Pilot clinical trial of macimorelin to assess safety and efficacy in patients with cancer cachexia.

Introduction

Roughly 19.3 million people globally were diagnosed with cancer in 2020. 1 More than half of these patients will experience unintentional weight loss due to cancer‐related changes in appetite and metabolic processes, known as cachexia 2 with an 86% incidence of weight loss 1–2 weeks prior to cancer‐related death. 3 Cachexia is defined as ‘an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. 4 It is associated with catabolism in cancer and is linked to elevated resting energy expenditure (REE), decreased physical function and quality of life (QOL) and is responsible for 20% of cancer‐related deaths, particularly in those with lung, gastrointestinal, pancreatic or head and neck tumours. 5 Cancer‐related anorexia is also induced by cancer treatments and/or symptoms like anxiety, depression and pain. 6 Despite its relevance, cachexia is often undiagnosed and unmanaged as there are no approved treatments in the United States or Europe, and off‐label treatments like appetite stimulants are largely ineffective and can be associated with serious side effects. 7

The hormone ghrelin plays a key role in regulating food intake and energy homeostasis by stimulating the growth hormone secretagogue receptor‐1a (GHSR‐1a) in orexigenic neurons in the hypothalamus 8 thereby inducing positive energy balance. Ghrelin also increases anabolism by stimulating growth hormone (GH) release from somatotroph cells in the pituitary, 9 and by non‐GHSR‐1a‐mediated direct effects in skeletal muscle and fat. 10 , 11 Hence, ghrelin receptor agonists, known as GH secretagogues (GHS), are promising candidates for cachexia treatment. Clinical studies using GHS have shown positive effects on appetite, body weight and body composition in healthy volunteers and in patients with cancer cachexia 12 , 13 , 14 , 15 , 16 , 17 , 18 and one such drug, anamorelin, has been recently approved for cachexia treatment in Japan. 19 Macimorelin, a novel, orally active GHS with similar GHSR‐1a binding affinity as ghrelin, is well‐tolerated as a single dose in healthy volunteers and individuals at risk for pituitary dysfunction. 9 , 14 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 It received approval from the US Food and Drug Administration (FDA) in 2017 and European Medicines Agency (EMA) in 2019 as a single dose for adult GH deficiency (AGHD) diagnosis 9 , 22 , 29 but has not been examined in repeated doses or in the cancer setting.

This pilot study assessed safety and efficacy of daily, oral macimorelin for 1 week in cancer cachexia via body weight, insulin‐like growth factor‐1 (IGF‐1; biomarker of GH action) and QOL; appetite/food intake, functional performance, REE and other laboratory parameters were also assessed. Our primary hypothesis was that macimorelin would be safe and well‐tolerated and improve body weight, IGF‐1 and QOL compared with placebo. We also proposed that macimorelin would improve appetite/food intake, physical function and REE, compared with placebo.

Methods

Study design

This randomized, double‐blind, placebo‐controlled, clinical trial was initiated at the Michael E. DeBakey VA Medical Center in Houston, TX, USA, and then moved to the VA Puget Sound Health Care System in Seattle, WA, USA. A first cohort of subjects was randomized to macimorelin 0.5 mg/kg (the dose currently FDA and EMA approved for use in AGHD diagnosis, N = 8) or matching placebo ( N = 5). An interim analysis by the Data Review Committee found this 0.5‐mg/kg dose to be safe but not to meet the efficacy criteria set a priori . Subsequently, the plan was to randomize a second cohort of subjects to macimorelin 1 mg/kg or placebo. However, the study was closed due to poor accrual after randomizing two subjects to macimorelin and none to placebo ( Figure 2 ). Efficacy was defined as either ≥0.8‐kg body weight gain, ≥50‐ng/mL IGF‐1 increase or ≥15% QOL improvement, based on the observed results in a similar study in which anamorelin administered daily for 3 days significantly increased body weight in cancer cachexia patients by 0.77 kg, IGF‐1 by 54 ng/mL, and QoL by 12.5%. 14 Safety parameters included: complete blood count (CBC), comprehensive metabolic panel (CMP), urinalysis (UA), 12‐lead electrocardiogram (ECG) and adverse events. Study data were collected between January 2013 and October 2015.

