The Past and Present of ‘Miraculous Medicine’ Roxadustat

Roxadustat is a domestically produced Class 1 innovative drug originating from the United States. It was jointly developed by FibroGen (China) and AstraZeneca for clinical trials in China and was approved for marketing in December 2018. It was commercially launched in July 2019, achieved sales of over 1 billion yuan in 2021, and broke through 2 billion yuan in 2023. Since 2020, it has established itself as the leading brand in the treatment of anemia in patients with chronic kidney disease. As a chemical drug in the non-oncology field, such remarkable performance is unprecedented, and it is not an exaggeration to call it a “miraculous medicine.”

So, what kind of magic has given birth to this “miraculous medicine”?

Let’s trace back to its origins and explore its past and present.

The “Nobel Prize” mechanism, a lineage of excellence

Roxadustat is a first-in-class innovative drug, with its innovative mechanism being the hypoxia-inducible factor prolyl hydroxylase inhibitor. In hindsight, the three scientists who discovered the mechanism of action of Roxadustat were awarded the Nobel Prize in Physiology or Medicine in 2019, one of whom, William Kaelin, has long served as the chairman of the Scientific Advisory Board of FibroGen in the United States. With the endorsement of the “Nobel Prize,” Roxadustat, as a first-in-class innovative drug, can be said to be of noble origin and truly deserving of its name.

FibroGen in the United States has developed a relatively mature prolyl hydroxylase inhibitor (PHI) platform technology since the late 1990s, but at that time their research direction was anti-tissue fibrosis, not anemia. FibroGen and William Kaelin established contact in 2001. By chance, internal researchers at FibroGen observed through experiments that their experimental drugs might have the potential to treat anemia, so they adjusted their research direction to the field of anemia. They quickly found some candidate compounds, and then identified the preferred and second-choice drugs with ideal development characteristics. After continuous development and optimization, they gradually evolved into the compound known as FG-4592, which is Roxadustat. In 2006 and 2013, FibroGen successfully completed two very successful licensing deals with Astellas and AstraZeneca, respectively.

On April 28, 2006, FibroGen announced an exclusive licensing agreement with Astellas for the development and sale of the hypoxia-inducible factor prolyl hydroxylase inhibitors (FG-2216 and FG-4592) that had already begun human trials for the treatment of anemia in Europe, the Commonwealth of Independent States, the Middle East, and South Africa. According to the agreement, Astellas was to pay a $300 million upfront payment, with an additional $465 million in milestone payments based on the progress of drug development. If Roxadustat’s sales in the licensed area met expectations after 2010, FibroGen would receive more than $2 billion in revenue over the next 10-15 years. In addition, Astellas would also purchase $50 million worth of FibroGen’s shares.

On July 31, 2013, FibroGen announced a strategic agreement with AstraZeneca for the co-development and commercialization of FG-4592, with the licensed area including the United States, China, and other areas outside of Astellas’ licensed area. AstraZeneca will pay FibroGen a $350 million upfront payment, with an additional $465 million in milestone payments based on the progress of drug development. FibroGen also has the right to receive a licensing fee of no less than 20% of sales. In the Chinese market, the two companies will cooperate in commercial activities, with FibroGen responsible for clinical trials, registration affairs, production, and medical affairs, and AstraZeneca responsible for promotional activities and commercial distribution.

Foreseeing the future, landing in China

Before Roxadustat, almost all foreign pharmaceutical companies were accustomed to launching innovative drugs in developed countries or regions such as the United States first, and then applying to enter the Chinese market as imported drugs. For this innovative drug, FibroGen chose a different path. About 30% of FibroGen’s employees come from China, most of whom are R&D personnel, including core R&D personnel who played a key role in the development of Roxadustat. The founder and president, Mr. Tom Neff, with his keen business insight and forward-looking international perspective, has been paying continuous attention to and has a profound understanding of China. He believes that as China’s economic level improves, people’s demands for a healthy life and medical service standards will also increase. At the same time, the number of anemia patients with chronic kidney disease in China is large, and the rate of achieving anemia treatment is generally low. Roxadustat will be a drug urgently needed in China’s clinical practice. An innovative drug like Roxadustat is expected to gain a place in China’s pharmaceutical industry.

Against this backdrop, FibroGen obtained approval to conduct clinical trials of Roxadustat in China in 2010, striving to launch Roxadustat in China and globally simultaneously.

A Key Leap, From Carp to Dragon

During the Phase I and Phase II clinical trials of Roxadustat, it was still an imported drug, and the applicant, FibroGen from the United States, had not yet established a subsidiary in China. If it had continued on this path, Roxadustat would have been just another innovative imported drug. However, at the end of 2011, there was a significant turn of events when FibroGen invested in the establishment of FibroGen (China) Pharmaceutical Technology Development Co., Ltd., as the entity to implement the Roxadustat project in China. By the time Roxadustat reached Phase III clinical trials, it had undergone a transformation and obtained the status of a domestic Class 1.1 new drug (that is, a Class 1 innovative drug after the reform of the chemical drug registration classification), thus embarking on the path to become “the first-ever first-in-class drug with China as the first approval country in history.”

