Ponsegromab for use in treating cachexia in cancer patients

Abstract

The invention is directed to methods of treating cancer cachexia or cancer by administering to the patient a GDF15 antibody ponsegromab, and especially while the patient is receiving a systemic chemotherapy.

Description

[0001] PONSEGROMAB FOR USE IN TREATING CACHEXIA IN CANCER PATIENTS

[0002] Field

[0003] The present invention relates to both single agent and combination therapies useful for the treatment of cancer cachexia, cancer and heart failure using a GDF15 antibody.

[0004] Background

[0005] Cancer cachexia has long been studied and is generally defined according to international consensus. See K. Fearon et al Lancet Oncol 2011 ; 12:489-95, the disclosure of which is hereby incorporated by reference in its entirety. Ponsegromab, a GDF15 antibody, is described as GDF15_001 in International Patent Application Publication W02020039321 , the disclosure of which is herein incorporated by reference in its entirety. Ponsegromab has been in clinical trials since 2018, in healthy adults, cancer cachexia patients and heart failure patients. In a very recent and still on-going clinical trial where cancer cachexia patient was administered ponsegromab, outstanding results have been obtained demonstrating that ponsegromab is efficacious toward cancer cachexia and has a great safety profile under the dosing regimen used in the trial.

[0006] Summary

[0007] The invention is directed to a method of treating a condition in a patient with cancer, wherein the condition is cancer cachexia or cancer, comprising administering to the patient an anti-GDF15 antibody ponsegromab or a pharmaceutical product thereof, in a dosing regimen of 400 mg Q4W subcutaneous (SC) or 200 mg Q4W SC, wherein the patient also receives a systemic chemotherapy for the treatment of the cancer. In some embodiments, the condition is cancer cachexia. In some embodiments, the condition is the malignant solid tumor. In some embodiments, the condition is cancer. In some embodiments, the cancer is a malignant solid tumor.

[0008] In some embodiments, the malignant solid tumor is metastatic or locally advanced solid tumor. In some embodiments, the solid tumor is pancreatic cancer, lung cancer, colorectal cancer, gastric cancer, biliary cancer, or esophageal cancer. In some embodiments, the solid tumor is untreated metastatic or locally advanced pancreatic cancer. In some embodiments, the treatment of cancer cachexia with ponsegromab is a neoadjuvant to the surgery of the advanced or metastatic solid tumor, and the advanced solid tumor is borderline resectable before the treatment of ponsegromab and resectable after the treatment of ponsegromab. In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In some embodiments, the malignant solid tumor is metastatic or locally advanced pancreatic cancer, and the systemic chemotherapy is a nab-paclitaxel and gemcitabine chemotherapy regimen, or a FOLFIRINOX chemotherapy regimen.

[0009] In some embodiments, (i) a first dose of the systemic chemotherapy is administered before or on the same day when a first dose of the ponsegromab is administered, and (ii) the patient receives the systemic chemotherapy for at least 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks or 24 weeks starting from the administration of the first dose of ponsegromab. In some embodiments, the patient receives the first dose of systemic chemotherapy on the same day, or one day, two days, three days, one week, two weeks, or three weeks after the first dose of ponsegromab is administered. In some embodiments, the patient receives at least one cycle, two cycles, three cycles, or four cycles of systemic chemotherapy during the treatment of ponsegromab.

[0010] In some embodiments, the administration of ponsegromab is not conditioned on (i) the patient having an elevated GDF15 serum level, or (ii) the patient having an elevated GDF15 serum level as measured by a test including but not limited to a GDF15 binding assay, and the test is approved by a regulatory agency of United States Food and Drug Administration (USFDA), European Medicines Agency (EMA) or Japan’s Pharmaceutical and Medical Devices Agency (PMDA). In some embodiments, the elevated GDF15 serum level is 1.2 ng / mL or higher. In some embodiments, the elevated GDF15 serum level is 1.5 ng / mL or higher.

[0011] In some embodiments, the patient has an elevated GDF15 serum level at the baseline. In some embodiments, the elevated GDF15 serum level is 1.2 ng / mL or higher. In some embodiments, the elevated GDF15 serum level is 1.5 ng / mL or higher. In some embodiments, the patient has a GDF15 serum level of 0.6 ng / mL or higher or 1.0 ng / mL or higher. In some embodiments, the patient has a GDF15 serum level between 0.6 ng / mL and 1 .0 ng / mL at the baseline. In some embodiments, the patient has a GDF15 serum level less than 1 .2 ng / mL but more than 0.6 ng / mL or mor than 0.8 ng / mL, or more than 1 .0 ng / mL at the base line.

[0012] The invention is also directed to a method to treat a condition in a patient, wherein the condition is cancer cachexia, cancer, or heart failure, comprising administering to the patient an anti-GDF15 antibody ponsegromab, in a dosing regimen of 400 mg Q4W SC, 200 mg Q4W SC, or 200 mg Q2W SC, wherein the patient has an elevated GDF15 serum level. In some embodiments, the condition is cancer cachexia. In some embodiments, the patient is an adult. In some embodiments, the cancer is a solid malignant tumor.

[0013] The invention is also directed to a method to treat a condition in a patient, wherein the condition is cancer cachexia, cancer, or heart failure, comprising administering to the patient an anti-GDF15 antibody ponsegromab or a pharmaceutical composition thereof, in a dosage form that contains 150 mg / mL of ponsegromab, and in an dosing regimen of 200 -400 mg every 2 to 4 weeks SC, wherein the patient has an elevated GDF15 serum level. In some embodiments, the patient is an adult. In some embodiments, the cancer is a malignant solid tumor. In some embodiments, the dosage form contains 150 - 200 mg / mL including but not limited to 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 and 200 mg / mL of ponsegromab. In some embodiments, the patient has an elevated GDF15 serum level. In some embodiments, the elevated GDF1 5 serum level is 1 .2 ng / mL or higher. In some embodiments, the patient has a GDF1 5 serum level of 0.6 ng / mL or higher, 0.8 ng / mL, or 1 .0 ng / mL or higher.

[0014] In some embodiments, the elevated GDF15 serum level is 1 .5 ng / mL or higher. In some embodiments, the elevated GDF15 serum level is measured by a test including but not limited to a GDF15 antibody binding assay, and the test is approved by a regulatory agency of FDA, EMA or Japan PMDA.

[0015] In some embodiments, the dosing regimen is 400 Q4W SC. In some embodiments, the dosing regimen is 200 Q4W SC. In some embodiments, the dosing regimen is 200 mg Q2W SC. In some embodiments, if the patient takes one or more premedications on the same day when ponsegromab is administered, ponsegromab is administered prior to the patient taking any of the one or more premedications. In some embodiments, if the patient takes one or more antineoplastic medications on the same day that ponsegromab is administered, ponsegromab is administered prior to the patient taking any of the one or more antineoplastic medications.

[0016] In some embodiments, the dosing regimen is 400 mg Q4W SC, and the 400 mg ponsegromab is administered each time by dividing the 400 mg into two portions and administering to the patients in two separate SC injections in rapid succession on the same day. In some embodiments, the two portions are about equal amounts. In some embodiments, the two portions are about 1.1 :1 , 1.2 :1 , 1.3:1 , 1.4 :1 , 1.5 :1 , 1.6:1 , 1.7:1 , 1.8:1 , 1.9:1 , 2:1 in amounts. In some embodiments, the two separate subcutaneous injections are administered to the patient at two different injection sites. In some embodiments, the two different injections sites are selected from the group consisting of upper left arm, upper right arm, abdomen, left thigh and right thigh.

