EHL factor concentrates
Haemophilia is an X-linked inherited bleeding disorder characterised by reduced levels of Factor VIII or IX levels (haemophilia A and B) respectively [Shrivastava et al, 2013]. In its severe form (FVIII or IX <0.01IU/dl) haemophilia results in recurrent joint and muscle bleeds that predispose to arthropathy, muscle contracture and disability. Prophylaxis with clotting factor replacement prevents bleeding episodes and joint damage in people with haemophilia more effectively than episodic treatment [Manco-Johnson et al, 2007; De Podesta et al, 2011; Iorio et al, 2011].
In boys with haemophilia A, prophylaxis is initiated once-weekly then increased in frequency to every two days or three times weekly at a dose that prevents bleeds, maintaining trough Factor VIII blood levels above 1 IU/dl for those who are physically active [Richards et al, 2010]. This dose frequency is necessary because the half-life of Factor VIII in children is relatively short at about 9 hours [Björkman et al, 2012]. In adults, the half-life of Factor VIII is longer (11–12 hours) but variable. There is also a wide range in the rate at which Factor VIII is cleared from the body [Björkman et al, 2012]. Consequently, the dose regimen needs to be individualised according to bleeding phenotype and pharmacokinetics and the frequency of infusion varies from every 3–4 days for those with a long half-life to daily or alternate-day dosing if the half-life is shorter [Richards et al, 2010]. In clinical practice, this means that a large proportion of patients using Factor VIII prophylaxis need frequent doses.
Prophylaxis is also recommended for people with haemophilia B although variation between individuals in the pharmacokinetics of Factor IX is modest and its half-life is longer [Björkman and Ahlén, 2012]. This means that it is possible to recommend prophylaxis with a twice-weekly dose regimen and maintain effective trough levels of Factor IX [Shrivastava et al, 2013] and clinical trials show that such a once-weekly dose regimen prevents bleeds [Kavakli et al, 2016]. In clinical practice, a once weekly regimen is common and a dose frequency of three or more times a week is unusual [Berntorp et al, 2017].
Newer factor concentrates are now available in the UK; these have extended half-lives which reduce the frequency of infusions while still offering protection from bleeding. Prior to the introduction of these products, patient expectation was high, with many patients expressing optimism that these products would reduce treatment burden, including the impact of haemophilia on mobility and pain, as well as the time commitment required for treatment, which is reported to impact on treatment adherence [Thornburg, 2008]. The frequency of infusion is often cited as influencing adherence to treatment; decreased frequency of infusions may encourage adherence and better treatment outcomes [Hacker et al, 2001]. In a questionnaire survey of patients in Germany, Austria and Switzerland of expectations about EHL products more that 59% of patients expressed a wish to switch to these products because of reduction in infusions without loss of prophylaxis protection [von Mackensen et al 2017].
The half-life of clotting factors can be increased by modifications to the molecules that make them less recognisable to the proteins that normally bind to and degrade them, or reducing the rate at which they are excreted by the kidneys [Collins et al, 2016; Young et al, 2016]. In pharmacokinetic terms, this reduces their clearance. Two methods have been used in developing the extended half-life (EHL) factors [Collins et al, 2016]:
- PEGylation is the attachment of polyethylene glycol (PEG) molecules to the clotting factor protein. The PEG molecules can be of different sizes and can be attached to different sites on the clotting factor, allowing a range of options for developing a new molecular entity.
- Fusion proteins are bonded with the clotting factor molecule; the proteins used to date are albumin and immunoglobulin G.
These new molecules are based on recombinant clotting factors rather than factors derived from plasma. EHL factors now available are shown in Table 1. The mean half-lives of EHL Factor VIII preparations are about 50% greater than those of conventional Factor VIII and most EHL Factor IX preparations have half-lives that are three times greater than the conventional equivalent. Half-lives are shorter in children and young people than adults.
