Transfusion-related cost offsets and time burden in patients with myelofibrosis on momelotinib vs. danazol from MOMENTUM

ACVR1; anemia; cost; danazol; JAK inhibitor; momelotinib; my elofibr osis; time burden; transfusion

A im: To estimat e project ed US-based c ost and time burden for pa tien ts with my elofibr osis and anemia treated with momelotinib compared with danazol. M etho ds: Cost and time burden were calculated based on the transfusion status of patients in the MOMENTUM trial and estimates ex trac ted from previous studies.

Reductions in transfusion associated with momelotinib are project ed t o result in cost and time savings compared with danazol in transfusion-dependent and transfusion- independen t/requiring pa tien ts with my elofibr osis, r espectiv ely: annual medical costs ($53,143 and $46,455 per person), outpa tien t transfusion costs ($42,021 and $8,370 per person) and annual time savings (173 and 35 h per person).

Fewer transfusions with momelotinib are projected to result in cost and time savings in pa tien ts with my elofibr osis and anemia compared with danazol. PL AIN L ANGUAGE SUMMARY Estimated cost & time savings in patients with the blo o d cancer myelofibrosis My elofibr osis is a rare blood cancer often associated with bone marrow damage, too few of some types of blood cells and symptoms including tiredness, night sweating, itching and feelings of fullness and pain because of increased spleen size. Pa tien ts with anemia (too few red blood cells) may r equir e r egular blood transfusions and this is one sign that my elofibr osis is getting w orse. MOMENTUM was a Phase III clinical trial showing that the drug momelotinib was safe and effective in pa tien ts with my elofibr osis who w er e pr eviously tr eat ed with a type of drug called a JAK inhibit or. In particular, the trial showed that momelotinib reduced the need for transfusions compared with danazol, another drug typically used to treat patients with anemia. Based on this transfusion information from MOMENTUM and other publicly available information about estimated medical costs and pa tien ts’ time spen t in rec eiving transfusions, the analy sis described here show s that a reduction in the number of transfusions with momelotinib compared with danazol is estimated to lead t o c ost savings as well as reduced pa tien t time spen t in transfusion-rela ted trav el , pr eparing and waiting for transfusions and receiving and recovering from transfusions. TWEETABLE ABSTRACT Reductions in transfusions associated with momelotinib ar e pr oject ed t o result in savings in medical and transfusion-relat ed c osts and time burden relative to danazol in pa tien ts with my elofibr osis and anemia. 1. Background My elofibr osis (MF) is a chr onic , pr ogr essiv e, Philadelphia chr omosome–negativ e my elopr oliferativ e neoplasm (MPN) characteriz ed b y anemia, splenomegaly, debilitating symptoms and bone marrow fibrosis [ 1 ]. MPNs ar e rar e, with MF estimat ed t o hav e a w orldwide annual incidenc e rat e of 0.47 t o 1.98 per 100,000 and a prevalenc e rang ing from 1.76 to 4.05 per 100,000 [ 2 , 3 ]. While MF is often a primary disease, it may also occur post polycythemia vera (PV) or post essential thrombocythemia (ET) [ 1 ]. Primary MF is more aggressive CONTACT Lucia Masarova Tel.: + 1 855 707 8878; [email protected] ‡Former employee of GSK This article has been corrected with minor changes. These changes do not impact the academic con ten t of the article. Supplemental data for this article can be accessed at https:// doi.org/ 10.1080/ 14796694.2024.2368450 ©2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Ac c ess article distributed under the terms of the Cr eativ e Commons A ttribution-NonCommer cial-NoDerivativ es License ( http:// creativecommons.org/ licenses/by- nc- nd/ 4.0/ ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not alter ed , transformed , or built upon in any wa y. T he t erms on which this article has been published allo w the posting of the Ac c ept ed Manuscript in a reposit ory b y the author(s) or with their c onsent . 2260 L. MASAROVA ET AL. and has a poorer prognosis than PV or ET [ 4 ], as disease pr ogr ession with MF can include bone marr ow failur e, transformation t o acut e myeloid leukemia and early mortality [ 5 ]. While MF can occur at any age, it is most frequently diagnosed in older pa tien ts, with a median age of diagnosis between 65 and 70 years [ 6 , 7 ]. Among pa tien ts with MF, one-thir d hav e anemia and one-quarter have transfusion dependent (TD) anemia by the time of MF diagnosis [ 8 , 9 ]. Over time, most pa tien ts with MF develop anemia, which is associated with poor prognosis [ 9–11 ]. Any grade of anemia adversely affects the survival of patients with MF, and sev er e anemia is associated with a > 1.5-fold increase in the risk of death c ompared with moderat e anemia [ 12 ]. Ac c ording t o a r etr ospectiv e analysis of 1109 pa tien ts with primary MF, median survival was 4.9, 3.4 and 2.1 years for patients with mild (hemoglobin [Hb] ≥10 g/dl but below the sex- adjusted lower limit of normal), moderate (Hb between 8 g/dl and < 10 g/dl) and sev er e (Hb < 8 g/dl or TD) MF-associated anemia, r espectiv ely [ 12 ]. W hile the emer - gence of JAK inhibitors has provided substantial benefit for splenomegaly and c onstitutional sympt oms, and may impr ov e survival [ 13 ], anemia remains a challenge in MF management . A mong curr ently appr ov ed JAK inhibitor therapies for MF, ruxolitinib and fedratinib are intrinsically