cause neutropenia. These risks mean that, in some people whose infection is resistant or refractory to ganciclovir and valganciclovir, these medicines have to be reused because of a lack of alternative treatment options. The patient experts suggested that the psychological benefits of being able to have treatment at home would greatly improve the recovery process from both CMV infection and transplant, avoid the unpleasant side effects of current treatment options, and also reduce costs to the NHS. The clinical experts considered that maribavir would be an especially suitable option for people with refractory or resistant CMV whose comorbidities mean that side effects from current second-line antiviral options would be particularly unfavourable. The committee concluded that current treatment options are limited, and an oral treatment given at home would be beneficial.

The conduct and design of SOLSTICE could bias the results

3.2 The main clinical evidence came from SOLSTICE. This was a phase 3, randomised, open-label, active-controlled trial with a 20‑week follow up. Its aim was to evaluate the efficacy and safety of maribavir (n=235) compared with any of the investigator-assigned antiviral treatments (IAT, n=117). These included intravenous ganciclovir, foscarnet, cidofovir and oral valganciclovir. The choice of IAT was at the investigators' discretion but could include monotherapy or combination therapy with any of the 4 treatments. The ERG noted some concerns around the design and conduct of the trial. The open-label design meant that participants and investigators were aware of the choice of treatment from the start of the study. In the comparator arm, the investigators could choose treatment based on medical history and the clinical course of previous treatment for CMV. The investigators decided whether participants should continue previous therapy at the same or an increased dose, change treatment or select combination therapy. The investigators could also decide whether immunosuppressant therapy should be changed. The ERG considered this could lead to bias, especially for assessing recurrence. At the investigators' discretion, people having IAT could stop treatment after the third week (because of lack of efficacy or toxicity) and receive maribavir treatment instead, known as the rescue arm. The ERG thought that the rescue arm may introduce bias to some outcomes. The committee considered that 3 weeks of treatment may not be long enough to assess a lack of efficacy. The clinical experts explained that in clinical practice, people are likely to stay on treatment for longer before stopping. The committee concluded that some aspects of the conduct and design of SOLSTICE could bias the results.

Results of SOLSTICE may not be generalisable to clinical practice

3.3 The committee considered how generalisable SOLSTICE was to clinical practice. It discussed the following concerns:

SOLSTICE data suggests that maribavir improves clearance compared with IAT, but the results are highly uncertain

3.4 The primary outcome in SOLSTICE was viral clearance at week 8. In the intention to treat population, 55.7% of people who had maribavir had confirmed CMV viraemia clearance at the end of week 8 compared with 23.9% who had IAT. After adjusting for transplant type (SOT versus HSCT) and baseline plasma CMV DNA viral load (low versus intermediate or high), the difference was 32.8% (95% confidence interval [CI] 22.8% to 42.7%; p<0.001). At the end of the trial, in people whose infection responded by week 8, fewer people on maribavir had a clinically relevant recurrence than those who had IAT, although the difference was not statistically significant. There was no statistically significant difference in all-cause mortality between treatment arms. More deaths occurred in the HSCT group than in the SOT group, and there was a small difference in favour of maribavir for SOT, but in favour of IAT for HSCT. The committee concluded that SOLSTICE suggests an advantage for maribavir achieving clearance. But because of uncertainties in the SOLSTICE data (see sections 3.1 and 3.2), it could not be sure that the data was robust enough to confirm the size of this benefit.

The health states used in the company's model are appropriate

3.5 The company used a 2-stage Markov model to estimate the cost effectiveness of maribavir compared with IAT. Each health state was associated with different costs, quality of life and mortality risks. The stage 1 model included 3 health states: clinically significant CMV, no clinically significant CMV, and death. All people entered the model with clinically significant CMV. When the CMV infection cleared they could move to the no clinically significant CMV state or experience a CMV recurrence. Tunnel states were used to estimate time-dependent transitions between clinically significant and no clinically significant CMV. The stage 2 model comprised 2 health states: alive and dead. People could die at any point during either stage. The model had a lifetime time horizon, with stage 1 lasting 78 weeks. The committee concluded that the overall model structure and health states used by the company in both stages of the model were appropriate, but that it had some concerns about the duration of stage 1 of the model (see section 3.9).