Participants

Eligible participants were ≥18 years of age, had histological diagnosis of active malignancy, Eastern Oncology Cooperative Group (ECOG) Performance Status 0–2, cancer‐related cachexia (involuntary weight loss ≥5% over 6 months, ≥10% over 12 months or ≥2% over 6 months with body mass index [BMI] <20 4 ) and were able to provide written, informed consent. Exclusion criteria: obesity (weight >140 kg); recent/excessive alcohol/illicit drug use; severe depression; other conditions associated with cachexia (liver disease [aspartate/alanine transaminase {ALT/AST} > three times normal upper limit], renal failure [creatinine >1.5 mg/dL], untreated thyroid disease, a diagnosis of New York Heart Association Class III–IV congestive heart failure, 30 acquired immunodeficiency syndrome, severe chronic obstructive pulmonary disease), inability to increase food intake (e.g., pain with swallowing, dysphagia, etc.); use of GH, anabolic agents or appetite stimulants; tube feeding or parenteral nutrition within 1 month; systemic corticosteroid administration for >6 days/month; recent highly emetogenic chemotherapy (<1 week; Hesketh scale Class 4–5); pregnant/breastfeeding or might become pregnant; co‐administration of drugs that prolong QT interval and/or induce CYP3A4; corrected QT (QTc) interval >450 ms; or investigational agents.

Study procedures

Subjects underwent a screening/baseline visit and, following randomization, completed Day 1, Day 7 and post‐study visits ( Figure 1 ): participants fasted overnight prior to each visit. In the following order, the screening/baseline visit included medical history/physical exam (including body weight), ECG, safety (blood draw and UA; pregnancy test for females), and appetite and food intake assessment. Day 1 was completed within 24 days after screening/baseline, following completion of a 3‐day food diary in the week preceding Day 1, and included in order: medical history review/physical exam (including body weight), ECG, fasting blood draw and UA (pregnancy test for females) for safety and laboratory assessments (GH, IGF‐1, IGF binding protein‐3 [IGFBP‐3], glucose, and highly sensitive C‐reactive protein [hs‐CRP]), fasting REE, functional performance, patient‐reported QOL, study drug administration orally, blood draw one‐hour post‐dose for pharmacodynamics assessed by GH, ECG 1‐h post‐dose and post‐dose adverse events. Macimorelin was dissolved in a zero‐calorie flavoured drink (Powerade®); Powerade® alone was used as placebo by an unblinded pharmacist. Participants were provided with five doses of pre‐mixed study drug and were instructed to self‐administer one dose daily while fasting, at least 1 h before breakfast (Days 2–6). Participants were instructed to store the doses at 2–8°C and to return any unused doses on Day 7.

On Day 7, participants completed the same procedures as Day 1, in addition to an appetite and food intake assessment. Study drug administration (Dose 7) took place before the test meal. One‐hour post‐dose pharmacodynamics (GH) and ECG and 1‐h post‐meal appetite rating were the last procedures. The post‐study visit occurred 11–17 days following Day 7 for a medical history review/physical exam, ECG, safety parameters (blood draw, UA; pregnancy test for females) and adverse event review.

Primary outcomes

Efficacy: change in body weight, IGF‐1 (chemiluminescence immunoassay; standard deviation score [SDS] 31 was also calculated), and patient‐reported QOL (Anderson Symptom Assessment Scale [ASAS] 32 absolute score; Functional Assessment of Chronic Illness–Fatigue [FACIT‐F] 14 adjusted score) measured pre‐dose on Days 1 and 7; change was Day 7 − Day 1. Safety: CBC, CMP, UA, ECG and adverse events (National Cancer Institute Common Toxicity Criteria v4; Table 1 ).

