Entresto generic development speeds up ahead of patent expiry

The patent for Entresto, generating sales of KRW 80 billion, is set to expire next year

Domestic companies are initiating generic development

Chong Kun Dan has developed a strategy to dominate the market with its ​Incrementally modified drug

Novartis 'Entresto'

Generic drug development for 'Entresto (sacubitril·valsartan, Novartis),' a blockbuster heart failure and hypertension treatment generating sales of KRW 80 billion, is escalating again in South Korea.

​As the expiration date of the key patent, scheduled for September 2027, approaches, approvals for bioequivalence (BE) trials aimed at generic development are continuing to emerge. However, due to the drug's formulation characteristics, high regulatory hurdles for approval are expected to present substantial difficulties for actual commercialization.

​On August 5, Sinil Pharmaceutical received approval of the bioequivalence trial plan from the Ministry of Food and Drug Safety (MFDS) for an Entresto generic candidate (development code: SIL1129).

​Earlier this year, Sinil Pharmaceutical gave up midway on challenging the originator patent ('Pharmaceutical combinations of angiotensin receptor antagonists and NEP inhibitors,' set to expire on September 21, 2027), which other domestic drugmakers had successfully bypassed. However, with the patent expiration date drawing near, the company appears to have rejoined generic development targeting a market launch immediately following patent expiry.

​In addition to Sinil Pharmaceutical, companies such as Huvist Pharma and HK inno.N have also secured BE trial approvals for Entresto generic authorization this year.

Challenges of "co-crystal complex" generic approvals…zero approvals since 2022

​Despite these bioequivalence challenges by generic developers, significant skepticism remains regarding whether generic products will ultimately reach the market. This is because deriving valid bioequivalence results and securing MFDS approval for Entresto generics is overwhelmingly more challenging compared to other medications.

​Entresto is not a simple physical combination drug, but a 'co-crystal complex' structure in which two active ingredients (sacubitril and valsartan) are bound at the molecular level like a single compound. Because its in vivo absorption and dissolution patterns are highly unusual, proving pharmacokinetic (PK) equivalence through conventional standard analytical methods is extremely difficult.

​In fact, since April 2022, approximately 20 Korean pharmaceutical companies submitted marketing authorization applications for Entresto generics to the MFDS following first-instance patent trial victories. However, not a single approval has been granted to date due to failure to overcome the MFDS's rigorous demands for quality analysis and equivalence data supplementation. Even after dismantling patent barriers, developers remain blocked by regulatory hurdles, leaving the likelihood of commercial development highly uncertain.

​Incrementally modified drugs dominate amid generic absence… securing market dominance via completed Phase 3 trials

​With generic drug development stagnated, analysis suggest that drugmakers pursuing the incrementally modified drug (IMD) track are taking the lead in the generic development race.

​Among those most highly secured MFDS product approvals first are developers of IMDs, including Chong Kun Dang (CKD-202A). Chong Kun Dang completely circumvented co-crystal issues by applying proprietary salt-modification technology instead of the originator's 'sodium salt co-crystal' structure. Furthermore, beyond simple bioequivalence, the company secured data reliability by completing Phase 3 clinical trials in actual patients.

​The single biggest weapon of the IMD track lies in its 'scope of indications.' While originator Entresto holds an indication for "essential hypertension", a market of 10 million patients, alongside chronic heart failure, simple generics face barriers to immediate entry into the hypertension indication due to remaining data exclusivity periods.

​Conversely, IMDs that have proven safety and efficacy through independent Phase 3 trials are not constrained by the originator's data protection requirements. Consequently, they can secure initial approval complete with the "hypertension indication," establishing a decisive foothold to monopolize this massive prescription market.

​Generic manufacturers are expected to initially pursue approval for the "chronic heart failure" indication, where data exclusivity has expired, before adding the hypertension indication at a later date. However, overcoming the MFDS's regulatory approval hurdles remains a prerequisite challenge.

​A pharmaceutical industry insider stated, "Due to analytical limitations inherent to the co-crystal formulation, Entresto generics are exceptionally difficult to pass the MFDS approval threshold," and added, "Ultimately, IMD developers that have resolved approval uncertainties by completing Phase 3 trials and securing the hypertension indication are highly likely to take control of the generic market."

​Meanwhile, Entresto recorded KRW 79.4 billion in outpatient prescription sales last year, according to UBIST. Market size continues to expand as the drug secured the hypertension indication in addition to its established heart failure indication.