There is a wider opportunity for BESREMi; Jakafi is not a direct competitor to Besremi, and there is uncertainty around Rusfertide’s uptake. BESREMi is expanding its horizon in the first-line treatment of Polycythemia vera; JAKAFI’s impressive growth in second-line treatment

The polycythemia vera treatment paradigm for patients has shifted significantly in the last few years. Previously, the polycythemia vera treatment landscape was dominated by generic medicines such as aspirin, hydroxyurea, interferons, and phlebotomy until the approval of JAKAFI in the US in 2014, a JAK inhibitor developed by Incyte as a second-line treatment for polycythemia vera patients. Another achievement in this space emerged in 2021 when PharmaEssentia’s BESREMi, interferon, was approved in the United States as a monotherapy in the first-line setting. This content is a walkthrough of the most potential competitors in the polycythemia vera treatment market.

Incyte has already entrenched JAKAFI as second-line therapy in polycythemia vera treatment. In addition to polycythemia vera, the drug has been approved for multiple indications, including myelofibrosis (MF), the first indication in JAKAFI’s label, and more recently, in acute and chronic GvHD. Incyte has been successful in proving its market dominance by exploring multiple indications. In terms of polycythemia vera, the drug is also approved in the ex-US, including the EU and Japan, with Novartis as a commercial partner outside the US.

Approval Timeline for JAKAFI

Until 3Q 2022, JAKAFI had generated a global revenue (including all indications) of approximately USD 3 billion, where Delveinsight estimates polycythemia vera’s contribution to be around 30%. Additionally, Incyte reported that approximately 30–35% of the prescriptions of JAKAFI were in polycythemia vera. This attributes to JAKAFI’s well-established therapeutic efficacy and traction in patients as a second-line therapy. Given its well-established therapeutic efficacy and traction in patients as a second-line polycythemia vera therapy, we believe that the drug will attain its peak in polycythemia vera treatment due to the impact of emerging therapies in the US by 2026, with a revenue of approximately USD 1.3 billion. Moreover, a further decline in its revenue is expected by approximately >50% by 2032 due to its patent expiry in 2028 and the entry of rusfertide in the US market.

Jakafi’s generics: Possible delay in the entry?

The patent expiration in mid-2028 might be the most significant obstacle to JAKAFI’s supremacy in the polycythemia vera treatment market. To address this, Incyte introduced the LIMBER (Leadership in MPNs and GVHD BEyond Ruxolitinib) life-cycle management initiative, which was meant to explore different monotherapy and combination methods to enhance and expand therapies for patients with MPNs and GVHD. The initiative currently focuses on developing a novel once-daily ruxolitinib formulation; ruxolitinib-based combinations with new targets such as PI3K, BET, and ALK2; and new treatment alternatives such as mutant CALR. If this LIMBER initiative receives a green signal, the company may be able to prolong its patent, delaying the arrival of generics into the market.

In the long term, it will be fascinating to observe how JAKAFI is prescribed after BESREMi enters the polycythemia vera treatment market, or maybe rusfertide, which might be a contender if approved.

PharmaEssentia’s new entrant, entry into NCCN guidelines, insights on pricing, and launches

PharmaEssentia’s BESREMi, a monopegylated proline interferon, is a new entrant for first and more advanced-line polycythemia vera patients without symptomatic splenomegaly; it is one of the first to be approved for the condition. BESREMi was approved in 4Q 2021 in the US; therefore, meaningful sales began from 2022. Before the launch in the US, the drug was approved in the EU since 2019 and has been available in Germany, France, and the UK since 2020, whereas in April 2022, the drug was approved for reimbursement by Italy’s National Health Service (SSN). We estimate the launch of BESREMi in Japan in 2023.

Approval, Agreements, and Patents Key Events of Besremi

BESREMi is a subcutaneous pen self-administered once every 2 weeks or monthly during long-term maintenance with a wholesale acquisition cost (WAC) of approximately USD 180,000 annually in the United States, whereas in certain EU countries, annual pricing ranges from USD 60,000–110,000. 