[0017] In some embodiments, ponsegromab is administered to the patient using an autoinjector or a prefilled syringe. In some embodiments, the autoinjector is a SHL Molly 2.25mL Pre-filled Pen or a Ypsomate 2.25mL Pre-filled Pen.

[0018] In some embodiments, the method further comprising administering to the patient one or more premedication on the same day that ponsegromab is administered. In some embodiments, ponsegromab is administered prior to the administration of the premedications.

[0019] In some embodiments, the method further comprises administering to the patient one or more anti-neoplastic agent on the same day that ponsegromab is administered. In some embodiments, ponsegromab is administered prior to the administration of the antineoplastic agent. In some embodiments, ponsegromab is administered prior the administration of any of the premedications or any of the antineoplastic agents.

[0020] In some embodiments, the patient has more than 2.5 kg or 5% of body weight increase after 12 weeks of treatment of ponsegromab compared to the baseline. In some embodiments, the increase is placebo adjusted. In some embodiments, the patient has 1.5 - 3.3 kg of body weight increase after 12 weeks of treatment of ponsegromab comparing to the baseline. In some embodiments, the patient has 0.9 - 2.1 kg of body weight increase after 12 weeks of treatment of ponsegromab comparing to the baseline. In some embodiments, the patient has 5% or more increase in body weight after 24 weeks treatment of ponsegromab comparing to the baseline. In some embodiments, the patient has 3%, 2%, 1 % or more increase in body weight comparing to the baseline after 12 weeks or after 24 weeks treatment of ponsegromab. In some embodiments, the patient has maintained stable body weight comparing to the baseline after 12 weeks or after 24 weeks treatment of ponsegromab. As used herein, maintaining a stable body weight refers to the body weight remains within 1 %, within 2% or within 3% increase or decrease of the baseline.

[0021] In some embodiments, the patient experiences an increase of appetite, or a reduction of anorexia as shown in Table 2. In some embodiments, the patient experiences an increase in FAACT-Anorexia and Cachexia Subscale (ACS) score of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points or more after 12 weeks of treatment of ponsegromab compared to that at the baseline. In some embodiments, the patient experiences an increase in FAACT-5 item anorexia symptom scale (5IASS) of 1 point, 2 points, 3 points or more after 12 weeks of treatment of ponsegromab compared to that at the baseline.

[0022] In some embodiments, the patient experiences an increase of physical activity as measured by a wearable digital device as shown in Table 3. In some embodiments, the patient’s non-sedentary physical activity in minutes per day measured by the wearable digital device increases, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or more after 12 weeks of treatment of ponsegromab comparing to that at the baseline. In some embodiments, the patients total vector magnitude (total activity counts / 100 per day) measured by the digital wearable device increases 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or more after 12 weeks of treatment of ponsegromab comparing to that at the baseline.

[0023] In some embodiments, 30% of the patients experience clinically meaningful and / or patient deemed meaningful physical activity improvement, as defined herein, after 12 weeks or after 24 weeks treatment of ponsegromab. In some embodiments, the physical activity improvement is measured through passive quantitative measurement of physical activity by a digital device. In some embodiments, the digital device is deemed acceptable by a treating physician of the patient, or by the regulatory agency. In some embodiments, the physical activity improvement is an increased non- sedentary physical activity of more than 10, 15 or 20 minutes a day after 12 weeks or 24 weeks of treatment of ponsegromab. In some embodiments, the physical activity improvement is an increased total vector magnitude of more than 100, 200 or 300 per day after 12 weeks or 24 weeks of treatment of ponsegromab.

[0024] In some embodiments, 10%, 20%, 30%, 40% or 50% of the patients experience clinically meaningful symptom or function improvements, as defined herein, after 12 weeks or 24 weeks of ponsegromab treatment. In some embodiments, symptom or function improvement is (a) measured through Patient-Reported Outcomes Measurement Information System (PROMIS), Functional Assessment of Anorexia- Cachexia Therapy (FAACT), FAACT- 5 item anorexia symptom scale (5IASS) or Cancer Related Cachexia Symptom Diary (CRCSD); (b) measured by a digital device deemed acceptable by a treating physician of the patient; or (c) as determined by a treating physician of the patient. In some embodiments, the patient receives a 6 minute-walk test (6MWT) and the 6MWT results improves after 12 weeks or 24 weeks treatment of ponsegromab by 10 meters, 20 meters, 30 meters, 40 meters, 50 meters, 60 meters, 80 meters 100 meters, 125 meters, or 150 meters or higher than baseline.

[0025] In some embodiments, the patient does not experience any serious treatment related to TEAEs during the first 12 weeks of treatment as shown in Table 4. In some embodiments, less than 12%, 10%, 8% 6% of patients show treatment related TEAE during the first 12 weeks of treatment of ponsegromab.

[0026] In some embodiments, the patient does not experience any one of the adverse events as shown in Table 5. In some embodiments, the adverse event is nausea, vomiting, diarrhea or abdominal pain. In some embodiments, (i) TEAE of diarrhea occurs in 10% or less of the patients during the first 12 weeks of treatment of ponsegromab; (ii) TEAE of nausea occurs in 8% or less of patients during the first 12 weeks of treatment of ponsegromab, (iii) TEAE of vomiting occurs in 7%, 5%, 4% or less of patients during the first 12 weeks of treatment of ponsegromab, or any two or all three of (i) through (iii).

[0027] In some embodiments, the patient does not experience any significant blood pressure increase as shown in Table 6 or Table 7. In some embodiments, (i) the systolic blood pressure of the patient increases 2.5 - 11.6 mm Hg after 12 weeks of treatment of ponsegromab, (ii) the diastolic blood pressure of the patient increases -0.4 to 4.8 mm Hg after 12 weeks of treatment of ponsegromab, or both (i) and (ii). In some embodiments, the systolic blood pressure of the patient decreases 7.6 to -0.8 mm Hg after 12 weeks of treatment of ponsegromab, (ii) the diastolic blood pressure of the patient increases -2.55 to 2.25 mm Hg after 12 weeks of treatment of ponsegromab, or both (i) and (ii).

[0028] In some embodiments, a CT -derived lumbar skeletal muscle index (LSMI) is obtained for the patient, and the LSMI increases after 12 weeks or 24 weeks treatment of ponsegromab for at least 1 cm2 / m2comparing to that of the patient before the ponsegromab treatment. In some embodiments, the patient maintains a stable LSMI after 12 weeks or 24 weeks treatment of ponsegromab. As used herein, maintaining a stable LSMI refers to the LSMI remains within 1 cm2 / m2increase or decrease of the baseline. In some embodiments, the patient LSMI changed after 12 weeks of treatment of ponsegromab in the range of -0.9 to 1.1 cm comparing to the baseline. In some embodiments, the patient LSMI changed after 12 weeks of treatment of ponsegromab in the range of 0.27 - 2.5 cm comparing to the baseline.

[0029] In some embodiments, the patient has more than 2.5 kg or 5% of lean body mass (LBM) increase comparing to the baseline after 12 weeks of treatment of ponsegromab. In some embodiments, the patient has 5%, 4%, 3%, 2%, 1 % or more increase in LBM comparing to the baseline after 24 weeks treatment of ponsegromab. In some embodiments, the patient maintained a stable LBM comparing to the baseline after 12 weeks or after 24 weeks treatment of ponsegromab. As used herein, maintaining a stable LBM refers to the LBM remains within 1 %, within 2% or within 3% increase or decrease of the baseline.

[0030] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is pancreatic cancer, lung cancer, colorectal cancer, gastric cancer, biliary cancer, or esophageal cancer. In some embodiments, the cancer is 1 L metastatic pancreatic cancer, and prior to the treatment of ponsegromab, the patient had to delay, reduce, or discontinue systemic therapy due to cachexia related symptoms.

