There is a 2nd generation Type 2 Jak-i. This is two ways better than Rux in concept which is only 1st gen type 1.
Mouse studies have shown it is lots better than Rux, with their main focus being reduced mutant burden. The value of this (in context of IFN) is still debated on this forum and among experts, although I believe.
But if it can work for longer as they claim that could be its best feature.
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-"AJ1-10502 caused significant reductions in mutant cell fraction within bone marrow and spleen not observed with ruxolitinib" (reduce VAF)
-The 1st try at type 2's didn't work well: "a much-improved safety profile than first generation Type II inhibitors"
-"Type II JAK2 inhibitors have been shown to overcome disease persistence to ruxolitinib" where "(with Rux) efficacy wanes over time"
They say Rux allows "continued JAK/STAT signaling" and "sustained JAK/STAT signaling in the setting of type I inhibition plays a critical role in the MPN cell persistence "
- the bad actor can't hide: "Type II JAK2 inhibitors bind the inactive conformation of the kinase domain" I guess like hitting the enemy when they are sleeping. (Rux can find it only when it's active)
This company is "applying computational chemistry and structure-based technologies" to find new drugs. This sort of research is the future trend, finding new agents via software vs lab. It's far faster and good news for all patients.
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There are some plots in the 2nd reference, they don't look dramatically improved to me, but the authors do see lots to be excited about.
As someone who had Rux recommended [by my generalist Heme/Onc MD, and by my MPN specialist MD's Fellow] because of my age, which recommendations I of course declined in favor of INF [Besremi], I'm happy to see them looking for alternatives to Rux.
While I am very hopeful of achieving significant and lasting benefit from Besremi, I am always looking forward to the next possibly helpful therapy.
I support you point, I have take Rux for 4 years, I agree Rux is good enough on the MF and control of spleen size, it can return and mantain. And INF also is very useful drug.
First of all, the investigative compound formerly known as is now named: Fedratinib [Brand name= Inrebic], and secondly there have been some results that seem to answer your question:
Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts
Abstract
Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.
Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis
Wherein it states:
"Grades 3–4 treatment-related hematologic AEs included anemia (13/37 non-transfusion-dependent patient at baseline [35%]), thrombocytopenia (24%,) and neutropenia (10%), with most occurring in the first three fedratinib treatment cycles. Of the 13 patients who developed grades 3–4 anemia (all in the 680 mg dosing cohort), two-thirds (67%) had grade 2 anemia at study entry and 9 of 14 patients who developed grades 3–4 thrombocytopenia had grades 1–2 thrombocytopenia at baseline.
Effective management of fedratinib-related TEAEs [Treatment Emergent Adverse Effects] can facilitate long-term therapy. Hematologic events are anticipated with JAK2 inhibitors due to their mechanism of action [90]. These events typically occur within the first 3–4 months of initiating fedratinib therapy and hematology counts tend to improve over time during treatment [34, 35, 55]. Grades 3–4 laboratory abnormalities of anemia and thrombocytopenia were more frequent in the JAKARTA2 study in patients previously treated with ruxolitinib than in the JAKARTA trial, as might be expected for patients with more advanced disease and who were more likely to have low platelet counts and hemoglobin concentrations at study entry [24]. In both studies, permanent discontinuation of fedratinib due to these events was infrequent (2–3%), suggesting that these events could be managed effectively while continuing fedratinib treatment. Hematologic TEAEs can be managed with supportive interventions, including transfusions, and fedratinib dose modifications may be needed if supportive interventions are insufficient. Although not contraindicated, the benefit/risk ratio of fedratinib therapy should be carefully measured in patients with highly transfusion-dependent anemia or profound thrombocytopenia.
"intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential
thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L."
This is a type 1 jak-i.
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For AJ1-10502 I've not seen features about anemia or platelets. Its main feature seems to be better long term benefit. But it may turn out to help with anemia and PLT too.
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