Science

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

As the world's first prolyl hydroxylase inhibitor (PHI) for the treatment of renal anemia through stabilization of hypoxia-inducible factor (HIF), the new pharmacological mechanism of roxacostat solves many of the problems previously experienced by patients with renal anemia. Rosasta was developed in collaboration with AstraZeneca, with the former responsible for drug development and the latter for global market access.

Rosasta is based on the "star mechanism" of hypoxia-inducible factor, which won the Nobel Prize in Physiology/Medicine, and has attracted a lot of attention from the medical community since its introduction. It was considered a boon for patients with renal anemia.

Rosasta was approved for marketing in China by the State Drug Administration on December 17, 2018, making China the first country in the world to use hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). And later in 2019, after the price was agreed, roxacostat officially entered the medical insurance category in China.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

Subsequently, Rosasta has been approved for marketing in Japan, Chile and South Korea, and the European Union has given a relevant positive response (on August 19, 2021, the EU has announced the approval of Rosasta for the treatment of nephrogenic anemia). However, on August 11, 2021, the marketing application for roxacostat was rejected by the U.S. Food and Drug Administration (FDA) and its safety was again questioned.

Combined with an April 2021 statement from Enbrel that "the safety data criteria for Rosasta were indeed artificially modified in an attempt to obtain FDA marketing approval," Rosasta's path to market in the U.S. has been an awkward one.

Rosarostat, which has reached a 74% market share in China, has shown an exceptionally good safety profile.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

So, can the effectiveness and safety of Rosastat really be guaranteed and can it be a real boon for patients with renal anemia?

Does roxacostat work? Perhaps we need to understand the mechanism of action first

Renal anemia is a common complication in the middle and late stages of chronic renal failure. Clinical data show that the chance of nephrogenic anemia in patients with advanced chronic renal failure reaches a staggering 98%, mainly because the production of red blood cells is directly related to the kidneys. When the kidney parenchyma is damaged, it can no longer secrete erythropoietin, a hormone that plays a key role in the production of red blood cells, and once it is missing, patients will easily suffer from renal anemia.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

According to statistics, the prevalence of chronic kidney failure is over 10% worldwide. This means that one out of every 10 people in the world suffers from chronic renal failure, and one out of every five of these people experiences the ravages of chronic renal anemia. The quality of survival of patients with renal anemia will be severely reduced, with dizziness, panic, and weakness as typical manifestations, and the risk of death will be greatly increased in severe cases.

The traditional treatment for renal anemia is direct injection of erythropoietin, but there are limitations to this treatment. First of all, erythropoietin can lead to hypertension and stroke if over-injected; moreover, in order to maintain the effect of erythropoietin, patients need to inject iron at the same time.

The advantage of roxacostat, on the other hand, is that it is completely oral, eliminating the need for patients to have painful subcutaneous injections and the need for additional iron injections.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

The mechanism of action of Rosarostat is to increase endogenous erythropoietin and improve iron absorption and activity to promote hematopoiesis for the purpose of improving and treating anemia. Compared with the traditional treatment of renal anemia, roxacostat not only eliminates the pain of subcutaneous injection, but also improves renal anemia more thoroughly.

It is considered a landmark drug by many medical professionals because it works directly on the transcriptional level of the erythropoietin gene, improving the original "blood transfusion" mode to "blood production".

In addition, Rosasta is also indicated for patients with renal anemia who are on hemodialysis.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

The efficacy of roxacostat has been proven time and time again after its launch in China, with patients showing significant increases in red blood cell count, hemoglobin level, erythrocyte specific volume, ferritin and other indicators.

All in all, compared to the traditional treatment paradigm for renal anemia, roxacostat seems to perform quite perfectly. But why has roxacostat, which has performed so well, not been successfully marketed in the United States? Why was its safety once questioned? Perhaps we need to go back to the roots to understand.

The US denied the listing of the company by falsifying the experimental data? The dilemma of Rosarostat

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

On July 16, 2021, the U.S. FDA Cardiovascular and Renal Drug Advisory Committee held a voting meeting on the marketing application for roxacostat. At the meeting, the committee voted against the marketing application of Rosasta, and the vote ended with 13 votes in favor and 2 votes against, announcing that the marketing of Rosasta in the U.S. was again frustrated.

And Enabler entered the official website afterwards to publish the FDA's handling of the issue, and its stock plunged 34% at one time. In fact, Enbrel has a long history of "feud" with the FDA.

Back in 2019, the FDA had questions about the safety of roxacostat. In response to the results of clinical trials of roxacostat, the FDA concluded that roxacostat did not show any advantage for possible adverse cardiovascular events after taking the drug.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

Although it does not represent a potential risk of cardiovascular side effects, the FDA rejected the marketing application for roxacostat and delayed its marketing evaluation date.