my elosuppr essiv e and can cause or worsen anemia and exac erbat e transfusion dependency [ 8 , 14 ]. Red blood cell (RBC) transfusions are the main trea tmen t option for worsening or severe anemia in pa tien ts with MF. How ev er, transfusion dependence is associated with poor survival and may add to the economic burden on pa tien ts, their caregivers and the health sy st em via healthcar e r esour ce utilization (HCRU) and costs associated with transfusions and managing transfusion complications [ 15–18 ]. In a r etr ospectiv e analy sis, transfusion dependenc e imposed a high cost bur den on healthcar e sy st ems and pa tien ts, with annual total medical costs up to nine-times higher for TD pa tien ts than for non-TD pa tien ts ($255,200 vs. $27,800) [ 16 ]. Other approaches to managing MF-associated anemia include erythropoiesis-stimulating agents, c ortic ost er oids, andr ogens such as danazol , immunomodulatory drugs and splenectomy [ 8 , 19 , 20 ]. These strat eg ies have shown modest and transient clinical benefit, but none directly target key mechanistic c ontribut ors t o MF-associat ed anemia [ 21 , 22 ]. Momelotinib is an oral inhibitor that targets JAK1, JAK2 and ACVR1 [ 23 , 24 ]. While inhibition of JAK-STAT signaling in MF blocks the inflammatory cytokines and clonal pro- lifera tion tha t lead to extramedullary hematopoiesis and splenomegaly, ACVR1 inhibition incr eases ir on availabil- ity, thereby mitigating iron-restricted anemia associated with MF [ 14 , 25 ]. Based on three Phase III trials, momelo- tinib impr ov ed splenomegaly, disease-r elated symp- toms and anemia in pa tien ts with JAK inhibitor–naive or –experienced MF [ 26–28 ]. In the Phase III MOMEN- TUM trial (NCT04173494) of JAK inhibit or–experienc ed, symptoma tic pa tien ts with MF and anemia, momelo- tinib demonstrated reduced transfusion burden and achieved dur able tr ansfusion independenc e c ompared with danazol, a commonly used trea tmen t specifically for MF-associated anemia [ 20 , 28 ]. Given the dual JAK-STAT signaling and ACVR1 inhibitory activities of momelotinib and reported clinical trial efficacy, safety and observed effects on MF-associated anemia and transfusion depen- dence, there is a potential for cost savings and less r esour ce utilization with momelotinib r elativ e to other trea tmen ts. The objective of this study was to esti- mate the projected differences in total medical costs, transfusion-relat ed c osts and pa tien t time burden associ- ated with momelotinib vs. danazol from a US perspective. 2. Materials & methods 2.1. Data sources To address the study objec tive, projec t ed differenc es in cost and time burden associated with momelotinib and danazol w er e determined based on transfusion independence data from the MOMENTUM trial and cost and time burden data from the published literature. MOMENTUM is an in terna tional , double-blind , randomized , contr olled , Phase III study that enrolled pa tien ts a t 107 sit es across 21 c ountr ies wor ldwide [ 28 ]. The pa tien t popula tion for MOMENTUM w as previously descr ibed [ 28 ]. Br iefly, eligible pa tien ts w er e ≥18 y ears with a confirmed diagnosis of in termedia te-1–, in termedia te-2–, or high-r isk pr imar y or secondar y (post- PV or post-ET) MF who w er e symptomatic , w er e anemic , had baseline splenomegaly and w er e pr eviously tr eated with an appr ov ed JAK inhibitor. Pa tien ts w er e randomly assigned (2:1) to r eceiv e momelotinib (200 mg orally once per day) plus danazol placebo (i.e., the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (i.e., the danazol group) [ 28 ]. Data on clinical efficacy of momelotinib r elativ e to danazol w er e ex trac t ed or calculat ed from the MOMENTUM trial for use in calculations of projected cost and time burden differ ences betw een these gr oups. A target ed lit eratur e sear ch was c onduct ed t o obtain US-based estimates of costs and time burden for pa tien ts with MF. Cost estimates w er e ex trac ted fr om tw o separate studies of pa tien ts with MF, one a study of adults using the IBM M arketS can Commercial Database and the other a study of adults aged ≥65 years using the Medicare fee- for-service database [ 16 , 17 ]. Overall costs of care were ex trac ted from the IBM M arketS can Claims study, which FUTURE ONCOLOGY 2261 summar ized medical, phar macy and transfusion-specific costs of adult pa tien ts with MF [ 16 ]. Cost estima tes w er e r eport ed as annual c osts per person in USD, str at - ified by baseline transfusion status (TD and transfusion independen t/requiring [TI/TR]) ( Supplemen tary Table S1 for definition of transfusion status and Supplementary Table S2 for reported costs). Similarly, the Medicare fee- for-service study provided cost- of- care estimates among pa tien ts with MF aged ≥65 years, stratified by base- line transfusion status (TI, TR and TD) ( Supplementary Tables S1 & S2 ). While diagnoses of iron overload were captured in the health claims analyses, specific costs relat ed t o iron chelation therapy w er e not available in these data sources. Time burden estimates were from a cross-sectional w eb-based surv ey fr om the Cooley’s Anemia Foundation (the 2022 Knoth et al. study [ 29 ]), which provided estimates for a patient’s mean time spent for one RBC transfusion pr ocedur e in pa tien ts with β-thalassemia and included the following time componen ts: prepara tion, w aiting room, w aiting for blood , RBC transfusion pr o- cedure and recovery and total round trip travel time ( Supplementary Table S3 ) [ 29 ]. 