FDA Approves Pacritinib for Intermediate- or High-Risk Myelofibrosis With Severe Thrombocytopenia

The FDA has granted an accelerated approval to pacritinib (Vonjo) for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹/L.¹

Pacritinib previously demonstrated efficacy in the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials, as well as findings from the phase 2 PAC203 trial.² Patients enrolled to PERSIST-2 received pacritinib at a twice-daily dose of 200 mg. Of these patients, 29% experienced a reduction in spleen volume of at least 30% vs 3% of those who received best available therapy (BAT), which included ruxolitinib (Jakafi). Additionally, 23% of patients experienced a reduction in total symptom scores of at least 50% vs 13% of those who received BAT.

The approval marks the first treatment that specifically addresses the needs of patients with cytopenic myelofibrosis, according to CTI BioPharma Corp, the developer of pacritinib.

"Today's approval of Vonjo establishes a new standard of care for myelofibrosis patients suffering from cytopenic myelofibrosis," John Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology, at Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, stated in a press release. "Myelofibrosis with severe thrombocytopenia, defined as blood platelet counts below 50 × 10⁹/L, has been shown to result in poor survival outcomes coupled with debilitating symptoms. Limited treatment options have rendered this disease as an area of urgent unmet medical need. I am pleased to see that a new, efficacious and safe treatment option is now available for these patients."

The recommended dosage for pacritinib is 200 mg orally twice daily.

As part of the accelerated approval, CTI BioPharma will now be expected to demonstrate confirmatory findings of pacritinib in the phase 3 PACIFICA trial (NCT03165734), which is expected to have results in the middle of 2025.

In November 2021, the FDA had extended the review period for the new drug application (NDA) for pacritinib as a treatment for adult patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis and severe thrombocytopenia with a baseline platelet count of 50 x 10⁹/L.³

The application was previously granted priority review designation, with an action date of November 30, 2021. However, the Prescription Drug User Fee Act action date had been extended by 3 months to February 28, 2022.

In the announcement, CTI BioPharma Corp., the developer of pacritinib, noted that the FDA previously requested additional clinical data, which was submitted to the agency on November 24, 2021. The FDA recently informed CTI BioPharma that "it considers the data submission to constitute a 'major amendment' to the NDA and therefore the PDUFA date has been extended by 3 months to provide additional time for a full review of the submission."

The company had stated that it was unaware of any major deficiencies in the application.

PERSIST-1 enrolled a total of 327 patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis. Participants were randomized 2:1 to receive either pacritinib at a daily dose of 400 mg or physician’s choice of BAT, which excluded ruxolitinib.⁴ Approximately 60% (55.7%) of patients in the control arm received hydroxycarbamide; 25.5% were treated with the watch-and-wait strategy.

The trial did not require a specific platelet count for enrollment; however, 32% of patients had levels that were under 100,000 μL, and 16% had levels under 50,000 μL. The primary end point of the trial was a spleen volume reduction of 35% or greater.

The median duration of treatment in the investigative arm was 16.2 months and 5.9 months in the control arm. Seventy-nine percent of patients who originally received BAT crossed over to receive pacritinib.

At 24 weeks of follow-up, 19.1% of patients who received pacritinib experienced a 35% or greater reduction in spleen volume vs 4.7% of those given BAT (P = .0003).

PERSIST-2 enrolled a total of 311 patients with myelofibrosis who had platelet counts of 100,000 μL or less.⁵ Those in the intent-to-treat population were randomized 1:1:1 to receive once-daily pacritinib at a dose of 400 mg (n = 107) or at a twice-daily dose of 200 mg (n = 104), or BAT (n = 100). Forty-eight percent (n = 149) of participants previously received ruxolitinib.

Regarding safety, 31% of patients who received the once-daily dose of pacritinib reported grade 3 or 4 thrombocytopenia vs 32% of those who received the twice-daily dose, and 18% of those who received BAT. Grade 3 or 4 anemia was experienced by 27%, 22%, and 14%, of patients, respectively.

The FDA placed this trial on clinical hold in February 2016, along with other efforts dedicated to evaluating the agent, following reports of patient deaths linked with intracranial hemorrhage, cardiac failure, and cardiac arrest that had been observed on the trial. The pharmaceutical company provided the agency with final clinical study reports from both PERSIST-1 and PERSIST-2 in response to this decision; the PAC203 trial was also initiated. The following year, in January 2017, the FDA lifted the clinical hold placed on pacritinib trials.

PAC203 examined the safety and efficacy of pacritinib in patients with primary myelofibrosis who had received prior ruxolitinib.⁶ Participants received the agent at a once-daily dose of 100 mg, a twice-daily dose of 100 mg, or twice-daily dose of 200 mg.

Results showed that the twice-daily dose of pacritinib resulted in the most benefit in this population vs both once-daily doses. Patients with severe thrombocytopenia experienced spleen volume response to the agent. Pacritinib still had favorable tolerability when given at the higher dose, with no difference in incidence of high-grade cardiac or bleeding adverse effects vs the other doses examined.

"In the [United States], there are approximately 21,000 patients with myelofibrosis, two-thirds of which have cytopenias (thrombocytopenia or anemia), commonly resulting from the toxicity of other approved therapies. Severe thrombocytopenia, defined as a blood platelet count below 50 × 10⁹/L, occurs in one-third of the overall myelofibrosis population, and has a particularly poor prognosis. With the approval of Vonjo, we are excited to now be able to offer a new therapy that is specifically approved for patients with cytopenic myelofibrosis," Adam R. Craig, MD, PhD, president and chief executive officer of CTI Biopharma, stated in the press release.

Craig added that the company plans to provide pacritinib to patients within 10 days of the approval.

References

1. 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 February 28, 2022. https://prn.to/33ZY8lU
2. CTI BioPharma announces completion of rolling submission of new drug application (NDA) for pacritinib in myelofibrosis patients with severe thrombocytopenia. News release. CTI BioPharma Corp. March 31, 2021. Accessed October 27, 2021. https://prn.to/3dlvNY2
3. CTI BioPharma announces extension of FDA review period for pacritinib in myelofibrosis with severe thrombocytopenia. CTI BioPharma Corp. News release. Published November 30, 2021. Accessed November 30, 2021. https://prn.to/3FZPYHB
4. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. 2015;(suppl 33):LBA7006. https://bit.ly/2SgFNHL
5. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818
6. Gerds AT, Savona MR, Scott BL, et al. Results of PAC203: a randomized phase 2 dose-finding study and determination of the recommended dose of pacritinib in patients with myelofibrosis. Ann Oncol. 2019;134(suppl 1):667. doi:10.1182/blood-2019-129293