Amgen and Celgene Submit NDA for Apremilast in China, a Clinically Urgent PDE4 Inhibitor Acquired for $13.4 Billion

On February 3, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) released its latest announcement, revealing that the new drug application (NDA) for apremilast tablets, jointly submitted by Amgen and Celgene, has been accepted. Publicly available information indicates that apremilast has been included in the first batch of the List of Overseas New Drugs Urgently Needed for Clinical Use in China. It is an oral, non-biologic therapeutic agent. The product was originally developed by Celgene, a subsidiary of Bristol-Myers Squibb (BMS). In August 2019, Amgen announced the acquisition of global rights to apremilast for up to $13.4 billion.

Source: CDE Official Website

Publicly available information indicates that apremilast is a novel oral small-molecule phosphodiesterase 4 (PDE4) inhibitor that exerts its therapeutic effect by dose-dependently inhibiting the release of tumor necrosis factor (TNF)-α from human synovial cells. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase and the predominant PDE isoform in inflammatory cells. Inhibition of PDE4 leads to elevated intracellular cAMP levels, which is believed to indirectly modulate the production of inflammatory mediators.

Apremilast was first approved for marketing in the United States in March 2014. Currently, its FDA-approved indications in the U.S. include: 1) adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy; 2) adult patients with active psoriatic arthritis; and 3) adult patients with oral ulcers associated with Behçet’s disease.

In August 2019, Amgen announced it would acquire Otezla (apremilast) for $13.4 billion, thereby providing a strong complement to its existing portfolio of innovative biologic therapies for inflammatory diseases. According to an earlier press release issued by Amgen, Otezla’s sales reached $1.6 billion in 2018, and with new indications and global expansion, the drug is projected to achieve average annual double-digit sales growth over the next five years.

According to the earlier public announcement by the Center for Drug Evaluation (CDE), apremilast features a novel mechanism of action and has been demonstrated in studies conducted outside China to be therapeutically effective and well tolerated.

In the treatment of patients with psoriasis, a Phase 3, multicenter, randomized, placebo-controlled clinical trial named ADVANCE demonstrated that apremilast met the primary endpoint in patients with mild-to-moderate plaque psoriasis. Compared with the placebo group, apremilast resulted in a statistically significant improvement in skin condition as assessed by the static Physician’s Global Assessment (sPGA) at Week 16. Results from another study, ESTEEM 1, showed that the proportion of patients achieving a 75% improvement in the Psoriasis Area and Severity Index (PASI-75) at Week 16 was significantly higher among those receiving apremilast than among those receiving placebo (33.1% vs. 5.3%).

Several clinical studies have previously been conducted on apremilast for the treatment of patients with psoriatic arthritis. Results from one study, named PALACE 1, showed that at 16 weeks, the proportions of patients achieving the American College of Rheumatology 20% improvement criteria (ACR20) by week 24 were 30.4%, 38.1%, and 19% in the apremilast 20 mg, apremilast 30 mg, and placebo groups, respectively. At 156 weeks, 65% and 68% of patients in the apremilast 20 mg and 30 mg groups, respectively, still achieved ACR20, while the proportions achieving PASI-75 were 35.8% and 31.9%, respectively, indicating that long-term treatment with apremilast continues to demonstrate favorable efficacy.

In the treatment of oral ulcers caused by Behçet's disease, results from a randomized, placebo-controlled, double-blind Phase 3 clinical trial named RELIEFTM showed that apremilast reduced oral ulcer pain, as measured by the Visual Analog Scale (VAS), by 42.7 points from baseline at Week 12 compared with the placebo group. At Week 12, the proportion of patients achieving complete resolution of oral ulcers (no oral ulcers) was 52.9% (vs. 22.3%).

Psoriasis is a chronic, relapsing, immune-mediated multisystem disorder. Moderate-to-severe psoriasis can significantly impair quality of life and even lead to disability. Conventional systemic therapies (such as methotrexate, acitretin, cyclosporine, and other agents) have limited efficacy and are associated with various potential toxicities.

Psoriatic arthritis is a disabling chronic disease with symptoms manifesting in multiple parts of the body. In patients with psoriatic arthritis, immune-mediated inflammation can lead to psoriasis-associated skin lesions, joint pain, fatigue, and stiffness. Despite advances in therapeutic options for this condition, many patients still do not achieve adequate symptom relief.

Behçet's disease is a rare, chronic, multisystem inflammatory disorder that is difficult to treat. It is associated with immune system abnormalities and vascular inflammation. Symptoms include recurrent oral and genital ulcers, skin lesions, uveitis, arthritis, and involvement of the blood vessels, central nervous system, and gastrointestinal tract. Oral ulcers are present in more than 98% of patients with Behçet's disease, significantly impacting their daily lives.

Congratulations on the acceptance of the marketing application for Apremilast in China. We hope that this product will be approved in China soon, so that more Chinese patients can benefit from it.

References

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Feb 3, 2021, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21#

[2] MAmgen To Acquire Otezla® For $13.4 Billion In Cash, Or Approximately $11.2 Billion Net Of Anticipated Future Cash Tax Benefits. received Aug, 26th from http://investors.amgen.com/news-releases/news-release-details/amgen-acquire-otezlar-134-billion-cash-or-approximately-112

[3] Sun Jie, Gong Chunyan. New drug for the treatment of plaque psoriasis and psoriatic arthritis—apremilast [J]. Chinese Journal of Dermatology, 2017(2).

[4] Cheng Gangying, Yang Yang, Liu Jue. Meta-analysis of the efficacy and safety of apremilast in the treatment of psoriatic arthritis [J]. Chinese Journal of Hospital Pharmacy, 2017, 37(20): 2065-2071.

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