Romidepsin

Dizal is running three different confirmatory trial options by the FDA, hoping to file its lymphoma candidate golidocitinib for an accelerated approval in the near future. Just as the FDA revisits two accelerated approvals in peripheral T cell lymphoma (PTCL), AstraZeneca spinout Dizal Pharmaceutical is charting its own path for a potential conditional nod in the blood cancer. The Chinese biotech has phase 2 tumor response data for its JAK1 inhibitor golidocitinib that, as CEO Xiaolin Zhang, Ph.D., pointed out, look better than readouts from existing therapies in previously treated PTCL. Specifically, 44.3% of 88 PTCL patients who had received median two lines of prior therapies responded to golidocitinib, according to updated data from part B of the JACKPOT8 trial presented at the American Society of Hematology annual meeting. These include 21 patients (23.9%) who achieved a complete response. The responses were durable, lasting more than 20 months at median as more than half of patients were still responding after a median follow-up of 12.5 months. Besides, 46 patients (52.3%) were still alive at the data cutoff, with a median overall survival of 19.4 months. In contrast, current standard treatments can only give this type of patient about six to eight months of survival benefit, Zhang noted during an interview with Fierce Biotech. Armed with the phase 2 data, Dizal is discussing with the FDA about filing for an accelerated approval, although Zhang declined to offer a timeline. But before a potential application, the company still needs to jump through a couple more hoops. Dizal is advancing golidocitinib at a volatile time for the PTCL space. In fall 2021, Bristol Myers Squibb pulled its PTCL treatment Istodax off the market after the HDAC inhibitor failed to outdo the traditional CHOP regimen in a confirmatory phase 3 trial in newly diagnosed patients. During an advisory committee meeting last month, the FDA questioned two PTCL drugs that have significant delays in producing confirmatory evidence for their accelerated approvals. The two meds are Acrotech Biopharma’s folate analog inhibitor Folotyn and HDAC inhibitor Beleodaq. In their single-arm trials in pretreated patients, both agents showed an overall response rate below 30% and a median duration of response shorter than 10 months.   RELATED: FDA's oncology office uses advisory committee to spotlight timely accelerated approval confirmation   After some major delays, Acrotech has finally formed a confirmatory trial agreement with the FDA to test the two drugs in a phase 3 trial in the front-line setting. The phase 2/3 study, which includes an initial optimal dose-finding part, kicked off in October, and the final readout is expected in 2030. Dizal was AstraZeneca’s China R&D center until a spinoff in 2017. The company had originally planned to immediately file golidocitinib for approval based on tumor response data but now has to face an FDA reality. To prevent delays in completing postmarketing studies, the agency recently started to require that a confirmatory trial be underway at the time of a cancer drug’s accelerated approval. Now Dizal is left thinking what that phase 3 program should look like. The company is running three different options by the FDA, Zhang said. It could conduct a front-line study following Acrotech’s example. But such a trial will take a long time, given the current median survival of first-line patients is close to five years. And recruitment for a rare disease like PTCL will be slow, Zhang said.  Dizal could conduct another randomized study in the relapsed or refractory setting. But that plan isn’t very cost-efficient because golidocitinib would stay in the same indication. Alternatively, Dizal is proposing a novel trial design that evaluates golidocitinib as a first-line maintenance treatment in patients who’ve responded to their initial treatment. Dizal has some initial data to support that approach. An early analysis of the phase 2 JACKPOT26 trial showed that among patients who had achieved complete response after first-line treatment, golidocitinib kept 86.7% in response after a median follow-up of 8.1 months. Among patients who had a partial response after first-line treatment, the drug induced complete response in a third of patients. The data were shared in an abstract, and more updated details will be included in a poster presentation Monday. In addition to the randomized trial design, the current efficacy data from JACKPOT8 only includes five patients enrolled outside of Asia. Two (40%) of these patients responded to golidocitinib. Based on the FDA’s guidance on diversity, Dizal later expanded the trial to include more U.S. and Australian patients. Data from those individuals will be shared with the FDA during future discussions about a new drug application, a Dizal spokesperson told Fierce Biotech. Chinese authorities in September granted priority review to the drug’s PTCL application. Dizal is discussing with many potential partners to commercialize golidocitinib in the U.S., Zhang said. “Probably it’s not going to be realistic to build a commercial [presence] in the States given that drug could be approved in the near future, and you need to have a good organization,” Zhang said. “So for this, a more reasonable plan is to collaborate with someone who has an established salesforce.” But Dizal hasn’t ruled out going solo. The company has another drug, sunvozertinib, which in August got Chinese approval for treating non-small cell lung cancer with EGFR exon20 mutations following chemotherapy. The U.S. regulatory path for sunvozertinib is clearer. Dizal plans to file for an FDA accelerated approval using a single-arm trial that it’s following until the second quarter of 2024, Zhang said. A proposed confirmatory trial testing the EGFR inhibitor as a monotherapy in the first-line setting has already enrolled over 50% of patients. If approved, that drug will compete with Johnson & Johnson’s bispecific antibody Rybrevant, as Takeda has decided to withdraw its small-molecule rival Exkivity from the U.S. market. Dizal is talking to Big Pharmas about partnering up on sunvozertinib as well, Zhang said.