JP2024534464A - Methods for determining and providing clinically meaningful improvements in patient-reported outcomes in patients with anorexia/cachexia - Google Patents

Abstract

The use of anamorelin to improve patient-reported outcomes in anorexic/cachexia patients, specifically based on the patient population that would benefit from such use, and specific methods to define and provide a clinically meaningful treatment effect.

Description

The present invention relates to the use of anamorelin to improve patient-reported outcomes in anorexic/cachexia patients, particularly based on the patient population that would benefit from such use, and specific methods for defining and providing a clinically meaningful treatment effect.

Symptoms that characterize cancer cachexia, a multifactorial syndrome occurring in more than 80% of cancer patients before death, include weight loss and anorexia (Kumar (2010); von Haehling (2010); Aoyagi (2015)). According to the current consensus diagnostic criteria described in Fearon (2011), cancer cachexia is primarily diagnosed by either recent weight loss of more than 5% over the past 6 months (in the absence of simple hunger), or recent weight loss of more than 2% and a body mass index ("BMI") of less than 20 kg/ ^m2 , or sarcopenia.

Reduced food intake in cancer patients may be caused by primary anorexia and exacerbated by secondary nutritional impact symptoms. Several reports indicate that cancer patients describe symptoms of weight loss and anorexia as a source of anxiety and worry, with significant and varied impacts on their daily lives (Hinsley (2007); Hopkinson (2014); McGrath (2002); Hopkinson (2015); Oberholzer (2013)).

To better understand the experience of weight loss and low BMI in lung cancer patients, Rodriguez et al. conducted an online study of 95 patients: 35 patients (36.8%) were classified as having substantial weight loss (defined as weight loss of 5% or more in the past 6 months, or weight loss of 2% or more for BMIs less than 20 kg/ ^m2 ). Weight loss was found to represent a substantial problem for non-small cell lung cancer ("NSCLC") patients, associated with lower quality of life, higher distress levels, and more severe symptoms (including appetite loss). Patients were also asked to identify which weight loss symptom had the most significant impact on their lives. For these patients, the most frequently reported symptoms with significant impact were changes in food taste (38%), fatigue (38%), and decreased appetite (33%). Early satiety was also noted to have a significant impact in 14% of the surveyed patients (Rodriguez (2017)).

Anorexia is a major contributor to weight loss in cancer patients. Anorexia in cancer may be characterized as a generalized loss of appetite, early satiety, altered food preferences, or a combination of these (Molfino (2015)). Cancer-associated anorexia is also a major clinical problem; it has a detrimental effect on nutritional status in advanced cancer (Yavuzsen (2005)) and has been associated with poorer survival in multiple studies (Montazeri (2009); Sundstrom (2006); Fielding (2007); McKernan (2008); Collette (2004); Yeo (2006); Sullivan (2006)). Anorexia is the second most common symptom after fatigue in patients with advanced cancer (Lis (2009)). In a study conducted by Sundstrom et al., appetite loss emerged as the most significant independent indicator of survival in patients with advanced NSCLC, leading the researchers to conclude that the assessment of anorexia and appetite loss is a valuable tool in determining chest radiotherapy strategy (Sundstrom (2006)).

Reduced dose intensity and increased toxicity of chemotherapy have also been observed in patients with weight loss, which can lead to dose reductions, treatment delays, or eventual cessation of treatment (Ross (2004); Andreyev (1998)). Furthermore, a study in NSCLC patients comparing non-weight-losing patients with weight-losing/underweight patients (weight loss of 5% or more in the previous 6 months, or weight loss of more than 2% with a BMI of less than 20 kg/ ^m2 ) found that all patient-reported outcome ("PRO") measures (FACT-G, and specific domains from FAACT, FACIT-F, FACIT-L), and performance status (Karnofsky PS, and ECOG) were worse in weight-losing/underweight patients compared to non-weight-losing patients, and, although all these measures declined over a 6-month period, the rate of decline was more rapid in the weight-losing/underweight group (LeBlanc (2015)).

In summary, weight loss, along with anorexia (including loss of appetite), is a common, debilitating, and concerning event for patients with advanced cancer. Despite its high prevalence and association with poor prognosis, there have been few therapeutic advances in managing these symptoms in patients with advanced cancer, and pharmacological interventions remain limited.

Anamorelin HCl is an orally active selective ghrelin receptor agonist. Ghrelin is an endogenous ligand for the G protein-coupled ghrelin receptor (Kojima (1999)). Ghrelin is primarily synthesized in the stomach and has a short circulating half-life (around 15 minutes) in both animals and humans, limiting its therapeutic potential as long-term efficacy would require continuous infusion. Nevertheless, studies of the effects of ghrelin or longer-acting ghrelin mimetics have revealed that ghrelin has anabolic, appetite-enhancing, adiposity-enhancing and anti-inflammatory properties (Guillory (2013)) with prokinetic activity (Trudel (2002)).

In vitro, anamorelin exerts high affinity and selective binding to the ghrelin receptor and is a highly potent growth hormone ("GH") secretagogue in in vitro assays (EC50 = 1.5 nM). In vivo, anamorelin HCl induced robust GH release following oral administration to dogs and also induced a potent appetite-enhancing effect in rats following intracerebral administration; increases in food intake and body weight were also observed in animal models (Trudel (2002)). In clinical studies, anamorelin treatment was also associated with increases in appetite and body weight, along with increases in lean body mass ("LBM") and improvements in health-related quality of life ("QoL") measures (Currow (2014)). Nevertheless, in the Phase III ROMANA study undertaken to evaluate the efficacy and safety of anamorelin HCl for treating anorexic NSCLC patients with cachexia, anamorelin failed to demonstrate a statistically significant improvement in grip strength (one of two co-primary endpoints) (Temel (2016)).

Therefore, treating malignancy-associated weight loss and anorexia in cancer patients is an area of unmet medical need.

A cancer patient population was unexpectedly discovered in which anamorelin was surprisingly effective against anorexia and cachexia. In particular, it was discovered that patients with poorest personal perception of anorexia as judged by the novel symptom subscale of FAACT (5-IASS), in addition to low scores on the FAACT A/CS, responded remarkably well to anamorelin, even when they had poor ECOG performance status (reflecting healthier patients). The efficacy of treatment is particularly evident when measured with the 5-IASS symptom subscale using PGIS anchor-based and PGIC anchor-based methods to assess clinical benefit.