[0031] In some embodiments, the cancer is a solid tumor and is 1 L metastatic pancreatic cancer and the patient obtains 1 month, 2 months or 3 months of additional survival benefit.

[0032] In some embodiments, when the tumor size of the solid tumor is measured per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 using CT scan or MRI before the first dose of ponsegromab (baseline) and at 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks or 56 weeks after the first dose of ponsegromab, the patient, or 100%, at least 90%, 80% 70%, 60%, 50%, 40%, 30% 20% or 10% of the patients show stable disease, partial response or complete response based on the measurements. In some embodiments, the measurements at 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks or 56 weeks, comparing to the measurements at baseline, show a tumor size reduction of at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in 100%, at least 90%, 80%, 70%, 60%, 50%, 40%, 30% 20% or 10% of the patients. As used herein the patient or patients refer to the patient who received the same ponsegromab treatment or a reasonable or random sample of such patients whose tumor size is evaluated as described in this paragraph.

[0033] In some embodiments, a pivotal clinical trial was conducted in the regulatory approval of ponsegromab, during the trial, the tumor size of the solid tumor was measured per RECIST 1.1 by blinded independent central review (BICR) using CT scan or MRI before the first dose of ponsegromab (baseline) at 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, or 28 weeks after the first dose of ponsegromab, and 10%, 20%, 30%, 40% 50%, 60%, 70% 80%, 90% or more of the patient showed a tumor size reduction of at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0034] In some embodiments, the tumor size of the solid tumor was measured per RECIST 1.1 using CT scan or MRI before the first dose of ponsegromab (baseline) at 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, or 28 weeks after the first dose of ponsegromab, the patient shows a size reduction of at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0035] In some embodiments, a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, and median progression free survival (PFS) per RECIST 1.1 by BICR of the patients administered ponsegromab was at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months longer than the patients in the corresponding control arm who were not administered ponsegromab. In some embodiments, the median progression free survival (PFS) per RECIST 1.1 by BICR of the patients administered ponsegromab was at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, or two years.

[0036] In some embodiments, the progression free survival of the patient is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months 18 months, or two years.

[0037] In some embodiments, a pivotal clinical trial was conducted in the regulatory approval of ponsegromab, and the patient was treated with ponsegromab according to the method, and the objective response rate (ORR) per RECIST 1.1 by BICR for patients who are administrated ponsegromab was 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. In some embodiments, the ORR for patients administered ponsegromab was at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% higher than patients in the corresponding control arm who were not administrated ponsegromab.

[0038] In some embodiments, objective response rate (ORR) per RECIST 1.1 of the patients who are administrated ponsegromab is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0039] In some embodiments, a pivotal clinical trial was conducted in the regulatory approval of ponsegromab, and the patient was treated with ponsegromab according to the method, wherein the disease control rate (DCR) per RECIST 1.1 by BICR of the patient was 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher. In some embodiments, the DCR for patients who administered ponsegromab was at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% higher than patients in the corresponding control arm who were not administrated ponsegromab.

[0040] In some embodiments, the disease control rate (DCR) per RECIST 1.1 of the patient who received ponsegromab is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher.

[0041] In some embodiments, a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, and the medium duration of response (DOR) per RECIST 1 .1 by BICR was 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1 .5 years, 2 years, 2.5 years, 3 years or longer. In some embodiments, the DOR for patients administered ponsegromab was at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months longer than patients in the corresponding control arm who were not administrated ponsegromab.

[0042] In some embodiments, the duration of response, or the medium duration of response, of the patient who received ponsegromab is 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1 .5 years, 2 years, 2.5 years, 3 years or longer.

[0043] In some embodiments, a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, and the medium overall survival (OS) per RECIST 1 .1 by BICR was 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1 .5 years, 2 years, 2.5 years, 3 years or longer. In some embodiments, the OS for patients administered ponsegromab was at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months longer than patients in the corresponding control arm who were not administrated ponsegromab.

[0044] In some embodiments, the patient who is treated with ponsegromab has an overall survival, or medium overall survival, of 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1 .5 years, 2 years, 2.5 years, 3 years from when the first dose of ponsegromab is administered.

[0045] In some embodiments, the patient is administered a second therapeutic agent.

[0046] In some embodiments, the invention further provides the anti-GDF115 antibody ponsegromab or pharmaceutical composition as described herein for use in the described methods of treating cancer cachexia, cancer, or heart failure. The invention also provides the use of the anti-GDF15 antibody ponsegromab as described herein in the manufacture of a medicament for treating cancer cachexia, cancer, or heart failure according to the methods defined herein.

[0047] Therefore, in some embodiments, the invention provides the anti-GDF15 antibody ponsegromab or a pharmaceutical composition thereof for use in a method of treating a condition in a patient with a malignant solid tumor, wherein the condition is cancer cachexia or malignant solid tumor, comprising administering to the patient an anti-GDF15 antibody ponsegromab or a pharmaceutical product thereof, in a dosing regimen of 400 mg Q4W subcutaneous (SC) or 200 mg Q4W SC, wherein the patient also receives a systemic chemotherapy for the treatment of the malignant solid tumor. In some embodiments, the condition is cancer cachexia. In some embodiments, the condition is malignant solid tumor.

[0048] In some embodiments, the invention provides the use of the anti-GDF15 antibody ponsegromab or a pharmaceutical composition thereof in the manufacture of a medicament for treating a condition in a patient with a malignant solid tumor, wherein the condition is cancer cachexia or malignant solid tumor, comprising administering to the patient an anti-GDF15 antibody ponsegromab or a pharmaceutical product thereof, in a dosing regimen of 400 mg Q4W subcutaneous (SC) or 200 mg Q4W SC, wherein the patient also receives a systemic chemotherapy for the treatment of the malignant solid tumor. In some embodiments, the condition is cancer cachexia. In some embodiments, the condition is malignant solid tumor.

[0049] In some embodiments, the invention provides the anti-GDF15 antibody ponsegromab or a pharmaceutical composition thereof for use in a method of treating cancer cachexia, cancer, or heart failure, wherein the antibody is administered in a dosing regimen of 400 mg Q4W subcutaneous (SC), 200 mg Q4W SC, or 200 mg Q2W SC, wherein the patient has an elevated GDF15 serum level, optionally, the patient is an adult, and optionally, the cancer is a malignant solid tumor.

[0050] In some embodiments, the invention provides the use of the anti-GDF15 antibody ponsegromab or a pharmaceutical composition thereof in the manufacture of a medicament for treating cancer cachexia, cancer, or heart failure, wherein the antibody is administered in a dosing regimen of 400 mg Q4W subcutaneous (SC), 200 mg Q4W SC, or 200 mg Q2W SC, wherein the patient has an elevated GDF15 serum level, optionally, the patient is an adult, and optionally, the cancer is a malignant solid tumor.

[0051] Detailed Description

[0052] I. Definitions

[0053] So that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0054] As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the," include their corresponding plural references unless the context clearly dictates otherwise.

[0055] “About” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg.

[0056] An “antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab’, F(ab’)2, Fv), single chain (scFv) and domain antibodies (including, for example, shark and camelid antibodies), and fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0057] The terms “cancer”, “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "cancer" or "cancer tissue" can include a tumor. Examples of cancer include but are not limited to, carcinoma, lymphoma, leukemia, myeloma, blastoma, and sarcoma. Examples of cancers and cancer-associated diseases are further described herein. A “malignant solid tumor” as used herein, refers to a mass of tissue that is cancerous. Examples of malignant solid tumor includes, but are not limited to lung cancer (e.g. non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC)), breast cancer, colorectal cancer, prostate cancer, gastric cancer, pancreatic cancer, liver cancer, kidney cancer (renal cell carcinoma), bladder cancer, ovarian cancer, skin cancer, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, bone cancer, soft tissue sarcoma, and testicular cancer. The malignant solid tumor can be carcinomas, sarcomas, rhabodomyosarcoma, leiomyosarcoma, gliomas, neuroblastoma, medulloblastoma, melanoma, mesothelioma, and germ cell tumors. A malignant solid tumor can be metastatic or non-metastatic.