2.2. Analyses of transfusion status & rates in MOMENTUM Data on clinical efficacy of momelotinib r elativ e to dana- zol w er e ex trac t ed or calculat ed from the MOMENTUM trial for use in subsequent calculations of projected cost and time burden differences between groups. Individual pa tien t da ta fr om MOMENTUM w er e used t o det ermine the proportion of pa tien ts who were TI, TR and TD in the momelotinib and danazol trial arms at baseline and at week 24 of the study based on the transfusion status cr iter ia of the MOMENTUM tr ial ( Supplementary Table S1 ) and the average rate of transfusions in each arm. This TI rate at week 24 was based on the prespecified terminal 12-week definition of no transfusions and all Hb levels ≥8 g/dl in the last 12 weeks before week 24. Analyses w er e r epeated in the subset of pa tien ts aged 65 years and older. Estimates included only pa tien ts with known transfusion status at week 24 in the base case calculations of project ed c ost and time burden differenc es. A separat e analy sis also ev alua ted pa tien ts based on a rolling TI rate defined as no transfusions and all Hb levels ≥8 g/dl during any 12-week period through week 24 ( Supplementary Table S1 ). Sensitivity analyses under different assumptions about missing transfusion status w er e also explor ed . All analyses assumed a sus- tained effect of trea tmen t on transfusion status. 2.3. Calculating proje cte d differenc es in c ost & time burden Project ed medical c osts for momelotinib and danazol, stratified by baseline transfusion status, w er e calculated by multiplying the cost estimates from the IBM Mar- ketScan study with the proportion of pa tien ts with TD or TI/TR status in each group at week 24 in the MOMENTUM trial . Pr oject ed c ost differenc es w er e calculated as the differ ence betw een these pr oject ed c osts in the momelo- tinib and danazol groups ( Supplementary Figure S1 ). Cost estimates for momelotinib and danazol among patients aged ≥65 years were calculated by multiplying the cost estimates from the Medicare study by the proportion of pa tien ts aged ≥65 years with TD, TI or TR sta tus in each group at week 24 in the MOMENTUM trial, and project ed c ost differenc es w er e calculated as the differ ences betw een these gr oup-specific estimates. The proportions of pa tien ts with TD or TI/TR status w er e reported in the Clinical Study Report for the overall population and calculated using individual patient-level data for patients aged ≥65 years. Projected outpa tien t transfusion costs for momelo- tinib and danazol w er e calculated by multiplying cost estimates per outpatient transfusion visit ex trac ted from the literature with rates of transfusion visits for each group in the MOMENTUM trial. Costs per transfusion visit w er e r eported only in the IBM M arketS can Com- mercial Database study; cost estimates from this study w er e ther efor e also used in calcula tions for pa tien ts aged ≥65 years. Rates of transfusion visits for momelotinib and danazol pa tien ts w er e r eported in the Clinical Study Report for the overall population and calculated using individual pa tien t-level da ta for pa tien ts aged ≥65 years. Rates of RBC transfusion visits observed over the 24- week trial period in each group were rescaled to reflect annualized rates ( Supplementary Figure S1 ). Pr ojected transfusion-r elated time bur den for momelotinib and danazol was calculated by multiplying the estimated time spent on average per transfusion visit from the Knoth et al. study [ 29 ] with the average number of transfusion visits per pa tien t per year within the momelotinib and danazol arms from the MOMENTUM trial , r espectiv ely. Pr ojected time savings w er e calculated as the difference between the projected time burden estimates for momelotinib and danazol. ( Supplementary Figure S1 ). 2.4. Sensitivity analysis Sensitivity analyses w er e performed to assess the robust- ness of the base case estimates based on two methods 2262 L. MASAROVA ET AL. for imputing unknown transfusion sta tus a t week 24 in MOMENTUM. Unknown transfusion status was imputed either as TI/TR in both tr ial ar ms or as TD in both trial arms. These analyses assumed that patients w er e either TI/TR vs. TD without the potential for becoming disease- free (i.e., having no trea tmen t c ost). Project ed c ost and time bur den differ ences w er e then r ecalculated under these assumptions. 3. Results 3.1. Transfusion status & rates A t w eek 24, 143 pa tien ts w er e analyzed (momelotinib arm, n = 102; danazol arm, n = 41) in the MOMENTUM trial . A t baseline, 45.1% of pa tien ts in the momelotinib arm w er e TD, and 54.9% of pa tien ts w er e TI/TR; in the danazol arm, 39.0% w er e TD and 61.0% w er e TI/TR ( Supplementary Table S4A ). Among patients who w er e TD at baseline, 60.9% in the momelotinib arm w er e TI/TR at the end of the 24-week trial period and 39.1% remained TD. In the danazol arm, 37.5% w er e TI/TR and 62.5% r emained TD. A t w eek 24, 109 pa tien ts aged ≥65 years in the MOMENTUM trial w er e analyzed (momelotinib arm, n = 76; danazol arm, n = 33) ( Supplementary Table S4B ). In this subpopula tion, a t baseline, 47.4% of pa tien ts in the momelotinib arm w er e TD and 52.6% w er e TI/TR; in the danazol arm, 36.4% w er e TD and 63.6% w er e TI/TR ( Supplementary Table S4B ). Among patients aged ≥65 years who w er e TD at baseline, 63.9% in the momelotinib arm w er e TI/TR at the end of the 24-w eek tr ial per iod and 36.1% remained TD; in the danazol arm, 33.3% w er e TI/TR and 66.7% r emained TD. Pa tien ts in the momelotinib arm had reduc ed rat es of transfusion visits compared with pa tien ts in the danazol arm among those who w er e TD at baseline (mean, 15.26 vs. 26.34 visits/year) and among those who w er e TI/TR at baseline (mean, 5.00 vs. 7.21 visits/year) ( Supplementary Table S5A ). Similarly, pa tien ts aged ≥65 years in the momelotinib arm had reduced rates of transfusion visits compared with pa tien ts in the danazol arm among those who w er e TD at baseline (mean, 15.45 vs. 27.34 visits/y ear) and those who w er e TI/TR at baseline (mean, 5.81 vs. 6.10 visits/year) ( Supplementary Table S5B ). 