SOHO 2022: Pacritinib improves transfusion-dependent anemia by inhibiting ACVR1 in myelofibrosis

Pacritinib (pacotinib) is an ongoing oral kinase inhibitor specific for JAK2, FLT3, IRAK1, and CSF1R
.
The enzymes of the JAK family are core components of the signal transduction pathway and are essential
for normal blood cell growth and development, inflammatory cytokine expression, and immune response.
Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative tumors, leukemia, and lymphoma
.
FDA approval for marketing, see: FDA approves new myelofibrosis drug pacritinib

According to the results of a retrospective analysis of the Phase 3 PERSIST-2 trial (NCT02055781) presented at the 10th Annual Meeting of the American Society of Hematology-Oncology (SOHO), pacritinib treatment improved transfusion dependence and hemoglobin in patients with myelofibrosis
.
Accompanying pharmacodynamic data indicate that the ACVR1 pathway is involved in the mechanism
of action of pacritinib.

Pharmacodynamic data indicate that pacritinib inhibits ACVR1 with IC50s of 22.
6 and 10.
8 nM and mean IC50s of 16.
7 nM
in repeated trials.
Notably, the positive control had IC50s of 20.
4 and 32.
4 nM, respectively, and an average IC50 of 36.
6 nM
.
In addition, the only JAK2/ACVR1 inhibitor in development for the treatment of myelotinib, has IC50s of 34.
9 and 70.
2 nM
.
Fedratinib has limited activity, while ruxolitinib does not
.

"Pacritinib is a highly potent ACVR1 inhibitor with higher potency than other JAK2 inhibitors
.
In non-transfusion-independent patients who can be evaluated, pacitinib therapy improves transfusion independence and myelofibrosis symptoms
.
Therefore, the anemia benefits of pacritinib may be related to inhibition of ACVR1 and IRAK1," said
lead study author Stephen Oh, MD, a hematologist at Siteman Cancer Center in St.
Louis, Missouri.
"Taken together, these data demonstrate the important role
of pacritinib in addressing anemia in people with myelofibrosis.
"

Pacritinib is an oral JAK2/IRAK1 inhibitor approved at a dose of 200 mg twice daily for the treatment of myelofibrosis patients
with severe thrombocytopenia.
The investigators in the trial evaluated an approved dose and a once-daily dose
of 400 mg.

The primary results of the PERSIST-2 trial showed improvements in spleen volume, symptom scores, and anaemia, as well as a reduction
in transfusion burden.

ACVR1 is responsible for the regulation of hepcidin and its inhibition improves anemia
in myelofibrosis.
Although the anemia benefits of pacritinib are partly related to IRAK1 inhibition, the role of ACVR1 inhibition is unclear
.
Therefore, the researchers conducted an in vitro analysis to evaluate the effect
of ACVR1 inhibition on the efficacy of pacritinib.

In the analysis, the activity
of pacritinib was evaluated against momelotinib, fedratinib (Inrebic), ruxolitinib (Jakafi), and the positive control LDN193189.
Using the Reaction Biology Corporation's HotSpot assay, perform 10 IC50 evaluations with 3-fold serial dilutions
starting at 10 μM.

The analysis included patients with a 24-week presentation with platelet counts equal to or less than 100 x 109/L who were randomly assigned to receive 200 mg twice daily or 400 mg of pacritinib once daily, or the best available therapy
.

Non-transfusion-independent, evaluable patients were analysed, defined as any transfusion or haemoglobin below 8 g/dL, or haemoglobin below 10 g/dL
at baseline.

Other results showed a higher percentage of non-transfusion-independent patients with pacritinib at 200 mg and 400 mg doses achieving independent transfusion during any 12 weeks to 24 weeks, at 27% and 25 versus 5 percent, respectively
, compared with the best available therapy.
In addition, the cumulative probability of paxotinib in both doses is higher
compared to the best available therapy.

Regarding symptom improvement in this population, a larger proportion of patients reported "substantial improvement" or "very improvement" in symptoms of 200 mg pacritinib compared with the best available therapy, 50% and 16%, respectively (P = .
027).

In addition, patients treated with pacritinib had at least a 50% reduction in improved overall symptom scores, 46% and 16%, respectively, compared with those who received the best available treatment (P = .
054).

In patients with baseline hemoglobin below 10 g/dL, the percentage of improvement of at least 1 g/dL or at least 2 g/dL at any time during week 24 was higher at doses of 200 mg and 400 mg pacritinib was 15% and 23% versus 7%, and 9% and 7% versus 4%,
respectively, at the best available therapy.

Resources:

Oh S, Mesa R, Harrison C, et al.
Retrospective analysis of anemia benefit of pacritinib from the PERSIST-2 trial.
Presented at: the 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX.
Abstract MPN-145