[0058] “Cachexia” refers a condition that is associated with weight loss, reduced physical function, and often muscle wasting. Cancer cachexia refers to cachexia in a cancer patient, and is also associated with reduced tolerance to anticancer therapy. Cancer cachexia is well defined under the International Consensus. See K. Fearon et al Lancet Oncol 2011 ; 12:489-95.

[0059] “Chemotherapeutic agent” is a drug useful in the treatment of cancer and / or cancer-associated disease. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth. Chemotherapeutic agents are further described herein.

[0060] In some embodiments, chemotherapeutic agent is a chemical compound that kills rapidly dividing cells to treat cancer. Common types of such chemotherapeutic agent include alkylating agents, antimetabolites, plant alkaloids, anti-tumor antibiotics, nucleoside analog (gemcitabine) and topoisomerase I inhibitor (irinotecan). Examples of such chemotherapeutic agent include but are not limited to platinum containing chemotherapeutic agents. In some embodiments, a chemical compound is conjugated to an antibody (ADC). In some embodiments, the chemotherapeutic agent is a platinum containing chemotherapeutic agent including but are not limited to cisplatin, carboplatin and oxaliplatin.

[0061] In some embodiments, chemotherapeutic agent is a chemical compound, an antibody drug conjugates (ADC) or an antibody, that is a targeted therapy, which means that the drug interferes with a specific protein or gene (i.e. target) that are crucial for cancer cell survival, to treat cancer. Examples of targeted therapy to treat cancer include, but are by no means limited to, ALK inhibitors, CDK inhibitors, EFGR inhibitors, PARP inhibitors (e.g. talazoparib, olaparib, rucaparib, niraparib), VEGF inhibitors, VEGFR inhibitors, anti-CD20 antibodies, anti-CD3 antibodies, anti-CTLA4 antibodies, anti-HER2 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, BCMA x CD3 bispecific antibodies.

[0062] In some embodiments, chemotherapeutic agent is an oncolytic vaccine. Examples of such oncolytic vaccine include, but are not limited to, talimogene laherparepvec, pexa- vec, DNX-2401 , reolysin, CG0070, ONCOS-102.

[0063] “Chemotherapy” as used herein, refers to a chemotherapeutic agent, as defined above, or a combination of two, three or four chemotherapeutic agents, for the treatment of cancer and / or cancer-associated disease. When chemotherapy consists more than one chemotherapeutic agent, the chemotherapeutic agents can be administered to the patient on the same day or on different days in the same treatment cycle.

[0064] A “systemic chemotherapy”, as used herein, refers to the chemotherapy that a patient with solid tumor receives for the purpose of treating the solid tumor, and the chemotherapy is administered to the patient’s blood stream. For example, the chemotherapy can be administered intravenously or subcutaneously. Depending on the type of solid tumor that the patient has, the systemic chemotherapy the patient receives is different and is determined by the patient’s healthcare provider.

[0065] A “nab-paclitaxel and gemcitabine chemotherapy”, or “nab-paclitaxel and gemcitabine chemotherapy regimen” as used herein, refers to the combination therapy of nab-paclitaxel (Abraxane) and gemcitabine, used to treat pancreatic cancer.

[0066] A “FOLFIRINOX chemotherapy”, or a “FOLFIRINOX chemotherapy regimen”, as used herein, refers to the combination therapy of folinic acid(leucovorin), fluorouracil (5- FU), irinotecan and oxaliplatin, for the treatment of pancreatic cancer. The specific dosing, including the delivery route, amounts and dosing schedule, of the “systemic chemotherapy”, a “nab-paclitaxel and gemcitabine chemotherapy” or a “FOLFIRINOX chemotherapy”, depend on the patients’ condition, including any other therapeutic agents that the patient is administered, and are determined by the patient’s health care provider in accordance with local guidelines.

[0067] The term “elevated GDF15 serum level”, as used herein, refers to the GDF15 serum level that is higher than the normal range of GDF15 serum level of a healthy adult of a similar age and gender. When age or gender is not specified, an elevated GDF15 serum level refers to a GDF15 serum level that is higher than 0.8 ng / mL. When the term or an actual concentration of GDF15 serum level is used in the context of qualifying or selecting the patient for the treatment of ponsegromab in the method or use described in this invention, the GDF15 serum level is measured at the baseline, or at least one week, two weeks or one month before the first dose of ponsegromab treatment.

[0068] The terms “increase,” improve,” “decrease” or “reduce” refer to values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of treatment described herein, or a measurement in a control individual or subject (or multiple control individuals or subjects) in the absence of the treatment described herein. In some embodiments, a “control individual” is an individual afflicted with the same form of disease or injury as an individual being treated. In some embodiments, a “control individual” is an individual that is not afflicted with the same form of disease or injury as an individual being treated.

[0069] "Patient", "subject" or “individual” refers to any living organism suffering from or prone to a condition that can be prevented or treated by administration of a therapeutic agent or composition or combination as provided herein, such as a cancer and / or a cancer-associated disease, and includes both humans and animals. The terms “patients”, “subjects” and “individuals” include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and preferably are human.

[0070] “Sustained response” means a sustained therapeutic effect after cessation of treatment with a therapeutic agent, or a combination therapy described herein. In some aspects, the sustained response has a duration that is at least the same as the treatment duration, or at least 1 .5, 2.0, 2.5 or 3 times longer than the treatment duration. As used in herein, “administering" refers to the delivery of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. A therapeutic agent can be administered via a non- parenteral route, or orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0071] "Treat" or "treating" a cancer and / or a cancer-associated disease such as cancer cachexia, as used herein means to administer a therapy according to the present invention to a subject, patient or individual having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect. For treating cancer cachexia, such positive effects including but are not limited to increasing body weight, increasing lean body mass, increasing CT-derived lumbar skeletal muscle index (LSMI), improvement in Patient Reported Outcomes (PROs) such as FAACT-ACS, FAACT-5IASS, improvement of physical activity as measured by wearable digital devices such as non-sedentary physical activity (mins / day) and total vector magnitude. For treating cancer, such positive effects include, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1 S- 10S (2009)). In some aspects, the treatment achieved by a combination of the invention is any of the partial response (PR), complete response (CR), overall response (OR), objective response rate (ORR), progression free survival (PFS), radiographic PFS, disease free survival (DFS) and overall survival (OS). PFS, also referred to as “Time to T umor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or patients. In some aspects, response to a combination of the invention is any of PR, CR, PFS, DFS, ORR, OR or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1 ) response criteria (Eisenhauer et al., E.A. et al., Eur. J Cancer 45:228-247 (2009)). In some aspects, anti-myeloma activity may be evaluated by Overall response rate (ORR), time to response (TTR), complete response rate (CRR), duration of response (DOR), duration of complete response (DoCR), duration of stable disease (DOSD), progression-free survival (PFS), overall survival (OS), using International Myeloma Working Group (IMWG) criteria. The treatment regimen for a combination therapy as provided herein that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an aspect of any of the aspects of the invention may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as , but not limited to, the Cox log-rank test, the Cochran-Mantel-Haenszel log-rank test, the Student’s t-test, the chi2- test, the ll-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat-test and the Wilcon on-test. The term “treatment” also encompasses in vitro and ex vivo treatment, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.