Using OTUS data is more robust than using multiple data sources to model outcomes in the stage 1 Markov model

3.6 The company used data from OTUS to update its stage 1 model at technical engagement. OTUS is a retrospective real-world evidence analysis of CMV infection that is refractory or resistant to treatment, with a longer follow up than SOLSTICE. The company used the OTUS data to populate the model beyond the 20-week duration of SOLSTICE. This included modelling recurrences for the first 20 weeks based on SOLSTICE data, then using OTUS data to model outcomes for the remaining stage 1 time horizon. The ERG considered OTUS to be more generalisable to clinical practice than SOLSTICE, but had concerns with the way the company used the OTUS data, which assumed that the populations and outcomes in OTUS and SOLSTICE were interchangeable. The ERG highlighted that the ratio of SOT to HSCT populations, percentage of clearance, and time since transplant differed between the 2 sources. The ERG preferred to use OTUS to model the probability of clearance and recurrence for IAT in the stage 1 Markov model, with the outcomes for maribavir estimated by applying a relative treatment effect taken from SOLSTICE. OTUS could also be used to inform risk of mortality, time since transplant and event rates of complications such as graft failure and graft-versus-host disease. In a scenario analysis done by the company using the OTUS data, clearance rates were adjusted for 8-week mortality. The ERG was unclear about why this had been done, and preferred to use data that had not been adjusted for mortality at 8 weeks. The committee preferred the ERG's approach. It concluded that using OTUS data as far as possible, with the relative treatment effect of maribavir from SOLSTICE, would be more robust for modelling outcomes in the stage 1 Markov model, and that data from OTUS should not be adjusted for mortality at 8 weeks.

Maribavir may increase the likelihood of maintaining CMV clearance, but there is no evidence to support this

3.7 The company modelled different risks of CMV recurrence dependent on the treatment received. People having maribavir had a lower probability of CMV recurrence than those receiving IAT, even if they had experienced clearance for the same amount of time. The ERG stated that the risk of CMV recurrence should depend on the time spent in clearance rather than the treatment received, and included this in its updated model. One of the clinical experts advised that clearance with maribavir may be greater than with IAT, meaning reinfection is less likely to occur. The committee considered this reasonable, but had not seen any supporting evidence. It concluded that the risk of recurrence should not be treatment specific.

The number of CMV recurrences is overestimated in the model

3.8 The company's model included multiple recurrences based on OTUS data, which showed up to 6 recurrences after SOT and 4 recurrences after HSCT. The company assumed that the risk of third and further recurrences in the model was the same as that for second recurrences. The ERG noted that in OTUS, the risk of subsequent recurrences decreased with the number of recurrences and that the benefit of maribavir may be overestimated. The ERG limited its model to 2 recurrences because no robust data was identified to inform the risk of recurrence beyond this point. The committee accepted that the risk of CMV recurrence is likely to decrease with the number of recurrences, but that more than 2 recurrences are plausible. It concluded that the company's model likely overestimated the number of CMV recurrences, and that it would have preferred to have seen recurrence risk decrease as the number of recurrences increases.

The duration of the stage 1 Markov model should align with the duration that CMV recurrences can be accurately modelled