3.2. Proje cte d differences in medical costs Reduc ed rat es of transfusion dependenc e result ed in low er pr oject ed c osts for momelotinib r elativ e to danazol . Stratified by TD and TI/TR status at baseline and using a t erminal TI rat e, the project ed average annual total medical cost savings with momelotinib vs. danazol w er e $53,143 per pa tien t with baseline TD status ($116,772 vs. $169,915) and $46,455 per pa tien t with baseline TI/TR status ($35,910 vs. $82,365) ( Figure 1 A). Sensitivity anal- yses, assuming pa tien ts with unknown transfusion sta tus at week 24 were either all TD or all TI/TR, showed that total annual medical service cost savings with momelotinib in pa tien ts with baseline TD sta tus ranged from $1,911 to $60,938 per person ( Supplementary Table S6 ). Based on a rolling TI rate, the projected average annual total medical cost savings with momelotinib vs. danazol w er e $23,780 per pa tien t with baseline TD status ($204,656 vs. $228,437) and $39,305 per pa tien t with baseline TI/TR status ($105,852 vs. $145,157) ( Supplementary Figure S2 ). Among pa tien ts aged ≥65 years with baseline TD status, the projected average annual cost of care was similar in pa tien ts trea ted with momelotinib vs. danazol ($125,625 vs. $124,618), with a $1,007 savings with danazol ( Figure 1 B). In pa tien ts with baseline TI/TR status, the pr ojected av erage annual cost of car e show ed savings of $6,482 per pa tien t - year ($100,296 vs. $106,778) with momelotinib compared with danazol ( Figure 1 B). 3.3. Proje cte d differences in outpatient transfusion cost Reductions in transfusions w er e associated with savings in projected outpa tien t transfusion cost with momelo- tinib r elativ e to danazol . Among pa tien ts who w er e TD at baseline, there was a projected outpatient transfusion cost savings of $42,021 per pa tien t for momelotinib vs. danazol ( Figure 2 A). Among pa tien ts who were TI/TR at baseline, there was a projected outpa tien t transfusion cost savings of $8,370 per pa tien t for momelotinib vs. danazol ( Figure 2 A). Similarly, among pa tien ts aged ≥65 years who w er e TD at baseline, projected outpatient transfusion cost savings w er e $45,060 per pa tien t with momelotinib vs. danazol ( Figure 2 B). Among pa tien ts aged ≥65 years who w er e TI/TR at baseline, pr ojected outpa tien t transfusion cost savings w er e $1,107 per pa tien t for momelotinib vs. danazol ( Figure 2 B). 3.4. Proje cte d differences in transfusion-related patient time burden Reduc ed rat es of transfusions associat ed with momelo- tinib also corresponded to reduced transfusion-related time burden for pa tien ts. Among pa tien ts who w er e TD at baseline, the pr ojected av erage annual savings in transfusion visit time associated with momelotinib v s. danazol t otaled 173 h per pa tien t (238 vs. 411 h) ( Figure 3 A). Projected savings with momelotinib vs. danazol in pa tien ts with baseline TD status included 68 h for preparation and waiting time, 82 h for trans- fusion pr ocedur e and r ecov ery and 24 h for travel time ( Supplementary Table S7 ). Among patients who w er e FUTURE ONCOLOGY 2263 $116,772 $35,910 $169,915 $82,365 $0 $40,000 $80,000 $120,000 $160,000 $200,000 Baseline TD Baseline TI/TR IBM MarketScan Commercial Database: Total Annual Medical Costs ($USD/Per-Person)† -$53,143‡ -$46,455‡ $125,625 $100,296$124,618 $106,778 $0 $40,000 $80,000 $120,000 $160,000 $200,000 Baseline TD Baseline TI/TR Momelotinib Danazol Momelotinib Danazol $1,007‡ -$6,482‡ Medicare Database (patients ≥65 years): Total Annual Medical Costs ($USD/Per-Person)§ A B Figure 1. Projected medical costs based on transfusion status associated with momelotinib vs. danazol. Projected total annual medical costs in $USD/per person based on transfusion status associated with momelotinib vs. danazol based on the IBM MarketScan Commercial Database (A) and Medicare database (B) . †The IBM MarketScan Commercial Database categorized patients with MF into two groups (TI/TR and TD). Refer to Supplementary Table S1. Costs are stratified by transfusion status at baseline. Refer to Supplementary Table S4. Bars r epr esent costs, which w er e aggr egated acr oss pa tients with known TI/TR or TD sta tus a t week 24. ‡Differences in cost burden are calculated as cost burden for momelotinib minus cost burden for danazol. Differences 0 indicate cost savings for danazol r elativ e to momelotinib. §The Medicare f ee-f or-servic e da tabase ca tegorized pa tien ts with MF in to thr ee gr oups (TI, TR and TD). Refer to Supplementary Table S1. Each bar includes costs for patients with a status of TD or TI/TR at week 24; costs are stratified by transfusion status at baseline. The sample size of patients in the MOMENTUM trial who w er e aged ≥65 years was 155. The numbers of individuals in this subpopulation in the momelotinib and