[0072] "Treat" or "treating" a heart failure by ponsegromab, as used herein, means to administer ponsegromab to a subject, patient or individual having heart failure, or diagnosed with heart failure or a high risk of having heart failure, together with a standard of care therapy of heart failure to reduce the composite risk of cardiovascular death and heart failure hospitalization with improvement of quality of life and functional capacity.

[0073] As used herein, “baseline”, when used in the context of being compared to in describing the patient’s body weight increase, physical activity improvement, symptom or functional improvement, lumbar skeletal muscle index (LSMI) improvement, tumor size reduction, and the like, refers to the corresponding measurement, e.g. body weight, physical activity etc, of the patient right before, preferably within 12 hours, within 24 hours, within 48 hours or within 72 hours before, the treatment of ponsegromab in week 1 , which is the same as before the first dose of ponsegromab treatment.

[0074] As used herein, “lean body mass” (LBM) refers to the total weight, such as in kg or lbs, of a person’s body minus the fat weight. It includes muscles, bones, organs, skin, blood and all other components of the body except fat. LBM can be measured by Dualenergy X-ray Absorptiometry (DEXA), hydrostatic weighing, air displacement, skinfold measurements, magnetic resonance imaging (MRI), and computed tomography (CT) scans.

[0075] As used herein, Cancer Related Cancer Symptom Diary (CRCSD), refers to a daily, self-reported questionnaire that measures seventy of symptoms related to cancer cachexia: appetite, nausea, vomiting and fatigue. It was developed based on qualitative research with patients as well as review of literature and other existing relevant measures. The measure consists of 4 questions that ask study participants to rate the seventy of their symptoms over the past 24 hours on an 11 point NRS.

[0076] As used herein, Functional Assessment of anorexia-Cachexia Therapy (FAACT) refers to a scoring system where the patients self-assess and report the patients’ physical, social / family, emotional and functional well-being. See Blauwhoff-Buskermolen et. al., Support Care Cancer 2016; 24: 661 - 666. The FAACT system and scoring are widely accepted and used globally by organizations such as FACIT.org. FAACT-5-item Anorexia Symptom Scale (5IASS) typically refers to (i) loss of appetite, (ii) early satiety, (iii) taste changes, (iv) difficulty or enjoyment of eating, and (v) weight loss, each item is measured within FAACT. Patient will provide a score from 0 to 4 for each item. FAACT- 5IASS typically has a highest score of 20. A higher score indicates better outcome and better quality of life.

[0077] As used herein, Patient-Reported Outcomes Measurement Information System (PROMIS) refers to a system of patient reported health status for physical, mental, and social wellbeing, developed by National Institute of Health (NIH). PROMIS offers a set of standardized questions that cover physical function, pain, fatigue, emotional distress such as depression and anxiety and social function.

[0078] As used herein, clinically meaningful symptom or function improvements refer to

[0079] (i) improvements of at least one item by 1 point in FAACT-5IASS; (ii) improvements of at least two items each by 1 point in FAACT (ACS) or FAACT; (iii) improvements of at least one item measured in FAACT-5IASS or two items measured in FAACT or FAACT(ACS) by a digital device deemed acceptable by a treating physician of the patient for at least 10%; (iv) as reported or deemed so by the patient, or (v) as determined by a treating physician of the patient. Unless otherwise specified, all of the (i) to (v) are comparing to the baseline.

[0080] As used herein, “sedentary activity” refers to activity while awaking, and the person is sitting, lying or reclining and has an energy expenditure equal or less than one metabolic equivalent (MET). “Non sedentary activity” refers to activities while the person is awaking and is not a sedentary activity. See D. Thivel et. al. , Front Public Health, 2018; 6:288.

[0081] As used herein, “total vector magnitude” refers to the patient’s total movement during a day, such as total activity count, and is generally measured by methods known to those skill in the art.

[0082] As used herein, “clinical meaningful physical activity improvement” refers to (i) an increase of the patient’s daily non-sedentary physical activity time of 10 minutes or more,

[0083] (ii) an increase of the patient’s total vector magnitude of at least 5% or at least 10%, (iii) as reported or deemed so by the patient, (iv) as determined by a treating physician of the patient, or (v) as defined the regulatory agency, such as US FDA, EMA, Japan PMDA , after 12 weeks or 24 weeks treatment of ponsegromab. Unless otherwise specified, all of the (i) to (v) are comparing to the baseline.

[0084] As used herein, lumbar skeletal muscle index (LSMI) is determined using cross sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI), by measuring the cross-sectional area (cm2) of skeletal muscles at the L3 level and normalized to a person’s height square (m2). Unless otherwise specified, improvement in LSMI is compared to the baseline.

[0085] As used herein, “pharmaceutical product” or “pharmaceutical composition” refers to a drug product that comprises an actively pharmaceutical ingredient and is regulated by the US FDA, EMA or other counterpart regulatory agencies in the other markets. A pharmaceutical product can be an investigational drug or a drug product that has already been approved by a regulatory agency.

[0086] The term “premedication” or “pre-medication” refers to a medication administered to the patient for the purpose of helping with the patient’s tolerance or reducing the undesired side effects of another medication such as an anti-cancer agent.

[0087] The terms “treatment regimen”, “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination of the invention.

[0088] As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing incidence or amelioration of one or more symptoms of various diseases or conditions (such as for example cancer), decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, and / or delaying the progression of the disease. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0089] "Tumor" as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms). Multiple myeloma is a cancer of the plasma cells

[0090] "T umor burden" also referred to as "tumor load", refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.

[0091] The term "tumor size" refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.

[0092] The term "immunotherapy" refers to the treatment of a subject by a method comprising inducing, enhancing, suppressing, or otherwise modifying an immune response.

[0093] The term “immune effector cell” or “effector cell” as used herein refers to a cell within the natural repertoire of cells in the human immune system which can be activated to affect the viability of a target cell. The viability of a target cell can include cell survival, proliferation, and / or ability to interact with other cells.

[0094] "Pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a component that may be included in the compositions described herein and causes no significant adverse toxicological effects to a subject.

[0095] The terms "protein", "polypeptide" and "peptide" are used interchangeably herein and refer to any peptide-linked chain of amino acids, regardless of length co-translational or post-translational modification.

[0096] As used in herein, "substantially" or "essentially" means nearly totally or completely, for instance, 95% or greater of a given quantity.

[0097] The terms “synergy” or “synergistic” are used to mean that the result of the combination of two or more compounds, components or targeted agents is greater than the sum of each agent together. The terms “synergy” or “synergistic” also means that there is an improvement in the disease condition or disorder being treated, over the use of the two or more compounds, components or targeted agents while each compound, component or targeted agent individually. This improvement in the disease condition or disorder being treated is a “synergistic effect”. A “synergistic amount” is an amount of the combination of the two compounds, components or targeted agents that results in a synergistic effect, as “synergistic” is defined herein. Determining a synergistic interaction between one or two components, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different w / w (weight per weight) ratio ranges and doses to patients in need of treatment. However, the observation of synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species and in vitro models or in vivo models exist, as described herein, to measure a synergistic effect and the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species by the application of pharmacokinetic / pharmacodynamic methods.

[0098] The term Response Evaluation Criteria in Solid Tumors 1 .1 or “RECIST 1 .1 ” is well known and used in the art and described in European Journal of Cancer, 45 (2), 228 - 247, 2009. Tumor size reduction, stable disease (SD), partial response (PR), complete response (CR), progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) as used herein are all according to the definition in accordance to RECIST 1.1.