Thus, in a first main embodiment, the present invention provides a method of providing a clinically meaningful treatment benefit in a 5-IASS score, based on a PGIS anchor-based and a PGIC anchor-based benefit scale, in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily, wherein: (a) said patient has had a weight loss of more than 2% in the preceding six months; (b) said patient has a body mass index of less than 20 kg/ ^m2 ; (c) said patient has a 5-IASS score of 17 points or less; and (d) said patient has a 12-item FAACT A/CS score of 37 points or less.

The benefit is also particularly evident with respect to the combination of weight gain and 5-IASS score. Thus, in a second main embodiment, the present invention provides a method of providing a clinically meaningful treatment benefit in 5-IASS score and/or body weight, where necessary based on a PGIS anchor-based and PGIC anchor-based benefit scale, in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily, wherein: (a) said patient has had a weight loss of more than 2% in the preceding six months, (b) said patient has a body mass index of less than 20 kg/ ^m2 , (c) said patient has a 5-IASS score of 17 points or less, and (d) said patient has a 12-item FAACT A/CS score of 37 points or less.

Benefits are also evident in the composite clinical response, as that term is specifically defined herein. Thus, in a third main embodiment, the present invention provides a method of achieving a composite clinical response in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period, wherein (a) said composite clinical response comprises (i) increasing said patient's body weight by 5% or more, and (ii) improving said patient's 5-IASS score by 2 points or more, and (b) said patient is characterized by (i) a weight loss of more than 2% in the preceding 6 months, (ii) a body mass index of less than 20 kg/ ^m2 , (iii) a 5-IASS score of 17 points or less, and (iv) a 12-item FAACT A/CS score of 37 points or less. These methods have general applicability to treating patients with cancer cachexia. Accordingly, in a fourth main embodiment, the present invention provides a method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein said patient optionally has anorexia and is characterized by: (a) weight loss of more than 2% in the preceding six months, (b) a body mass index of less than 20 kg/ ^m2 , (c) a 5-IASS score of 17 points or less, and (d) a 12-item FAACT A/CS score of 37 points or less.

In a fifth main embodiment, the present invention provides a method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein said patient optionally has anorexia, and is characterized by (a) weight loss of more than 2% in the preceding six months, (b) a body mass index of less than 20 kg/ ^m2 , (c) a 5-IASS score of 17 points or less, and optionally (d) a 12-item FAACT A/CS score of 37 points or less.

In a sixth main embodiment, the present invention provides a method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to the patient once daily for a therapeutically effective period of time, wherein the patient optionally has anorexia and is characterized by (a) a 5-IASS score of 17 points or less, and optionally (b) a 12-item FAACT A/CS score of 37 points or less.

Yet further methods relate to methods used to determine a clinically meaningful treatment benefit for use in the present invention, and treatment of patients using such methods. Thus, in a seventh main embodiment, the present invention relates to a method for determining a clinically meaningful 5-IASS improvement threshold in a human patient suffering from anorexia and cachexia, comprising the steps of: (a) determining whether or not the patient has a 12-item FAACT A/CS score of 37 or less (see Blauwhoff (2016)), a 5-IASS score of 17 or less, and a mean improvement of 20 kg/m2 with more than 2% unintentional weight loss in the preceding 6 months. The method includes the steps of: providing a plurality of patients suffering from anorexia and cachexia characterized by a BMI of less than ² (see Fearon (2011)); (b) providing within-patient clinically meaningful changes (CMC) on PGIS-A to enable determination of a clinically meaningful threshold for anorexia symptom improvement in said plurality of patients; (c) providing within-patient clinically meaningful changes (CMC) on PGIC-A to enable determination of a clinically meaningful threshold for anorexia symptom improvement in said plurality of patients; (d) administering a therapeutically effective amount of anamorelin once daily to said plurality of patients for a treatment period; (e) generating a dataset comprising 5-IASS scores, PGIS-A scores and PGIC-A scores for said plurality of patients obtained from equal time points during said treatment period; and (f) determining a 5-IASS improvement threshold that correlates to said PGIS-A CMC and said PGIC-A CMC. Of course, the ultimate goal of the present invention is to treat anorexia and cachexia, and therefore the seventh main embodiment is always preferably practiced by administering said therapeutically effective amount of anamorelin to said patient once daily to achieve these clinically meaningful treatment benefits.

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

DEFINITIONS AND USAGE OF TERMS As used herein and in the claims, the singular forms a, an, and the include plural references unless the context clearly dictates otherwise. For example, the term "a specification" refers to one or more specifications for use in the presently disclosed methods and systems. "An ingredient" includes mixtures of two or more such ingredients, and the like. The word "or" or similar terms, as used herein, means any one member of a particular list, and also includes any combination of members of that list.

As used herein, the term "about" will account for and offset variability inherent in the pharmaceutical industry, such as differences in product strength due to manufacturing variations and time-induced product degradation, as well as differences due to water of hydration and different salts. The term also allows for any variation that, in the practice of good manufacturing practice, would allow the product being evaluated to be considered therapeutically equivalent or bioequivalent in humans to the stated strength of the claimed product. In some embodiments, the term allows for any variation within 5% or 10% of the stated specification or specification.

As used herein and in the claims that follow, the word "comprise" and variations of that word (e.g., "comprising" and "comprises") mean "including but not limited to" and are not intended to exclude, for example, other additives, components, wholes, or steps. When an element is described as including one or more components, steps, or conditions, it will be understood that the element may also be described as "consisting of" or "consisting essentially of" that one component, step, or condition, or multiple components, steps, or conditions.

When "drug therapy," "drug administration," and similar terms are used herein, it will be understood that the therapy may be accomplished via any suitable route of administration using any acceptable dosage form, and that the drug may be administered as a free base, a salt, or an ester or other prodrug moiety.