3.9 The company originally used 20-week data from SOLSTICE to model CMV recurrences up to 52 weeks, meaning its stage 1 Markov model had a duration of 52 weeks. But based on the OTUS data (which provided evidence for multiple recurrences over a longer time), the company increased the duration of the stage 1 model to 78 weeks. The ERG was unclear about the company's reasoning for using 78 weeks. The company explained that OTUS data in the SOT population provided evidence that would allow the stage 1 model to be extended beyond 78 weeks, but had applied 78 weeks as a pragmatic option because of heterogeneity in the treatment pathway at longer time horizons and to mitigate uncertainty. The ERG highlighted there were few third (or further) recurrences in OTUS and so to model further recurrences the company had to use the risk of second recurrence from OTUS (see section 3.8). This created uncertainty in the modelling. The ERG thought that the duration of the stage 1 Markov model should reflect the time frame over which the first and second recurrences happened in OTUS (39.2 weeks) because the data for this was robust. It included this assumption in its base case. The committee recognised there was some uncertainty around the appropriate duration of the stage 1 Markov model. But it considered that if OTUS is used as the main source of data for the IAT arm of the model, the stage 1 Markov model should accurately reflect the time to last recurrence in OTUS. The committee concluded that the stage 1 Markov model should align with the duration of time that CMV recurrences can be accurately modelled. It specified that more than 2 CMV recurrences should be modelled, with the risk of recurrence decreasing as the number of recurrences increases, if data is available to model this. In the absence of robust data, the stage 1 Markov model should be restricted to 39.2 weeks and 2 CMV recurrences, and scenario analyses should be done to show the potential impact of further CMV recurrences, with a stage 1 duration of between 39.2 and 78 weeks.

Risk of mortality in the stage 1 Markov model should be the same for people having maribavir and IAT

3.10 The company had originally modelled survival in the stage 1 Markov model using individual patient data from SOLSTICE to estimate the risk of mortality in the clinically significant CMV and no clinically significant CMV health states. But the ERG noted that the Kaplan–Meier data, which incorporated the difference in CMV events across treatment arms, showed no statistically significant difference in overall mortality between maribavir and IAT (see section 3.4). So this was inconsistent with the company's approach of assuming there was a difference in mortality for clinically significant CMV compared with no clinically significant CMV. At technical engagement, the company reiterated its view that the SOLSTICE data was the most appropriate source. It provided Kaplan–Meier data for time to all-cause mortality from SOLSTICE (adjusted to account for people in the IAT arm crossing over to have rescue treatment). The company did not provide details of how the adjustment was carried out, so the ERG could not validate the adjusted survival data. The company considered its analysis supported the use of the unadjusted SOLSTICE data in the model. It reiterated its view that SOLSTICE suggested that mortality for maribavir was lower than for IAT, and that this justified using CMV-related mortality risks taken from SOLSTICE in the model. Additionally, the company provided 2 scenario analyses based on OTUS and using published data to inform mortality risks for people that had clinically significant CMV and no clinically significant CMV. The committee recognised there was a lot of uncertainty in the assumptions for mortality in the stage 1 model, but that SOLSTICE had not shown a survival benefit. It considered that mortality should not differ for people based on treatment, so there should be no life year gain with maribavir in the model. It concluded that risk of mortality in the stage 1 model should be the same for the maribavir and IAT groups.

The mean time since transplant should be used at model entry

3.11 Time since transplant at entry to the model affected both the risk of mortality and the risk of CMV recurrence. In its base case, the company used the median time since transplant from SOLSTICE to inform the baseline characteristics of the modelled population. It suggested this was reasonable because the mean and median values were not the same and outliers could influence the mean estimate. The ERG preferred to use the mean time since transplant to fully reflect the whole population. The committee was aware that time since transplant had a substantial effect on outcomes and would have preferred to see data on the distribution of this (see section 3.3). In the absence of this information, it concluded that it was more appropriate to use the mean value.

The impact of disease complications should be included in the economic model

3.12 The committee discussed the inclusion of disease complications in the model:

The committee concluded that disease complications should be included in the model, and accepted the ERG's approach to modelling recurrences of leukaemia, graft-versus-host disease and graft failure.

The model should include different intravenous administration costs for first and subsequent administrations

3.13 The company assumed that the daily intravenous (IV) administration cost used for various IATs was equal to an NHS reference cost for complex chemotherapy at first attendance. The ERG had noted this cost should only apply to the first administration of IV IATs, when a central line would be inserted, but that the same line could be used for subsequent administrations so subsequent costs would be lower. The ERG judged that the administration costs applied for IV treatments in the IAT arm had been overestimated in the model. It suggested that a lower reference cost for subsequent elements of a chemotherapy cycle should be used for subsequent administration of IV IATs. It did a scenario analysis that explored the impact of using first and subsequent administration NHS reference costs, and another in which daily administration costs for IV treatments were based on the hourly cost of a critical care nurse. The committee considered that both were plausible, but that using the first and subsequent IV administration NHS reference costs would be more appropriate.

