Horizon Scanning Research July 2016 & Intelligence Centre

Momelotinib for myelofibrosis

LAY SUMMARY

Myelofibrosis is a rare condition affecting the bone marrow and most people with this condition do not have any symptoms. Bone marrow is where blood cells are made. In myelofibrosis, scar tissue builds up inside the bone marrow and blood cells are not made properly. Occasionally the spleen (which functions as a blood filter) may grow in size due to making too many blood cells. This can cause discomfort and feeling full when eating. This briefing is based on information Momelotinib is a new drug which will offer an additional oral treatment available at the time option for myelofibrosis. Momelotinib is taken as a tablet twice every of research and a day. limited literature search. It is not Momelotinib is currently being studied to see how well it works and intended to be a whether it is safe to use. definitive statement on the safety, efficacy or NIHR HSRIC ID: 5272 effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Primary myelofibrosis (MF) or post-polycythaemia vera MF or post-essential thrombocythaemia MF – patients who have not yet received treatment with a Janus kinase (JAK) inhibitor or those with anaemia or thrombocytopenia who have been previously treated with ruxolitinib.

TECHNOLOGY

DESCRIPTION

Momelotinib (CYT-387; GS-0387; momelotinib dihydrochloride; JAK1/2 inhibitors, MPD, Cytopia) is a selective small molecule JAK1/JAK2 inhibitor. Janus kinases are involved in blood cell formation through the JAK-STAT signalling pathway. In the phase III clinical trial, momelotinib is administered orally as one tablet daily. In a phase II study, momelotinib was administered orally at up to 400mg once daily or 150mg twice daily1.

Momelotinib does not currently have Marketing Authorisation in the EU for any indication. Momelotinib is also in phase III clinical trials for essential thrombocythaemia, pancreatic cancer and polycythaemia vera.

INNOVATION and/or ADVANTAGES

If licensed, momelotinib will offer an additional oral treatment option for myelofibrosis.

DEVELOPER

Gilead Sciences Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Myelofibrosis (MF) is a rare condition affecting the bone marrow2. In MF, fibrosis and scar tissue replaces the normal bone marrow, leading to a reduction in normal bone marrow function. MF is one of a group of conditions known as myeloproliferative disorders (MPDs). MF may be primary (PMF), or secondary to polycythaemia vera (PV – a blood disorder characterised by overproduction of red blood cells in the bone marrow) or essential thrombocythaemia (ET – a blood disorder characterised by the overproduction of platelets by megakaryocytes in the bone marrow). MF can affect people at all ages but is most common amongst those over 502. Initially, patients may have few if any symptoms, such as repeated infections, shortness of breath, fevers and night sweats, weight loss and tiredness1. Other symptoms may develop including gout, nosebleeds, bruising, abnormal vaginal bleeding, bleeding gums, and splenomegaly3. Occasionally the spleen may grow in size due to overproduction of blood cells, this can cause discomfort and feeling full when eating2.

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Approximately 95% of people with PV and 50-60% of people with ET and PMF have a common transformation in the early haematopoietic stem cell of the Janus-associated kinase (JAK) 2 gene3.

CLINICAL NEED and BURDEN OF DISEASE

The annual incidence of all forms of MF is approximately 0.75 per 100,000 population; with a peak incidence of PMF between the ages of 50 and 70 years2,4. The population likely to require treatment for MF is suggested to be 1 in 100,000 per year5.

In 2014-15, there were 3,246 admissions for chronic MPD (ICD-10 D47.1) in England, resulting in 1,399 bed-days and 3,336 finished consultant episodes6. 147 deaths were registered in England and Wales for chronic MPD during 20147.

The population likely to be eligible to receive momelotinib could not easily be estimated from available routine published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386). March 2016. • NICE technology appraisal. Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA289). June 2013.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a. • NHS England. Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation (HSCT) (All Ages). NHSCB/B04/P/a. April 2013.

Other Guidance

• British Committee for Standards in Haematology and the British Society for Haematology Committee. Guideline for the diagnosis and management of myelofibrosis. 20128.

