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Guideline 4.7 – Prescribing HIF-PHI in Sub-Groups of People with CKD

Guideline 4.7 – Prescribing HIF-PHI in Sub-Groups of People with CKD

We recommend that HIF-PHI should be avoided or used cautiously in people with active malignancy. (1B)

Guideline 4.7.1

We recommend that HIF-PHI should be avoided or used cautiously in people with autosomal dominant polycystic kidney disease until further data is available. (1D)

Guideline 4.7.2

We recommend that HIF-PHI should be avoided or used cautiously in people with a history of seizures. (1B)

Guideline 4.7.3

We recommend caution in using HIF-PHI in people with uncontrolled hypertension. (1B)

Guideline 4.7.4

We recommend caution in using HIF-PHI therapy in people with retinopathy. (1D)

Guideline 4.7.5

We recommend caution in people with a history of thrombotic events following the SmPC for contra-indications. (1A)

Guideline 4.7.6

We suggest consideration of use of HIF-PHI in people with hyporesponsiveness to ESA therapy or underlying inflammation, but further high-quality randomised trials are needed to confirm its effectiveness. (2C)

Rationale

Malignancy

Hypoxia inducible factor-1 alpha (HIF-1α) is a key transcription factor in tumour progression (1). HIF- 1α inhibitors are currently used in cancer treatment (1). Genetic HIF activation is a central mechanism of tumorigenesis in people with the von Hippel-Lindau (VHL) disease and clear cell renal carcinomas (2). These data suggest that HIF-PHI may potentially increase the risk of initiation/ progression of malignancy in people with CKD. Data from the most recent metanalysis of over 24,000 people indicate the risk estimate for malignancy was 7% lower in the HIF-PHI arm compared to ESA (non-significant RR 0.93; 95% CI 0.76 to 1.13) (3). However, once again follow-up was relatively short- and longer-term data is needed to assess for the development of new cancers and impact on previous cancers. Those with established cancer or a history of cancer were excluded from all trials.

In the ASCEND-ND trial, cancer-related death or tumour progression or recurrence was numerically more common in those randomised to daprodustat (72 of 1937, 3.7%) versus darbepoetin alfa (49 of 1933, 2.5%), with a relative risk of 1.47 (95% CI: 1.03- 2.10) (4). Post hoc analyses that accounted for differential dosing frequency attenuated this observed risk (4). Molidustat in clinical trials also reported neoplasms in 9.8% of trial participants in the molidustat group compared with 5.3% in the darbepoetin group (5).

There has been no consistent signal across the published HIF-PHI trials of an excess risk of malignancy-related adverse events, but since patients with a history of recent or active malignancy were excluded from trials, it is difficult to conclude with confidence of the absence of a clinically relevant risk of the use of these drugs compared with ESAs. It is therefore advisable that the use of this product should be avoided or used cautiously in people with known active malignancy.

Polycystic Kidney Disease

People with CKD who have underlying Polycystic Kidney Disease were excluded from trials using HIF PHI’s because of the potential risk of malignant transformation of cysts. HIF activation occurs in polycystic kidneys in humans and rodents and activation of the HIF–pathway has been shown to enhance cyst expansion in preclinical models. However, whether the use of HIF-PHI therapy to treat anaemia may enhance cyst growth remains to be further clarified. It has been postulated that cyst formation is related to chloride-dependent fluid secretion into the cyst lumen (6).

Hypertension

Pre-clinical studies in healthy rats and rats with CKD demonstrated that HIF-PHI therapy generate significant dose-dependent blood-pressure lowering effects (7, 8). However, so far, no significant blood pressure safety concerns have been reported in any HIF-PHI phase 3 programs.

