Bottom Line

Nephrologists see promise for hypoxia-inducible factor prolyl hydroxylase inhibitors

Few will argue that the renal space is rife with unmet need for new therapeutic agents. In a recent survey about anemia treatments completed by 200 U.S. nephrologists, more than one-third classified the need as “high” (rating of 8, 9 or 10 on a 10-point scale) in both the dialysis and non-dialysis setting. Furthermore, an even greater percentage acknowledged there is a substantial opportunity to improve anemia outcomes compared to the current state of care.

Jennifer Robinson

Interest

Spherix Global Insights surveys nephrologists in clinical practice each quarter on a range of renal topics, including their familiarity with and perceptions of products in the pipeline. Recently, that has included roxadustat (FibroGen/AstraZeneca/Astellas), vadadustat (Akebia/Otsuka/Mitsubishi Tanabe) and daprodustat (GSK).

Familiarity with the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) class has been steadily increasing during the past 2 years, and 26% of the survey respondents in the Spherix fourth-quarter 2019 survey (gathered between Nov. 27 and Dec. 9, 2019) had high familiarity with roxadustat, which is presently the most advanced HIF-PHI in development. The more familiar nephrologists are with the HIF-PHI class, the survey showed, the more bullish they are about the future role of the drug in anemia management (Figure 1).

Surveyed nephrologists with greater familiarity with the HIF-PHI class more strongly believe they could improve anemia outcomes.

Source: Jennifer Robinson, Spherix Global Insights

When presented with roxadustat highlights from ASN Kidney Week in November 2019, 77% of the survey respondents indicated they are “more enthusiastic” about the product, while 1% indicated less enthusiasm, and 22% said results were in line with their expectations.

With the growing familiarity, there is also a corresponding perception among nephrologists that these agents may be “safer” than erythropoiesis-stimulating agents (ESAs; Figure 2). When asked to expand upon what “safer” means, nephrologists most frequently noted improved safety in patients with high cardiovascular risk, avoidance of supraphysiologic doses of exogenous erythropoietin, and potentially lower concomitant IV iron requirements. As expanded upon by one respondent, “[HIF-PHIs offer a] more physiological approach and avoid supra-high non-physiological dose of ESA. My impression is that ESA doses are way too high and lead to the problems.”

Dialysis or non-dialysis for HIF-PHIs

Nephrologists are somewhat divided as to which setting – dialysis or non-dialysis – these agents will provide the greatest benefit, although those with greater familiarity tend to select the non-dialysis setting. In the dialysis setting, nephrologists largely acknowledge their use of roxadustat, if FDA approved,will be dictated by dialysis chain formulary status and protocols. That aside, 67% indicate a high likelihood of use in ESA hypo-responders, 47% say use of roxadustat is likely in patients with increased CV risk factors, 45% see likely use in patients on home modalities and 38% say they would preferentially use roxadustat for patients on incident dialysis who have never been exposed to ESAs. Far fewer nephrologists indicate a likelihood of switching patients who are stable on ESAs to roxadustat.

Most nephrologists expect HIF-PHIs to have an improved safety profile over ESAs.

Source: Jennifer Robinson, Spherix Global Insights

In the non-dialysis setting, “convenience in terms of an oral alternative to ESAs” was selected by the greatest percentage of nephrologists in the fourth-quarter survey as the aspect of anemia needing the most improvement, presenting an enormous opportunity for the HIF-PHIs. As in dialysis, anticipated use of roxadustat is most likely in patients who have had a suboptimal response to ESAs. However, 46% indicate a likelihood of using roxadustat first line before ESAs in this setting, and most are favorable toward the idea of maintaining a patient on roxadustat as they transition to dialysis. Aligned with use during transition from non-dialysis to dialysis, roxadustat data in patients on incident dialysis presented at ASN Kidney Week was among the most compelling, according to the survey respondents.

