Pegcetacoplan for treating paroxysmal nocturnal haemoglobinuria

3.1 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare blood condition in which red blood cells are attacked by the body's immune system. The breakdown of red blood cells can happen within the blood vessels (intravascular haemolysis) or outside the blood vessels (extravascular haemolysis). This often results in anaemia, which needs blood transfusions, and severe symptoms of haemolysis. Current treatments for PNH include the C5 complement protein inhibitors eculizumab and ravulizumab. Submissions from the clinical and patient experts advised that people with PNH who are having these treatments often continue to experience anaemia because of extravascular haemolysis. This causes suboptimal disease control and the need for blood transfusions. The committee understood that because pegcetacoplan works by inhibiting the C3 complement protein rather than the C5 complement protein in the immune system, it would likely target both intravascular and extravascular haemolysis. This means it could offer benefits for people who continue to have anaemia while having C5 complement protein inhibitors that only target intravascular haemolysis. Patient expert statements described how current treatments can be inconvenient. This is because of frequent cannulation and because a healthcare professional is needed to administer the treatment by intravenous infusion at a person's home. The committee understood that pegcetacoplan is available as a subcutaneous infusion that can be self-administered and so would offer greater flexibility to people with PNH. The patient expert statements explained that, because pegcetacoplan is given more frequently than eculizumab and ravulizumab, this could be difficult for some people to manage and may increase the likelihood of injection site reactions. However, they considered these to be minor inconveniences compared with the benefits that pegcetacoplan offers. Patient expert statements also described how treatment with pegcetacoplan has resulted in fewer blood transfusions and improved fatigue levels and quality of life, including a positive effect on their mental wellbeing and ability to work. The committee concluded that people with PNH would welcome pegcetacoplan as a new treatment option.

3.2 In England, PNH is managed by the PNH National Service. This consists of 2 centres and 8 outreach clinics, and a local haematologist through a shared care agreement. The severity of symptoms varies between people and over time, which means that not everyone with PNH needs treatment with eculizumab or ravulizumab. The indications for treatment with the current C5 inhibitors are included in the PNH National Service's indications for treatment with eculizumab and NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria. The committee considered that more people are likely to have ravulizumab in the future because of its lower treatment frequency compared with eculizumab. It discussed the company's positioning of pegcetacoplan for adults who have anaemia after at least 3 months of treatment with a C5 inhibitor. It recalled comments from the clinical and patient expert submissions that C5 inhibitors had significantly reduced the disease burden of PNH. However, some people still experience symptoms despite treatment because of extravascular haemolysis. The company's proposed positioning of pegcetacoplan would mean that it would only be offered to people if they still had anaemia after treatment with eculizumab or ravulizumab. The committee noted that the positioning was in line with the marketing authorisation and clinical trial evidence for pegcetacoplan. It was satisfied that this reflected how pegcetacoplan would likely be used in the NHS. Therefore, it concluded that the company's positioning of pegcetacoplan in the treatment pathway was appropriate.

3.3 The company submission included the PEGASUS open-label, active-comparator, randomised controlled trial that compared pegcetacoplan with eculizumab in adults who had haemoglobin levels of less than 105 g/litre despite treatment with eculizumab. People were randomised to have either pegcetacoplan or eculizumab. People randomised to the eculizumab arm continued to have it at their current dose that had been stable for at least 3 months before screening. The trial was done in 3 phases:

3.4 The PEGASUS trial was done across 44 sites internationally including at a PNH specialist centre in England. The company considered the generalisability of the trial evidence with an advisory board, including UK clinical experts experienced in the treatment of PNH. The committee acknowledged opinion from both the company's and ERG's clinical experts that the PEGASUS trial results were generalisable to the population who would likely have pegcetacoplan in NHS clinical practice. The committee discussed the company's definition of anaemia in the PEGASUS trial, defined as a haemoglobin level of less than 105 g/litre. It noted comments from the ERG's clinical experts, which suggested that higher haemoglobin levels could also be considered as uncontrolled anaemia in some people with PNH. The company explained that the haemoglobin threshold had been selected based on clinical expert opinion and because it aligned with previous clinical trials in PNH, the published literature and haemoglobin levels observed in PNH registries. It highlighted that based on the literature, the median haemoglobin level of people enrolled in the international PNH Registry was 106 g/litre and in people referred to the UK PNH National Service was 109 g/litre, which are both similar to the threshold used in the PEGASUS trial. The committee considered that although there is some variation in clinical judgement, the company's definition of anaemia would include most people who would be considered to have anaemia after having treatment with eculizumab or ravulizumab in NHS clinical practice. It therefore concluded that the trial results were generalisable to clinical practice in England.