[0099] Medium overall survival, as used herein when it’s outside of the context of a clinical trial, refers to the medium overall survival of a patient cohort treated under the specified treatment method, and the patient cohort is reasonably identified by an ordinary skill in the art, or by a random selection of at least 20, 30, 40, 50, 60, 80, 100 or 200 patients thus treated. Medium progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), medium duration of response (DOR), when used outside of the context of a clinical trial, are similarly defined. Other similar terms describing the patient’s response to the treatment or effectiveness of the treatment, when a patient cohort is needed to determine the value of the term, when used outside of the context of a clinical trial, are also similarly defined.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of the ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise," or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0101] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the invention. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0102] EXAMPLES

[0103] Example 1 : A Phase 2 Study of the Efficacy and Safety of Ponsegromab in Patients with Cancer, Cachexia and Elevated GDF-15.

[0104] Study design: This is a Phase 2, randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of three different doses of ponsegromab compared to placebo, administered for 12 weeks, in patients with NSCLC, PANC, or CRC who have elevated concentrations of GDF-15 and cachexia. The double-blind period is followed by an optional open-label (Part B) extension period.

[0105] The Screening visit will occur no more than 28 days and no less than 7 days, prior to Randomization. Following the Screening period to confirm eligibility, approximately 168 study participants, who meet the entry criteria, will be randomized to study intervention (100 mg, 200 mg or 400 mg Q4W SC, of ponsegromab or matching placebo) and will be stratified by treatment with or without platinum-based chemotherapy, which is known to induce GDF-15 and therefore may impact the response to ponsegromab treatment. The 12-week double-blind dosing period (Part A) will consist of a total of 3 doses administered Q4W SC.

[0106] On completion of Part A, participants will have the opportunity to enter an optional OLT period (Part B) consisting of ponsegromab 400 mg Q4W SC, for up to 1 year.

[0107] Participants opting to continue to the optional OLT period will receive their first dose of open-label ponsegromab 400 mg at the Week 12 visit, which is the last visit of the double-blind portion. Upon completion of the optional OLT period, there will be a follow-up visit (Week 72) which is to occur 56 to 63 days post last dose of study Patient Inclusion:

[0108] (i) patient has documented histologic or cytologic active diagnosis of NSCLC, PANC, or CRC and are currently receiving, or have completed, standard of care treatment for this cancer (which may include systemic therapy);

[0109] (ii) (ii) Cachexia defined by Fearon criteria of weight loss as BMI <20 kg / m2with involuntary weight loss of >2% within 6 months prior to screening, or Involuntary weight loss of >5% within 6 months prior to screening irrespective of BMI;

[0110] (iii) Serum GDF-15 concentrations of >1 .5 ng / mL (as measured using an GDF-15 assay) at Screening

[0111] Study Arms and Durations:

[0112] Following a 28-day screening period to confirm eligibility, study participants who meet the entry criteria will be randomized to study intervention. The 12-week doubleblind dosing period (Part A) will consist of a total of 3 SC doses, administered Q4W. On completion of Part A, participants will have the opportunity to enter an optional openlabel treatment period (Part B) consisting of ponsegromab 400 mg Q4W SC for up to 1 year. Study Results:

[0113] Change from baseline in body weight at week 12 are summarized in below

[0114] Table 1 . As shown, all ponsegromab treatment groups had an increase in the observed mean change from baseline at Week 12 (+0.89 kg, +1.31 kg and +3.02 kg, for the 100 mg, 200 mg and 400 mg doses respectively), whereas the placebo group had an observed mean decrease of -0.45 kg. The placebo-adjusted modelled median changes from baseline were +1.33 kg (100 mg), +2.08 kg (200 mg) and +3.00 kg (400 mg).

[0115] Table 1. Baseline and Change from Baseline in Body Weight at Week 12

[0116] N1 : Number of participants randomized and treated, with available baseline data. N2: Number of participants with available change from baseline data at Week Change from baseline in Patient Reported Outcomes (PROs): Changes from baseline at Week 12 and differences from placebo are presented in Table 2. Statistically significant (one-sided p-value < 0.05) improvements, relative to placebo, were observed at Week 12 in FAACT-ACS, FAACT-5IASS and CRCSD-Appetite in the 400 mg ponsegromab dose group. There were also statistically significant improvements in FAACT-ACS and FAACT-5IASS in the 100 mg ponsegromab dose group, relative to placebo at Week 12, with no apparent dose response across these endpoints. There were no significant differences in CFB in nausea, vomiting frequency or physical fatigue components of the CRCSD in any ponsegromab dose group at Week 12, relative to placebo. Of note, the mean baseline CRCSD scores for nausea (1 .21 - 2.02 on a scale of 0 [no nausea] to 10 [worst possible nausea]) and vomiting frequency (0.11 - 0.65 vomiting episodes / day) were low and similar across all treatment groups.

[0117] Table 2: Baseline and Change from Baseline in PROs at Week 12

[0118] N2: Number of participants with available change from baseline data at Week 12 for given endpoint.

[0119] 1 FAACT-ACS ranges from 0 to 48, with lower scores indicating a higher burden of anorexia and cachexia symptoms.

[0120] 2 FAACT-5IASS ranges from 0 to 20, with lower scores indicating a higher burden of anorexia symptoms.

[0121] 3 CRCSD-Appetite ranges from 0 to 10, with lower scores indicating a worse appetite.

[0122] Change from Baseline in Digital Physical Activity and Gait Endpoints: Changes from baseline at Week 12 and differences from placebo are presented in Table 3 for the subset of digital physical activity and gait endpoints for which significant placebo-adjusted improvements were noted at Week 12 in one or more ponsegromab treatment groups. Data for wrist and lumbar sensor-derived digital endpoints were available for 60 (43.8%) and 82 (59.9%) of 137 participants at Week 12, respectively. Reasons for incomplete data included failure to meet prespecified requirements for minimum wear time during a monitoring period, hardware issues (e.g. battery depletion) and site-related issues (e.g. incomplete data uploads). In the subset of participants with available data, statistically significant (one-sided p-value < 0.05) increases, relative to placebo, were observed at Week 12 in non-sedentary activity (+50 minutes / day) and total vector magnitude, a measure of overall activity (+2203 total activity counts / 100 per day), in the 400 mg ponsegromab dose group. Additionally, a statistically significant increase in non-sedentary activity (+38 minutes / day) was observed in the 100 mg dose group, relative to placebo at Week 12. Otherwise, there were no significant differences observed for other digital physical activity and gait endpoints at Week 12, relative to placebo. Table 3. Baseline and Change from Baseline in Digital Physical Activity and Gait

[0123] Endpoints at Week 12

[0124] N1 : Number of participants randomized and treated, with available baseline data. N2: number of participants with available change from baseline data at Week 12 for given endpoint.

[0125] For wrist-sensor derived endpoints above, participants were included in analyses for any given 7-day monitoring period if there were data for a minimum of 7 hours of awake wear and / or 18 hours of total wear time per day for at least 3 days. Modelled LS means, differences and confidence intervals (Cis) are from an

[0126] MMRM analysis.

[0127] Treatment emergent adverse event (TEAE) is summarized in below Table 4.

[0128] As shown, overall, 72.7% of participants reported at least one all-causality TEAE, including 80.0% of participants assigned to placebo and 70.4% of participants assigned to ponsegromab. The majority of the total 562 all-causality TEAEs were reported as mild (40.7%) or moderate (30.8%) in severity and only 24 (4.3%) were considered treatment related. Treatment-related TEAEs occurred in 8.9% of placebo participants and 7.7% of ponsegromab-treated participants, and the majority (62.5%) were mild in seventy, with 25.0% reported as moderate and 12.5% reported as severe. For this cohort of participants with advanced cancer and high baseline rate

[0129] (89.8%) of treatment with systemic anti-cancer therapies, treatment-emergent serious

[0130] AEs (SAEs) were common, occurring in 24.4% of participants assigned to placebo and 21 .7 to 40.0% of participants assigned to ponsegromab treatment groups. However, treatment-related SAEs were limited to 2 (1.1 %) participants only, one participant each in the ponsegromab 100 mg and 200 mg treatment groups, which were abdominal pain and dyspnea, respectively.