"ECOG" (Eastern Cooperative Oncology Group) status refers to the scales and criteria used by physicians and researchers to assess how a patient's disease is progressing, how it is affecting the patient's ability to perform daily activities, and to determine appropriate treatment and prognosis, as described by Oken (1982). The questionnaire for scoring on the ECOG performance scale is reproduced in Table 1.

"FAACT" refers to the Functional Assessment of Anorexia Cachexia Therapy (FAACT) Questionnaire, as previously described by Small (2002). "FAACT A/CS", or "FAACT in Anorexia/Cachexia Domain", refers to a set of 12 questions, as described by Ribaudo (2001), selected from the FAACT to assess patient perception of appetite, food consumption, weight gain/loss, vomiting and abdominal pain, which can be scored from 0 to 4, and patient concerns associated therewith, for a range of possible scores from 0 to 48. The questions that make up the FAACT A/CS are reproduced in Table 2.

"FAACT Total Score" refers to the patient's score on the FACT-G which is added to the patient's score on the FAACT A/CS giving a possible score range of 0-156. "FACT-G", or "Functional Assessment Cancer Therapy-General Version", is a 27-item compilation of general questions as previously described in Webster (2003). The FACT-G is divided into four major domains: physical well-being, social/family well-being, emotional well-being and functional well-being. The FACT-G total score is obtained by summing the subscale scores on these major domains giving a possible score range of 0-108.

The "5-IASS", or "5-Item Anorexia Subscale", refers to the following five items from the FAACT A/CS questionnaire: "I have a good appetite", "Most foods seem unpalatable", "Interest in food decreases as soon as I try to eat", "I have difficulty eating fatty or heavy foods", and "I seem to feel full quickly after eating" (Gelhorn (2016)).

"First-line treatment" is a treatment regimen or regimens generally accepted by medical authorities for initially treating a given type and stage of cancer. Also called induction therapy, this first-line treatment is the initial attack of chemotherapy drugs against the malignancy. "Second-line treatment" is one that is attempted when the first-line treatment does not work adequately. Managing cancer cases requires regular evaluation of treatment and adjustments as needed. Discontinuing the first-line treatment and adopting a new regimen is what is meant by "second-line treatment".

"PGIS" and "PGIC": The PGIS (Patient Global Impression of Severity) is a one-item questionnaire with a 4-point Likert-type response scale ranging from "no" symptoms related to appetite/eating or weight to "severe" symptoms related to appetite/eating or weight. The PGIC (Patient Global Impression of Change) is also a one-item questionnaire with a 7-point Likert-type response scale ranging from "much worse" to "much improved." The actual questionnaires for appetite/eating-related symptoms (PGIS-A and PGIC-A) and weight concerns (PGIS-W and PGIC-W) are reported in Tables 4, 5, 6, and 7 in the Examples to this specification.

As used herein, the term "significantly" refers to a level of statistical significance. The level of statistical significance can be p<0.1, p<0.05, p<0.01, p<0.005, or p<0.001. Unless otherwise specified, the level of statistical significance when the term "significant", the term "significantly", or other variations of this term are used is p<0.05. When a measurable result or effect is expressed or identified herein, it will be understood that the result or effect is preferably evaluated based on its statistical significance relative to a baseline (e.g., placebo, etc.). Similarly, when a treatment or benefit is described herein, it will be understood that the treatment or benefit preferably demonstrates efficacy to a degree of statistical significance.

"Targeted therapy" is a form of molecular medicine that blocks the growth of cancer cells not by simply interfering with all rapidly dividing cells (e.g., by conventional chemotherapy), but rather by interfering with specific targeted molecules required for carcinogenesis and tumor growth. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy (and thus distinct from chemotherapy, i.e., cytotoxic therapy).

"Therapeutically effective amount" means an amount that, when administered to a human to support or affect a metabolic process, or to treat or prevent a disease, is sufficient to cause such treatment or prevention of the disease, or to support or affect the metabolic process. In any of the embodiments or subembodiments of the present invention, a therapeutically effective amount preferably comprises 100 mg of anamorelin or a pharma- ceutically acceptable salt thereof when orally administered once daily.

When published test methodologies and diagnostic instruments are referred to herein, it will be understood that the test methodology or diagnostic instrument is performed based on the version in effect on January 1, 2021, unless otherwise specified to the contrary herein. This is true even when the methodology or instrument is defined herein based on a publication reporting an earlier version. When a scoring questionnaire is administered for the purpose of assessing clinical benefit, all responses of negatively worded items are reverse coded and summed according to the recommendations of the FACIT Administration and Scoring Guidelines published by FACIT.org, so that higher scores indicate lower levels of QoL/symptom burden.

When a range is expressed herein by specifying alternative upper and lower limits of the range, it will be understood that the endpoints may be combined in any manner that is mathematically feasible. Thus, for example, a range from 50 or 80 to 100 or 70 may alternatively be expressed as a series of ranges from 50 to 100, 50 to 70, and 80 to 100. When a series of upper and lower limits are related using the phase "and" or "or", it will be understood that the upper limit may not be limited by or combined with the lower limit, and conversely, the lower limit may not be limited by or combined with the upper limit. Thus, for example, a range of more than 40% and/or less than 80% includes a range of more than 40%, a range of less than 80%, and a range of more than 40% but less than 80%. Unless otherwise specified by the term "between," the boundaries of the ranges (the lower and upper ends of the ranges) are included in the claimed range and may be preceded by the term "about."

When an element of a process or product is defined by reference to one or more examples, components, properties or characteristics, it will be understood that any one of those components, properties or characteristics, or any combination of those components, properties or characteristics may also be used to define the matter at issue. This may occur, for example, when specific examples of an element are recited in the claims (as in a Markush group), or when an element is defined by multiple features. Thus, for example, if the claimed system includes element A defined by elements A1, A2 and A3 in combination with element B defined by elements B1, B2 and B3, it will be understood that the invention also encompasses systems defined by element A without element B, systems in which element A is defined by elements A1 and A2 in combination with element B defined by elements B2 and B3, and all other possible permutations.

