Major hurdles still remain for Entresto generics

Entresto posted KRW 79.4 billion in prescriptions last year, up 2.5-fold in four years

Patent risk resolved, but zero generic approvals to date

Co-crystal complex structure remains a regulatory barrier

Patent risks surrounding Novartis’ heart failure drug Entresto (sacubitril/valsartan) have effectively been resolved with the recent Supreme Court ruling. Although patent disputes concluded in favor of generic companies and the patent barriers have now been lifted, the launch of generic versions remains far from straightforward.

Now firmly established as a blockbuster with annual prescriptions of nearly KRW 80 billion, Entresto presents a structural challenge in which generic manufacturers have successfully defeated the patents but are still unable to enter the market due to approval delays.

Entresto’s repeated surge in prescription sales drives the generic companies’ patent challenges

According to the pharmaceutical market research firm UBIST on the 20th, Entresto recorded KRW 79.4 billion in outpatient prescriptions last year.

Entresto rapidly expanded its prescription sales since its launch in 2018. After recording KRW 6.3 billion in prescription sales in its first year (2018), it surged to KRW 15 billion in 2019 and KRW 22.4 billion in 2020.

This rapid expansion of its presence in the heart failure treatment market led to patent challenges from generic companies. Starting with Elyson Pharm in January 2021, over 20 companies filed comprehensive patent invalidation lawsuits against Entresto's five patents.

Novartis ‘Entresto’ annual prescription sales (Unit: KRW billion, Source: UBIST)

The generics companies' judgment ultimately proved correct. Over the past five years of patent disputes (2021-2025), Entresto's prescription sales surged 2.5-fold in just four years, from KRW 32.4 billion in 2021 to KRW 79.4 billion last year.

Not a simple combination drug but a ‘co-crystal complex’... Generic approvals remain at ‘0’

Despite the favorable court ruling, generic launches are unlikely anytime soon. The regulatory approval for generic products is holding things back.

To date, there have been zero approvals for Entresto generics. More than 10 patent challengers filed marketing authorization applications between April 2022 and July 2023, based on their first-instance patent victories.

However, nearly three years later, there is still no news of Entresto's generic product approvals. Considering that generic product approvals typically take about a year and a half after application, this is considered unusual.

According to industry sources, the Ministry of Food and Drug Safety (MFDS) has requested multiple rounds of supplementary data. The root cause lies in Entresto’s unique solid-state structure. The pharmaceutical industry points to Entresto's unique crystalline structure as the reason behind these supplementary requests. Entresto works by having its two components, sacubitril and valsartan, act on cardiac neurohormones via separate pathways. What is unique is that these two components form a single crystalline structure in a ‘co-crystal’ form.

Most fixed-dose combinations consist of two separate crystalline APIs physically blended together. In contrast, a cocrystal involves two or more components bonded at the molecular level like a single compound, exhibiting properties similar to a single compound, right up until absorption in the body. For this reason, the industry describes Entresto not as a simple ‘combination drug’ but as a molecular ‘complex’ with its own distinct characteristics.

The problem is that there are almost no precedents for approving drugs in this co-crystal form. Entresto is known to be the only drug approved as an API-API co-crystal complex, not only in Korea but also in the US and Europe. There are also no known cases worldwide of generic approval for co-crystal complex drugs. This is where the MFDS's dilemma begins. It is reported that they are struggling to find an appropriate analytical method for generic approval. The differing physicochemical properties of co-crystal structures compared to conventional compounds are cited as a burden in the approval review process, making it difficult to apply existing analytical methods directly.

Approval Variables remain despite supreme court bictory... early launch may be delayed

Entresto has five patents listed in Korea’s patent registry. Following the Supreme Court’s rulings, all five patent barriers have effectively been removed. From a patent perspective, generic manufacturers are now free to launch their products once marketing authorization is granted.

However, regulatory approval has emerged as a new bottleneck. Despite the elimination of patent risk, prolonged MFDS review has made it difficult for generic firms to predict their market entry timelines.

The pharmaceutical industry interprets this as Entresto's structural uniqueness, creating a new barrier at the approval stage. This means that even with a blockbuster market worth KRW 80 billion annually within reach, a regulatory hurdle separate from the patent dispute remains. Ultimately, the timing of generic approval and actual launch will depend on the regulatory authority's judgment and review direction.