On November 3, 2023 Dizal reported that it will have four presentations from its hematological oncology pipeline, including golidocitinib and DZD8586, at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (2023 ASH (Free ASH Whitepaper), San Diego) (Press release, Dizal Pharma, NOV 3, 2023, View Source [SID1234636939]). Its global multicenter pivotal study of golidocitinib (JACKPOT8 PARTB) has been selected for oral presentation.

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Golidocitinib

Golidocitinib is the first and only Janus kinase 1 (JAK1) selective inhibitor in the NDA stage for the treatment of r/r PTCL. Dizal will release the latest results from two clinical studies: the full analysis of the multinational pivotal study of golidocitinib (JACKPOT8 PARTB) in r/r PTCL and a phase 2 study evaluating golidocitinib as a maintenance therapy in patients with PTCL after first-line systemic therapy (JACKPOT26).

Golidocitinib monotherapy demonstrated superior efficacy and safety profile in the full analysis of the JACKPOT8 PARTB study, which was consistent with the preliminary findings presented at 2023 ASCO (Free ASCO Whitepaper). An IRC-assessed overall response rate (ORR) was 44.3%, nearly double the existing treatment options. The response was durable. The final data for duration of response (DOR), progression-free survival (PFS), as well as overall survival (OS) will be reported at the meeting.

Approximately 40% of patients with complete response and 80% of patients with partial response have disease relapse within 2 years following first-line standard therapy, and the prognosis of relapsed patients was typically poor. According to the results of phase 2 study of golidocitinib as maintenance therapy in patients with PTCL after first-line systemic therapy (JACKPOT26), golidocitinib showed manageable safety profile and promising efficacy in maintaining and enhancing tumor response in patients with PTCL post first-line therapies.

DZD8586

DZD8586 is a rationally designed, oral, non-covalent, LYN and BTK dual inhibitor with excellent blood-brain barrier (BBB) penetration. Dizal will report its preclinical data as well as the ongoing clinical study results in B-NHL.

While Bruton’s Tyrosine Kinase (BTK) inhibitors have been approved for the treatment of B-NHL, resistance can emerge due to various mechanisms, including acquired mutations at residue C481 of BTK and non BTK-driven mutations. Currently, there is no targeted therapy available to address both resistance mechanisms, highlighting an urgent need for a safe and effective treatment option for patients with r/r B-NHL.

Preclinical studies have shown that DZD8586 can overcome resistance mutations observed with approved covalent and non-covalent BTK inhibitors. DZD8586 has exhibited potent inhibition of cell growth by blocking both BTK-dependent and BTK-independent signaling pathways.

Key highlights of DZD8586 are as follows:

Potent inhibition of LYN and BTK, with good selectivity against other kinases.
Significant inhibitory effects on mutations at residue C481 of BTK, as well as BTK mutations associated with resistance to Pirtobrutinib (LOXO-305).
Potent cell growth inhibition observed in diffuse large B-cell lymphoma (DLBCL) cell lines.
Excellent BBB penetration, as evidenced by a CSF-to-plasma concentration ratio (Kpuu,CSF) greater than 1 in animal models, suggesting potential effectiveness in humans.
Currently, DZD8586 is conducting two global phase 1 studies (TAI-SHAN1 and TAI-SHAN5) for the treatment of r/r B-NHL. The preliminary results of the studies have shown encouraging pharmacokinetic (PK) properties, safety profile and antitumor efficacy. The pooled analysis results from these two studies will be presented for the first time at 2023 ASH (Free ASH Whitepaper).

Dizal’s Presentation at 2023 ASH (Free ASH Whitepaper)

Lead Author

Abstract Title

Presentation Details

Prof. Yuqin Song

Golidocitinib in Treating Refractory or Relapsed Peripheral T- Cell Lymphoma: Full Analysis of the Multinational Pivotal Study Results (JACKPOT8)

Abstract #305

Session Type: Oral

Oral Abstract Session

Date and Time: December 9, 2023, 5 PM PST

Location: Hall B

Prof. Jie Jin

Phase 2 Study of Golidocitinib, a JAK1 Selective Inhibitor, As Maintenance Therapy in Patients with Peripheral T Cell Lymphomas after First-Line Systemic Therapy (JACKPOT26)

Abstract #4430

Poster Session

Date and Time: December 11, 2023, 6 PM – 8 PM PST

Location: Hall G-H

Dr. Yu Bai

Preclinical Study of DZD8586, a Non-Covalent LYN/BTK Dual Inhibitor with Excellent BBB Penetration, for the Treatment of B-Cell Non-Hodgkin Lymphoma (B-NHL)

Abstract #2822

Poster Session

Date and Time: December 10, 2023, 6 PM – 8 PM PST

Location: Hall G-H

Prof. Yuqin Song

First Report of Phase 1 Studies of DZD8586, a BBB Penetrant LYN/BTK Dual Inhibitor, in Patients with B-Cell Non-Hodgkin Lymphoma (B-NHL)

Abstract #4465

Poster Session

Date and Time: December 11, 2023, 6 PM – 8 PM PST

Location: Hall G-H

About golidocitinib (DZD4205)

Golidocitinib is the first-in-class Janus kinase 1 (JAK1) only inhibitor currently being evaluated in a global, multicenter pivotal study (JACKPOT8 PARTB) in r/r PTCL. At the data cut-off date of February 16, 2023, Golidocitinib has demonstrated robust and durable anti-tumor activity, with an ORR of 44.3%. More than 50% of the patients with tumor remission achieved a complete response. The median relative dose intensity was 100%. Golidocitinib was granted Fast Track Designation by the U.S. FDA for the treatment of r/r PTCL in February 2022. In September 2023, the CDE accepted the NDA and granted the Priority Review status for the treatment of r/r PTCL. And the Phase I clinical data of golidocitinib for the treatment of r/r PTCL (JACKPOT8 PARTA) was published in Annals of Oncology (Impact Factor: 51.8).

About DZD8586

DZD8586 is an orally available, highly selective small molecule inhibitor to target both BTK-dependent and BTK-independent B-cell receptor (BCR) signaling pathways, with full blood-brain barrier penetration. Pre-clinical research revealed that DZD8586 demonstrated good safety profile and could effectively inhibit the growth of B-NHL cells. A healthy volunteer study of DZD8586 has been conducted to investigate the clinical safety and PK/PD correlation. Additionally, a global phase I/II study is ongoing to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor efficacy of DZD8586 in patients with r/r B-NHL. Preliminary results from the clinical trial suggest that DZD8586 exhibits favorable PK properties, good safety profile, and preliminary anti-tumor activity in patients with B-NHL.