ESAs still viable

While enthusiasm for the HIF-PHIs appears to be mounting, survey results suggest there may be reluctance to move away from ESAs altogether and that nephrologists will be most comfortable using HIF-PHIs in patients they deem inappropriate for ESAs, such as hypo-responders. Importantly, nephrologists have been using ESAs for decades and most report they are comfortable with the risk-benefit ratio of these drugs in both patients on dialysis and patients with CKD who are not on dialysis. Despite the robust estimates for HIF-PHI use, about 10% report in the fourth-quarter survey that they would prescribe a HIF-PHI soon after FDA approval, indicating some trepidation (Figure 3).

The uptake of roxadustat will be tempered by market access issues – how soon dialysis units place roxadustat on formulary, how restrictive the protocol is, whether managed care plans cover these agents, how burdensome the prior authorization process may be, and ultimately, out-of-pocket costs for patients. Most survey respondents expect roxadustat to be priced at a premium to ESAs.

Once FDA approved, 28% of nephrologists surveyed said they expect to test HIF-PHIs in their dialysis clinics within 6 months.

Source: Jennifer Robinson, Spherix Global Insights

In addition to market access issues, there is some concern about adherence to an oral agent. As much as an oral formulation may offer convenience to patients, there is a high degree of comfort with in-center or in-office administration of ESAs and knowing the patient received the medication as directed.

Finally, nephrologists are hoping for a product label that proclaims a safety advantage of HIF-PHIs over ESAs and, perhaps even more importantly, no new off-target effects of this new class of agents. For nephrologists with prior clinical experience with omontys (peginesatide), an ESA which was recalled shortly after launch in 2013 due to hypersensitivity reactions, concern about potential off-target effects is higher and these physicians express an intent to wait slightly longer before trialing roxadustat post-approval. In that post-ASN Kidney Week survey, 42% selected roxadustat as one of the top three most desired pipeline agents amidst a choice of 15 agents in late-stage development, followed by Retrophin’s sparsentan (for FGSG and IgA nephropathy) and Ardelyx’s tenapanor (for hyperphosphatemia).

Summary

The HIF-PHIs are poised to shift the treatment paradigm for anemia in both the dialysis and non-dialysis settings. Whether they will “revolutionize” treatment, as close to half of the nephrologists agree they will, remains to be seen.

Disclosure: Robinson reports she is the president of Spherix Global Insights.

Few will argue that the renal space is rife with unmet need for new therapeutic agents. In a recent survey about anemia treatments completed by 200 U.S. nephrologists, more than one-third classified the need as “high” (rating of 8, 9 or 10 on a 10-point scale) in both the dialysis and non-dialysis setting. Furthermore, an even greater percentage acknowledged there is a substantial opportunity to improve anemia outcomes compared to the current state of care.

Jennifer Robinson

Interest

Spherix Global Insights surveys nephrologists in clinical practice each quarter on a range of renal topics, including their familiarity with and perceptions of products in the pipeline. Recently, that has included roxadustat (FibroGen/AstraZeneca/Astellas), vadadustat (Akebia/Otsuka/Mitsubishi Tanabe) and daprodustat (GSK).

Familiarity with the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) class has been steadily increasing during the past 2 years, and 26% of the survey respondents in the Spherix fourth-quarter 2019 survey (gathered between Nov. 27 and Dec. 9, 2019) had high familiarity with roxadustat, which is presently the most advanced HIF-PHI in development. The more familiar nephrologists are with the HIF-PHI class, the survey showed, the more bullish they are about the future role of the drug in anemia management (Figure 1).

Surveyed nephrologists with greater familiarity with the HIF-PHI class more strongly believe they could improve anemia outcomes.

Source: Jennifer Robinson, Spherix Global Insights

When presented with roxadustat highlights from ASN Kidney Week in November 2019, 77% of the survey respondents indicated they are “more enthusiastic” about the product, while 1% indicated less enthusiasm, and 22% said results were in line with their expectations.

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With the growing familiarity, there is also a corresponding perception among nephrologists that these agents may be “safer” than erythropoiesis-stimulating agents (ESAs; Figure 2). When asked to expand upon what “safer” means, nephrologists most frequently noted improved safety in patients with high cardiovascular risk, avoidance of supraphysiologic doses of exogenous erythropoietin, and potentially lower concomitant IV iron requirements. As expanded upon by one respondent, “[HIF-PHIs offer a] more physiological approach and avoid supra-high non-physiological dose of ESA. My impression is that ESA doses are way too high and lead to the problems.”