Secondary outcomes

Food intake: 3‐day food diary 33 and free‐choice test meal. Appetite/hunger: Visual Analogue Scale (VAS) assessed while fasting before and 1‐h post‐meal. Functional performance: handgrip strength (HGS), stair climbing power (SCP), ECOG and Karnofsky Performance Scale (KPS). Indirect calorimetry: absolute REE (kcals/day), %predicted REE (absolute REE/predicted REE) and respiratory quotient (RQ). Fasting blood sample: pre‐dose for plasma GH, IGFBP‐3, glucose and hs‐CRP; change was Day 7 − Day 1. Another sample was taken 1‐h post‐dose for pharmacodynamics via plasma GH (post‐dose − pre‐dose).

Statistics

Because this is the first study that exposed subjects to more than a single dose of macimorelin, no data was available to perform a power analysis. Hence, this pilot, exploratory study was designed to assess safety and efficacy with the intent to generate data to power a future, larger clinical trial. An intent‐to‐treat non‐parametric analysis was conducted (SPSSv18, Inc., Chicago, IL, USA); data are presented as median (SEM) or N (%); statistical significance was two sided with α ≤ 0.05. Between‐ and within‐group comparisons were assessed via Mann–Whitney U test or Fisher's exact test. Associations between QOL change and other outcome changes were assessed via Spearman correlations.

Results

Participants

Of 9,129 patients screened for eligibility, 15 were eligible ( Figure 2 ), with the use of exclusionary medications (corticosteroids, highly emetogenic chemotherapy, drugs that prolong the QT interval) and exclusionary ALT/AST and creatinine lab values as the highest exclusionary factors ( n = 706). In Phase 1, subjects were randomized to Group 1: 0.5 mg/kg macimorelin ( N = 8) or placebo ( N = 5). One patient from each arm discontinued before receiving all doses. Patients achieving the a priori efficacy criteria were: ≥0.8 kg body weight gain (macimorelin N = 2; placebo N = 0); ≥50 ng/mL IGF‐1 increase (macimorelin N = 0; placebo N = 0); or ≥15% QOL improvement from ASAS (macimorelin N = 2; placebo N = 1) or FACIT‐F (macimorelin N = 3; placebo N = 0). No adverse events were reported. The Data Review Committee conducted an interim analysis and determined that 0.5 mg/kg was safe with inadequate efficacy, and enrolment for Phase 2 began with Group 2 (1.0 mg/kg). New patients were randomized to macimorelin ( N = 2) or placebo ( N = 0) before the trial was closed due to poor accrual and study relocation. Participants receiving at least one of either macimorelin dose were combined ( N = 10) for comparison to placebo ( N = 5) due to the small sample size.

Primary outcomes

Efficacy

Descriptive Characteristics at Day 1 were not different between groups ( Table 2 ); however, there was a trend for lower body weight and higher IGF‐1 in placebo than macimorelin. Proportion of patients achieving the a priori efficacy criteria was not different between groups; neither were changes (Day 7 − Day 1) in body weight, IGF‐1, ASAS or FACIT‐F ( Table 3 ). Macimorelin recipients scored better on ASAS pain ( P = 0.05) and fatigue ( P = 0.05) subscales at Day 7 ( Table 4 ).

Safety

One patient in placebo discontinued the study after one dose due to initiation of an exclusionary medication (QT‐prolonging chemotherapy); one patient in macimorelin (0.5 mg/kg) discontinued the study after receiving two doses due to non‐compliance. No related serious or non‐serious adverse events were reported, including no abnormal laboratory or ECG parameters. One unrelated serious adverse event occurred in one patient who received 0.5 mg/kg macimorelin and reported hospitalization with infection treatment for forearm soft tissue necrosis at the post‐study visit; this patient had initiated radiation treatment 3 days after Day 7, and the oncology providers determined that it was a radiation‐related infection. Non‐serious, unrelated events included (1) one patient who received 1.0‐mg/kg macimorelin reported abdominal pain, nausea and herpes breakout at Day 7 (all symptoms were recurrent); (2) one patient who received 1.0 mg/kg macimorelin reported pedal oedema at the post‐study visit (determined a likely chemotherapy effect).