CURRENT TREATMENT OPTIONS

Patients with MF who have no symptoms may not require immediate treatment. Current treatment options for MF aim to control symptoms and include2: • Chemotherapy – e.g. hydroxycarbamide. Chemotherapy may be recommended if symptoms are severe. Chemotherapy can reduce the size of the spleen and liver and can help to control other symptoms. • Blood transfusion – for patients with a low red blood cell count (anaemia), administered as often as required. • Drugs to stimulate haematopoiesis – e.g. danazol, erythropoietin.

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• Targeted therapies – e.g. thalidomide may be given as monotherapy or in combination with corticosteroids. Ruxolitinib inhibits proteins in the JAK/STAT pathway. • Corticosteroids. • Surgery – to remove the enlarged spleen (splenectomy). • Radiotherapy – to shrink the enlarged spleen. • Allogeneic donor stem cell or bone marrow transplant – after high dose chemotherapy. • Interferon alpha – slows down the production of blood cells, including platelets.

EFFICACY and SAFETY

Trial Simplify 2, NCT02101268, GS-US-352- Simplify 1, NCT01969838, GS-US-352- 1214, 2013-005007-13; momelotinib vs 0101, 2013-002707-33; momelotinib vs best available therapy; phase III. ruxolitinib vs placebo; phase III. Sponsor Gilead Sciences Ltd. Gilead Sciences Ltd. Status Ongoing. Ongoing. Source of Trial registry9, manufacturer. Trial registry10, manufacturer. information Location EU (incl UK), USA, Canada and Israel. EU (incl UK), USA, Canada and other countries. Design Randomised, active-controlled. Randomised, active- and placebo- controlled. Participants n=150 (planned); aged 18 yrs and older; n=432 (planned); aged 18 yrs and older; palpable splenomegaly ≥5cm below left palpable splenomegaly ≥5cm below the costal margin; PMF or post-PV/ET MF; left costal margin; confirmed diagnosis of currently or previously treated with PMF or post-PV/ET MF; pts who have ruxolitinib for ≥28 days; high risk or not received prior treatment with a JAK intermediate-2 risk as defined by inhibitor; high risk or intermediate-2 risk Dynamic International Prognostic Scoring as defined by the International Prognostic System (DIPSS), or intermediate-1 risk Scoring System (IPPS) for PMF, or as defined by DIPSS and associated with intermediate-1 risk associated with symptomatic splenomegaly and/or symptomatic splenomegaly, hepatomegaly; therapy for MF must be a hepatomegaly, and/or anaemia; stable dose of the same regimen for ≥2 unresponsive to available therapy. wks prior to screening. Schedule Patients (pts) randomised to receive Pts randomised to receive 200mg 200mg momelotinib oral once daily for 24 momelotinib oral once daily; or ruxolitinib wks; or best available therapy (regimens oral twice daily; or oral placebo once or for best available therapy may include twice daily. Pts meeting symptomatic but are not limited to chemotherapy, spleen growth criteria may be unblinded anagrelide, corticosteroid, by the investigator. Pts in the ruxolitinib haematopoietic growth factor, treatment arm will have the option to immunomodulating agent, androgen, immediately begin the open-label phase interferon or no treatment.), all of the study or proceed to the follow-up administered at doses and schedules phases. determined by the investigator in accordance with standard of care. Therapy may be changed at any time during the study except during the screening period.

After 24 wks all pts may be eligible to receive momelotinib in an extended treatment phase for up to an additional 168 wks (momelotinib arm pts who have tolerated and derived clinical benefit from the randomised treatment phase will be

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eligible. Best available therapy pts with symptomatic spleen growth will be eligible).