3.5 The company did not identify any direct evidence comparing the clinical effectiveness of pegcetacoplan with ravulizumab. Therefore, it did an anchored matching-adjusted indirect comparison to compare the effectiveness of pegcetacoplan and ravulizumab in people who had previously had eculizumab. The company used individual patient data from the PEGASUS trial for pegcetacoplan and eculizumab and from Study 302 for ravulizumab and eculizumab, which was considered in NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria. The company identified key differences in the designs of the 2 trials that could not be adjusted to make them comparable. It also identified important differences in the trial eligibility criteria, which meant that it was not possible to accurately match the haemoglobin levels of patients between trials. Both the company and ERG considered that the results of the indirect comparison may be subject to bias because of these differences and because the effect of key effect modifiers (haemoglobin level and history of transfusions) could not be considered in the matching process. The committee concluded that the results of the company's indirect treatment comparison were not robust for decision making.

3.6 There is no robust evidence comparing the treatment efficacy of pegcetacoplan and ravulizumab (see section 3.5). So, the company assumed equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population (people with anaemia despite treatment with eculizumab). The results from Study 302 showed that ravulizumab was non-inferior to eculizumab, with point estimates favouring ravulizumab for all primary and secondary endpoints, but these differences were not statistically significant. The committee noted that NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria concluded that ravulizumab and eculizumab were similarly effective and had a similar safety profile. The ERG considered that it was not possible to be certain from the available evidence that the efficacy of ravulizumab would be the same as eculizumab in the PEGASUS trial population. This is because of key differences between the PEGASUS trial and Study 302 (see section 3.5). The committee considered that ravulizumab is a re-engineered form of eculizumab and both technologies are biologically very similar with over 99% homology. It noted that the ERG's clinical experts considered that the efficacy of both treatments is likely to be equal in any population. Therefore, the committee concluded that the company's assumption of equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population was reasonable.

3.7 The company presented a cohort-level state transition model that reflected the evidence available from the PEGASUS trial and included 4 health states:

3.8 The committee considered the ERG's preferred modelling assumptions that included 2 minor revisions to the company's base case:

3.9 The committee discussed the potential equality issues raised during scoping. It noted stakeholder comments that pegcetacoplan is given by a subcutaneous infusion and can be self-administered at home. This may have implications for people with physical or learning disabilities, particularly if they have manual dexterity issues. The company explained that if pegcetacoplan was recommended by the committee, it would provide a patient support programme that would identify and support people who may need additional help to take their subcutaneous infusions at home. The committee considered that this would help to reduce inequalities in access to pegcetacoplan treatment because of its method of administration. It noted stakeholder comments that age and pregnancy are protected characteristics and inequalities may arise if different recommendations are made for children and pregnant women. The committee discussed that children and pregnant women were excluded from the PEGASUS trial. It noted a comment from a clinical expert submission that pegcetacoplan should not be used in pregnancy. The committee considered the pegcetacoplan indication is currently limited to adults and it can only recommend a treatment within its marketing authorisation. The committee concluded that there were no equality issues relevant to the recommendations.

3.10 The company considers pegcetacoplan to be innovative because it prevents both intravascular and extravascular haemolysis by targeting the complement cascade earlier than C5 inhibitors. The committee agreed that these are important benefits and recognised that pegcetacoplan will be the first C3 inhibitor licensed for PNH. It recalled patient expert statements highlighting that treatment with eculizumab and ravulizumab can be inconvenient for some people because of frequent cannulation and because a healthcare professional is needed to administer the intravenous infusion at a person's home. The committee recognised that pegcetacoplan is available as a subcutaneous infusion that can be self-administered and that this may offer benefits for some people compared with current treatments. However, it recalled patient expert statements that because pegcetacoplan is administered more frequently than existing treatments, it may be less convenient for other people. The committee considered that these potential advantages and disadvantages associated with pegcetacoplan's administration may have already been captured in the company's model. This is because the company modelled a disutility for eculizumab to reflect that it has more regular dosing than ravulizumab, and that it is an intravenous infusion whereas pegcetacoplan is a subcutaneous infusion. It assumed no disutility for ravulizumab and pegcetacoplan because they were both assumed to reduce the burden of administration compared with eculizumab. The committee concluded that the benefits of pegcetacoplan are captured in the cost-effectiveness analysis.