Riding the Trend of Pharmaceutical Innovation，Creating a “Three Firsts” History

The new era of pharmaceutical innovation reform began in 2015, and Roxadustat also ushered in a beautiful time after its “change of attire.” The Phase III clinical trial was approved in August 2015, and even received support from the national “Major New Drug Creation” special science and technology project twice in 2016 and 2017. Finally, in December 2018, it was approved for marketing, truly becoming “the first-ever first-in-class drug with China as the first approval country in history.” Since Roxadustat only completed clinical transformation in China, it cannot be considered an original result developed locally in China. Although this record-breaking achievement is slightly less impressive, from the history of drug registration, before Roxadustat, Chinese domestic pharmaceutical companies indeed had not marketed any first-in-class drugs. The “me-too” products of follow-up innovation were already the best innovative results that could be presented under the historical conditions at that time, and all the first-in-class drugs that best represent original innovation results all came from multinational pharmaceutical companies.

The Path to Commercial Launch，The Delayed Half-Year

According to the official announcement on the website of the National Medical Products Administration, Roxadustat was approved for marketing on December 18, 2018. However, it is peculiar that it was not until eight months later, in mid-July 2019, that Roxadustat began to be shipped from the factory and officially launched commercially. This is an unusual occurrence. Generally speaking, time is money, and pharmaceutical companies will do their utmost to start selling their products at the fastest speed after approval for marketing. On the one hand, this can benefit patients as soon as possible, and on the other hand, it allows the company to generate revenue quickly. By today’s standards, achieving official commercial launch within two weeks after drug approval is a basic operation. Even in the market environment of 2019, pharmaceutical companies were generally able to achieve official commercial launch within one to two months after product approval. However, Roxadustat took an astonishing eight months after approval to deliver the product to patients. In the fiercely competitive Chinese market, such a pace is indeed a bit hard to believe.

Clinical Data Controversy，Dreams Shattered in the U.S. Market

Roxadustat was smoothly approved for marketing in China and made significant progress on the path to commercialization, but it faced a bumpy road in the United States, eventually ending in a disappointing outcome.

On May 10, 2019, AstraZeneca and FibroGen announced that a retrospective analysis of the safety data from the Phase III clinical trial of Roxadustat showed positive results. However, oddly enough, after this “good news” was released, FibroGen’s stock price plummeted by more than 20%. The reason was that some restrictive statements in the announcement confused investors, such as “We believe there is no clinically meaningful difference in risk issues,” which could be interpreted as Roxadustat’s safety endpoint data being less favorable than that of Aflibercept. In a conference call with investors, then-CEO of FibroGen, Thomas Neff, said that “non-inferiority” is a strict statistical method to assess whether two drugs are equally safe, and the company and the FDA had not yet reached a consensus on this. This statement led to speculation that future analysis might find that Roxadustat might not be as safe as believed.

Later, then-CEO of FibroGen, Thomas Neff, suddenly passed away in August 2019, and the then-chairman of the board of directors served as the interim CEO. Despite some setbacks, FibroGen continued to advance the New Drug Application (NDA) for Roxadustat in the United States.

On December 23, 2019, FibroGen announced that it had submitted the NDA for Roxadustat to the FDA.

On February 11, 2020, FibroGen announced that the FDA had accepted the NDA for Roxadustat and set the Prescription Drug User Fee Act date (PDUFA date, equivalent to the drug’s approval and marketing date) for December 20, 2020.

On December 18, 2020, the fate of Roxadustat took its first turn when the FDA unexpectedly requested further clarification of the clinical data analysis to complete the review of the NDA for Roxadustat, setting a new PDUFA date for March 20, 2021.

However, on March 1, 2021, the FDA further requested a meeting of the Advisory Committee to review the NDA for Roxadustat, dealing another blow to the drug.

What was even more astonishing was that on April 6, 2021, FibroGen voluntarily stated that it had “artificially modified the standard for new safety data of Roxadustat to make the data look better than the actual situation.” This action was interpreted by outsiders as “tampering” or “manipulating” clinical data. In subsequent internal FDA reviews, more safety issues were found, including increased risk of death, thrombosis, and severe infections. These negative news again cast a shadow over the marketing of Roxadustat.

Despite the positive opinion on the approval of the NDA for Roxadustat issued by the European Union on June 25, 2021, this good fortune did not extend to the United States.

On July 15, 2021, the FDA’s Cardiovascular and Renal Drugs Advisory Committee held a voting meeting on the marketing application of Roxadustat. At the meeting, the committee voted against the marketing application of Roxadustat, with a result of 13 in favor and 2 against, making the hope for Roxadustat’s marketing in the United States very slim.