Table 1: EHL clotting factors under development or (in bold) introduced in the UK [Collins et al, 2016, Elocta SmPC, 2016; Alprolix SmPC, 2017; Idelvion SmPC, 2017]
| Factor | Name | EHL mechanism | Mean half life (hr)
(age studied where available) |
| Factor VIII | efmoroctocog alfa (Elocta) | fusion protein (IgG) | 19 (≥15 yrs) 12 (<6 yrs) 14 (6 – <12 yrs) 16 (12 – <18) |
| rurioctocog alfa pegol (BAX 855) | PEGylation | 14 (12 – 65 yrs) | |
| damoctocog alfa pegol (BAY-94-9027) | PEGylation | 18 (≥18 yrs) | |
| turoctocog alfa pegol (N8-GP) | PEGylation | 19 (≥18 yrs) | |
| Factor IX
|
albutrepenonacog alfa (Idelvion) | fusion protein (albumin) | 95 (adults) 86 – 89 (1 – 18 yrs) |
| eftrenonacog alfa (Alprolix) | fusion protein (IgG) | 77 (≥19 yrs) 66 (<6 yrs) 70 (6 – <12 yrs) 82 (12 – <18 yrs) |
The UK Haemophilia Centre Doctors’ Organisation interprets the increase in half lives of the EHL factors cautiously, stating: ‘These are average prolongations and there is wide inter-patient variability. As a consequence, the range of half-life with EHL-FVIII/IXs is larger than with the standard half-life products and it will not be appropriate to prescribe based on average half-life data for many patients. All published data on EHLCFCs have excluded patients with a history of an inhibitor and it is possible that some of these patients will have shorter half-lives than those reported in clinical studies.’ [Collins et al, 2016].
How effective are EHL factors?
The efficacy outcomes of the major trials of EHL clotting factors are summarised in Table 2. They have shown that prophylaxis with twice weekly (or every 4 days) EHL Factor VIII or EHL Factor IX every 1–2 weeks is associated with a low annualised bleeding rate, ranging from zero to about 4 in most studies. However, a minority of trials have reported that some patients experience bleeding rates that are ‘unacceptably high compared to standard UK care’ [Collins et al, 2016]. Whether this reflects a relative lack of clinical expertise in selecting patients for trials, dose adjustment or other factors is unclear. No trials have directly and prospectively compared conventional and ELH clotting factors (though historical comparisons suggest EHL factors may be superior in preventing bleeds [Konkle et al, 2015; Collins et al, 2014]). So far, no trials of prophylaxis with EHL clotting factors in previously untreated patients have been reported. EHL clotting factors appear to be effective in the treatment of bleeds, requiring one or two doses in almost all patients.
Table 2: Summary of efficacy outcomes in major trials of EH: clotting factors
| Trial | EHL factor | Design | Efficacy
(prophylaxis) |
Efficacy (treatment) |
| Konkle et al, 2015 | rurioctocog alfa pegol (EHL FVIII) | n=137
Patients assigned to same treatment as received before trial until 17 assigned to on demand, then all assigned to prophylaxis 45 +/- 5 IU/kg twice-weekly vs on demand Duration: 6 months or 50 exposure days |
ABR was primary endpoint (means)
Overall: Joint: Spontaneous/unknown: 70% of patients reduced infusion frequency by about one per week compared with previous regimen |
518 bleeding episodes
Treatment rated excellent or good for 92% 96% treated with 1 or 2 infusions Median dose 31 IU/kg per episode plus 29 IU/kg for maintenance |
| A-LONG
[Mahlangu et al, 2014] |
Efmoroctocog alfa (Elocta)
EHL Factor VIII |
Individualized prophylaxis (twice-weekly 25 IU/kg on day 1, 50 IU/kg on day 4, then 25-65 IU/kg every 3-5 days; n=118)
weekly prophylaxis (65 IU/kg; n=24) on demand (n=23)
|
ABR was primary endpoint (median)
Overall: Lower ABR with prophylaxis vs on demand evident in all subgroups Individualised regimen: mean dose frequency was every 3.5 days (30% every 5 days after 3 months), mean weekly dose was 78 IU/kg |
757 bleeding episodes
87% resolved with one dose, 98% with ≤2 doses. Median dose 27 IU/kg |
| Paradigm 2
[Collins et al, 2014] |
nonacog beta pegol (EHL FIX) | n=74
10 or 40 IU/kg once weekly for 52 weeks vs on-demand for 28 weeks. |
Primary endpoint was inhibitor formation (there were none).