danazol arms w er e 101 and 54, r espectiv ely. Refer to Supplementary Table S4. MF: My elofibr osis; TD: T ransfusion dependent; TI: T ransfusion independent; TR: T ransfusion requiring; USD: US dollar. TI/TR at baseline, the projected average annual savings in transfusion visit time associated with momelotinib vs. danazol totaled 34 h per pa tien t (78 vs. 113 h) ( Figure 3 A). Among pa tien ts aged ≥65 years who w er e TD at baseline, pr ojected av erage annual savings in transfusion visit time associated with momelotinib vs. danazol totaled 186 h per pa tien t (241 vs. 427 h) ( Figur e 3 B). Pr ojected savings with momelotinib vs. danazol in pa tien ts with baseline TD status included 73 h for preparation and waiting time, 88 h for transfusion pr ocedur e and r ecov ery and 25 h for travel time ( Supplementary Table S7 ). Among pa tien ts who w er e TI/TR at baseline, the pr ojected av er- age annual savings in transfusion visit time associated with momelotinib vs. danazol totaled 5 h per pa tien t (91 vs. 95 h) ( Figure 3 B). 4. Discussion T his analysis sho w ed that r eduction in transfusions asso- ciated with momelotinib ar e pr oject ed t o result in savings in medical and transfusion-related costs and pa tien t time bur den r elativ e to danazol in TD and TI/TR pa tien ts with MF in the US. Project ed c ost and time burden offsets estimat ed for momelotinib w er e larger for TD pa tien ts owing to the larger reductions in transfusions relative to danazol in this population compared with the TI/TR patients. Projected savings in total annual medical costs with momelotinib compared with danazol were shown using both terminal TI rates and rolling TI rates. A potential for cost savings with momelotinib in TD pa tien ts is particularly relev an t because TD pa tien ts experience a higher burden than TI/TR pa tien ts. For example, a r etr ospectiv e analysis of the Medicare f ee-f or-service da tabase estima t ed t otal c osts (medical and pharmacy) w er e appr oximat ely 1.8-times g reat er for pa tien ts who w er e TD vs. TI and for pa tien ts with sev er e vs. mild anemia, demonstra ting tha t achieving or main taining transfusion independence and maintaining Hb levels in pa tien ts diagnosed with MF can minimize healthcare c osts and reduc e the financial burden for pa tien ts and healthcare sy st ems [ 17 ]. Similarly, a r etr ospectiv e analysis using the IBM M arketS can Da tabase estima ted tha t total medical costs w er e appr oximately nine-times higher for pa tien ts who w er e TD vs. TI [ 16 ]. While w e observ ed some differences in the magnitude of projected cost and time burdens when restricting to pa tien ts aged ≥65 years, our findings of potential offsets with momelotinib with respect to transfusion-related costs and time burden were c onsist ent with the broader adult popula tion. Insigh ts on the cost of care for older pa tien ts are particularly important because MF occurs most frequently in this population (median age at diagnosis for primary MF, 65– 70 years), with advanced age correlated with a worse prognosis in MF [ 7 , 30 ]. Notably, pa tien ts who require transfusions in the first year of diagnosis w er e older than pa tien ts who did not r equir e transfusions, with median 2264 L. MASAROVA ET AL. $57 ,819 $18,968 $99,840 $27 ,338 $0 $20,000 $40,000 $60,000 $80,000 $100,000 $120,000 Baseline TD Baseline TI/TR Momelotenib Danazol -$42,021 § -$8,370§ IBM MarketScan Commercial Database: Total Annual Outpatient Visit Costs ($USD/Per-Person)†,‡ $58,555 $22,027 $103,614 $23,134 $0 $20,000 $40,000 $60,000 $80,000 $100,000 $120,000 Baseline TD Baseline TI/TR Momelotinib Danazol -$45,060 § -$1,107§ Medicare Database (patients ≥65 years): Total Annual Outpatient Visit Costs ($USD/Per-Person)†,‡ A B Figure 2. Projected annual outpatient visit cost per patient based on transfusion status associated with momelotinib vs. danazol. Projected annual outpatient visit cost in $USD/per person based on transfusion status associated with momelotinib vs. danazol based on the IBM MarketScan Commercial Database (A) and Medicare database (B) . †Costs of care from the IBM MarketScan Commercial Database and the Medicare f ee-f or-servic e da tabase determined the average c ost per person per visit for an outpatient transfusion among those treated for MF. Refer to Supplementary Table S2. Costs are stratified by transfusion status at baseline. Refer to Supplementary Table S4. Bars r epr esent costs, which w er e aggr egated acr oss patients with known TI/TR or TD status at week 24. ‡The mean number of RBC transfusion visits was calculated using individual patien t -level data from the MOMENTUM trial. RBC transfusions utilized included those r eceiv ed by trial patients and r ecor ded in the GSK raw transfusion data within the 24-week trial period (inclusive). Under the assumption that an RBC transfusion represented a single transfusion visit, RBC transfusion visits w er e stratified by treatment arm and baseline transfusion status such that the mean RBC visits could be calculated for each subgroup. Dimensional analysis was subsequently used to adjust the time parameter from per 24 weeks to per year. Refer to Supplementary Table S5. §Differences in cost burden are calculated as cost burden for momelotinib minus cost burden for danazol. Differences 0 indicate cost savings for danazol r elativ e to momelotinib. MF: My elofibr osis; RBC: Red blood cell; TD: T ransfusion dependent; TI: T ransfusion independent; TR: T ransfusion requiring; USD: US dollar. ages of 68 (range, 47–85) vs. 57 (range, 28–87) years, r espectiv ely [ 31 ]. The differences in the magnitude of project ed c ost and time offset estimat es for the broader population and the patients aged ≥65 years may be partially attribut ed t o differenc es in charact eristics of pa tien ts in the Medicare f ee-f or-servic e database v s. the IBM M arketS can Database. M or e generally, differ ences in costs paid by Medicare vs. costs paid by priv a te insur ers captur ed in the M arketS can Database likely also c ontribut e t o the observ ed differ ences, particularly when considering overall medical costs. Importantly, the pr ojected decr ease in transfusion time burden with momelotinib observed in both the overall population and pa tien ts aged ≥65 years may c ontribut e t o improving pa tien ts’ quality of life. In pa tien ts with MF, transfusion dependence was shown to have detrimental effects on multiple aspects of quality of life [ 32 ]. In a post hoc analysis of the SIMPLIFY-1 and SIMPLIFY-2 studies, g reat er improvement across quality of life domains w er e reported in pa tien ts who w er e TD at baseline but became TI compared with those who remained TD [ 32 ]. In addition, reducing transfusion burden, and thereby tra vel time, ma y be especially beneficial for pa tien ts in limited-r esour ce settings including rural areas with fewer transfusion facilities [ 33 ].

of this study include the use of extrap- ola ted da ta, which pr ovides pr ojections but may not reflect the actual cost and time savings with momelotinib compar ed with danazol . An additional limitation may be the differences in the definitions of transfusion status between data sources. However, for this study, transfusion cr iter ia w er e expect ed t o be functionally similar because all the studies defined TI status as 0 RBC transfusions and TD status as approximately 0.5 transfusions per week. Furthermore, an estimate on the costs of transfusion visits was not available in the Medicare study and was approx- imated by the estimate from the IBM M arketS can study. Ther e w er e also differ ences in the pa tien t popula tions and time frame in the MOMENTUM trial compared with the IBM M arketS can Database, M edicare database and the 2022 Knoth et al. study. While MOMENTUM included JAK FUTURE ONCOLOGY 2265 93 161 31 44 112 194 37 53 33 56 11 15 0 50 100 150 200 250 300 350 400 450 Momelotinib Danazol Momelotinib Danazol Travel time RBCT procedure and recovery Preparation and waiting § Baseline TD Baseline TI/TR 238 411 78 113 -173 Hours‡ -35 Hours‡ IBM MarketScan Commercial Database: Time Burden of Transfusion (Hour/Person-Year)† 95 167 36 37 114 201 43 45 33 59 12 13 0 50 100 150 200 250 300 350 400 450 Momelotinib Danazol Momelotinib Danazol Travel time RBCT procedure and recovery Preparation and waiting§ Baseline TD Baseline TI/TR 241 427 91 95 -186 Hours‡ -5 Hours‡ Medicare Database (patients ≥65 years): Time Burden of Transfusion (Hour/Person-Year)†,¶ A B Figure 3. Pr ojected transfusion-r elated time burden for patients based on transfusion status associated with momelotinib vs. danazol. Pr ojected transfusion-r elated time burden for patients in h/person-year associated with momelotinib vs. danazol based on the IBM MarketScan Commercial Database (A) and Medicare database (B) . †Costs of care were extracted from the 2022 Knoth et al. study. This source provided estimates for mean time spent for one RBCT pr ocedur e stratified by time spent during pr ocedur e pr epar ations, w aiting room, w aiting for blood , RBCT pr ocedur e and r ecov ery and r ound-trip trav el time . Refer to Supplementary Table S3. T ime bur dens ar e str atified by tr ansfusion sta tus a t baseline. Refer to Supplementary Table S4. Bars r epr esent time burdens, which were aggregated across patients with known TI/TR or TD status at week 24. ‡Differences in time burden are calculated as time burden for momelotinib minus time burden for danazol. Differences 0 indicate time savings for danazol r elativ e to momelotinib. §Preparation and waiting included time in preparation, waiting room and waiting for blood. Refer to Supplementary Table S7. ¶The sample size of patients in the MOMENTUM trial who w er e aged ≥65 years was 155. The numbers of individuals in this subpopulation in the momelotinib and danazol arms w er e 101 and 54, r espectiv ely. Refer to Supplementary Table S4. RBCT: Red blood cell transfusion; TD: Transfusion dependent; TI: Transfusion independent; TR: Transfusion requiring; USD: US dollar. 2266 L. MASAROVA ET AL. inhibit or–experienc ed, sympt oma tic pa tien ts with ane- mia, both the IBM M arketS can and M edicare databases included both JAK inhibit or–experienc ed and –naive pa tien ts [ 16 , 17 , 28 ]. Time burden for transfusion was esti- mated using the 2022 Knoth et al. study in pa tien ts with transfusion-dependen t β-thalassemia, as estima tes for pa tien ts with MF w er e not available [ 29 ]. Compared with MOMENTUM, this study also had differences in pa tien t characteristics including age and race [ 29 ]. How ev er, pa tien ts with β-thalassemia, similar to those with MF, hav e r educed RBC pr oduction, which oft en nec essitat es RBC transfusions [ 34 ]. Time frames of follow-up also varied across the underlying data sources (i.e., MOMEN- TUM assessed transfusion sta tus a t week 24, the IBM M arketS can analysis included a 2–calendar year study period with continuous enrollment for each pa tien t and the 2022 Knoth et al. study reported transfusion time bur den ov er a 6-month period); ther efor e, transfusion rates, time burden and costs w er e annualized in our analysis [ 16 , 28 , 29 ]. Population sizes also differed and for pa tien ts aged ≥65 years were especially small in the cohort of TD pa tien ts trea ted with danazol (n = 12). Finally, early study discon tinua tion in this population with advanc ed, sympt omatic MF and anemia resulted in unknown or missing transfusion status at week 24. How ev er, sensitivity analyses w er e performed t o ac c ount for these missing data and showed broadly similar results. Based on these limita tions, in terpreta tion of these