Methods of Treatment The present invention relates to various methods of treating anorexia and cachexia, and affected patient populations that are responsive to anamorelin treatment. Thus, in a first main embodiment, the present invention provides a method of providing a clinically meaningful treatment benefit in a 5-IASS score, based on a PGIS anchor-based benefit scale, in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily, wherein (a) said patient has had a weight loss of more than 2% in the preceding six months, (b) said patient has a body mass index of less than 20 kg/ ^m2 , (c) said patient has a 5-IASS score of 17 points or less, and (d) said patient has a 12-item FAACT A/CS score of 37 points or less.

In a second main embodiment, the present invention provides a method of providing a clinically meaningful treatment benefit in a 5-IASS score and/or body weight, if necessary based on a PGIS anchor-based benefit scale, in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily, wherein: (a) said patient has had a weight loss of more than 2% in the preceding six months; (b) said patient has a body mass index of less than 20 kg/ ^m2 ; (c) said patient has a 5-IASS score of 17 points or less; and (d) said patient has a 12-item FAACT A/CS score of 37 points or less.

In a third main embodiment, the present invention provides a method of achieving a composite clinical response in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein (a) said composite clinical response comprises (i) increasing said patient's body weight by 5% or more, and/or (ii) improving said patient's 5-IASS score by 2 points or more, and (b) said patient is characterized by (i) a weight loss of more than 2% in the preceding 6 months, (ii) a body mass index of less than 20 kg/ ^m2 , (iii) a 5-IASS score of 17 points or less, and (iv) a 12-item FAACT A/CS score of 37 points or less.

These methods have general applicability to treating patients with cancer cachexia. Thus, in a fourth main embodiment, the present invention provides a method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, said patient optionally having anorexia, and characterized by (a) weight loss of more than 2% in the preceding 6 months, (b) a body mass index of less than 20 kg/ ^m2 , (c) a 5-IASS score of 17 points or less, and (d) a 12-item FAACT A/CS score of 37 points or less.

In a fifth main embodiment, the present invention provides a method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein said patient optionally has anorexia, and is characterized by (a) weight loss of more than 2% in the preceding six months, (b) a body mass index of less than 20 kg/ ^m2 , (c) a 5-IASS score of 17 points or less, and optionally (d) a 12-item FAACT A/CS score of 37 points or less.

In a sixth main embodiment, the present invention provides a method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to the patient once daily for a therapeutically effective period of time, wherein the patient optionally has anorexia and is characterized by (a) a 5-IASS score of 17 points or less, and optionally (b) a 12-item FAACT A/CS score of 37 points or less.

These methods of treatment can be further understood with reference to various subembodiments that can modify any of the first through sixth main embodiments. It will be understood that these subembodiments can be combined in whatever manner is both mathematically and physically possible to create additional subembodiments that can in turn modify any of the main embodiments. Generally speaking, in any of the embodiments or subembodiments of the present invention, the patient can be characterized as suffering from weight loss and a general loss of appetite, early satiety, altered food preferences, or a combination thereof.

In one subembodiment, the patient may be further defined based on recent unintentional weight loss and body mass index ("BMI"). As with all instances herein where the patient is characterized by a criterion, it will be understood that such characterization applies when drug treatment is initiated, and that the characterization may be determined by testing immediately prior to the initiation of the method. Thus, in one subembodiment, the patient has a weight loss of more than 2% in the previous six months and a body mass index of less than 20 kg/ ^m2 . Alternatively, the patient may be characterized based on a weight loss of more than 2%, more than 4%, more than 5%, more than 8%, or more than 10% in the previous six months. As another alternative, the patient may have a body mass index of less than 19 kg/ ^m2 , ^less than 18 kg/m2, less ^than 17 kg/m2, or less than 16 kg/ ^m2 . In one particular subembodiment, the patient has a weight loss of more than 5% in the previous six months and a body mass index of less than 20 kg/ ^m2 .

The patient may also be characterized by more stringent criteria for 5-IASS, FAACT A/CS, and ECOG performance status. Thus, in one subembodiment, the patient has a 5-IASS score of 16 points or less, 14 points or less, 12 points or less, 10 points or less, or 8 points or less. In the alternative, the patient may be characterized as having a 5-IASS score of 10 points or less, or a 5-IASS score of more than 10 points and 17 points or less. In another subembodiment, the patient has a 12-item FAACT A/CS score of 35 points or less, 30 points or less, 28 points or less, 26 points or less, 24 points or less, 22 points or less, or 20 points or less. In the alternative, the patient may be characterized as having a 12-item FAACT A/CS score of 28 points or less, or a 12-item FAACT A/CS score of more than 28 points and 37 points or less.

Patients can be characterized by any of the defining parameters set forth herein, or by any combination of parameters. In one embodiment, patients are characterized as having a 5-IASS score of 10 points or less, and a weight loss of more than 2% in the previous 6 months. In another embodiment, patients are characterized as having a 5-IASS score of 10 points or less, a weight loss of more than 2% in the previous 6 months, and a 12-item FAACT A/CS score of 28 points or less. In yet another embodiment, patients are characterized as having a 5-IASS score of 10 points or less, a weight loss of more than 2% in the previous 6 months, and either a second-line or third-line treatment.

Yet further embodiments are based on the patient's ECOG performance status. Thus, in other subembodiments, the patient has an ECOG performance status of 0, 1, or 2.

The patient may also be characterized based on disease status. Thus, in one subembodiment, the patient has cancer. In another subembodiment, the patient has unresectable NSCLC. In yet another subembodiment, the patient has gastrointestinal cancer, optionally selected from colorectal, gastric, or pancreatic cancer.

The patient may also be characterized by a combination therapy. Thus, in any of the embodiments or subembodiments of the present invention, the patient is not receiving systemic anti-cancer treatment. In the alternative, the patient is receiving systemic anti-cancer treatment. When the patient is receiving systemic anti-cancer treatment, the systemic anti-cancer treatment may be, for example, a first treatment choice, a second treatment choice, or a third treatment choice, and may be chemotherapy, radiation therapy, immunotherapy, or targeted therapy, or a combination thereof.