Follow-up Active treatment for 24 wks, follow-up 24 Active treatment for 24 wks followed by wks. open-label momelotinib for 168 wks, follow-up 5 yrs. Primary Splenic response measured by MRI or Splenic response measured by MRI or outcome CT. CT. Secondary Total symptom score (measured by the Total symptom score (MPNSAF TSS outcomes modified Myeloproliferative Neoplasm v2.0 diary); rate of RBC transfusions; Symptom Assessment Form Total RBC transfusion independence (absence Symptom Score [MPNSAF TSS] v2.0 of RBC transfusions and no haemoglobin diary); rate of red blood cell (RBC) level ≤8g/dL); RBC transfusion transfusions; RBC transfusion dependence (pts who have ≥4 units of independence (absence of RBC RBC, or a haemoglobin level ≤8g/dL); transfusions and no haemoglobin level patient reported outcomes: modified below 8g/dL in the prior 12 wks); RBC MPNSAF TSS, MPNSAF, EQ-5D, SF- transfusion dependence (pts who have 36v2. ≥4 units of RBC, or a haemoglobin level <8g/dL in the prior 8 wks); patient reported outcomes: modified MPNSAF TSS, MPNSAF, EQ-5D, SF-36v2. Expected Estimated primary completion date Estimated primary completion date reporting October 2016. September 2016. date

Trial NCT02515630; GS-US- NCT01236638, NCT02124746; GS-US- 352-1672; momelotinib; CCL09101E, YM387-II-02; 352-1154; 2013-004476- phase II. momelotinib; phase II 36; momelotinib; phase II extension. extension. Sponsor Gilead Sciences Ltd. Gilead Sciences Ltd. Gilead Sciences Ltd. Status Ongoing. Completed and published Ongoing. in abstract. Source of Trial registry11. Abstract12, trial registry13. Trial registry14. information Location Canada and USA. Australia, Canada and EU (not UK), USA, USA. Canada and Australia. Design Non-randomised, Non-randomised, Non-randomised, uncontrolled. uncontrolled. uncontrolled. Participants n=40 (planned); PMF or n=120; completed ≥9 n=105 (planned); pts post PV/ET-MF; high risk cycles of treatment on enrolled in NCT01236638 or intermediate-2 risk by NCT00935987 and or successfully completed DIPSS or intermediate-1 achieved stable disease, 24 wks of NCT02515630. risk by DIPSS and clinical improvement, associated symptomatic partial remission or splenomegaly and/or complete remission using hepatomegaly; transfusion the International Working dependent at baseline, Group consensus criteria defined as ≥4 units RBC for treatment responses in transfusions in the 8 wks myelofibrosis with myeloid prior to first dose of metaplasia (IWG-MRT); momelotinib. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

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Schedule Pts receive momelotinib Pts continue receiving Pts receive momelotinib oral once daily. The same dose of momelotinib orally once daily for ≤4 yrs. dosage is not reported. assigned during the The dosage is not NCT00935987 protocol reported. (≤400mg once daily); momelotinib administered orally as a single daily dose, except for pts on the twice daily 150mg dosing regimen. Follow-up Active treatment 24 wks, Active treatment up to 24 Active treatment up to 4 follow-up 24 wks. cycles (24 mths), follow-up yrs, follow-up up to 4 yrs. up to 25 mths. Primary Transfusion Long term safety and AEs; safety data; outcomes independence. tolerability; complete incidence and severity of response (CR), partial clinical laboratory response (PR) and clinical abnormalities. improvement (CI) according to IWG-MRT consensus criteria. Secondary Transfusion response; No quality of life Overall survival; outcomes anaemia markers; measurement included in progression-free survival; pharmacodynamic trial outcomes. leukaemia-free survival; biomarkers; splenic rate of RBC transfusion; response rate measured duration of splenic by MRI; MPNSAF TSS; response; duration of pharmacokinetics; change transfusion independence in circulating cytokine and response; duration of inflammatory markers. anaemia response; transfusion response rate. No quality of life measurement included in trial outcomes. Key results - Median time to onset of - spleen response (SR) was not yet reached (range 6- 693 days); median duration of SR was 324 days (range 56-936); median duration of 12-wk transfusion independence was not yet reached (range 91-987 days); median duration of anaemia response was not yet reached (range 57- 987). Constitutional symptoms assessment at 3 mths for the core study showed ≥50% improvement in 72%, 46%, 77%, 100%, and 74% of pts for pruritus, cough, bone pain, fever, and night sweats, respectively. Adverse - Most common grade 3 or - effects (AEs) 4 treatment-related AEs were thrombocytopenia

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(29%), neutropenia (5%), and elevated lipase (4%) without clinical pancreatitis. Peripheral neuropathy was reported by 38% of pts, all ≤grade 2, with 17 pts experiencing neuropathy at baseline. Four pts developed acute leukaemia (1 in core study, 3 in extension study).There were no treatment-related deaths. Expected Estimated study - Estimated study reporting completion date May completion date Jun 2019. date 2017.

Trial NCT01423058; YM387-II-02; NCT00935987, CCL09101; momelotinib; momelotinib; phase I/II. phase I/II. Sponsor Gilead Sciences Ltd. Gilead Sciences Ltd. Status Completed but unpublished. Completed but unpublished. Source of Trial registry15. Trial registry16. information Location USA and Canada. USA, Canada and Australia.

Design Non-randomised, uncontrolled. Non-randomised, uncontrolled. Participants n=61; PMF or post-PV/ET MF; high-risk, n=166; aged 18 yrs and older; PMF or intermediate-2 risk, or intermediate-1 risk post-PV/ET MF; high-risk or by IPSS associated with symptomatic intermediate-2 risk MF myelofibrosis or splenomegaly/hepatomegaly and/or intermediate-1 risk MF (IPSS) associated unresponsive to available therapy; ECOG with symptomatic performance status of 0, 1 or 2. splenomegaly/hepatomegaly and/or unresponsive to available therapy; ECOG performance status of 0, 1 or 2. Schedule Pts assigned to dose levels in successive Pts assigned to dose levels in successive cohorts from oral 200mg momelotinib cohorts, from oral 100mg momelotinib twice daily; doses escalated by 50mg once daily or oral 150mg momelotinib (twice daily) in successive cohorts of 3 twice daily. In the later stage of this trial, pts per dose level. Maximum dosage not pts will be assigned to either 150mg or reported. 300mg once daily oral dose groups.

Follow-up Length of active treatment not reported. Active treatment for 9 cycles (9 mths), Follow-up 6 cycles. follow-up 10 mths. Primary Safety by AEs, vital signs, laboratory Safety and tolerability, dose-limiting outcomes parameters, QTc intervals and dose toxicities and maximum tolerated dose; limiting toxicities; pharmacokinetics; objective response rate measured by CR, spleen and liver size, disease related PR and CI according to IWG-MRT constitutional symptoms, transfusion consensus criteria; pharmacokinetics. dependence and anaemia response. Secondary JAK2V617F mutant allele burden; Bone marrow or peripheral blood outcomes plasma levels of inflammatory, fibrogenic cytogenetics; peripheral blood and angiogenic cytokines; bone marrow granulocyte JAK2V617F allele burden; or peripheral blood cytogenetic findings. peripheral blood endogenous myeloid No quality of life measurement included colony formation; plasma levels of in trial outcomes. inflammatory, fibrogenic and angiogenic cytokines; pharmacodynamics. No quality of life measurement included in trial outcomes.

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Expected Previously reported as June 2014. Previously reported as April 2012. reporting date

ESTIMATED COST and IMPACT

COST

The cost of momelotinib is not yet known.

Ruxolitinib is licensed for the treatment of disease-related splenomegaly or symptoms in patients with PMF, post-PV/ET MF, or post-EV MF; a pack of 56 x 20mg ruxolitinib tablets costs £3,36017.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: may cause reduced transfusion  No impact identified dependence.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: may cause reduced transfusion dependence.

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs: may cause reduced transfusion dependence.

 Other: uncertain unit cost compared to  None identified existing comparator treatments.

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion suggests that the patients who have not received prior treatment need to be better defined, i.e. whether the treatment is intended for intermediate-2 and high risk MFa.

Expert opinion suggests that there is an unmet need in patients with MF, as patients will eventually lose their response to all current treatments as they are not curativea.

a Expert personal opinion.

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The research question posed by experts concerns the real outcomes of momelotinib therapy; research is required into whether this drug will improve survival which would require a longer follow-up of patientsa.

Experts question the use of momelotinib as a preparation for bone marrow transplant and whether it would be effective in shrinking the spleen and getting the patient in better shape, and then how long should it be continued for and when should it be stopped. Clinical trials to address this question would be neededa.

REFERENCES

1 ClinicalTrials.gov. A phase II, open-label extension study evaluating the long term safety, tolerability & efficacy of orally-administered CYT387 in primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis. www.clinicaltrials.gov/ct2/show/NCT01236638 Accessed 20 July 2016. 2 Macmillan. Myelofibrosis (MF). www.macmillan.org.uk/information-and-support/blood- cancer/blood-disorders-neoplasms/myelofibrosis.html Accessed 20 July 2016. 3 National Institute for Health and Clinical Excellence. Final scope for the proposed appraisal of ruxolitinib for the treatment of myelofibrosis. Technology appraisal. London: NICE; August 2012. 4 National Institute for Health and Care Excellence. Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. Technology appraisal TA386. London: NICE; March 2016. 5 National Institute for Health and Care Excellence. Ruxolitinib for disease-related splenomegaly or symptoms in adults with myelofibrosis. Technology appraisal TA289. Costing statement. London: NICE; June 2013. 6 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk 7 Office for National Statistics. Deaths registered in England and Wales (series DR), 2014. www.ons.gov.uk 8 Reilly JT, McMullin MF, Beer PA et al. Guideline for the diagnosis and management of myelofibrosis. British Journal of Haematology 2012;158(4):453-471. 9 ClinicalTrials.gov. A phase 3, randomized study to evaluate the efficacy of momelotinib versus best available therapy in anemic or thrombocytopenic subjects with primary myelofibrosis, post- polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who were treated with ruxolitinib. www.clinicaltrials.gov/ct2/show/NCT02101268 Accessed 20 July 2016. 10 ClinicalTrials.gov. A phase 3, randomized, double-blind active-controlled study evaluating momelotinib vs. ruxolitinib in subjects with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/ET MF). www.clinicaltrials.gov/ct2/show/NCT01969838 Accessed 20 July 2016. 11 ClinicalTrials.gov. A phase 2, open-label, translational biology study of momelotinib in transfusion- dependent subjects with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/ET MF). www.clinicaltrials.gov/ct2/show/NCT02515630 Accessed 20 July 2016. 12 Pardanani A, Gotlib JR, Gupta V et al. Update on the long-term efficacy and safety of momelotinib, a JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis. 55th American Society of Hematology Annual Meeting and Exposition. December 2013. Abstract number 108. Oral presentation. 13 ClinicalTrials.gov. A phase II, open-label extension study evaluating the long term safety, tolerability & efficacy of orally-administered CYT387 in primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis. www.clinicaltrials.gov/ct2/show/NCT01236638 Accessed 20 July 2016.

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14 ClinicalTrials.gov. Open-label study to assess the long-term safety and efficacy of momelotinib in subjects with primary myelofibrosis, post-polycythemia vera myelofibrosis, post essential thrombocythemia myelofibrosis, polycythemia vera or essential thrombocythemia. www.clinicaltrials.gov/ct2/show/NCT02124746 Accessed 20 July 2016. 15 ClinicalTrials.gov. A phase I/II, open-label study evaluating twice-daily administration of CYT387 in primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis. www.clinicaltrials.gov/ct2/show/NCT01423058 Accessed 20 July 2016. 16 ClinicalTrials.gov. A phase I/II, open-label, dose-escalation study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of orally-administered CYT387 in primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis. www.clinicaltrials.gov/ct2/show/NCT00935987 Accessed 20 July 2016. 17 Joint Formulary Committee. British National Formulary. BNF June 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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