Retinopathy

Diabetic retinopathy may be exacerbated potentially by the effect of HIF-PHI therapy on neo-vascularisation (9). There were few participants with significant retinopathy recruited to the current published phase 3 clinical trials. Data from a pooled Japanese analysis of trials in NDD-CKD and DD-CKD using daprodustat did not report any increased risk for retinal events or deterioration in disease (10). One relatively large study, the SYMPHONY-ND study which compared enarodustat ESA therapy did show an increase in the levels of VEGF levels and an increase in reported retinal adverse events (3.7 vs 0.9%) (11). Other NDD-CKD trials have not shown increased risk of eye disease with HIF-PHI therapy (12, 13, 14, 15).

In dialysis patients the SYMPHONY-HD trial which examined enarodustat versus darbepoetin did find an increased risk of retinal adverse events (6.9 vs 3.5%) (16). Again, in the ASCEND-ID trial of daprodustat compared to ESA therapy there was a reported increased incidence of eye disease (3.4 vs 0.79/100 patient-years) (17).

Thromboembolic events

Administration of HIF-PHI therapy has been associated with a higher risk of thrombotic events, including dialysis vascular access thrombosis compared with ESAs or placebo (8, 18). The underlying mechanisms are complex and may be related to the rapid rate of rise in Hb for roxadustat. (19) In addition, the impact of HIF-PHI on iron metabolism (upregulation of transferrin, (20) or interference of the coagulation system (increased expression of plasminogen activator inhibitor) may contribute to thrombotic risk (21). Roxadustat showed an excess risk of thrombosis in both NDD-CKD (versus ESA) and DD-CKD (versus placebo) trials (22). Vascular access thrombosis occurred in 1.5 versus 0.9/100 patients years and DVT was 0.7 versus 0.2/100 patients years (23). A pooled analysis of roxadustat trials demonstrated higher risks were associated with the rate of Hb rise (24). Lower doses of roxadustat, may lead to a slower rate of Hb rise, and thus ameliorate thrombosis risk while maintaining efficacy. Thrombotic risk with vadadustat were not noted in published data (25). Daprodustat trials have not reported a significant excess risk of thrombosis compared with active comparator although there was a numerical increased risk of vascular access thrombosis (2.1% versus 1.5%) (4, 25, 26).

Data from the meta-analysis from 17 of the trials reported on DVT and PE events and found no difference. Again, there was no difference in AVF thrombosis incidence (14 trials) (3).

Patients hyporesponsive to ESAs

By lowering hepcidin levels, HIF-PHI therapy may theoretically be more effective in treating people who are hyporesponsive to ESAs because of chronic inflammation or functional iron deficiency. Preliminary data from the randomised trials suggest that whereas higher doses of ESAs are needed for people with high C-reactive protein (CRP) levels, this may not be true for HIF-PHI therapy. (27, 28) However, CRP concentrations that were considered high in trial participants were only slightly elevated, and sicker and more inflamed patients may have been less likely to have been enrolled in trials of HIF-PHI therapy. Therefore, more evidence from randomised controlled trials are needed before recommendations for routine use in the population can be made.

Although the use of HIF-PHI therapy in combination with ESAs might theoretically be advantageous for people who are ESA hyporesponsive, there are no data available to support this strategy in clinical practice at present (29). As with all drugs, there is a risk for drug-drug interactions with the use of HIF-PHI therapy, particularly in combination with other oral agents.

Children

There are insufficient data supporting the use of HIF-PHI therapy in paediatric patients with anaemia of CKD because people under the age of 18 years were excluded from all Phase 3 trials.