[0131] Table 4. Summary of All-Causality and Treatment-Related Treatment-Emergent

[0132] Adverse Events

[0133] Below Table 5 provides a summary of all-causality TEAEs occurring in > 5% of participants in any treatment group. The most common (> 7.0%) TEAEs were diarrhea, neoplasm progression, anemia, hypokalemia, nausea, vomiting and pyrexia. Diarrhea, nausea and vomiting were reported less frequently across ponsegromab combined treatment groups (8.5%, 4.2% and 4.9%, respectively) compared to placebo (17.8%, 15.6% and 13.3%, respectively).

[0134] Table 5. Summary of All-Causality Treatment Emergent Adverse Events occurring in >5% of participants in any treatment group

[0135] ‘Combines preferred terms of ‘malignant neoplasm progression’ and ‘neoplasm progression

[0136] The observed mean change from the base line (CFB) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 12 was +2.2 and +0.1 mmHg, respectively for participants in the ponsegromab 400 mg treatment group, compared with placebo who showed declines in SBP and DBP of -2.2 and -1 .5 mmHg, respectively. The differences in SBP and DBP, relative to placebo, were statistically significant for the 400 mg group, with LS mean differences to placebo of +10.24 and +4.18 mmHg, respectively (2-sided p-value < 0.10) (Table 6); no such differences were noted in other ponsegromab treatment groups. Tables 6 and 7 summarize the results.

[0137] Table 6._Categorical Summary of Post-Baseline Systolic and Diastolic Blood Pressure At any point post-baseline during Part A. n=number of participants who met the criterion. N1 =number of participants with at least one post-baseline blood pressure assessment evaluated against criterion Table 7: Baseline and Systolic and Diastolic Blood Pressure at Week 12

[0138] N1 : Number of participants randomized and treated, with available baseline data.

[0139] N2: number of participants with available change from baseline data at Week 12 for given endpoint. CT- derived Lumbar Skeletal Muscle Index (LSMI): Changes from baseline at

[0140] Week 12 and differences from placebo are presented in Table 11 . The placebo group had a decrease in LSMI at Week 12 (-0.76 cm2 / m2), whereas the ponsegromab treatment groups demonstrated stable or increased LSMI (+0.09 to +1 .39 cm2 / m2). There was a statistically significant (one-sided p-value < 0.05) increase in LSMI at Week 12, relative to placebo, in the 400 mg ponsegromab dose group (+2.15 cm2 / m2). There was no apparent dose response.

[0141] Table 8. Baseline and Change from Baseline in LSMI at Week 12.

[0142] N1 : Number of participants randomized and treated, with available baseline data. N2: Number of participants with available CFB data at Week 12.

[0143] Modelled LS means, differences, and confidence intervals (Cis) are from an ANCOVA model.

[0144] Example 2. A phase 2b / 3 study of chemotherapy plus ponsegromab for the first-line treatment in adult participants with cachexia and previously untreated mPDAC.

[0145] Study Design:

[0146] Initial enrollment will be in Phase 2b (Part A). If all eligibility criteria are met, participants will be randomized in a 1 :1 :1 allocation to study intervention (200 mg Q4W ponsegromab, 400 mg Q4W ponsegromab, or placebo Q4W) plus first-line systemic chemotherapy, (nab-paclitaxel and gemcitabine chemotherapy regimen or FOLFIRINOX chemotherapy regimen). Participants can receive Cycle 1 of their first- line systemic chemotherapy approximately one month prior to the start of receiving their first dose (Day 1 ) of study intervention (200 mg or 400 mg Q4W ponsegromab or placebo) plus first-line systemic chemotherapy. Day 1 study intervention must be taken prior to participants receiving Cycle 2 nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy. All chemotherapy dosing is to be determined by the participant’s health care provider in accordance with local guidelines. Study intervention will be administered Q4W SC. Phase 2b (Part A) Interventions

[0147] Following enrollment completion of Phase 2b (Part A), Phase 3 (Part B) enrollment will begin, and eligible participants will be randomized in a 1 :1 :1 allocation to study intervention. Once all Phase 2b participants have completed Week 12 procedures, an interim analysis of Phase 2b (Part A) will be performed, from which one of the 2 ponsegromab doses will be selected.

[0148] Phase 3 participants enrolled after dose selection will be randomized 1 :1 (ponsegromab selected dose or placebo). During the Phase 3 portion of the study, there will be an optional sub-study for primary caregivers of participants with cachexia and mPDAC to evaluate the effectiveness of ponsegromab in improving the quality of life and well-being of the primary caregivers.

[0149] Study intervention (ponsegromab selected dose or placebo) will continue regardless of chemotherapy treatment until permanent discontinuation of study intervention, withdrawal of consent, death, or the end of study has been reached when the approximate number of survival events have been accrued for the Phase 3 analysis of survival. Participants will have tumor assessments performed approximately every 6 to 8 weeks during the double-blind period by blinded, independent, central reader radiologists.

[0150] After the completion of Part B of the Study, an optional open-label extension period (Part C) will continue. Additional follow-up may be conducted for safety evaluation, at the discretion of the investigator.

[0151] Patient inclusion

[0152] Participants must satisfy all of the following criteria: 1 . 18 or over 18 years of age.

[0153] 2. Documented histologic or cytologic active diagnosis of mPDAC (locally advanced disease is not eligible) and;

[0154] • Planning to initiate first-line systemic nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy prior to randomization; or

[0155] • Currently receiving Cycle 1 , first-line systemic nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy (and must be prior to receiving Cycle 2, nab-paclitaxel plus gemcitabine chemotherapy or FOLFIRINOX chemotherapy)

[0156] 3. Cachexia as defined by Fearon criteria:

[0157] • BMI <20 kg / m2and involuntary weight loss of >2% within 6 months prior to screening or

[0158] • Involuntary weight loss of >5% over the past 6 months prior to screening irrespective of BMI

[0159] 4. Participants who are assessed by the investigator to have:

[0160] • an ECOG PS <1 and a life expectancy of >4 months.

[0161] Primary End Points of the Study are (1 ) Change from baseline in body weight (kg) at Week 12; (2) Change from baseline in FAACT-5IASS subscale scores at Week 12.

[0162] Key Secondary End Points of the Study are: (1 ) Change from baseline at Week 12 in physical activity as measured by time spent in non-sedentary-activity time; and (2) Overall survival, defined as the time from randomization to occurrence of all-cause death.

[0163] Other Secondary End Points of the Study includes: Percent change from baseline in body weight at Week 12; Change from baseline at Week 12 in physical activity as measured by total vector magnitude; PFS (progression free survival), ORR (objective response rate), DCR (disease control rate), DOR (duration of response), as determined by BICR assessment per RECIST 1.1 ; Change from baseline in body composition as measured by CT scan at Week 12; incidence of adverse events of nausea, vomiting, loss of appetite, or fatigue; tumor status (e.g., size) as determined by BICR assessment per RECIST 1.1 using CT scan (or MRI) at week 12. Patients will be given a 6 minute walk test (6MWT) at baseline and 12 weeks or selected time to measure the distance that the patient can walk in six minutes.

[0164] Sequences

[0165] Table 9 lists the sequences of the GDF15 antibody ponsegromab.