Secondary outcomes

Food intake, appetite, energy expenditure and functional performance

Fasted hunger rating (macimorelin: 45.5 [9.7] vs. placebo: 48.0 [3.7] mm; P = 1.00) and test meal caloric intake (macimorelin: 1094 [122] vs. placebo: 1082 [188] kcals; P = 0.62) were not different between groups at the screening/baseline visit. Neither was the change (Day 7 − Day 1) in fasted hunger rating (macimorelin: 7.0 [11.3] vs. placebo: −27.5 [23.6] mm; P = 0.54). Test meal‐induced change (post‐meal − fasted) in hunger rating was not different between groups at screening/baseline or Day 7 ( Table 3 ). Change in test meal caloric intake was not different between‐groups ( Table 3 ), but caloric intake was greater in macimorelin on Day 7 (macimorelin: 1110.0 [141.2] vs. placebo: 509.0 [311.9], P = 0.03). At Day 1, absolute REE (macimorelin: 1432 [109] vs. placebo: 1400 [67] kcals/day; P = 0.86), percentage of predicted REE (macimorelin: 112.0 [7.3] vs. placebo: 101.0 [6.7] %; P = 0.94) and RQ (macimorelin: 0.81 [0.0] vs. placebo: 0.82 [0.0] VCO 2 /VO 2 ; P = 1.00) were not different between groups; neither were change scores ( Table 3 ). Neither Day 1 nor change in HGS, SCP, ECOG KPS or average daily caloric intake from the 3‐day food diary were different between groups ( Table 4 ).

Laboratory assays

There was no difference between groups in pre‐dose (fasting) GH (macimorelin: 2.2 [0.6] vs. placebo: 2.1 [1.1] ng/mL; P = 0.78), IGFBP‐3, glucose, or hs‐CRP Day 1 ( Table 4 ). Neither was change at Day 7 in pre‐dose GH (macimorelin: 0.70 [1.17] vs. placebo: −0.50 [0.99] ng/mL; P = 0.20), IGFBP‐3, glucose, or hs‐CRP ( Table 4 ). One‐hour post‐dose GH was elevated compared with fasting GH for macimorelin group but not placebo at Days 1 and 7 ( Figure 3 A,B ). The within‐group GH difference (post‐dose − fasting) was not different between Days 1 and 7 for macimorelin (Day 1: 18.5 [2.8] vs. Day 7: 8.8 [2.7] ng/mL; P = 0.21) or placebo (Day 1: 0.7 [1.0] vs. Day 7: 0.3 [0.5] ng/mL; P = 0.35).

Correlations between QOL and other outcome measures

In macimorelin recipients, percentage of change in ASAS total score was indirectly correlated with change in daily relative protein intake ( r = −0.686; P = 0.04). Relative change in FACIT‐F adjusted score was directly correlated with change in body weight, IGF‐1 and test meal caloric intake and indirectly correlated with change in absolute REE ( Figure 4 A–D ).

Discussion

Cachexia is a common cancer sequela associated with poor prognosis and development of new treatment options is greatly needed. The ghrelin/GHSR‐1a pathway is the most advanced pathway being targeted for this indication, although no approved drug is currently available in most countries. This pilot study is the first to test efficacy and safety of the novel ghrelin mimetic, macimorelin, as a cancer cachexia treatment and the first multi‐dose study of this drug. Macimorelin was well‐tolerated with no related serious or non‐serious adverse events, including no abnormal laboratory or ECG parameters. While no significant improvements in efficacy were observed after 1 week of daily macimorelin compared with placebo, the proportion of patients achieving the a priori efficacy criteria for change in body weight and QOL were numerically higher in macimorelin, and QOL improvement was associated with improved body weight, IGF‐1 and caloric intake and with reduced energy expenditure in macimorelin recipients.