ABR (‘main efficacy endpoint’) median: Prophylaxis was associated with fewer spontaneous bleeds and fewer traumatic bleeds than on demand treatment In 37 patients previously managed with prophylaxis, bleeding rates were lower during the trial than in the previous 12 months |
345 bleeding episodes
Overall success rate 92% In the 40 IU/kg group, 99% of episodes resolved with one dose vs 84% in each of the 10 IU/kg and on-demand groups |
| B-LONG
[Powell et al, 2013] |
Eftrenonacog alfa (Alprolix)
EHL Factor IX |
Duration 41 – 58 weeks
Weekly prophylaxis, adjusted by dose (50 IU/kg initially; median for last 3 months 41 IU/kg, range 17 – 88 IU/kg) (n=61) Prophylaxis adjusted by interval (initially 100 IU/kg every 10 days, median for last 3 months 14 days, range 8 – 21 days) (n=26) On demand (20 – 100 IU/kg) (n=27) |
ABR was primary endpoint (in non-surgical groups)
Weekly dose adjusted 3.12 Prophylaxis, interval adjusted 2.40 On demand 18.67
|
636 bleeding episodes
90% resolved with a single dose, 97% with ≤2 doses Median dose required to resolve bleeding 46 IU/Kg |
| PROLONG-9FP
[Santagostino et al, 2016] |
albutrepenonacog alfa (Idelvion)
(EHL Factor IX) |
n=65
Weekly prophylaxis (35 to 50 IU/kg) for 26 weeks, switching to 75 IU/kg every 10 or 14 days if non-bleeding criteria met On-demand for 26 weeks then weekly prophylaxis (35 and 50 IU/kg) |
ABR for spontaneous bleeds was primary endpoint; the figures below are for total ABR
On demand switch to prophylaxis: Prophylaxis from outset (treatment duration): |
358 bleeding episodes
94% treated with a single dose, 99% with ≤2 doses Dose was 35 – 50 IU/kg, median not reported |
Trough levels were maintained above 1% with the long dosing intervals available with EHL clotting factors (Table 3). The time taken to reach trough levels of 1% or 3% were longer than with conventional recombinant agents, a finding which is consistent with their longer half-life.
Table 3: Reported trough levels in major efficacy trials
| Trial | Dose adjustment | Trough levels |
| Factor VIII | ||
| Konkle et al, 2015 | Prophylactic dose (45 – 65 IU/kg twice-weekly) designed to ensure that most patients maintained FVIII levels above 1% at all times; trough levels not reported | Not reported |
| A-LONG
[Mahlangu et al, 2014] |
Pharmacokinetic parameters used to guide individual dose interval adjustment (down to 3 days or up to 5 days) and dose (up to 65
IU/kg) to target a steady-state trough FVIII level of 1 – 3 IU/dL or higher as needed to maintain good control of breakthrough bleeding |
Time to 1 IU/dL (1%) FVIII trough level above baseline was longer for EHL factor (4.9 days) than for recombinant FVIII (3.3 days) (p=0.001)
EHL factor had ‘longer time above a trough FVIII level of 1 IU/dL (1%)’ (figures not reported) vs recombinant FVIII in patients for whom these parameters were evaluated |
| Factor IX | ||
| Paradigm 2
[Collins et al, 2014] |
Doses were selected according by pharmacokinetic modelling. Trough activity was a secondary endpoint | Estimated mean FIX trough activities were 8.5 IU/dL for a dose of 10 IU/kg and 27.3 IU/dL for a dose of 40 IU/kg
Throughout the trial, mean trough FIX activities were statistically significantly above 1 IU/dL for both doses |
| B-LONG
[Powell et al, 2013] |
The dose or interval were adjusted to maintain a trough level of 1 to 3 IU/dL above baseline, or higher if clinically necessary | Times to achieve trough levels of 1 above baseline were longer for EHL Factor IX (11.2 days) than recombinant Factor IX (5.1 days)
Trough levels not reported |
| PROLONG-9FP
[Santagostino et al, 2016] |
Dose decided by investigator following pharmacokinetic analysis | Mean trough levels were 20.0 IU/dL (range, 2.5-36.2 IU/dL) after weekly dosing and 12.4 IU/dL (range, 3.1-25.4 IU/dL) after dosing every 14 days |
The UKHCDO concludes [Collins et al, 2016]:
- Prophylactic regimens with EHL clotting factors should be tailored according to individual pharmacokinetics and personal circumstances. Accurate records of infusions and bleeds are important for optimising treatment. Some patients may prefer to continue with standard half-life products.
