EMA Grants Orphan Drug Designation to Pimicotinib for Inoperable TGCT

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The European Medicines Agency (EMA) has granted orphan drug designation to pimicotinib (ABSK021) for use as a potential therapeutic option in patients with inoperable tenosynovial giant cell tumor (TGCT), according to an announcement from Abbisko Therapeutics.¹

The safety, tolerability, pharmacokinetics (PK), and early efficacy of the highly selective small molecule CSF-1R inhibitor is under investigation in patients with advanced solid tumors as part of a phase 1 study (NCT04192344).²

Earlier data from the study indicated that when the agent was given at 50 mg once daily (n = 32), it led to an objective response rate (ORR) of 87.5% by independent review committee (IRC) assessment and RECIST v1.1 criteria in evaluable patients with TGCT; this included 3 complete responses (CRs).³ In the cohort of patients with TGCT who received pimicotinib at 25 mg once daily (n = 12), the ORR was 66.7%; in this group, 2 CRs were achieved.

Updated data presented at the 2023 Connective Tissue Oncology Society Annual Meeting revealed ORRs of 87.5% and 66.7% in the 50-mg (n = 44) and 25-mg (n = 12) cohorts, respectively. Of the patients who experienced a partial response (PR) within the first 6 months of treatment and who had follow-up data available (n = 16), 93.8% continued to respond. Of the patients who achieved stable disease within the first 6 months and who had available follow-up data, 80% improved to a PR after 6 months. In both cohorts, the median duration of response (DOR) had not yet been reached.

“Following the successful orphan drug designation granted by the EMA, the product will benefit from incentives, including protocol assistance, fee reductions, procedural advantages for market authorization, and market exclusivity, and so on,” according to a press release issued by Abbisko Therapeutics.¹ “In addition to the above-mentioned benefits within the European Union, member states may also offer specific stimuli for orphan drugs.”

For the phase 1 study, patients needed to have an ECOG performance status ranging from 0 to 1, a life expectancy of at least 3 months, and acceptable organ and bone marrow function.² Specifically, those with TGCT included in the trial needed to have a diagnosis that was histologically confirmed by a pathologist at the treating institution or a central pathologist, and where resection would be linked with potentially worsened functional limitation or severe morbidity. They also needed to have measurable disease by RECIST v1.1 criteria.

Key exclusion criteria included having a known additional malignancy that is progressing or in need of active treatment within 3 years of study treatment initiation; prior receipt of anticancer therapy such as chemotherapy, radiation, endocrine therapy, or targeted therapy; having undergone surgery within 4 weeks of study treatment initiation; and having any toxicities from prior anticancer therapy that have not resolved to grade 2 or less severity; among others.

The study utilized 3+3 dose-escalation rules, which leveraged safety findings until a maximum tolerated dose had been determined or a recommended dose for expansion. Pimicotinib was given at a starting dose of 25 mg once daily. For each dose level, the patient received the agent on day -3; this was followed by a 3-day-off run-in period to evaluate the safety and PK. Patients then continually received the agent once daily in repeated 28-day treatment cycles.

The primary outcome measures of the research were to examine the incidence of dose-limiting toxicities and the incidence and severity of adverse effects (AEs). Secondary measures included progression-free survival, DOR, disease control rate, the peak plasma concentration of a drug following administration, time to reach Cmax, bioavailability, and the time required for the concentration of the agent to reach half of its original value.

In terms of safety, pimicotinib was found to be well tolerated. With a median treatment duration of 12.2 months and a maximum duration of 17.5 months, 83.9% had remained on the agent.³ Most treatment-emergent AEs (TEAEs) were grade 1 or 2.

The most common TEAEs experienced by at least 15% of patients included increased lactate dehydrogenase (80.4%), increased creatinine phosphokinase (67.9%), increased α-hydroxybutyrate dehydrogenase (62.5%), increased aspartate aminotransferase (42.9%), increased amylase (30.4%), increased alanine aminotransferase (25.0%), pruritus (21.4%), rash (19.6%), face edema (19.6%), and dyslipidemia (19.6%).

In January 2023, the FDA granted breakthrough therapy designation to pimicotinib for the treatment of patients with TGCT who were not amenable for surgery.⁴

In the randomized, double-blind, placebo-controlled, multicenter phase 3 MANEUVER study (NCT05804045), the safety and efficacy of pimicotinib will be further evaluated in patients with TGCT.5 The trial is currently recruiting.

References

1. Abbisko Therapeutic announces that EMA has granted orphan drug designation for its CSF-1R inhibitor pimicotinib (ABSK021). News release. Abbisko Therapeutics. January 9, 2024. Accessed January 15, 2024. https://www.abbisko.com/newsDetail/167.html
2. A study to assess the safety, tolerability, and pharmacokinetics of ABSK-021 in patients with advanced solid tumor. ClinicalTrials.gov. Updated October 18, 2023. Accessed January 15, 2024. https://clinicaltrials.gov/study/NCT04192344
3. Abbisko presented two clinical updates of pimicotinib (ABSK021) at the 2023 Connective Tissue Oncology Society (CTOS) Annual Meeting. News release. Abbisko Therapeutics. November 3, 2023. Accessed January 15, 2024. https://abbisko.com/newsDetail/157.html
4. Abbisko Therapeutics announces that US FDA has granted breakthrough therapy designation for its CSF-1R inhibitor pimicotinib (ABSK021). News release. Abbisko Therapeutics. January 29, 2022. Accessed January 15, 2024. https://abbisko.com/newsDetail/127.html
5. Study of pimicotinib (ABSK021) for tenosynovial giant cell tumor (MANEUVER). ClinicalTrials.gov. Updated January 5, 2024. Accessed January 15, 2024. https://clinicaltrials.gov/study/NCT05804045