The methods of the invention may also be characterized by associated outcomes or benefits. Thus, in any of the embodiments or subembodiments of the invention, the treatment effect may include 1 week, 2 weeks, 3 weeks, 6 weeks, 9 weeks, or 12 weeks. In other subembodiments, the treatment may additionally or alternatively increase the patient's 5-IASS score by 2 points or more, 3 points or more, or 4 points or more. Alternatively or additionally, the method may increase the patient's body weight by 2% or more, 3% or more, 4% or more, or 5% or more, or increase the patient's FAACT total score by 15 points or more, 20 points or more, 25 points or more, 30 points or more, or 35 points or more.

In any of the treatment methods of the present invention, a clinically meaningful treatment benefit in 5-IASS can also be defined as being equal to or greater than the 5-IASS improvement threshold determined by the method of the seventh main embodiment, or by any of its subembodiments/parameters. In a similar manner, a clinically meaningful treatment benefit in weight can be defined as being equal to or greater than the weight improvement threshold determined by the method of the seventh main embodiment.

Methods for Determining Improvement Thresholds The present invention also provides methods for determining improvement thresholds for 5-IASS and weight gain that correspond to clinically meaningful improvements in a patient's health status based on patient-reported improvements in disease severity and physical condition. In preferred embodiments, these thresholds correspond to the clinically meaningful benefits that define the treatment methods of the present invention.

Accordingly, in a seventh main embodiment, the present invention provides a method for determining a clinically meaningful 5-IASS improvement threshold in a human patient suffering from anorexia and cachexia, comprising the steps of: (a) determining whether or not a patient meets the criteria for a 12-item FAACT A/CS score of 37 or less, a 5-IASS score of 17 or less, and a mean improvement of 20 kg/m2 with more than 2% unintentional weight loss in the preceding 6 months; The method includes the steps of: providing a plurality of patients suffering from anorexia and cachexia, characterized by a BMI of less than ² ; (b) providing within-patient clinically meaningful changes (CMC) for PGIS-A to enable determination of a clinically meaningful threshold for anorexia symptom improvement in said plurality of patients; (c) providing within-patient clinically meaningful changes (CMC) for PGIC-A to enable determination of a clinically meaningful threshold for anorexia symptom improvement in said plurality of patients; (d) administering a therapeutically effective amount of anamorelin once daily to said plurality of patients for a treatment period; (e) generating a dataset comprising 5-IASS scores, PGIS-A scores and PGIC-A scores for said plurality of patients obtained from equal time points during said treatment period; and (f) determining a 5-IASS improvement threshold that correlates to said PGIS-A CMC and said PGIC-A CMC.

The method for determining a 5-IASS improvement threshold according to the seventh main embodiment can be further characterized by various subembodiments or parameters. In one particular subembodiment, the method is also used to determine a clinically meaningful weight improvement threshold in a human patient suffering from anorexia and cachexia. In this subembodiment, the method further comprises the following additional steps: (a) providing a clinically meaningful change (CMC) within a patient with respect to PGIS-W to enable a clinically meaningful threshold for weight improvement in the plurality of patients to be determined; (b) providing a clinically meaningful change (CMC) within a patient with respect to PGIC-W to enable a clinically meaningful threshold for weight improvement in the plurality of patients to be determined; (c) generating a data set including weight scores, PGIS-W scores, and PGIC-W scores for the plurality of patients obtained from equal time points during the treatment period; and (d) determining a weight improvement threshold that correlates with the PGIS-W CMC and the PGIC-W CMC. The term "weight score" refers to the observed increase or decrease in weight on a kilogram basis from baseline (i.e., the start of treatment).

The PGIS-A CMC, PGIC-A CMC, PGIS-W CMC, and PGIC-W CMC can be generated from various data sets using methodologies generally described in various U.S. Food and Drug Administration publications, including FDA 2018, FDA 2019, and FDA 2020. In preferred embodiments, these CMCs correspond to clinically meaningful changes within patients as determined based on patient interviews characterized by the seventh principal embodiment according to the principles of Pokrzywinski (2018), Norman (2003), and Revicki (2008).

The 5-IASS improvement threshold can be determined by calculating the improvement in 5-IASS score required to achieve PGIS-A CMC and PGIC-A CMC. In a similar manner, the weight improvement threshold can be determined by calculating the improvement in weight score required to achieve PGIS-W CMC and PGIC-W CMC.

Dosage Form/Route of Administration Further provided is a pharmaceutical composition for preventing and/or treating a subject, comprising a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or adduct thereof and one or more pharma-ceutically acceptable excipients. A "pharma-ceutically acceptable" excipient is one that is not biologically or non-biologically undesirable, i.e., the substance can be administered to a subject without causing any undesirable biological effects or interacting in a detrimental manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one skilled in the art. The carrier can be a solid, a liquid, or both.

The disclosed compounds can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such route, and in a dose that is effective for the intended treatment or prevention. The active compounds and compositions can be administered, for example, orally, rectally, parenterally, ophthalmically, by inhalation, or topically. In particular, administration can be epicutaneous, inhalation, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, vaginal, intravaginal, ocular, intraocular, ocular, enteral, oral, buccal, transoral, intestinal, rectal, intrarectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intraventricular, intracardiac, subcutaneous, intraosseous, intradermal, intraarachnoid, intraperitoneal, intravesical, intracavernous, intramedullary, intraocular, intracranial, transdermal, transmucosal, nasal, inhalation, intracisternal, epidural, peridural, intravitreal, and the like.

The pharmaceutical composition may be administered orally, for example, with an inert diluent or an assimilable edible carrier. The pharmaceutical composition and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or simply incorporated into the individual's diet. For oral therapeutic administration, the pharmaceutical composition may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 1% by weight of the active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 80% of the weight of the unit.

Tablets, troches, pills, capsules, and the like can also contain: binders, such as gum gragacanth, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, lactose, or saccharin, or flavoring agents, such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, the capsule can contain a liquid carrier in addition to materials of the above types. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules can be coated with shellac, sugar, or both. The syrup or elixir may contain the drug, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring agent (such as cherry or orange flavoring). Of course, any material used in preparing any dosage unit form should be pharma- ceutical pure and substantially non-toxic/biocompatible in the amounts used. In addition, the pharmaceutical composition may be incorporated into sustained release preparations and formulations.

