Momelotinib's Spleen, Symptom and Anemia Efficacy Is Maintained in Intermediate/High Risk Myelofibrosis Patients with Thrombocytopenia
Authors: Kiladjian Jean Jacques , Platzbecker Uwe , Mayer Jiri , Illés Árpád , Prejzner Witold , Wozny Tomasz , Tzvetkov Nikolay , Vannucchi Alessandro M. , Kirgner Ilya , Nagy Zsolt , Grosicki Sebastian , Rangert Derolf Åsa , Lazaroiu Mihaela , Yoon Sung-Soo , Goh Yeow Tee , Von Bubnoff Nikolas , Verstovsek Srdan , Klencke Barbara Jane , Donahue Rafe , Mesa Ruben 
Published: February 2021

Momelotinib (MMB), a JAK1, JAK2 and ACVR1 inhibitor, has demonstrated clinically comparable splenic and symptomatic benefits to ruxolitinib (RUX), the standard-of-care JAK1/JAK2 inhibitor for myelofibrosis (MF), a condition marked by splenomegaly, constitutional symptoms and progressive anemia and thrombocytopenia. MMB also uniquely restores iron homeostasis and red blood cell production, reduces or eliminates the need for transfusions and improves or maintains platelet (PLT) counts. Consistent with MMB's differentiated biological profile, low myelosuppressive potential and favorable hematological tolerability, prolonged, near-maximal MMB dose intensity can be maintained regardless of underlying PLT values. In contrast, RUX's hematological toxicity profile necessitates attenuated starting doses for thrombocytopenic (TCP) patients with PLTs &lt;200 × 109/L and substantive, progressive dose reduction to mitigate against RUX-induced thrombocytopenia. Here we report post-hoc comparative efficacy analyses for RUX and MMB for spleen, symptom and transfusion independence (TI) response in patients with a baseline PLTs &lt;150 × 109/L versus the ITT populations from the two previously-completed global Phase 3 SIMPLIFY studies.
A retrospective analysis of spleen, symptom and TI response rates at week 24 was conducted in the TCP and ITT groups from SIMPLIFY-1 (S1), a double-blind Phase 3 study in intermediate/high risk MF patients randomized 1:1 to MMB or RUX over a 24-week treatment period, and SIMPLIFY-2 (S2), a Phase 3 study comparing MMB to best available therapy (BAT) in previously RUX-exposed MF patients. A baseline PLTs ≥50 × 109/L was required in S1, while there was no lower PLT limit for S2. Most subjects randomized to BAT (88%) received RUX during the 24-week randomized period.
In S1, 9.5% and 24% of 432 subjects randomized had a PLT count of &lt;100 and &lt;150 × 109/L, respectively, at baseline. At week 24, MMB demonstrated a consistent splenic response rate (SRR) of 23% in patients with baseline PLTs &lt;150 × 109/L and 27% in the ITT. A markedly reduced SRR was observed for the TCP group on RUX (4%) in comparison to the ITT (29%). Total symptom score (TSS) response rate was 28% in both the TCP and ITT in the MMB arm. In the RUX arm, the TSS response rate was lower in the TCP group (32%) than in the ITT (42%). MMB treatment elicited a TI response rate of 62% and 67% in the TCP and ITT groups, respectively, while for RUX the equivalent response rates were 43% and 49%. Of the 40 MMB subjects that discontinued therapy prior to week 24, 1 (2.5%) and 7 (17.5%) had a baseline PLTs &lt;100 and &lt;150 × 109/L, respectively. Of the 16 RUX subjects who discontinued therapy prior to week 24, 5 (31.4%) and 11 (69%) had baseline PLTs &lt;100 and &lt;150 × 109/L, respectively.
In S2, 44% of 156 subjects randomized had a PLT count of &lt;100 and another 22% had PLTs 100-150 × 109/L at baseline. The TSS response with MMB was 24% for the TCP and 26% in the ITT. Notably, this TSS response rate was retained even in patients with PLTs &lt;100 × 109/L. Similarly, splenic and TI outcomes with MMB in the TCP were within 1-2% of the ITT response rates for these endpoints. Response rates in the control arm of S2 were low for both TCP and ITT (SRR 7 vs 6%, TSS 3 vs 6% and TI 22 vs 21%).
These retrospective analyses of data from the two Phase 3 SIMPLIFY studies demonstrate that MMB efficacy is maintained in TCP patients and is comparable to that observed in the broader JAKi-naïve and previously JAKi-treated ITT populations in S1 and S2. These data contrast with RUX data from S1 where the SRR was markedly decreased and the TSS moderately decreased in TCP patients, consistent with reduced RUX dose intensity and higher rates of early discontinuation in this subset. Consequently, for patients in S1 with low PLTs, MMB and RUX demonstrated similar symptomatic benefit, while MMB had a more favorable profile for splenic volume reduction and TI. Response rates for the three parameters in the MMB arm of S2 were comparable between the TCP and ITT groups. Response rates in the control arm were low and not substantially different between the TCP and ITT groups, with most patients receiving very low dose intensity of RUX. Together, the findings of comparable spleen, symptom and TI response in the TCP and ITT groups treated with MMB suggest that the compound could become the optimal JAK inhibitor therapy for intermediate/high risk MF patients with underlying disease-related or prior RUX-induced thrombocytopenia.

Disclosures
Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Mayer:Principia Biopharma: Research Funding; AbbVie: Research Funding. Illés:Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nagy:MorphoSys AG: Patents & Royalties. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding; YuhanPharma: Research Funding. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Verstovsek:Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding. Klencke:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Donahue:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Mesa:Incyte: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; Novartis: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding.