Momelotinib a JAK inhibitor vs Danazol in Myelofibrosis

Momelotinib Shows Promising JAK and ALK2 Inhabitation in Patients With Anemic Myelofibrosis: MOMENTUM Study

It’s my pleasure today to discuss with you the results of the MOMENTUM study as presented at EHA 2022. The MOMENTUM study is an incredibly important study in the development of a drug called Momelotinib, a JAK inhibitor that differentiates itself from other inhibitors that are already approved for the treatment of patients with myelofibrosis.

What Effects Did Momelotinib Have on ACVR1?

A key off-target effect on a molecule called ACVR1, also known as ALK2, It does have the kind of canonical JAK inhibition of JAK2 that we see with other JAK inhibitors. But again, the standout feature is this off-target effect on ACVR1/ALK2 CVR. What that does is it’s a master regulator of iron metabolism in our body and actually affects hepcidin levels.

Momelotinib and the Concerns for Patients with Myelofibrosis

It can lower hepcidin levels, thus treating the inflammatory component of anemia. To treat anemia is an incredibly important problem in patients with myelofibrosis. It is a diagnostic criterion as well as a prognostic criterion for patients with this disease. And there is some retrospective analysis suggesting that if we could impact disease-related anemia and improve it, patients could have better overall survival in addition to better quality of life and potentially better resource utilization.

Momelotinib and Previously Treated Patients with Myelofibrosis

So, in this trial, the MOMENTUM study, momelotinib as a JAK inhibitor slash ACVR1 inhibitor was pitted against Danazol in anemic patients with myelofibrosis previously treated with JAK inhibitors. These patients also had to be symptomatic and have enlarged spleens. The top line results were previously released in a press release from the company.

But in these abstracts, we have much more detail on the outcomes for the primary endpoint of this study. The primary endpoint of the study was an improvement in symptom burden at week 24. Additional key secondary endpoints included spleen vine responses at week 24, as well as red blood cell transfusions independence at week 24. So, taking that last point is key because Danazol was selected as a comparator arm because it is used to treat anemia in myelofibrosis patients as recommended by the NCCN and ESMO guidelines.

Results From the Momelotinib Arm of the Trial

So, in those results, the Momelotinib arm outperformed the Danazol arm in terms of transfusion independence at week 24. Moreover, Momelotinib was able to shrink spleens as well as improve disease related symptoms in patients to a much greater degree as compared to Danazol. I think that is really the key take-home point from the momelotinib study. The top-line total study results were presented by Dr. Verstovsek, and the special subset of patients with thrombocytopenia were presented by Dr. Verstovsek at this year’s EHA meeting in two separate abstracts. And the reason that we focused on patients with lower platelet counts is that earlier momelotinib trials, as well as this trial, did include patients with thrombocytopenia.

What Other Factors Were Include in this Arm of the Momelotinib Trial?

In fact, we included patients with a platelet count as low as 25,000. Therefore, severe thrombocytopenia was included in the momelotinib study, and a fair number of patients did have severe thrombocytopenia. And I think that’s really important to note because currently available Ruxolitinib and Fedratinib have limits on how much we can use them in clinical oncology and what doses because of thrombocytopenia.

Of course, there is the approved Pacritinib that can be safely given to patients with platelet counts of less than 50,000. So as more and more JAK inhibitors come into clinical use every day in the clinic, I think it’s going to be really important how we try to separate these things out and which patient populations have data that supports the use of these drugs as well.

In Which Patient Populations do These Drugs Work Best?

Again, these were a lot of the top-line results from the momelotinib study, but the work going forward would really be on identifying the best populations for each of these JAK inhibitors. Now that we have almost an embarrassment of riches in the number of JAK inhibitors approved, the next step for this particular momelotinib is really regulatory approval.

The momelotinib trial was registration and the data is being further cleaned up and correlated and is being put together for regulatory submission to the FDA for hopefully regulatory momelotinib approval sometime in the year 2023. The quicker we can get momelotinib to our patients, the better.

Momelotinib Trial Details and Information

What Type of Cancer is Myelofibrosis (MF)?

Is one of the “myeloproliferative neoplasms (MPNs),” a type of blood cancer in which bone marrow cells that make blood cells grow and behave improperly.

Severe Anemia In Patients with Myelofibrosis?

Transfusions of blood If you have severe anemia, regular blood transfusions can boost your red blood cell count and alleviate symptoms like exhaustion and weakness. Medication like momelotinib can sometimes help improve anemia in patients with myelofibrosis.

What is Transfusion Dependence?

Despite the lack of a unified definition, transfusion dependence (TD) is typically defined as patients who require regular platelet and/or red blood cell (RBC) transfusions more frequently than every 8 weeks due to a consistently low count.

Author Credentials and Affiliations

Aaron T. Gerds, MD, MS from the Cleveland Clinic, Dr. Aaron Gerds earned his bachelor’s degree in biology and chemistry with honors from Hope College in Holland, Michigan. Following that, he earned his M.D. from Loyola University Chicago Stritch School of Medicine. Dr. Gerds completed his Internal Medicine residency at Loyola University Hospital, where he also served as head resident. While examining clinical trial results under the tutelage of Dr. Patrick Stiff, he became interested in hematology for the first time. During his residency, he decided to pursue a master’s degree in clinical research methodologies and epidemiology. Dr. Gerds then moved to Seattle to finish his hematology/oncology fellowship at the University of Washington’s Fred Hutchinson Cancer Research Center. He received the ASBMT’s New Investigator Award during his fellowship. Dr. Gerds subspecialized in treating patients with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML), with a special emphasis on allogeneic hematopoietic cell transplantation Dr. Gerds is also an active member of the American Society of Hematology, having participated in the Advocacy Leadership Institute, Clinical Research Training Institute, and Test Materials Development Committee. Dr. Gerds, an Assistant Professor of Medicine (Hematology and Medical Oncology) at the Cleveland Clinic Taussig Cancer Institute, is the principal investigator for a number of clinical trials for the emerging treatment of MPNs, and her research is focused on identifying novel therapeutics for these patients.

MOMENTUM Design and Results of Momelotinib Trial

Momelotinib, a new oral ACVR1/ALK2 and JAK1/2 inhibitor, demonstrated clinical activity in the SIMPLIFY trials for MF symptoms, RBC transfusion requirements (anemia), and spleen volume.

Targets: Patients With Myelofibrosis Treated

This pivotal phase 3 research compared Momelotinib to Danazol on major symptoms, anemia, and spleen volume endpoints at 24 weeks in MF patients previously treated with a JAK inhibitor (JAKi) (wks), looking at the total symptom score.

Eligibility requirements include – Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) 10; hemoglobin (Hgb) 10 g/dL; prior JAKi for 90 days, or 28 days if RBC transfusions 4 units in 8 wks or Gr 3/4 thrombocytopenia, anemia in patients with myelofibrosis, or hematoma; palp TSS (22 vs 22), palpable spleen (12 cm vs 12 cm), and RBC units transfused (0, 1-4, and 5+) stratification The JAKi taper and washout took 21 days. Randomization – Momelotinib 200 mg QD + Danazol placebo or Danazol 600 mg QD plus Momelotinib placebo for 24 weeks, followed by open-label Momelotinib. Assessments: The patient kept a daily eDiary and had his spleen volume measured with an MRI or CT. TSS response (50 percent reduction from baseline [BL]) rate was the primary goal at week 24. Secondary objectives were RBC TI rate, splenic response rate (SRR; 25% reduction in volume from BL), change from BL in TSS, SRR (35 % reduction from BL), and rate of zero transfusions since BL, all examined sequentially at wk 24. All participants provided informed consent.

Clinical Oncology Outcomes and Conclusions

The 24-week randomized treatment (RT) phase was completed by 94 of 130 (72%) Momelotinib patients and 38 of 65 (58%) Danazol patients. Hgb levels were 8.1 (Momelotinib) and 7.9 (Danazol) g/dL, and platelets were 97 (Momelotinib) and 94 (Danazol) x109/L, respectively. BL TI was 13% (Momelotinib) and 15% (LMB) (Danazol). The mean spleen volume in BL patients was 2367 (Momelotinib) and 2288 (Danazol) cm3. Prior JAK inhibitor was treated with ruxolitinib in 195 patients treated (100%) and fedratinib in 9 patients (5%); the mean duration of prior JAK inhibitor was 134 weeks. All of the primary and key secondary endpoints were met (Table). The most common grade 3 treatment-emergent adverse events (TEAEs) in the RT phase of the research were thrombocytopenia (Momelotinib, 22%; Danazol, 12%). (Momelotinib, 8 percent ; Danazol, 11 percent ). Gr 3 infections occurred in 15% of Momelotinib patients and 17% of Danazol patients. Peripheral neuropathy (PN) occurred in 5% of Momelotinib (all Gr 2) and 2% of Danazol (Gr 2) Pts during the RT phase, with no patients discontinuing study medication due to PN. Overall, TEAEs caused study drug discontinuation in 18% of Momelotinib and 23% of Danazol patients, with significant TEAEs observed in 35% of Momelotinib and 40% of Danazol patients during the RT phase. Momelotinib vs Danazol showed a trend toward improved overall survival up to week 24 (HR=0.506, p=0.0719).

Momelotinib was superior to Danazol in symptomatic and anemic MF patients for symptom responses, transfusion requirements, and spleen responses, with comparable safety and good survival. Momelotinib may fill a crucial unmet need, especially in patients with myelofibrosis with anemia. NCT04173494.

From Sierra Oncology, Inc

MOMENTUM  is a randomized, double-blind Phase 3 clinical trial comparing momelotinib to danazol (n=180; 2:1) in symptomatic, anemic patients who have previously received treatment with an authorized JAK inhibitor. The study’s goal is to confirm [in a statistically significant way] momelotinib’s distinctive advantages on all three hallmarks of myelofibrosis (MF): symptoms, anemia, and splenomegaly in patients with myelofibrosis.

The MFSAF Total Symptom Score (TSS) response rate at Week 24 is the study’s primary goal. Secondary objectives were anemia benefit and splenic response rate confirmation.

Danazol was chosen as an appropriate therapy comparator since it has been shown to improve anemia in myelofibrosis patients, as suggested by NCCN and ESMO guidelines. Patients will be randomly assigned to either momelotinib or danazol. Patients on danazol will be able to switch to momelotinib after 24 weeks of treatment. For confirmed symptomatic splenic progression, an early cross-over to momelotinib is available.

Dr. Srdan Verstovsek, Chief, Section for Myeloproliferative Neoplasms, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and Dr. Ruben Mesa, Director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center, are the study’s co-Chief Investigators. Dr. Verstovsek and Dr. Mesa are both world-renowned clinician scientists in the field of myeloproliferative neoplasms. Most investigational and authorized medications for the treatment of myelofibrosis have been developed by Drs. Verstovsek and Mesa. Dr. Verstovsek and Dr. Mesa, in particular, have been involved in the development of momelotinib as consultants and clinical investigators since 2011.

Criterias:

Momelotinib Criteria for Inclusion:

• 18 years old.

• A PMF diagnosis has been verified, according to the World Health Organization.

• World Health Organization (WHO) 2016 standards, or Post-PV/ET MF in accordance with

• Myeloproliferative Neoplasms Research and Treatment (MRT) International Working Group (IWG-MRT criteria).

• Symptomatic, defined as a TSS of 10 units as determined by a single MFSAF v4.0 evaluation prior to Day BL1.

• Anemia is defined as a Hgb level of less than 10 g/dL during the screening or baseline period.

• Previously treated for 90 days with an authorized JAK inhibitor for PMF or Post-PV/ET MF, or 28 days if JAK inhibitor therapy is complicated by an RBC transfusion requirement of 4 units every 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma.

• Baseline splenomegaly is defined as having a palpable spleen at 5 cm, below the left costal margin, or with a volume of 450 cm3 on imaging (ultrasound, MRI, or CT are acceptable) at any point before randomization.

• DIPSS or DIPSS-plus defines high risk, intermediate-2, or intermediate-1 risk MF.

• There are no plans for an allogeneic stem cell transplant.

• Acceptable laboratory evaluations:

• The absolute neutrophil count (ANC) was 0.75 109/L.

• PLT (platelet count): 25 109/L (without requirement for platelet transfusion).

• Peripheral blast count is 10%.

• Alanine aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) 3 ULN ( 5 ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy started within

• Cockcroft-Gault calculated creatinine clearance (CCr) of 30 mL/min.

• 2.0 ULN for direct bilirubin.

Momelotinib Criteria for Exclusion:

1. Use the following approved therapies within the time frames specified:

   1. Prior momelotinib treatment is possible at any moment.

   2. Approved JAK inhibitor medication (e.g., fedratinib or ruxolitinib) must be started within one week of the first day of Baseline.

   3. Active anti-MF therapy should begin no later than one week before the first day of Baseline.

   4. Potent inducers of Cytochrome P450 3A4 (CYP3A4) within 1 week of Randomization

   5. Within 4 weeks of Randomization, the investigational medication (including investigational JAK inhibitors) was administered.

   6. ESA (erythropoiesis stimulating agent) within 4 weeks of Randomization

   7. Danazol was administered within three months of the randomization.

   8. Irradiation of the spleen within three months of the randomization.

   9. Current medication includes simvastatin, atorvastatin, lovastatin, or rosuvastatin.

2. Prostate cancer history, with the exception of localized prostate cancer treated surgically or with radiotherapy with curative aim and deemed cured.

3. PSA concentrations more than 4 ng/mL.

4. Unsuitable for spleen volume measurements due to prior splenectomy or reluctant or unable to have an MRI or CT scan as required by protocol.

5. Any of the following (criteria a through k):

   1. Active uncontrolled infection (subjects receiving outpatient antibacterial and/or antiviral therapy for infection that is under control or as infection prophylaxis may be included in the experiment).

   2. Significant active or persistent bleeding incident grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks of Randomization.

   3. Unstable angina pectoris within the last 6 months.

   4. Symptomatic congestive heart failure within the previous 6 months of Randomization.

   5. Uncontrollable heart arrhythmia within 6 months of randomization

   6. Unless attributed to a bundle branch block, the QTcF interval is greater than 500 msec.

   7. Thrombosis is currently progressing despite treatment.

   8. Porphyria has a long history.

   9. Child-Pugh score of ten

   10. Psychiatric illness, social position, or any other condition that, in the opinion of the investigator or sponsor, may impede compliance with trial conditions or may interfere with the interpretation of study data.

   11. Failure or reluctance to adhere to protocol limits on MF therapy and other drugs prior to and during trial treatment.

6. Subjects having a past or concurrent malignancy whose natural history or treatment has a considerable potential to interfere with the investigational regimen’s safety or clinically important efficacy assessment.

7. Anemia caused by iron, vitamin B12, or folate deficits, autoimmune or genetic hemolytic anemia, gastrointestinal hemorrhage, or thalassemia.

8. The HIV status is known to be positive.

9. Acute or chronic viral hepatitis A, B, or C infection, or hepatitis B or C carrier (testing required for hepatitis B and C).

10. Unresolved non hematological toxicity from prior therapy that are greater than Grade 1 according to CTCAE v5.0.

11. Peripheral neuropathy, grade 2 according to CTCAE v5.0.

12. Women who are pregnant or breastfeeding.

Additional criteria for inclusion or exclusion may apply.

References

Aaron T. Gerds, MD, Cleveland Clinic – OncologyTube Interview, May 18, 2022

Sierra Oncology, Inc. – MOMENTUM Clinical Trial for Momelotinib – Sierra Oncology Trials, February 11, 2022

ClinicalTrials.gov – A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Patients (MOMENTUM). ClinicalTrials.gov, February 11, 2022