should focus on the overall trend demonstrating transfusion-relat ed c ost and pa tien t time savings with momelotinib compared with danazol rather than the numeric cost values, which may not be generalizable for all circumstances. Although transfusion dependency and anemia are crit- ical negative prognostic factors in MF and lead to greater HCRU, cost and time bur den, tr ea tmen t options for TD pa tien ts appear to have minimal impact on the under- lying cause of MF-associated anemia [ 12 , 16 , 18 , 35 , 36 ]. W hile tr ansfusions r apidly incr ease Hb lev els, they do not provide long-term clinical benefits alone and are associated with lower survival , r educed quality of life and complications including iron overload [ 8 , 37–39 ]. Transfusions also increase the burden on healthcare sy st ems because they r equir e infrastructur e, logistics, human r esour c es and financial capital t o ensure blood availability, processing and delivery [ 40 ]. Mor eov er, transfusion dependence and subsequently g reat er HCRU and c osts may r esult fr om my elosuppr es- sive JAK inhibitors such as ruxolitinib and fedratinib, which have been shown to exacerbate anemia [ 41 , 42 ]. In addition, disease-associated or treatment-exac erbat ed anemia may lead to JAK inhibitor dose adjustmen ts, in ter- ruptions or discon tinua tion, which may limit trea tmen t efficacy and are associated with poor survival [ 14 , 42– 46 ]. A r etr ospectiv e r eal-w orld study of 1191 pa tien ts with MF in the US enrolled in the Medicare Adv an tage health plan r ev ealed tha t significan t HCRU and costs remained in pa tien ts trea ted with ruxolitinib, and major drivers of costs included inpa tien t hospitaliza tions and pharmacy costs [ 47 ]. While this study did not analyze pa tien ts with TD vs. TI status or identify what proportion of costs w er e due to transfusions, mean all-cause and MF-relat ed t otal medical c osts w er e incr eased fr om 6 months before MF diagnosis to 6 months after MF diagnosis (all cause, $24,216 to $48,966 and MF r elated , $16,502 to $39,383) [ 47 ]. Beyond JAK inhibitors, common supportiv e tr ea tmen ts for MF-rela ted anemia, including danazol, immunomodulatory drugs and erythropoiesis- stimula ting agen ts, have shown inadequa te efficacy, durability and tolerability [ 8 , 19 , 21 , 22 , 35 , 48 , 49 ]. In c ontrast t o these my elosuppr essiv e JAK inhibitors and supportiv e tr ea tmen ts, momelotinib decreases aber- ran t inflamma tion and facilita tes normalized Hb levels, addressing a high unmet need in pa tien ts with MF- associated anemia, effects driven at least in part by its inhibition of ACVR1 [ 14 ]. In the Phase III MOMEN- TUM trial, momelotinib not only demonstrated clinically significant impr ov ement in MF-associated symptoms, anemia measures and spleen response, but also had higher transfusion independence at week 24 compared with danazol (30% vs. 20%; p = .0116, noninferior) [ 28 ]. Tr ansfusion independence r ate from baseline to week 24 increased by 17% in the momelotinib group vs. 5% in the danazol group [ 28 ]. This analysis using both the IBM M arketS can Commercial Database and the Medicare f ee-f or-service database demonstrates that reductions in transfusions due to trea tmen t with momelotinib may transla te in to meaningful cost offsets and time savings for pa tien ts and the healthcare sy st em. 5. Conclusion While this study focuses on comparing the projected cost and time burden for pa tien ts trea ted with momelotinib and danazol in the MOMENTUM trial, additional analyses will assess the economic and humanistic costs associated with momelotinib r elativ e to ruxolitinib in JAK inhibitor–naive pa tien ts with MF as well as r elativ e to best available therapies in JAK inhibitor –experienced pa tien ts using corresponding analyses from the SIMPLIFY-1 and SIMPLIFY-2 trials. While ac quisition c osts for momelotinib w er e not y et available at the time of the present analysis, budget impact and cost effectiveness models that incorporate this FUTURE ONCOLOGY 2267 informa tion complemen t the r esults described her e and may help determine whether reduced transfusion- relat ed c osts and supportiv e car e c osts associat ed with anemia and other comorbidities can offset drug c osts [ 50 , 51 ]. A s the present analy sis was limit ed t o the 24- week r andomized period of MOMENTUM, futur e r eal- world analyses may be required to ev alua te long-term effects beyond this time point . A nalyses of r eal-w orld data may also be considered to assess pa tien t costs in specific trea tmen t settings. Given tha t initial regula tory approval of momelotinib was in the US, the present analysis is focused on projected cost and time savings from a US perspective; additional analyses to determine impacts in other markets, which are likely to vary, may be w arran ted based on further regulatory decisions. Finally, futur e w ork estimating the time bur den and r esour