Cardiovascular Disease

For MACE outcomes, all trials with a HIF-PHI met the non-inferiority margin set by the regulator except Vadadustat in people with NDD-CKD. However, there is bias in these trials due to the withdrawal of large number of people in both arms (over 20%). A recent meta-analysis has shown no difference as described previously (3). A cochrane meta-analysis of 51 trials with almost 31,000 participants with NDD-CKD or DD-CKD found no difference in CV death (RR 1.05: 95% CI 0.88 to 1.26); non-fatal MI (RR 0.91: 95% CI 0.76 to 1.00 or non-fatal stroke (RR 1.06: 95% CI 0.71 to 1.56) (30). The secondary outcome studied in the DOLOMITES trial was the impact of roxadustat compared to the active comparator (darbepoetin alfa) on CV safety, based on the number of major adverse cardiac events (26, 27). The hazard ratio (HR) For MACE was 0.89; 95%; CI 0.60 to 1.33 and for MACE+ (a composite of MACE plus unstable angina or congestive heart failure requiring hospitalisation) was 0.93; 95% CI 0.65 to 1.32, indicating no increased risk with roxadustat compared to darbepoetin alfa. In addition, there was no extension of the risk beyond the non-inferiority margin set by the regulator. It must be noted that in the dialysis patients, there was a potential increase in risk in the pooled analysis of those patients who switched therapy from ESA to Roxadustat (18, 19).

Roxadustat was previously reviewed by the FDA for its potential use in CKD (29, 31). Data submitted included 3 separate trials comparing Roxadustat with placebo that were pooled for meta-analyses in the NDD-CKD (n = 4270) population (32). A fourth study comparing roxadustat to darbepoetin alfa was analysed separately (DOLOMITES) (33). The pooled analyses for roxadustat did not have prespecified agreed (FDA) noninferiority margins (32, 33). Further, this risk was accentuated during on-treatment sensitivity analyses (as opposed to intention-to-treat analysis). This analysis was suggested by the FDA to minimise the effect of including unexposed person-times or events that may not be affected by the intervention (18). When assessing events occurring while people were on treatment and for one week after discontinuation (on-treatment + 7 days analyses), 277 (7.2%) events were recorded in the roxadustat arm compared with 131 (5.6%) events in the placebo arm (HR 1.38; 95% CI: 1.11- 1.70). However, there was higher dropout rates in the placebo compared to roxadustat arms, with potential for bias that may have disadvantaged roxadustat (33).

Three studies of roxadustat compared to ESA involving people receiving dialysis (N=3880) were meta-analysed (33). The analyses of the effect of roxadustat for MACE were discordant based on the analytical approach: in the primary, on-treatment + 7-day analyses, the risk of MACE was similar in the roxadustat and ESA groups: HR 1.02; 95% CI: 0.88-1.20. In the sensitivity, on-treatment analysis, the HR for the risk of MACE in patients treated with roxadustat versus ESA was 1.14; 95% CI: 1.00- 1.30 (not statistical significance for non-inferiority). A fourth trial conducted in Europe and not included in the pooled meta-analysis, permitted the use of two different ESAs (epoetin alfa or darbepoetin alfa) as comparators, demonstrated a higher risk of death in roxadustat vs. ESA-treated patients (8.9 per 100 patient years (PY) vs. 6.3 per 100 PY; HR 1.54, 95% CI 1.04-2.28) (29).

The differences observed in the stable DD population maybe somewhat challenging to accurately interpret due to the different treatment strategies for the Roxadustat and the comparator arm. While in the comparator arm in the stable dialysis dependent CKD (SDD) studies the treatment was not changed (patients continued ESA therapy) in the Roxadustat arm were switched from ESA therapy with inherent risks related to this change which created an imbalance between the two arms (35). Several contributing factors may impact this risk, including treatment non-responsiveness, and converting stable ESA treated people receiving dialysis.

In the case of non-responsiveness, treatment with roxadustat should not be continued beyond 24 weeks after the start of treatment. Conversion of people receiving dialysis otherwise stable on ESA treatment is only to be considered when there is a valid clinical reason and after a shared decision with the patient on the risks and benefits. For stable ESA treated people with anaemia associated with CKD and not on dialysis, this risk could not be estimated as these patients have not been studied. A decision to treat these patients with roxadustat should be based on a shared decision with the patient of the benefits and risks for that particular individual patient.