It is particularly advantageous to formulate parenteral compositions in dosage unit forms for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages for treating an individual, where each unit contains a predetermined amount of pharmaceutical composition calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present disclosure relate to the characteristics of the pharmaceutical composition and the particular therapeutic effect to be achieved.

The therapeutically effective amount of anamorelin may vary over a suitable dosage range depending on the subject's health condition, the desired response, the dosage form and the route of administration. In a preferred subembodiment, when administration is oral, the therapeutically effective amount is about 10 mg/day to about 500 mg/day of anamorelin, preferably 25 mg/day to 300 mg/day, more preferably 50 mg/day to 150 mg/day, and most preferably 100 mg/day. The dosage is administered once a day as a single dose, preferably before the first meal of the day. The most preferred form of the compound is anamorelin HCl, and the dosages given above are preferably based on the weight of the salt.

In the following examples, various efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be allowed for. The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein are made and evaluated, are intended to be purely illustrative of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

Example 1. A randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of anamorelin for treating tumor-associated weight loss and anorexia in adult patients with advanced non-small cell lung cancer.

This is a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of anamorelin HCl. Approximately 316 patients with advanced NSCLC and cachexia will be randomized 1:1 to anamorelin HCl (100 mg) or placebo taken orally once daily (QD) for a total of 24 weeks. Patients will be instructed to take the study medication at least 1 hour before their first meal of the day.

The target study population is adult patients with advanced NSCLC with a body mass index less than 20 kg/ ^m2 with unintentional weight loss of more than 2% within 6 months prior to screening and anorexia. Important inclusion and exclusion criteria include:

Inclusion criteria : Male or female, aged 18 or over.
Documented histologic or cytologic diagnosis of American Joint Committee on Cancer (AJCC) stage III or stage IV NSCLC. Stage III patients must have unresectable disease.
- Body mass index less than 20 kg/ ^m2 with involuntary weight loss of more than 2% within 6 months prior to screening.
Ongoing problems with appetite/eating associated with the underlying cancer as determined by having a score of 17 points or less on the 5-IASS and a score of 37 points or less on the 12-item FAACT A/CS.
Patients who are or are not receiving systemic anti-cancer treatment at screening are eligible to participate, including first, second, and third line of chemotherapy/radiotherapy, immunotherapy, or targeted therapy.
- ECOG performance status of 0, 1 or 2 at screening.

Exclusion Criteria : Patients with other forms of lung cancer (e.g., small cell, neuroendocrine tumors).
-Pregnant or breastfeeding women.
- Reversible causes of reduced food intake. These causes may include, but are not limited to:
oNCI CTCAE grade 3 or 4 oral mucositis oNCI CTCAE grade 3 or 4 GI disorders (nausea, vomiting, diarrhea, and constipation)
o An organic disorder making it impossible to eat, or o Severe depression.
- Patient undergoing major surgery within 4 weeks prior to randomization (central venous access placement and tumor biopsy are not considered major surgery).
- Patients currently taking androgenic compounds including, but not limited to, testosterone, testosterone-like agents, oxandrolone, megestrol acetate, corticosteroids, olanzapine, mirtazapine, dronabinol, marijuana (cannabis), or currently taking any amount of other prescription medications or off-label products intended to increase appetite or treat involuntary weight loss.

The co-primary efficacy endpoints include:

Co-primary efficacy endpoints : Duration of clinically meaningful treatment benefit on body weight, extended through Week 12.
- Duration of clinically meaningful treatment benefit on the 5-IASS through Week 12.

Duration of treatment benefit is measured as the duration that patients experience a change from baseline that is equal to or greater than a predefined threshold of clinical significance. For computational purposes, linear progression is assumed between the two measures. Secondary efficacy endpoints include:

Secondary Efficacy Endpoints - Mean change in body weight from baseline to Week 12.
- Mean change in 5-IASS by week 12.
- Mean change in FAACT total score from baseline to Week 12.

A partial flowchart for this study is shown in Table 3.

Example 2.5 - Determining the improvement threshold for IASS

The PGIS and PGIC questionnaires will be used as anchors to determine clinically meaningful differences (i.e., "improvement thresholds") in 5-IASS scores, using within-patient clinically meaningful changes ("CMCs") on the PGIS and PGIC determined through patient interviews according to the principles described in Pokrzywinski (2018), Revicki (2008), and FDA guidance documents.

The PGIS and PGIC each consist of one question to assess the severity and change in appetite/eating related symptoms. The PGIS is a single-item questionnaire with a 4-point Likert-type response scale ranging from "no" appetite/eating related symptoms to "severe" appetite/eating related symptoms. The PGIC is also a single-item questionnaire with a 7-point Likert-type response scale ranging from "much worse" to "much improved." The PGIS will be administered at baseline, weeks 6 and 9. The PGIC will be administered at weeks 6 and 9.

The PGIS and PGIC questionnaires for assessing 5-IASS thresholds are reported below in Tables 4 and 5.

Clinically meaningful changes ("CMC") will be determined according to standard practice for these anchors and will be supported by distribution-based methods (Pokrzywinski (2018); Norman (2003); Revicki (2008)). A 5-IASS improvement threshold will be determined as the smallest difference or change in score from baseline that is considered important to patients (i.e., improvement on PGIS and PGIC). As such, the difference in scores on PGIS from baseline to weeks 6 and 9 will be determined, and the improvement on PGIS will be used to define meaningful change based on the mean value of 5-IASS. Similarly, the mean value of 5-IASS among patients indicating that appetite/eating symptoms have improved since the start of treatment (based on PGIC) will be calculated; this value will be used to help define meaningful change in symptom scales.

The results of these anchor-based methods will be corroborated by distribution-based methods that calculate 0.2 standard deviations (SD), 0.3 SD, and 0.5 SD; whereby an estimate of 0.5 SD can be considered to provide an upper bound for what would constitute meaningful change, while 0.2 SD provides a lower bound (Revicki (2008)). Both the anchor-based and distribution-based estimates will be plotted together for comparison and triangulation; whereby different response thresholds will be graphed to visually depict the range of estimates, and the anchor-based estimates will be assigned a greater weight than the corroborating distribution-based methods. Cumulative distributions of response curves for the 5-item anorexia symptoms subscale, i.e., cumulative distributions of response curves for the treatment group and cumulative distributions of response curves for the placebo group, will also be generated encompassing all available data to allow the various response thresholds to be examined simultaneously and collectively.