ce utiliza tion associa ted with MF-rela ted transfusions from the provider and pa tien t’s quality of life perspectives will be important to further describe the potential impact of momelotinib. Article highlights • Momelotinib is a JAK1, JAK2 and ACVR1 inhibitor that targets both the complex drivers of iron-restricted anemia and chronic inflammation in MF, thereby improving constitutional symptoms and splenomegaly while also maintaining or improving Hb levels across the continuum of JAK inhibitor–naive and previously JAK inhibit or–treat ed patients. • Transfusion dependency and moderat e-t o-sev er e anemia are critical negative prognostic factors in MF and lead to significantly higher rates of HCRU and costs in affected patients compared with non-TD patients. • MOMENTUM is a randomized, double-blind study comparing momelotinib and danazol in symptomatic patients with MF and anemia who previously received JAK inhibitor therapy. •P r ojected differ enc es in c ost and time burden associa ted with momelotinib r elativ e to danazol w er e based on patient transfusion data from the MOMENTUM trial and cost estimates from studies using the IBM MarketScan Commercial Database and Medicare f ee-f or-servic e da tabase as w ell as time bur den estimates fr om the 2022 Knoth et al. study. • Reductions in transfusions associated with momelotinib are project ed t o r esult in savings in medical and transfusion-r elated costs and patient time savings r elativ e to danazol in patients with baseline TD and TI/TR status, r espectiv ely, using a terminal TI rate: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and time savings (173 and 35 h per person). •P r o j e c t e d savings in total annual medical costs with momelotinib r elativ e to danazol w er e also shown using a rolling TI rate in patients with baseline TD and TI/TR status ($23,780 and $39,305). •P r o j e c t e d savings in transfusion-related costs and patient time savings with momelotinib r elativ e to danazol w er e also observed for patients aged ≥65 years. •T h e results of this analysis demonstrate that momelotinib not only addresses a high unmet need in patients with MF-associated anemia but may also provide medical cost and time savings for patients by reducing their transfusion dependency. Acknowledgments This study was funded by GSK. Writing support was provided by J Chu (Nucleus Global, an Inizio Company), in ac c ordanc e with the In terna tional Committee of Medical Journal Editors and Good Publication Practice guidelines, and was supported by GSK. We also thank the pa tien ts and families who participated in the trial and all study investigators and site staff. Author contributions All authors w er e inv olv ed in the c ont ent, writing and revising of this r esear ch article. Financial disclosure Funding was provided by GSK. The authors have no other rele- v an t affilia tions or financial inv olv emen t with any organiza tion or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Competing interests disclosure L Masar ova r eports advisory board participation with Cogent, GSK, MorphoSys, and PharmaEssentia. S Verst ov sek rec eived consulting fees from GSK. T Liu is a current employee of GSK. S Rao is a curr ent employ ee of GSK, has st ock/st ock options and r eceiv ed support for attending meetings and/or travel from GSK. G Sajeev is an employee of Analysis Gr oup, Inc ., which r eceiv ed consulting fees fr om GSK for this r esear ch. M Fillbrunn is an employee of Analysis Group, Inc., which received consulting fees from GSK for this r esear ch. R Simpson is an employee of Analysis Group, Inc., which rec eived c onsulting f ees from GSK f or this r esear ch. W Li is an employ ee of Analysis Gr oup, Inc ., which r eceiv ed consulting fees fr om GSK for this r esear ch. J Yang is a former employee of GSK. Y Le Lorier was a former GSK employee. B Gorsh was a former GSK employee and has st ock/st ock options and received support for attending meetings and/or trav el fr om GSK and Daiichi-Sankyo. J Sig norovit ch is an employee of Analysis Group, Inc., which r eceiv ed consulting fees from GSK for this r esear ch. The authors have no other c ompeting int erests or relev an t affilia tions with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing disclosure E ditorial support w as pro vided b y Nucleus Global and funded by GSK plc (Philadelphia, PA). Neither GSK plc nor Nucleus Global influenced the con ten t of this manuscript. Ethical conduct of r esear ch The MOMENTUM study was c onduct ed in ac c ordanc e with the Declaration of Helsinki and the International Council for Harmonisation guidelines on Good Clinical Practice. The institutional review board or independent ethics c ommitt ee at each study site appr ov ed the pr otocol . A full list of the ethics 2268 L. MASAROVA ET AL. c ommitt ees can be found in the associated Supplementary

. All participants provided written informed consent. Data availability statement The authors certify that this manuscript reports the secondary analysis of clinical trial data that have been shared with them, and that the use of these shared data is in ac c ordanc e with the terms (if any) agreed upon their rec eipt. The sourc e of these data is GSK plc (MOMENTUM; ClinicalTrials.gov: NCT04173494). Pr evious pr esenta tion Presented in abstract form at: European Hematology Associa- tion 2023 C ongress , June 8–11, 2023, Frankfurt, Germany [ 52 ]. ORCID Lucia Masarova https://or cid .org/0000-0001-6624-4196

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