To confirm the absence of cardiovascular side effects, Enbrel conducted a phase III clinical trial and demonstrated the superior safety profile of roxacostat compared to alfaiplatin (an erythropoietin-like drug). In the clinical trial, cardiovascular safety was the focus of the study, and the final study data appear to be quite good.

However, in 2020, the marketing application for roxacostat was again denied and the FDA requested a clear explanation of the Phase III clinical data analysis from Enbrel, and also postponed the marketing evaluation date for several more months.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

By April of the following year, Enabash was pressured to issue a statement admitting that it had artificially modified its safety data standards in order to go public in the United States.

Thus, it is not so surprising that the marketing application for roxacostat was rejected again in 2021.

So, is the safety of roxacostat really guaranteed and does it have any side effects?

Is the safety of roxacostat guaranteed? And what are the side effects?

Although roxacostat is next door in the United States, clinical trial data on roxacostat in China show a very good safety profile.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

It is understood that Enbreljin initially conducted a clinical study in Singapore in order to verify that roxacostat is also reliable for Asians, and then they targeted China.

Nearly 700 million patients with chronic renal failure exist worldwide, and China alone occupies 130 million. As China has the largest number of patients with renal anemia, the application prospect of roxacostat is very promising.

In the years since Rosasta was developed and launched, two clinical trials have been conducted in China, the first in Peking Union Medical College Hospital in Phases I-III and the second in Huashan and Ruijin Hospitals in Shanghai in Phases I-III, and its safety has been proven in several rigorous trials.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

Later, the New England Journal of Medicine also published two research papers independently authored by our medical staff on the treatment of renal anemia with roxacostat. It is reported that this is the first time that the New England Journal of Medicine has published a research paper by doctors from mainland China.

And on August 27, 2021, a trial called DOLOMITES, conducted by a multinational team in Europe and the United States, confirmed that roxacostat not only had good efficacy in patients with non-dialysis-dependent renal anemia, but also had a lower incidence of cardiovascular side effects compared to alfadabepo (a biosynthetic erythropoietin) (11.8% incidence) than alfadabepo ( 14% incidence).

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

The results of the trial, which covered more than six hundred participants for up to 104 weeks (about two years), suggest that roxacitab has not only reliable efficacy, but also proven safety and longevity.

From the results and data of the studies, the reliability and safety of Rosastat can be guaranteed, except for the fact that "the experimental data criteria were modified to obtain FDA approval for marketing", which raises questions about its safety.

In addition, side effects are a particular concern for those taking the drug. The side effects of roxacostat are mainly in the digestive and respiratory systems, and nausea, headache, diarrhea, and fatigue are common side effects of the drug. However, in clinical studies, most of the adverse reactions caused by roxacostat were mild, and there was no significant difference in the performance of adverse reactions between roxacostat users and placebo users.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

Summary

Renal anemia is the most common complication in patients with severe chronic renal failure, and its occurrence is directly related to the fact that the kidneys are damaged and can no longer secrete erythropoietin. The traditional treatment for renal anemia is the combination of erythropoietin and iron injections to improve anemia, but there are still limitations to this treatment and subcutaneous injections often cause unnecessary pain to patients.

Rosasta, which was launched in China in 2018, solves this set of problems well, as it can be administered orally only and does not require additional iron supplementation.

Is the safety of roxacostat, which has been hailed as a "boon" for patients with renal anemia, guaranteed?

The mechanism of action of Rosasta also ensures a more complete improvement of anemia by its ability to modulate erythropoietin gene transcription factors in a hypoxic environment to increase endogenous erythropoietin and to increase the activity of iron absorption.

Although the safety of roxacostat in terms of cardiovascular side effects has been questioned and the FDA has rejected the last application several times, the available study data show that roxacostat has been performing very well in terms of cardiovascular safety and patients can take it with confidence.

Reference.

[1] Yu YJ, Wu SJ, Xu JH, Kong XD. Short-term efficacy of roxacostat in 8 cases of renal anemia on maintenance hemodialysis. [J]. Chinese Journal of Integrated Chinese and Western Medicine and Nephrology.2020.21(09)

[2] Zhou, Chunhua. Application and efficacy analysis of roxacostat in the treatment of renal anemia in patients with chronic kidney disease. [J]. Chinese community physicians.2021.37(18)

[3] Jiang H, Yu H, Zhang JL, Bai L. Effectiveness and safety study of roxacostat in the treatment of renal anemia. [J]. Contemporary Medicine Series.2021.19(13)