Example 3. Determination of improvement threshold for weight change

The PGIS and PGIC questionnaires will also be used as anchors to determine meaningfully important differences in weight change (i.e., "improvement thresholds") using within-patient clinically meaningful changes ("CMCs") on the PGIS and PGIC determined through patient interviews according to the principles described in Pokrzywinski (2018), Revicki (2008), and FDA guidance documents.

The PGIS and PGIC questionnaires for assessing weight change thresholds are reported below in Tables 6 and 7.

As with the anorexia anchors, clinically meaningful changes will be determined according to standard practice for these anchors and will be supported by distribution-based methods (Norman (2003); Revicki (2008)). A weight change improvement threshold will be determined as the smallest difference or change in score from baseline that is considered important to patients (i.e., improvement on the PGIS and PGIC). As such, the difference in scores on the PGIS from baseline to weeks 6 and 9 will be determined, and the improvement on the PGIS will be used to define meaningful change based on the mean weight change in kg. Similarly, the mean percent weight change among patients who indicate that their weight concerns have improved since the start of treatment (based on the PGIC) will be calculated; this value will be used to help define meaningful change in the concerns scale.

The results of these anchor-based methods will be corroborated by distribution-based methods that calculate 0.2 standard deviations (SD), 0.3 SD, and 0.5 SD; whereby the 0.5 SD estimate can be considered to provide an upper bound for what would constitute a meaningful change, while 0.2 SD provides a lower bound (Revicki (2008)). Both the anchor-based and distribution-based estimates will be plotted together for comparison and triangulation; whereby different response thresholds will be graphed to visually depict the range of estimates, and the anchor-based estimates will be assigned a greater weight than the corroborating distribution-based methods. Cumulative distributions of response curves for percentage weight change, i.e., cumulative distributions of response curves for treatment groups and cumulative distributions of response curves for placebo groups, will also be generated encompassing all available data to allow various response thresholds to be examined simultaneously and collectively.

Example 4. Efficacy and safety of anamorelin in cachectic patients with low body mass index and advanced non-small cell lung cancer or gastrointestinal cancer.

This was a single-arm, multicenter clinical study to evaluate the efficacy and safety of anamorelin in Japanese patients with cancer cachexia and low BMI (BMI less than 20 kg/ ^m2 ).

Inclusion criteria Patients with advanced cancer (non-small cell lung, colorectal, gastric or pancreatic cancer) were eligible for the study if they met the following criteria: unsuitable for curative resection/radical radiotherapy or postoperative recurrence, BMI less than 20 kg/ ^m2 and unintentional weight loss of more than 2% in the past 6 months, cancer-related anorexia, performance status of 0-2 (0-1 for pancreatic cancer). Cancer-related anorexia was defined as a FAACT-5 IASS score of 17 points or less and a FAACT anorexia/cachexia specific subscale score of 37 points or less.

Intervention: After a screening/observation period of up to 4 weeks, eligible patients entered a 24-week treatment period in which 100 mg of anamorelin was administered once a day, 1 hour before breakfast. After 24 weeks, patients entered a 2-week follow-up period. Patients were prohibited from using any medications or treatments for anorexia (e.g., systemic corticosteroids, growth hormone and androgen preparations, medroxyprogesterone and megestrol, herbal medicines, and tube feeding). Adjunctive use of corticosteroids was permitted for up to 5 consecutive days in chemotherapy or radiotherapy regimens.

Outcomes and Evaluations The primary outcome was composite clinical response (CCR) at 9 weeks, defined as the proportion of patients meeting the following three outcomes: 1) weight increase of ≥5% from baseline, 2) FAACT-5 IASS score increase of ≥2, and 3) survival. Secondary outcomes were change in weight and FAACT-5 IASS score at 9 weeks. Exploratory outcomes included the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD), and Patient Global Impression of Change (PGIC).

The FAACT (version 4) and QOL-ACD questionnaires were completed by the patients every 3 weeks during the treatment period. For the QOL-ACD, we assessed changes in items 8, 9 and 11, which deal with appetite-related questions, namely "Did you have a good appetite?", "Did you find the food tasty?" and "Did you lose weight?". These items were scored on a 5-point scale, with 1 corresponding to the worst perception and 5 corresponding to the best perception.

The PGIC was also used to assess patient perception of change in disease/symptom severity over time, including cancer-related symptoms. Patients were asked to rate at 6 and 9 weeks whether their appetite/symptoms related to eating had improved since starting treatment and how their general physical condition had changed. Both questions included seven possible answers: very improved, very improved, slightly improved, no change, slightly worse, very worse, or very worse.

Patients: 102 patients were scheduled to start treatment with anamorelin and were included in the intention to treat analysis group. However, one patient met the criteria for withdrawal from the study (occurrence of uncontrolled pleural or pericardial effusion) and did not start treatment. Therefore, this patient was excluded from the safety analysis group, which included 101 patients. The mean age, mean weight, and mean BMI of the study population were 71.0 years, 44.62 kg, and 17.47 kg/ ^m2, respectively. Two-thirds (66.7%) had a performance status of 1. Eighty-one patients had NSCLC, 21 patients had gastrointestinal cancer, 10 of the 21 had colorectal cancer, 5 had gastric cancer, and 6 had pancreatic cancer. Disease status was primary in 74.5% of patients and recurrent in 25.5%. Approximately half of the patients had received one prior anticancer regimen, and most (87.3%) had received concomitant cancer treatment that included immunotherapy. Twenty-four patients died due to disease progression during the study period.

Among 102 patients in the intention to treat composite clinical response analysis patient population, 26 met all three CCR criteria at 9 weeks (25.9%; 95% CI, 18.3%-35.3%). The lower 95% CI exceeded the predefined threshold efficacy rate of 8.0%, meeting the primary endpoint. The responder rates ranged from 20.6% to 33.6% over the 24-week treatment period. By cancer type, 23 of 81 NSCLC patients (29.0%; 95% CI, 20.1%-39.7%) and 3 of 21 GI cancer patients (14.3%; 95% CI, 5.0%-34.6%) achieved CCR at 9 weeks. The proportion of patients with a ≥5% weight gain was 43.2% at week 9, and the proportion remained above 37% throughout the 24-week study period. The proportion of patients achieving a 2 or greater increase in FAACT-5IASS score was 61.0% at week 9 and remained above 45% throughout the 24-week study period.

