From CDMO Pharmaceutical Crisaborole First Generic Drug, Look at the Domestic PDE-4 Inhibitor R&D Development Layout

Recently, the NMPA official website showed that Zhejiang CDMO Pharmaceutical had submitted an application for the marketing application of crisaborole ointment as a generic drug (Category 4) and it was accepted by the Center for Drug Evaluation (CDE). Currently, only the original research pharmaceutical company Pfizer has approved for marketing of the crisaborole ointment in China, and no other company has been approved to produce crisaborole ointment generics. 

The Race for the First Generic Drug Crisaborole 

Crisaborole is a novel small-molecule, non-steroidal, non-hormonal phosphodiesterase 4 (PDE-4) inhibitor originally developed by Anacor. In 2016, Pfizer acquired Anacor for USD 5.2 billion, gaining access to crisaborole, etc. In the same year, crisaborole was approved by the FDA (brand name: Eucrisa) for the treatment of patients with mild to moderate atopic dermatitis (AD) aged 2 years and older. 

In China, crisaborole ointment was included in the Second Batch of Overseas New Drugs Urgently Needed in Clinical Settings in 2019. In July 2020, crisaborole was approved by the NMPA for marketing in China, and its indication is for the treatment of mild to moderate AD in patients aged 2 years and older, becoming the first non-steroidal PDE-4 inhibitor approved in China. In August 2023, crisaborole ointment obtained approval for a new indication, expanding its use to patients aged 3 months and above. 

Besides Pfizer's approved crisaborole ointment, no other domestic companies have approved for marketing. However, the core compound patent of crisaborole will expire in 2026. At present, many domestic pharmaceutical companies have submitted marketing applications for marketing of crisaborole ointment generics, including Nanjing Wanrong Jiancheng Pharmaceutical, Qilu Pharmaceutical, Hangzhou Solipharma, Zhejiang Gaozhi Pharmaceutical, Jiangxi Kerui Pharmaceutical, Jiangsu Wangao Pharmaceutical. It remains uncertain who will secure the first generic drug approval in the future. 

PDE-4 Inhibitor R&D Landscape in China 

Due to the huge potential market demand for AD treatment, this "profitable prospect" has spurred a wave of R&D for PDE-4 inhibitors in China. By inhibiting the degradation of intracellular cyclic adenosine monophosphate (cAMP) and increasing its levels within cells, PDE-4 inhibitors regulate the levels of proinflammatory cytokines to suppress inflammatory responses. They have significant clinical significance and value in the treatment of immune and inflammatory diseases, including AD and psoriasis. 

Currently, there are only two PDE-4 inhibitors approved for marketing in China: crisaborole by Pfizer and apremilast by Amgen (approved by the NMPA in 2021 for the treatment of moderate to severe plaque psoriasis). There are approximately more than ten PDE-4 inhibitors in clinical development stages in China. 

In June 2021, Nuance Pharma reached an agreement with Verona Pharma, with Nuance Pharma obtaining the exclusive rights to Verona Pharma's new drug dual PDE3/4 inhibitor drug, Ensifentrine (RPL554), which is currently under development. 

Ensifentrine's dual inhibitory mechanism allows it to possess both bronchodilatory and anti-inflammatory activities through a single compound. Additionally, Ensifentrine can activate the cystic fibrosis transmembrane conductance regulator (CFTR), which helps reduce mucus viscosity and improve mucosal ciliary clearance, thus offering potential applications in cystic fibrosis, asthma, and other respiratory diseases. 

In a Phase III study, the results showed that the change in the average FEV1 area under the curve (a lung function test indicator) from baseline to Week 12 in the Ensifentrine group was 94mL (P<0.0001), indicating that the study had reached its primary endpoint. 

In September 2021, Innovent Biologics and UNION Therapeutics jointly announced that they had reached an agreement regarding orismilast, UNION's lead candidate drug for the treatment of inflammatory skin diseases, a PDE-4 inhibitor currently in clinical Phase II. Under the agreement, Innovent will obtain exclusive rights for the research, development, and commercialization of orismilast in China. UNION will receive an upfront payment of USD 20 million and is entitled to receive cumulative milestone payments totaling up to USD 247 million. 

In a Phase IIa clinical research targeting atopic dermatitis, orismilast demonstrated potential best-in-class (BIC) qualities, showing superior anti-inflammatory effects and better tolerability through an innovative sustained release formulation. It is expected to address the unmet needs of patients with inflammatory skin diseases. 

In November 2022, Jumpcan Pharmaceutical and Newsoara jointly announced that they agreed to cooperate on the agreed indications such as a PDE-4 inhibitor and combination products owned by Newsoara in mainland China. Under the agreement, Jumpcan Pharmaceutical will pay an upfront payment of no more than RMB 180 million and development milestone payments of no more than USD 12.125 million, etc. 

In October 2023, Livzon and Lansson jointly announced the signing of a patent and technology transfer agreement in Greater China for the LS21031 developed by Lansson. LS21031 is an innovative and highly selective PDE-4 allosteric modulator R&D by Lansson, which was approved for clinical use in China in March 2023, with its indication being depression. 

According to the agreement, Livzon will obtain relevant technologies, while Lansson will receive an upfront payment of RMB 15 million, and can also receive a development milestone fee of no more than RMB 70 million and a sales mileage fee of RMB 80 million in the future. 

PDE-4 inhibitor, as a next-generation of drugs for the treatment of inflammatory diseases, has achieved outstanding clinical results. The research and investment boom in this field continues, both domestically and abroad. In addition, with some drug patents expiring, competition in the generics market is becoming increasingly fierce. In the future, facing the PDE-4 track will be a fierce battle. 

Primary reference material: 

1、 https://www.prnasia.com/story/321878-1.shtml.

2、Luelmo J, Gratacós J, Martínez-Losa M M, et al. A report of 4 years of experience of a multidisciplinary unit of psoriasis and psoriatic arthritis[J]. Reumatología Clínica (English Edition), 2014, 10(3): 141-146.

3、Torre Alonso JC,  et al. Expert recommendations for the use of apremilast in psoriatic arthritis. Reumatol Clin (Engl Ed). 2022 May 7:S2173-5743(22)00092-2. 

About the Author:

Xiaobin

Xiaobin holds a Master's degree in Pharmacy and currently work as a public health control staff. Navigating through the intricate and complex data each day and feeling a sense of insignificance of herself. While being happy to witness the golden time of the development of Chinese bio-pharmaceutical industry. Hope to learn and improve together with everyone.