Golidocitinib Shows Efficacy, Durability as Treatment for Aggressive Refractory, Relapsed Peripheral T-Cell Lymphoma

Xiaolin Zhang, PhD, Founder, CEO and Chairman of Dizal Pharmaceutical Co., Ltd and adjunct professor at Peking University, joins Pharmacy Times at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, to discuss golidocitinib an oral, highly selective Janus kinase 1 (JAK1) inhibitor that is showing promising results for relapsed or refractory peripheral T-cell lymphoma (r/r PTCL).

PT Staff: What important updates can you report on since golidocitinib first entered Dizal’s Oncology pipeline?

Xiaolin Zhang, PhD: Absolutely, yes. We—for the last couple of years (3 years or so—have made tremendous progress in terms of clinical development for the second year. Now, we have a complete dose escalation that we finally based on the the JACKPOT8 Part A study with fixed dose 250 mg as our (what we call) recommended phase 2 dose (RP2D) for the phase 2 study.

Now in the report for this year's ASCO, we release the first pivotal results of this study, with the intention to use the study results to support registration filing. Now this study is a global study with the patients from China, Korea, Australia, the United States, and some other countries—it is truly a multinational multicenter study, [and] the study results are very exciting.

Compared to the current available treatment, we feel that it has acquired improvement over the [current] treatment as a potentially very useful treatment option for patients with relapsed and refractory r/r PTCL. As you know, for PTCL patients, especially when they are r/r to the frontline treatment, the process is dismal. [So] the progression-free survival (PFS) for second-line treatment is less than 3 months. Survival is usually around 1 year or less. So we really need more effective and safe treatment for this group of patients.

Currently—after the frontline treatment— there's no approved second-line treatment. And there are a couple of drugs that are on the condition of approval by the USFDA available in the United States, namely chemotherapy drugs and histone deacetylase (HDAC) inhibitors. But for HDAC inhibitors, there were 2 available in the United States. Another one is romidepsin (Istodax; Bristol Myers Squibb). But, in a larger confirmatory study, it failed the first-line treatment so that one is withdrawn from market for the second-line treatment. So that means you have very few effective treatments available. That's why we're so excited that our data support that golidocitinib has that potential to provide another effective option for patients.

PT Staff: What are the mechanisms of action of a JAK1 inhibitor? How does this make it effective against relapsed or refractory peripheral T-cell lymphoma (r/r PTCL)?

Xiaolin Zhang, PhD: Right. A few years ago, we noticed through profiling that we have over 1000 tumor cell lines in our collection. And when we screen a compound for our JAK1 inhibitor, we found some cell lines (tumor cell lines) are extremely sensitive to our compound. And we then dug into this [and found] many of these cell lines are a T cell (lymphoma type) of cell. So we then further dug into it and found that many of them have the JAK-STAT (signal transducer and activator of transcription) pathway over-activation. And the suggestion was that this pathway is important for this disease.

As a as a startup company, we were all a bit cautious because no one is really doing the JAK1 inhibitor in for this disease. And there are 1 or 2 smaller-sized study, but there wasn't really a conclusive [result] because of small sample size. However, the more we looked into it, [the more] we were convinced that this pathway is important. And so we launched our first translational science studies and the data was very encouraging. And because of that, we got Fast Track Designation from FDA and we immediately jumped into this single-arm pivotal study. I mean, accelerate approval is only granted for novel new therapies that have demonstrated superior efficacy and safety over the current standard of care (SoC). And so our data, not only do we think has potential, [but] obviously the FDA thinks it is worthwhile to accelerate the development. And we will also put a lot of effort behind this during the whole pandemic period. During our global study, I can tell you that we had a lot to overcome, lots of new challenges. But, you know, we were happy with the results.

And as to the mechanism, we think there's 2 main mechanisms. One is that the compound directly hits the tumor cells. We know that the compound—with the dose that we used used—itself can directly kill the tumor cells. That clearly is 1 of the mechanisms. But we also noticed that some of the patients, about 50% of the patients, responded for a very long time. We were still following this group of patients, and about half of our responders are what we call complete responders, and they had a very long response time. We have patients from our study, now almost 4 years [later], who are still responding. That tells us that the mechanism probably is, in addition to directly killing the tumor cells, [that] we influence the immune environment and normalize some of the immune response—part of the mechanism as well. We have some preliminary results to support that hypothesis. But we, at this moment, need to create more clinical samples and to further study before we can publish it.