On August 11, 2021, the second shoe dropped. Based on the recommendations of the Advisory Committee, the FDA rejected Roxadustat for safety reasons and issued a Complete Response Letter to FibroGen, requiring it to conduct another clinical trial on safety before reconsidering the review of the NDA for Roxadustat.

After the NDA for Roxadustat was rejected by the FDA, it also experienced a failure in the Phase III clinical trial for anemia in patients with myelodysplastic syndromes (MDS). Finally, on February 26, 2024, AstraZeneca announced the return of the commercial rights for Roxadustat in the United States and other regions to FibroGen, retaining only the rights in the Chinese and Korean markets where it has been approved for marketing.

Inclusion in the Medical Insurance Catalogue Three Times，A Unique Success in the Chinese Market

In 2019, despite the delay in the official commercial launch of Roxadustat for half a year and unimpressive sales data for that period, the highlight was its successful negotiation into the 2019 medical insurance catalogue, laying a solid foundation for sales over the next two years. As expected, Roxadustat quickly increased its sales volume in 2020, achieving nearly 500 million yuan in sales. In 2021, it made even greater progress, with sales reaching 1.2 billion yuan, and successfully renewed its contract in the year-end medical insurance negotiations. Even with the renewal negotiation price in the medical insurance catalogue being nearly halved, Roxadustat still achieved sales of 1.4 billion yuan in 2022. In 2023, Roxadustat continued to make significant progress in the Chinese market, with sales reaching 2 billion yuan, and once again achieved good results in the year-end medical insurance renewal negotiations, not only successfully renewing the contract but also maintaining a relatively stable price.

In contrast, Astellas Pharma holds the rights to market Roxadustat in Japan, the European Union, and several other markets including the Commonwealth of Independent States, the Middle East, and South Africa, and has not encountered a “black swan” event like the FDA’s rejection. However, the performance of Roxadustat in the Japanese and European markets is unremarkable. According to Astellas Pharma’s annual report, the annual sales of Roxadustat in 2020, 2021, and 2022 were only 1.1 billion yen, 2.6 billion yen, and 3.2 billion yen, respectively. Perhaps due to the market performance of Roxadustat being far below expectations, after the new CEO of Astellas Pharma took office, an impairment of the Roxadustat asset was made in April 2023, with a loss of about 340 million US dollars.

Approaching the “Patent Cliff”，A Sharp Turn of Events

Beautiful things, like fragile clouds and brittle glass, always seem to have an inescapable destiny of frailty. The same is true for Roxadustat. Its success in the Chinese market is entirely due to its monopoly status as an exclusive product, which is entirely based on the short-lived and fragile drug patents.

The core of Roxadustat’s drug patents is its compound patent, which is the key to maintaining a patent barrier and a monopoly market position.

There are three compound patents for Roxadustat, one registered under the name of FibroGen (China), and the other two registered under the name of FibroGen in the United States. The expiration date for these three compound patents is June 4, 2024, and they have now completely expired. In addition to the compound patents, there are crystal form patents and formulation patents. In the pharmaceutical industry, these two types of patents are generally considered to be relatively easy for generic drug companies to circumvent and are not effective in forming a patent barrier. Moreover, the three crystal form patents for Roxadustat were declared invalid in August 2022. In September 2023, FibroGen (China) obtained a patent authorization for a Roxadustat drug combination, but the effectiveness of this new patent in maintaining its patent barrier remains to be observed.

In fact, since May 22, 2023, with about one year left in the protection period of the Roxadustat compound patent, the National Medical Products Administration’s Center for Drug Evaluation has begun to officially accept applications for the marketing of generic Roxadustat. As of the end of June 2024, 24 generic drug companies have submitted applications for the marketing of generic Roxadustat to the Center for Drug Evaluation and have been accepted, and the review and approval procedures are also progressing normally. Among them, the Roxadustat capsule generic drug of ShiYao Group was approved for marketing on July 5, 2024.

Like all innovative drugs, once the patent rights for Roxadustat expire, generic drugs will be approved for marketing and will capture market share at very low prices. After the number of generic drugs reaches more than three, volume-based procurement will be triggered, and the innovative drug will have to compete more fiercely with generic drugs. In the fierce competition in the Chinese market, the prospects for Roxadustat may be bleak, and its glory may be no longer. The sales target of 2.5-3 billion yuan expected to be achieved in 2024 is also very likely to become the swan song of this “miraculous drug” before it exits the stage.

Epilogue

Since the initiation of Phase I clinical trials in China in 2010, Roxadustat has experienced the ups and downs of China’s pharmaceutical innovation journey for over a decade. Coupled with its tumultuous fate in overseas markets, it has reached the summit and also plummeted to the abyss. Its overall performance is commendable, yet there are aspects that evoke a sigh of regret. It is also a drop in the ocean of China’s pharmaceutical innovation process, reflecting the joys and sorrows within the journey of medical innovation.

【Editor’s Note】This is quick translation of a Chinese article published on DrugTimes. To read the original article, please click here. All comments are highly welcome. Many thanks!