The only approved treatment for cancer cachexia is anamorelin, another GHS, approved in Japan and undergoing Phase III trials elsewhere. 16 , 17 Macimorelin was recently approved by the FDA and EMA for AGHD diagnosis, 9 , 22 , 29 which occurred after the current trial began. The most common adverse reactions reported in the related US prescribing information include dysgeusia (4.5%), dizziness, headache, fatigue (4% each), nausea, hunger (3% each), diarrhoea, upper respiratory tract infection (2% each), feeling hot, hyperhidrosis, nasopharyngitis and sinus bradycardia (1% each). In a thorough QT trial, macimorelin caused an increase of about 11 ms in the QTc interval. In our study, the use of QT‐prolonging drugs was exclusionary, and no adverse events, including QT‐prolongation, were reported with 7 days of administration.

Cachexia‐related weight loss is adversely associated with cancer prognosis, QOL and physical function. 34 While macimorelin did not significantly improve body weight in the current study, two of the nine macimorelin participants receiving all seven doses met the weight gain efficacy criterion, which was not met by any placebo patients. This criterion was based on a similar study where 3 days of daily anamorelin significantly increased body weight in cancer cachexia patients by 0.77 kg, while those on placebo lost 0.33 kg. 14 These differences could be due to variability in potency of doses used in these compounds or malabsorption due to gastrointestinal malignancy, although other factors like sex differences may have contributed. Longer duration anamorelin treatment increased lean mass in addition to body weight in patients with cancer cachexia. 12 , 16 , 17 , 18 Like the current study, those studies did not report improved physical function. Future studies with higher doses and/or longer duration macimorelin may benefit from assessment of body composition and clinically relevant outcomes like fatigue, appetite and physical function, including potential sex differences.

Cancer cachexia may promote ghrelin resistance, wherein elevated ghrelin is seen simultaneously with depressed appetite, which might be overcome by exogenous ghrelin/GHS administration. 35 , 36 Macimorelin did not impact appetite, food intake or energy expenditure in the current study, which could suggest ghrelin resistance, but more likely suggests an insufficient macimorelin dose because appetite stimulation is a known class effect of ghrelin/GHS. 14 , 37 , 38 Cancer cachexia may also promote GH resistance wherein elevated GH is observed alongside low IGF‐1, which may be similarly overcome by exogenous ghrelin/GHS administration. 35 , 36 Anamorelin increased IGF‐1 by 54 ng/mL in cancer cachexia patients after 3 days of administration, 14 which was the basis for the IGF‐1 efficacy criterion in the current study. No macimorelin recipients achieved IGF‐1 efficacy here despite maintained GH secretion. In that study, GH response (30 min post–pre‐anamorelin) averaged over twice that observed here, likely due to the larger dose (~1.0 mg/kg) 14 ; however, macimorelin consistently induced acute GH secretion after single‐dose administration in non‐cancer individuals. 9 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 Therefore, GH resistance is an unlikely contributor to the lack of efficacy observed here, evidenced by post‐macimorelin GH ≥ 5.1 ng/mL 39 for all macimorelin recipients. One‐hour post‐macimorelin GH decreased approximately 50% (non‐significantly) after 1 week in the current study. The potential waning of GH stimulation could be from a compensatory somatostatin increase, which antagonizes GHS action on somatotrophs, 40 but our observations imply that this potential negative feedback did not impede somatotropic axis activation.

