ACVR1 Inhibition With Pacritinib Leads to Anemia Improvement in MF

Red blood cells: © vipman4 - stock.adobe.com

Pacritinib (Vonjo), a JAK2/IRAK1 inhibitor, demonstrated anemia benefits among patients with cytopenic myelofibrosis (MF), according to an analysis of the phase 3 PERSIST-2 study (NCT02055781).¹

Compared with momelotinib (Ojjaara), a 4-fold higher potency and longer exposure time for A receptor, type 1 (ACVR1) inhibition in vitro was seen with pacritinib. The mean IC₅₀ of pacritinib 200 mg twice daily (BID) against ACVR1 was 16.7 nM vs a mean IC₅₀ of 52.5 nM with momelotinib based on 200 mg daily dosing.

These findings also contrast data of JAK2 inhibitors that do not inhibit ACVR1, including ruxolitinib (Jakafi) and fedratinib (Inrebic), which tend to worsen anemia. Ruxolitinib did not have any inhibitory activity against ACVR1, and fedratinib is not a potent ACVR1 inhibitor based on a mean IC₅₀ of 273.5 nM. This is similar to its Cmax of 275 nM for a 400 mg daily dose.

At the clinically recommended dose, pacritinib also correlated with a clinically meaningful and statistically significant improvement in transfusion independence (TI) in this patient population.

“Pacritinib’s inhibition of ACVR1 provides a strong rationale for its clinical benefit in patients with MF who are anemic. Additional studies are needed to further elucidate the mechanisms underlying this benefit, including the relative roles of IRAK1 and ACVR1 inhibition,” wrote study authors in findings published in Blood.

PERSIST-2 included patients with MF with platelet counts of ≤100 × 10⁹/L. Patients were randomly assigned to receive pacritinib 200 mg BID, which is the FDA-approved dose, pacritinib 400 mg once daily, or best available therapy (BAT).²

“The most important response [patients] had was the spleen volume response, which is an important mark for drug approval in myelofibrosis. In the treatment arm, 29% had a spleen volume reduction of 35% compared [with] BAT of 3%. Then looking at the total symptom score, this is one of the main indications why we initiate treatment for this patient population. The treatment arm had a 26% reduction in symptom score at week 24 compared [with] 9% in the BAT arm. With these fantastic findings, pacritinib received FDA approval in patients with platelet count less than 50,000/µL,” Ashwin Kishtagari, MD, assistant professor of medicine at Vanderbilt University Medical Center, previously told Targeted Oncology^TM.

In this analysis of PERSIST-2, patients treated with pacritinib 200 mg BID were compared with those treated with BAT, as well as the subgroup of patients treated with BAT who received erythroid supportive therapies, including erythropoiesis-stimulating agents, danazol, thalidomide or its analogs, and corticosteroids. Patients enrolled ≥12 weeks before study termination and those who were not transfusion-independent at baseline were included in the analysis.¹

A similar proportion of patients from each arm of the PERSIST-2 study were included in this analysis. Baseline characteristics were comparable between these groups. In the pacritinib vs BAT arms, the median age of patients was 67 (range,29-85) years vs 70 (range, 50-83), 16 (39%) and 17 (40%) were female, 34 (83%) and 27 (63%) had primary MF, and 18 (44%) and 19 (44%) were DIPSS high-risk. The median time since MF diagnosis in the pacritinib arm was 2.5 years and 2.9 years in the BAT arm, 23 (56%) vs 25 (58%) received a prior JAK2 inhibitor, 26 (63%) vs 25 (58%) had grade 3 bone marrow fibrosis, and 35 vs 34 had a JAK2V617F mutation.

Pacritinib also demonstrated inhibitory activity against ACVR1 based on inhibition of both STAT5 and SMAD1/5/9 phosphorylation in HepG2 liver cells after BMP6 stimulation. Looking at SMAD phosphorylation and hepcidin expression, while all JAK inhibitors reduced HAMP messenger RNA expression in BMP6-stimulated HepG2 cells, pacritinib and momelotinib showed the most potent reductions vs ruxolitinib and fedratinib. Expression was reduced to levels below those seen in control cells in the absence of BMP6 stimulation using pacritinib or momelotinib.

In PERSIST-2, 106 and 98 patients were treated with pacritinib 200 mg BID and BAT, respectively, and 41 and 43 were not transfusion independent at baseline based on Gale criteria. A significantly greater proportion of these patients achieved TI on pacritinib vs those treated with BAT at 37% vs 7% (P =.001). Additionally, significantly more patients had a ≥50% reduction in transfusion burden (49% v 9%; P <.0001), showing the anemia benefit of pacritinib and how it may be a function of potent ACVR1 inhibition.

Moreover, the rates of overall survival among patients given pacritinib vs BAT were similar over the first 12 weeks of study follow-up. However, results were subsequently diverged with a trend toward improved survival for patients given pacritinib (HR, 0.61; 95% CI, 0.22-1.68). After adjustment for baseline red blood cell count transfusion rate, the trend continued (HR, 0.64; 95% CI, 0.23-1.76).

“Pacritinib’s potent inhibition of ACVR1 and hepcidin production in conjunction with its anemia benefit support the hypothesis that ACVR1 is an important drug target for patients with cytopenic MF. Further studies are warranted to confirm that the TI benefit seen with pacritinib results from ACVR1 inhibition in patients with MF and whether dual inhibition of ACVR1 and IRAK1 could act synergistically to ameliorate anemia,” concluded the study authors.

REFERENCES

1. Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023;7(19):5835-5842. doi:10.1182/bloodadvances.2023010151

2. CTI BioPharma announces FDA accelerated approval of VONJO™ (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed November 27, 2023. https://bit.ly/3vsDPsO