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Tucidinostat/Chidamide (Trade name in Mandarin :剋必達®, Trade name in English : Kepida®)

Overview Anti-cancer mechanism First indication Second indication

Tucidinostat new indications - for the treatment of relapsed/refractory peripheral T-cell lymphoma (R/R PTCL)

 

R/R PTCL
 

R/R PTCL is a rare disease, and according to the WHO classification in 2018, there are more than 20 subtypes. R/R PTCL subtypes are heterogeneous and disease progresses aggressively, and there is a lack of standard treatment drugs for many years. Treatment with conventional chemotherapy results in low response rate, poor tolerability, easy to relapse, and 5-year overall survival rate only about 25%.

The US FDA approved Adcetris (brentuximab vedotin) as first-line therapy for PTCL in combination with chemotherapy in 2018, and Adcetris is an ADC (Antibody-drug conjugate) drug. The trial was based on the CHOP chemotherapy regimen for the traditional treatment of PTCL as the control group, and Adcetris (substituted O) + CHP as the  experimental group.

The US FDA approved three new drugs for the treatment of R/R PTCL, including Pralatrexate (Folotyn®), Romidepsin (FK228, Istodax®) and Belinostat (PXD101, Beleodaq®) in 2009, 2011 and 2014, respectively. The NMPA approved Tucidinostat for the treatment of R/R PTCL in 2014 in China . The Ministry of Health, Labor and Welfare approved Tucidinostat for the treatment of R/R PTCL in 2021 in Japan.

At present, only Folotyn® has entered the Taiwan market for the treatment of R/R PTCL, and the clinical demand for effective and safe treatment drugs for patients with R/R PTCL in Taiwan has not been met.

 

Overall evaluation of the effectiveness of Tucidinostat in the treatment of R/R PTCL in pivotal trials in China and Japan


Pivotal clinical data in China
 

The primary endpoint of Tucidinostat clinical trial for the treatment of R/R PTCL is the objective response rate (ORR), which was used as the efficacy indicator in the other three international pivotal trials of the new drugs approved. In the pivotal phase II clinical trial of Tucidinostat, at a dose of 30 mg twice a week, the clinical investigators assessed the ORR to be 29.1% (23/79), 95% CI: 19.4%~40.4%. Tucidinostat trial in China was designed in accordance with the three international new drug pivotal clinical trials, in addition to the clinical investigators' evaluation of efficacy, an independent review committee (IRC) has been established to independently evaluate the ORR, the main efficacy indicator of the pivotal clinical trial. The ORR of the four new drugs in the treatment of R/R PTCL were 28%, 27%, 25% and 26%, respectively. Tucidinostat has similar ORR when compared with the other three international new drugs.

In addition to the ORR, the results of the Tucidinostat pivotal Phase II clinical trial showed that the 3-month duration of response rate (DORR) in the FAS population was 24.1% (19/79), much higher than Pralatrexate's 12% (13/109), indicating that Tucidinostat may have better efficacy for R/R PTCL than Pralatrexate. Tucidinostat was approved by China NMPA in December 2014.

 

Pivotal clinical data in Japan and South Korea

 

In pivotal clinical trials in Japan and South Korea with HBI-8000 (Tucidinostat) for the treatment of R/R PTCL, the primary endpoint was objective response rate (ORR), and the ORR evaluation by IOERC (Independent Overall Efficacy Review Committee) was 46%, and the disease control rate was 72%. Among them, the second largest subtype of PTCL, AITL, obtained an ORR of 88%. Tucidinostat was approved by the Ministry of Health, Labor and Welfare  on November 30, 2021 in Japan.

Benefit and Risk Assessment 
 

Tucidinostat is a subtype-selective HDAC inhibitor, and according to the comprehensive results of their respective pivotal clinical trials with R/R PTCL as indication, the comprehensive efficacy evaluation results show that Tucidinostat may have better efficacy (ORR 46% in Japan and South Korea) or at least the same efficacy (ORR 28% in China) than the other three international approved drugs in the world.
 

Convenience and Compliance 

 

Tucidinostat is orally administered twice per week; compared with the three intravenously administered new drugs marketed globally, it offers a more convenient administration route, which is expected to have a higher compliance. Even with oral administration, the incidence and severity of adverse events and the severe adverse events (SAE) with digestive system manifestations, such as diarrhea and nausea, were much lower than those of the three intravenously administered drugs. 

 

Tucidinostat for compassionate treatment and new drug application for new indication of R/R PTCL treatment in Taiwan 

 

In February 2020, Taiwan's TFDA approved Compassionate Therapy for the first time to use Tucidinostat (Taiwan trade name: Kepida®) 5 mg tablet manufactured by GNTbm in Taiwan for the treatment of R/R PTCL. GNTbm has provided compassionate therapy for more than 2 years free of charge, with a total of 36 patients showing treatment benefits.

Among these patients in Taiwan, the main disease subtypes of R/R PTCL are as follows: PTCL-NOS, AITL, NK/T Lymphoma, ALK-/ALK+ ALCL, MEITL, and ATL/L.

According to data from large-scale international studies, the median survival for R/R PTCL is only 5.8 months. Among the patients treated with compassionate therapy in Taiwan, many patients have been treated with Kepida® tablet for more than 1 year, showing significant efficacy with an ORR of about 45%, and safe and controllable adverse events.

At present, GNTbm has submitted new drug application for Tucidinostat for the treatment of relapsed/refractory peripheral T-cell lymphoma.