As the first approved medicine in the first line, it is expected to be the primary promotional voice in this market. Though interferon alfa-2b-based medications have been used to treat polycythemia vera for a long time, BESREMi differs from its predecessors due to its effectiveness, infrequent dose, and safety profile. More significantly, BESREMi’s long-term efficacy data over current SOC based on 7.5 years of evaluation is impressive and could provide strong support for the drug’s long-term treatment benefit over competing treatments. Because BESREMi’s label is broad (first and subsequent lines of therapy), PharmaEssentia has more leeway in positioning BESREMi in diverse therapeutic situations. Given BESREMi’s position upstream of JAKAFI in the NCCN recommendations, the drug is not a direct competitor for JAKAFI, but it can potentially hinder the progression of patients to JAKAFI usage, which might affect JAKAFI’s overall revenue. 

We expect approval of BESREMI in Japan in 2023 and its peak in the US by 2027 until other late-stage assets, such as rusfertide, establish themselves in the polycythemia vera treatment market. Based on our analysis, BESREMi could potentially have at least 5 years, if not more lead time, in the polycythemia vera treatment market before other entrants, such as rusfertide, create stability for themselves. Moreover, the patent for BESREMi is expected to expire in 2034, allowing generics to enter the polycythemia vera treatment market and hinting at a rapid decline in revenue.

BESREMi Roadmap

Protagonist therapeutics’ Rusfertide: Uncertainty in uptake even with promising results?

Rusfertide, under Phase III development, differs from the polycythemia vera drugs discussed above. It inhibits the production of hepcidin, an inflammatory protein produced in the liver that regulates iron absorption from the stomach and iron release to the bone marrow. Rusfertide in polycythemia vera Phase II study demonstrated very promising results in both safety and efficacy, and Phase III was initiated in 2022; if this study could replicate the results of Phase II, this drug could potentially have a substantial commercial opportunity. Rusfertide would initially be approved in both first and second-line settings for polycythemia vera patients inadequately treated by other drugs. 

Revenue Share Estimates by PV Therapies in 2032

Given its very different MoA compared to JAKAFI and BESREMi, rusfertide could become a viable alternative as an earlier line of therapy. Rusfertide might have the edge over current polycythemia vera treatment, considering that JAK inhibitors have side effects that can be fatal, and the data available till date shows that rusfertide has the ability to become the new standard of care as the drug substantially reduces the frequency of phlebotomy, which affects the quality of life.

The findings from Phase II REVIVE study showed that all participants were essentially phlebotomy-free, HCTs maintained at <45%, and ferritin normalized when rusfertide was added to their treatment, and this data provides support for the ongoing, randomized Phase III VERIFY trial, with 250 patients with polycythemia vera who require frequent phlebotomy.

Polycythemia Vera Emerging Therapies

Withdrawal of Breakthrough Therapy Designation (BTD)

Before the results were published, the US FDA slapped a full clinical hold in 2H 2021 after an animal study showed that mice developed benign and malignant skin tumors using the drug. Still, the hold was lifted soon after the company handed over individual patient clinical safety reports. This did not stop here; in 1Q 2022, the company received a letter from the FDA indicating the FDA’s intent to rescind Breakthrough Therapy Designation (BTD) for rusfertide in polycythemia vera treatment, following which the company voluntarily withdrew its BTD following correspondence with the FDA and based on the internal analysis of the relative utility of BTD for Phase III trials and beyond. DelveInsight estimates that rusfertide is expected to be launched by late 2024 in the US polycythemia vera treatment market. With BESREMI’s patent set to expire in 2034, rusfertide will have an edge in catering to the market share if no other potential emerging therapy enters the polycythemia vera treatment market.

Polycythemia Vera Market Size by Therapies in the 7MM

In a nutshell, the polycythemia vera treatment market over the next few years is expected to substantially change and experience growth, as it will be dominated by two already approved products, JAKAFI and BESREMi. In contrast, we also anticipate the launch of a third product, rusfertide, in the US market in the coming 2–3 years. Considering that the symptomatic cases of polycythemia vera are the ones that get diagnosed, around a moderate range of 60–70%, we expect the polycythemia vera treatment market to expand, especially as safer and more effective therapies enter the market. Apart from rusfertide, we also have other key players entering the polycythemia vera treatment market.

Polycythemia Vera Market Outlook