Longer duration GHS administration consistently improved patient‐reported QOL in cancer cachexia. 16 , 17 , 18 The ROMANA1/2 trials reported anorexia/cachexia improvement after 12 weeks of daily anamorelin compared with placebo, which was detectable after 3 weeks, with a trend for stable fatigue with anamorelin and a worsening with placebo. 18 Anorexia/cachexia improvement was only sustained for an additional 4 weeks of a 12‐week ROMANA1/2 extension trial (ROMANA3), implying that anamorelin efficacy may wane over time. 12 In two subsequent trials, 12 weeks of anamorelin improved various patient‐reported parameters (activity, function, appetite, meal satisfaction and overall QOL) compared with placebo 16 , 17 ; fatigue was unaffected. 16 A significant impact on QOL was undetected presently, but macimorelin recipients reported less pain and fatigue than placebo at Day 7. Additionally, two of the four macimorelin participants who met the QOL efficacy requirement received 1.0 mg/kg, suggesting that higher doses would have been more efficacious, although our final sample size was not powered to detect differences between doses. In macimorelin recipients, change in adjusted FACIT‐F total score displayed very strong, direct correlations with changes in body weight, IGF‐1 and test meal caloric intake and a strong, indirect correlation with change in REE. These findings are consistent with a meta‐analysis, which identified nutritional intake maximization as among the most propitious interventions for QOL improvement. 41 While limited by sample size, these preliminary observations suggest a potential mechanism for macimorelin‐induced QOL improvement via increased body weight, IGF‐1 (as a marker of GH action), and nutritional intake and reduced metabolic demand.

This is the first study to administer macimorelin in the cancer setting and first to administer repeated doses. This pilot clinical trial was designed with many strengths including double‐blinding, placebo controls, sequential doses and an array of clinically relevant outcomes. However, the small/uneven sample size, somewhat arbitrary efficacy criteria used to guide dose selection, trend for imbalanced Day 1 weight and combined doses limit interpretation of observations. We report that 1‐week daily macimorelin for cancer cachexia is safe and well‐tolerated. Efficacy of GHSR1a stimulation from this regimen was only sufficient for improving QOL and body weight in some individuals; however, these observations may provide preliminary evidence of macimorelin‐mediated QOL improvement through improved body weight, caloric intake and energy expenditure. This pilot study supports development of well‐powered, long‐term, dose‐escalation studies to examine efficacy of macimorelin on QOL, body composition, appetite/food intake, energy expenditure and physical function in cancer cachexia.

Funding

Macimorelin was provided by Aeterna Zentaris Inc. Work was funded by Puget Sound Veterans Affairs Health Care System and Michael E. DeBakey Veterans Affairs Medical Center. Jose Garcia receives research support from the Veterans Affairs (BX002807), the Congressionally Directed Medical Research Program (PC170059), and the National Institutes of Health (R01CA239208, R01AG061558 and R01AR067319). Lindsey Anderson receives research support from the University of Washington (DK007247) and the Veterans Affairs (RX03245). Ramiro Salas receives research support from the Veterans Affairs (I01CX001937).

Conflict of interest

Megan Herodes declares that she has no conflict of interest. Lindsey Anderson declares that she has no conflict of interest. Samuel Shober declares that he has no conflict of interest. Ellen Schur declares that she has no conflict of interest. Solomon Graf declares that he has no conflict of interest. Nicola Ammer is an employee of Aeterna Zentaris GmbH. Marco Marcelli declares that he has no conflict of interest. Jose Garcia received research support from Aeterna Zentaris GmbH. and Novo Nordisk. Submitting authors have liaised with all co‐authors and confirm agreement with the final manuscript.

The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle . 42 This protocol was approved by the respective Institutional Review Boards and Research and Development Committees and was conducted in accordance with the Declaration of Helsinki and its amendments and the International Conference on Harmonization Guideline for Good Clinical Practices; all persons gave their informed consent prior to their inclusion in the study.

Acknowledgements

This project was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases‐funded Nutrition Obesity Research Center (DK035816) and Diabetes Research Center (P30 DK017047) at the University of Washington.

Herodes M., Anderson L. J., Shober S., Schur E. A., Graf S. A., Ammer N., Salas R., Marcelli M., and Garcia J. M. (2023) Pilot clinical trial of macimorelin to assess safety and efficacy in patients with cancer cachexia, Journal of Cachexia, Sarcopenia and Muscle, 14, 835–846, 10.1002/jcsm.13191

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