- Typical initial regimens with EHL clotting factors in adults will be every third or fourth day or twice a week depending on individual half-life in haemophilia A and once weekly in haemophilia B.
- It may be possible to increase the dose interval in some adults to every 5 days or once weekly for haemophilia A and every 10–14 days for haemophilia B. However, these regimens are less cost effective because they need a higher total dose to maintain a target trough level.
- The target bleeding rate in children is zero. Due to shorter half-lives in this age group, it is unlikely that regimens less frequent than every 3rd or 4th day for haemophilia A and once weekly for haemophilia B will provide adequate prophylaxis. In addition, more frequent infusions may be required, especially for children under 6 years old.
Impact on quality of life
People with haemophilia and their parents say that the biggest challenge associated with prophylaxis is the time needed to administer the infusions [Hacker et al, 2001], and some parents find it stressful to inject their children [Hacker et al, 2001; Shaw and Riley, 2008; Furmedge et al, 2013].Reducing the frequency of injections should therefore have a positive impact on quality of life. Schwartz et al [2018] have shown that reduced frequency of infusions of EHL products reduces emotional distress and caregiver burden.
Switching from on demand therapy to prophylaxis is itself associated with improved quality of life, according to a systematic review of clinical trials, which found that improvements come mainly from reductions in pain and interference from pain, less restriction on physical activity and better perception of general health [Oladapo et al, 2015]. However, this review (which included two trials of EHL products) noted that this was not a consistent finding of all trials: they were designed to measure efficacy, not quality of life; their small size made it difficult to demonstrate statistical significance; and some of the reported differences in quality of life scores were not clinically meaningful. This is relevant to assessing the impact of prophylaxis with EHL clotting factors on quality of life: what is the EHL product being compared with, and is any difference in outcome important?
Table 4shows that the clinical trials reported to date do not answer the question, ‘Do EHL clotting factors improve quality of life compared with current prophylaxis strategies?’ Where comparisons have been made, they have been between dose regimens or with baseline quality of life assessments in mixed groups of patients with a history of on-demand treatment and prophylaxis. Three of the four trials were not blinded or randomised (doubtless reflecting the challenges of conducting trials of haemophilia treatment); quality of life was a secondary endpoint in two and analysed post hocin two. In general, trends to improve quality of life scores were evident in each trial but they did not consistently reach a clinically meaningful change or achieve statistical significance – another difficulty created by the small numbers of patients in these studies. It does appear that some people feel better after treatment with an EHL clotting factor than they did before but as no trial was blinded with respect to their type of treatment this finding cannot be relied on. It is possible that, with longer dose intervals, EHL Factor IX may avoid the need for a port-a-cath in some young children but the advantages of EHL Factor VIII in children under 2 years old appear to be ‘modest’ [Collins et al, 2016].