In a published analysis of the four roxadustat trials in the DD-CKD population (8), MACE and MACE+ in the on-treatment plus 7 day analyses showed different results in incident vs. prevalent dialysis patients, noted similar risk of MACE (HR 0.83; 95% CI: 0.61-1.13) and nominally lower risk of MACE+ (HR 0.76; 95% CI: 0.57-1.00) among incident dialysis patients treated with roxadustat, whereas roxadustat was less favourable for MACE (HR 1.18; 95% CI: 1.00-1.38) and all-cause mortality (HR 1.23; 95% CI: 1.02-1.49) in prevalent dialysis patients (33).

Pooled results from two randomized trials involving NDD-CKD persons in which vadadustat was compared with darbepoetin alfa were analysed (19). One trial involved ESA naïve patients (n=1751) and the other involved patients who were receiving active ESA therapy (n =1725). Pooled analysis showed that while vadadustat met its margin with respect to hematologic efficacy in each trial, it did not meet its pre-specified non inferiority margin (HR 1.3) with respect to MACE, defined as death from any cause, non-fatal myocardial infarction, or non-fatal stroke, with a higher risk of MACE in the vadadustat arm (25). The excess risk was accounted for by non-fatal MI and death from non-cardiovascular causes. Subgroup analyses found a regional difference in the study results, with the increased MACE risk observed in non-U.S. study sites (HR 1.30; 95% CI 1.05-1.62) but no difference in risk in the U.S. study sites (HR 1.06; 95% CI 0.87-1.29).

Two randomised trials involving DD-CKD patients compared vadadustat with darbepoetin alfa. One trial involved prevalent (n = 3554) and the other incident (n = 369) participants (34). Pooled analysis of results from both trials showed similar MACE rates in the two arms and met non-inferiority (HR 0.96; 95% CI: 0.83-1.11) (34).

A phase 3 trial assessed the safety and efficacy of daprodustat against an active comparator (darbepoetin alfa) for the treatment in people with NDD-CKD. Daprodustat was non-inferior to the active comparator as it met the pre-specified non-inferiority margins of a HR of 1.25 in primary analyses (HR: 1.03; 95% CI: 0.89-1.19) (24). However, in the sensitivity on-treatment MACE analysis, which censored patients at 28 days after the last dose, participants randomised to daprodustat had a higher incidence of MACE than those randomised to ESA (14.1% vs. 10.5%, HR 1.40; 95% CI: 1.17- 1.68). The trial authors suggested that differences in the dosing frequency of daprodustat versus ESAs in this trial and differences in definitions of treatment periods may have led to potential bias that disadvantaged daprodustat (24).

Daprodustat was evaluated in randomised, open-label, phase 3 trial, in patients with DD-CKD subjects using the active comparator of epoetin alfa if they were receiving haemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis (5). A total of 2964 patients underwent randomization. Daprodustat, compared to the active comparators, met the pre-specified non-inferiority margin of 1.25 in primary analyses of the DD-CKD populations (DD: 0.93; 95% CI: 0.81- 1.07). Similar conclusions were obtained from sensitivity analysis.

Overall meta-analyses have reassured the short-term safety of these drugs in comparison to ESA therapy. Natale et al (30) found not difference in MACE and MACE+; similar to those from Takkavatakarn et al (37). A meta-analysis limited to only non-dialysis and active comparator (9 studies with 9470 people) there was no difference in CV outcomes (3).

More long-term data will be needed to reassure on the impact of HIF-PHI therapy and their potential off-target effects including the systemic response to their action via inhibition of alpha ketoglutarate which may have effects of cardiovascular and heart failure complications (38). Several studies are ongoning including comparing roxadustat combined with sacubitril/valsartan versus recombinant human erythropoietin combined with ACEI or ARB in Chinese patients with cardiorenal syndrome and anaemia (NCT05053893) and examining the safety and efficacy of roxadustat in the treatment of HF in patients with CKD and anaemia (NCT05691257).

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