Dialysis or non-dialysis for HIF-PHIs

Nephrologists are somewhat divided as to which setting – dialysis or non-dialysis – these agents will provide the greatest benefit, although those with greater familiarity tend to select the non-dialysis setting. In the dialysis setting, nephrologists largely acknowledge their use of roxadustat, if FDA approved,will be dictated by dialysis chain formulary status and protocols. That aside, 67% indicate a high likelihood of use in ESA hypo-responders, 47% say use of roxadustat is likely in patients with increased CV risk factors, 45% see likely use in patients on home modalities and 38% say they would preferentially use roxadustat for patients on incident dialysis who have never been exposed to ESAs. Far fewer nephrologists indicate a likelihood of switching patients who are stable on ESAs to roxadustat.

Most nephrologists expect HIF-PHIs to have an improved safety profile over ESAs.

Source: Jennifer Robinson, Spherix Global Insights

In the non-dialysis setting, “convenience in terms of an oral alternative to ESAs” was selected by the greatest percentage of nephrologists in the fourth-quarter survey as the aspect of anemia needing the most improvement, presenting an enormous opportunity for the HIF-PHIs. As in dialysis, anticipated use of roxadustat is most likely in patients who have had a suboptimal response to ESAs. However, 46% indicate a likelihood of using roxadustat first line before ESAs in this setting, and most are favorable toward the idea of maintaining a patient on roxadustat as they transition to dialysis. Aligned with use during transition from non-dialysis to dialysis, roxadustat data in patients on incident dialysis presented at ASN Kidney Week was among the most compelling, according to the survey respondents.

PAGE BREAK

ESAs still viable

While enthusiasm for the HIF-PHIs appears to be mounting, survey results suggest there may be reluctance to move away from ESAs altogether and that nephrologists will be most comfortable using HIF-PHIs in patients they deem inappropriate for ESAs, such as hypo-responders. Importantly, nephrologists have been using ESAs for decades and most report they are comfortable with the risk-benefit ratio of these drugs in both patients on dialysis and patients with CKD who are not on dialysis. Despite the robust estimates for HIF-PHI use, about 10% report in the fourth-quarter survey that they would prescribe a HIF-PHI soon after FDA approval, indicating some trepidation (Figure 3).

The uptake of roxadustat will be tempered by market access issues – how soon dialysis units place roxadustat on formulary, how restrictive the protocol is, whether managed care plans cover these agents, how burdensome the prior authorization process may be, and ultimately, out-of-pocket costs for patients. Most survey respondents expect roxadustat to be priced at a premium to ESAs.

Once FDA approved, 28% of nephrologists surveyed said they expect to test HIF-PHIs in their dialysis clinics within 6 months.

Source: Jennifer Robinson, Spherix Global Insights

In addition to market access issues, there is some concern about adherence to an oral agent. As much as an oral formulation may offer convenience to patients, there is a high degree of comfort with in-center or in-office administration of ESAs and knowing the patient received the medication as directed.

Finally, nephrologists are hoping for a product label that proclaims a safety advantage of HIF-PHIs over ESAs and, perhaps even more importantly, no new off-target effects of this new class of agents. For nephrologists with prior clinical experience with omontys (peginesatide), an ESA which was recalled shortly after launch in 2013 due to hypersensitivity reactions, concern about potential off-target effects is higher and these physicians express an intent to wait slightly longer before trialing roxadustat post-approval. In that post-ASN Kidney Week survey, 42% selected roxadustat as one of the top three most desired pipeline agents amidst a choice of 15 agents in late-stage development, followed by Retrophin’s sparsentan (for FGSG and IgA nephropathy) and Ardelyx’s tenapanor (for hyperphosphatemia).

Summary

The HIF-PHIs are poised to shift the treatment paradigm for anemia in both the dialysis and non-dialysis settings. Whether they will “revolutionize” treatment, as close to half of the nephrologists agree they will, remains to be seen.

Disclosure: Robinson reports she is the president of Spherix Global Insights.