Table 4: Summary of quality of life outcomes in trials of EHL clotting factors
| EHL clotting factor | Study design | Comparator | Outcome |
| rurioctocog alfa pegol
(EHL Factor VIII) [Mullins et al, 2017] |
Phase III, non-randomised, non-blinded trial in children with severe haemophilia A aged <6 and 6 – 12 yrs. 92% previously received prophylaxis (n=66)
Quality of life was an ‘exploratory outcome’ assessed by Pediatric Quality of Life Inventory, visual analogue Pain Scale and Physical Activity Question Set. |
Twice-weekly rurioctocog alfa for 6 months. | Compared with baseline, clinically meaningful and significant improvement
in the Psychosocial Summary and Physical Health Summary domains of PedsQLTM overall, but not in younger cohort alone. Significant reductions in pain scores and physical activity scores. |
| rurioctocog alfa pegol
(EHL Factor VIII) [Konkle et al, 2015] |
Phase III trial (non-blinded, non-randomised) in adolescents and adults with severe haemophilia A (n=137). 72% were previously managed with prophylaxis. 17 patients previously managed with on-demand therapy continued with this regimen
Quality of life assessed by Short Form 36 and Haemo-SYM |
Twice weekly prophylaxis vs on demand
Duration was 6 months or 50 exposure days |
No statistically significant differences in quality of life scores or symptoms but the changes over baseline were greater in the group receiving prophylaxis and above thresholds for clinically meaningful change |
| Efmoroctocog alfa (Elocta)
EHL Factor VIII [Wyrwich et al, 2016] |
A-LONG Phase III trial (non-blinded, partially randomised) in adolescents and adults. 53% previously received prophylaxis (n=67)
Quality of life assessed using HAEMAQOL. This was not part of the original trial report
|
Efmoroctocog alfa every 3 – 5 days, weekly or on demand. Data mostly from 57 patients who received tailored prophylaxis, of whom 70% had previously received prophylaxis. Quality of life reported at 28 weeks | Individualised prophylaxis: significant improvement in total score borderline clinically meaningful,22 not so for physical change (except in patients previously treated on-demand). No overall improvement in Sports/leisure domain in any group
The proportions of patients whose HAEMAQOL scores exceeded the threshold for ‘clinically meaningful’ in different domains (termed ‘responders’) were: Total score 24% Physical health 47% Sports/leisure 36% |
| Eftrenonacog alfa (Alprolix)
EHL Factor IX [Wyrwich et al, 2016] |
B-LONG Phase III trial (non-blinded, non-randomised) in adolescents and adults with severe haemophilia B. 41% previously received prophylaxis (n=38)
Quality of life assessed using HAEMAQOL. This was not part of the original trial report |
Eftrenonacog alfa weekly, initially every 10 days then individualised, or on demand; 53% of these patients previously received prophylaxis (there was also a surgery group but quality of life was not assessed in these patients)
Quality of life was assessed at 26 weeks
|
Improvements in all domains overall, clinically meaningful for Physical health.
‘Responder rates’ (defined as above) for weekly prophylaxis were: For individualised prophylaxis: Prior treatment type did not affect quality of life outcome |
| nonacog beta pegol
(EHL Factor IX) [Chowdary et al, 2016] |
Paradigm2: single-blind (with respect to dose) phase III trial in adolescents and adults with haemophilia B
Paradigm4: open-label extension trial. Quality of life was secondary endpoint. Measures were HAEMOQOL III, HAEMAQOL and EQ5D3L |
Once-weekly 10 or 40 IU/kg for 52 weeks (n=59) vs on demand for 28 weeks (n=15).
All received nonacog beta pegol
|
HAEMAQOL/HAEMOQOL: Compared with before treatment (half previously received prophylaxis), no differences in change between treatment arms. Higher dose of nonacog beta pegol associated with significant changes vs lower dose in some domains; clinically meaningful change only for sports/leisure domain. In extension trial, switching from lower to higher dose associated with significant and meaningful changes in several domains
EQ5D3L: Scores improved in all patients but no differences between treatment arms. Trend to improvement with prophylaxis, little change with on-demand; significant improvement only with higher dose |
In summary, compared with the products currently in use, the pharmacokinetic characteristics of an EHL clotting factor potentially offer a longer dose interval, and therefore fewer injections, and easier maintenance of effective trough levels. But the variation in individual response that is a challenge with conventional products also occurs with EHL factors, particularly in children, and there is no ‘one size fits all’ or ‘inject and forget’ regimen on the horizon. It looks as if prophylaxis with EHL clotting factors will involve fewer injections for some people but perhaps not as few as hoped for others. EHL product have not been shown to improve quality of life more than conventional clotting factors.