[0166] Table 9. Sequences of GDF15 antibody Ponsegromab

Claims

Claims1 . A method of treating a condition in a patient with a malignant solid tumor, wherein the condition is cancer cachexia or the malignant solid tumor, comprising administering to the patient ponsegromab or a pharmaceutical product thereof, in a dosing regimen of 400 mg once every four weeks (Q4W) subcutaneous (SC) or 200 mg Q4W SC, wherein the patient also receives a systemic chemotherapy for the treatment of the malignant solid tumor.

2. The method of claim 1 , wherein the malignant solid tumor is pancreatic cancer, lung cancer, colorectal cancer, gastric cancer, biliary cancer, or esophageal cancer.

3. The method of claim 1 , wherein the malignant solid tumor is metastatic pancreatic cancer, and the systemic chemotherapy is a nab-paclitaxel and gemcitabine chemotherapy regimen, or a FOLFIRINOX chemotherapy regimen.

4. The method of any of the preceding claims, wherein (i) the patient receives a first dose of the systemic chemotherapy before or on the same day when a first dose of the ponsegromab is administered, and (ii) the patient receives the systemic chemotherapy for at least 8 weeks starting from the administration of the first dose of ponsegromab.

5. The method of any of the preceding claims, wherein the administration of ponsegromab is not conditioned on (i) the patient having an elevated GDF15 serum level, or (ii) the patient having an elevated GDF15 serum level as measured by a test, and the test is approved by United States Food and Drug Administration (FDA), European Medicine Agency (EMA) or Japan Pharmaceuticals and Medical Devices Agency (PMDA).

6. A method to treat a condition in a patient, wherein the condition is cancer cachexia, cancer, or heart failure, comprising administering to the patient ponsegromab or a pharmaceutical product thereof, in a dosing regimen of 400 mg Q4W subcutaneous (SC) or 200 mg Q2W SC, wherein the patient has an elevated GDF15 serum level, optionally, the patient is an adult, and optionally, the cancer is a malignant solid tumor7. A method to treat a condition in a patient, wherein the condition is cancer cachexia, cancer, or heart failure, comprising administering to the patient ponsegromab or a pharmaceutical composition thereof, in a dosage form that contains 150 mg / mL of ponsegromab, and in an dosing regimen of 200 -400 mg every 2 to 4 weeks SC,wherein the patient has an elevated GDF15 serum level, optionally, the patient is an adult, and optionally, the cancer is a malignant solid tumor.

8. The method of any of the preceding claims, wherein the patient has an elevated GDF15 serum level of 1.5 ng / mL or higher as measured by a test including but not limited to a GDF15 binding assay, and the test is approved by a regulatory agency such as FDA, EMA or Japan PMDA.

9. The method of any one of the preceding claims, wherein if the patient takes one or more premedications on the same day when ponsegromab is administered, ponsegromab is administered prior to the patient taking any of the one or more premedications.

10. The method of any one of the preceding claims, wherein the patient has more than 2.5 kg or 5% of body weight increase after 12 weeks of treatment of ponsegromab comparing to the baseline.11 . The method of any one of the preceding claims, wherein the patient has 3% or more increase in body weight after 24 weeks treatment of ponsegromab comparing to the baseline.

12. The method of any one of the preceding claims, wherein the patient has 5% or more increase in body weight after 12 weeks or after 24 weeks treatment of ponsegromab comparing to the baseline.

13. The method of any one of the preceding claims, wherein the patient experiences (i) an increase in FAACT-Anorexia and Cachexia Subscale (ACS) score of 4 points or more after 12 weeks of treatment of ponsegromab comparing to that at the baseline, (ii) an increase in FAACT-5 item anorexia symptom scale (5IASS) of 2 points or more after 12 weeks of treatment of ponsegromab comparing to the baseline, or both (i) and (ii).

14. The method of any one of the preceding claims, wherein (i) the patient’s non- sedentary physical activity in minutes per day measured by a wearable digital device increases 5% or more after 12 weeks of treatment of ponsegromab comparing to the baseline, (ii) the patients total vector magnitude (total activity counts / 100 per day) measured by a digital wearable device increases 5% or more after 12 weeks of treatment of ponsegromab comparing to the baseline, or both (i) and (ii) .

15. The method of any one of the preceding claims, wherein 30% of the patients experience clinically meaningful and / or patient deemed meaningful physical activity improvement after 12 weeks or after 24 weeks treatment of ponsegromab.

16. The method of claim 15, wherein the physical activity improvement is measured through passive quantitative measurement of physical activity by a digital device.

17. The method of claim 15, wherein the physical activity improvement is an increased non-sedentary physical activity of more than 10 minutes a day after 12 weeks or 24 weeks of treatment of ponsegromab.

18. The method of claim 15, wherein the physical activity improvement is an increased total vector magnitude of more than 200 per day after 12 weeks or 24 weeks of treatment of ponsegromab.

19. The method of any one of the preceding claims, wherein 30% of the patients experience clinically meaningful symptom or function improvements after 12 weeks or 24 weeks of ponsegromab treatment.

20. The method of claim 19, wherein symptom or function improvement is (a) measured through Patient-Reported Outcomes Measurement Information System (PROMIS), Functional Assessment of Anorexia-Cachexia Therapy (FAACT), FAACT- 5 item anorexia symptom scale (5IASS) or Cancer Related Cachexia Symptom Diary (CRCSD); (b) measured by a digital device deemed acceptable by a treating physician of the patient; or (c) as determined by a treating physician of the patient.21 . The method of any one of the preceding claims, wherein if a CT -derived lumbar skeletal muscle index (LSMI) is obtained for the patient, and (i) the LSMI increases after 12 weeks or 24 weeks treatment of ponsegromab for at least 1 cm2 / m2over the baseline, or (ii) the LSMI remains stable after 12 weeks or 24 weeks treatment of ponsegromab.

22. The method of any one of the preceding claims, wherein the cancer is 1 L metastatic pancreatic cancer, and prior to the treatment of ponsegromab, the patient had to delay, reduce, or discontinue systemic therapy due to cachexia related symptoms.

23. The method of any one of the preceding claims, wherein the cancer is 1 L metastatic pancreatic cancer and the patient obtains 1 month additional survival benefit.

24. The method of any one of the preceding claims, wherein the patient has more than 2.5 kg or 5% of lean body mass (LBM) increase after 12 weeks of treatment of ponsegromab comparing to the baseline.

25. The method of any one of the preceding claims, wherein the patient has 5%, 4%, 3%, 2%, 1 % or more increase in LBM after 24 weeks treatment of ponsegromab comparing to the baseline.

26. The method of any one of the preceding claims, wherein the patient maintained a stable LBM after 12 weeks or after 24 weeks treatment of ponsegromab comparing to the baseline.

27. The method of any one of the preceding claims, wherein a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, the tumor size of the solid tumor is measured per RECIST 1.1 using CT scan or MRI at the baseline and at 12 weeks after the first dose of ponsegromab, and 50% or more of the patient showed stable disease, partial response or complete response based on the measurements.

28. The method of any one of the preceding claims, wherein a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, and median progression free survival (PFS) of the patients administered ponsegromab is at least one month longer than the patients without administration of ponsegromab.

29. The method of any one of the preceding claims, wherein a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, and the objective response rate (ORR) was 50% or higher.

30. The method of any one of the preceding claims, wherein a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, wherein the disease control rate (DCR) of the patient was 50% or higher.31 . The method of any one of the preceding claims, wherein a pivotal clinical trial was conducted in the regulatory approval of ponsegromab and the patient was treated with ponsegromab according to the method, and the medium duration of response (DOR) was 6 months or longer.

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