The cost of hospitalisation for people with clinically significant CMV is likely to be higher than for people without clinically significant CMV

3.14 The committee considered whether the hospitalisation costs for people with clinically significant CMV would be different to those without clinically significant CMV. The company had applied a higher unit hospitalisation cost for clinically significant CMV than for no clinically significant CMV. This was based on weighted average NHS reference costs for a non-elective long stay for infectious diseases with or without interventions. The ERG preferred to apply an equal unit hospitalisation cost for clinically significant CMV and no clinically significant CMV, because it considered that the difference in costs would have already been incorporated into CMV treatment costs in the model. The committee considered that people hospitalised with clinically significant CMV would need extra care and incur greater costs (beyond treatment costs) than people hospitalised without clinically significant CMV. It concluded that the company's approach was appropriate.

Utilities are appropriately captured in the model

3.15 The ERG originally highlighted concerns about the company's approach to modelling estimated EQ-5D-3L values from the EQ-5D-5L data in SOLSTICE. At technical engagement, the company clarified the multiple imputation method it used. This was based on the approach used in the NICE technology appraisal for letermovir for preventing cytomegalovirus disease after a stem cell transplant. The committee was satisfied with this approach. The ERG also noted that the utility values applied for the stage 2 Markov model were slightly inconsistent with those applied in the stage 1 Markov model. It noted that the values might underestimate the health-related quality of life of people who did not have clinically significant CMV after SOT and overestimate the quality of life in people after HSCT. The committee recognised this slight inconsistency, but in the absence of further data considered the utilities used were appropriate.

Because of the uncertainty, an acceptable ICER is around £20,000 per QALY gained

NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained.

The most likely cost-effectiveness estimates are higher than those normally considered an acceptable use of NHS resources

3.17 Because of confidential commercial arrangements for maribavir and other comparators treatments, the ICER cannot be reported here. Taking into account all of the confidential discounts, the ERG's base-case ICER for maribavir compared with IATs was higher than the range NICE considers to be a cost-effective use of NHS resources. The committee acknowledged that the ICER using its preferred assumptions may differ to this. But even if the model could be considered robust for decision making, the committee's preferred ICER would likely be above the upper end of the range normally considered a cost-effective use of NHS resources (£30,000 per QALY gained). Therefore, maribavir is not recommended for use in the NHS.

Innovation

Maribavir is innovative in that it is an oral treatment that can be taken at home, but all of the benefits are captured in the modelling

3.18 The committee agreed that there is an unmet need for an effective and tolerable treatment for CMV infection that is refractory or resistant to treatment in adults who have had a SOT or HSCT. It considered that having an oral treatment was innovative and reduced the need for people to be in hospital to receive treatment, but that these benefits were captured in the model.

No relevant equalities issues were identified

3.19 The company stated that people from minority ethnic family backgrounds are more likely to develop comorbidities and therefore would be more likely to need a transplant. But they can also wait longer for a suitable organ donor. It also considered that older people have fewer treatment options because of toxicity. Both of these groups can need high levels of immunosuppression and so have an increased risk of CMV infection and graft rejection. Risk of transplant, time to transplant and age at transplant are not issues that can be addressed in a technology appraisal of a treatment for CMV. The company did not investigate whether treatment with maribavir works better in any particular groups. The committee concluded that no equalities issues were identified that could be addressed by this appraisal.

Conclusion

Maribavir is not recommended

3.20 The committee had not seen cost-effectiveness estimates based on its preferred modelling assumptions. Of those the committee did see, the scenarios most closely aligned with its assumptions gave cost-effectiveness estimates that exceeded what would be considered cost effective. The committee concluded that it could not recommend maribavir for treating CMV infection that is resistant or refractory to treatment in adults who have had a SOT or HSCT.

Stephen Smith
Chair, appraisal committee
September 2022