Body Weight Body weight had increased by week 3 (first assessment time). These improvements were maintained through week 24. Weight gain was observed in patients with NSCLC or GI cancer.

Appetite FAACT: FAACT-5IASS scores increased from a baseline score of 9.2±4.1 with a mean±SD difference of 3.9±4.8 at week 9. This increase occurred primarily by week 3 (4.0±4.7 from baseline) and the increase was maintained through 24 weeks. Increases in FAACT-5IASS scores from baseline were observed in patients with NSCLC or GI cancer.

QOL-ACD: As an exploratory endpoint, we also sought change in mean scores for appetite-related QOL-ACD items 8, 9, and 11. For all three items, there was an increase in mean score of approximately 1 point over baseline scores that was evident at 3 weeks and remained roughly stable thereafter.

Patient Global Impression Overall, 76 (74.5%) patients reported some improvement (slightly improved, very improved, or extremely improved) in appetite/eating-related symptoms at 6 and 9 weeks from baseline. Four patients reported worsening appetite/eating-related symptoms at 6 weeks and three patients at 9 weeks. With regard to overall health, 67 (65.7%) patients reported improvement at 6 weeks and 66 (64.7%) reported improvement at 9 weeks. Overall health was reported to have worsened by 12 (11.8%) patients at 6 weeks and by 6 (5.9%) patients at 9 weeks. Data for both PGIC outcomes were missing for 9 and 15 patients at 6 and 9 weeks, respectively. Results were comparable between NSCLC and GI cancer patients.

Conclusion This study provides further evidence of the clinical efficacy and safety of anamorelin for managing cancer cachexia. The study met its primary endpoint, with a CCR of 25.9%, accompanied by improvements in weight and patient-reported outcomes, including FAACT-5IASS, QOL-ACD items, and PGIC. Anamorelin was also generally well tolerated in this population. Overall, these findings support the clinical use of anamorelin for managing cancer cachexia in patients with low BMI.
[References]
・Andreyev HJ, Norman AR, Oates J, Cunningham D. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer. 1998 Mar;34(4):503-9.
・ Aoyagi T, Terracina KP, Raza A, Matsubara H, Takabe K. Cancer cachexia, mechanism and treatment. World Journal of Gastrointestinal Oncology. 2015;7(4):17-29. doi:10.4251/wjgo.v7.i4.17.
・ Blauwhoff-Buskermolen S, Ruijgrok C, Ostelo RW, de Vet HCW, Verheul MHW, de van der Schueren MAE, Langius JAE. The assessment of anorexia in patients with cancer: cut-off values for the FAACT-A/CS and the VAS for appetite. Support Care Cancer. 2016 Feb;24(2):661-666.
・ Currow DC, Abernethy AP. Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. Future oncology. 2014 Apr;10(5):789-802.
・ FACIT.org: Functional Assessment of Chronic Illness Therapy; http://www.facit.org/FACITOrg. Accessed on 28 Jun 2017.
・ Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011 May;12(5):489-95.
・Fielding R, Wong WS. Quality of life as a predictor of cancer survival among Chinese liver and lung cancer patients. Eur J Cancer. 2007; 43:1723-1730.
・ Food and Drug Administration (US). Discussion Document for Patient-Focused Drug Development Public Workshop on Guidance 3: SELECT, DEVELOP OR MODIFY FIT-FOR-PURPOSE CLINICAL OUTCOME ASSESSMENTS (including Appendices) (Published at Patient-Focused Drug Development Guidance: Methods to Identify What is Important to Patients and Select, Develop or Modify Fit-for-Purpose Clinical Outcome Assessments, Meeting October 15- 16, 2018) (“FDA 2018”)
・ Food and Drug Administration (US). Patient-Focused Drug Development: Methods to Identify What Is Important to Patients Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (October 2019) (“FDA 2019”)
・ Food and Drug Administration (US). Patient-Focused Drug Development: Collecting Comprehensive and Representative Input; Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (June 2020) (“FDA 2020”).
・ Gelhorn H. Psychometric Properties of the FAACT Additional Concerns Subscale (A/CS) for Measurement of Anorexia in Patients with Non- Small Cell Lung Cancer. Qual Life Res 2016; 24:71.
・ Gelhorn H, Gries KS, Speck RM, Duus EM, Bourne RK, Aggarwal D, Cella D. Comprehensive validation of the functional assessment of anorexia/ cachexia therapy (FAACT) anorexia/cachexia subscale (A/CS) in lung cancer patients with involuntary weight loss. Qual Life Res 2019 Jun;28(6):1641-1653.
・ Guillory B, Splenser A, Garcia J. The role of ghrelin in anorexia-cachexia syndromes. Vitam Horm. 2013;92:61-106.
・ Hinsley R, Hughes R. The reflections you get: an exploration of body image and cachexia. Int J Palliat Nurs. 2007;13:84-89.
・ Hopkinson J. Nutritional support of the elderly cancer patient: the role of the nurse. Nutrition. 2015; Apr;31(4).
・ Hopkinson J. Psychosocial impact of cancer cachexia. J Cachexia Sarcopenia Muscle. 2014;5:89-94.
・ Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth hormone-releasing acylated peptide from stomach. Nature. 1999 Dec 9;402(6762):656-60.
・ Kumar NB, Kazi A, Smith T, Crocker T, Yu D, Reich RR, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr Treat Options Oncol. 2010 Dec;11(3-4):107-17.
・ Lis CG, Gupta D, Grutsch JF. Can anorexia predict patient satisfaction with quality of life in cancer advanced? Support Care Cancer. 2009; 17: 129-35.
・ McGrath P. Reflections on nutritional issues associated with cancer therapy. Cancer Pract. Mar-Apr 2002;10(2):94-101.
・ McKernan M, Mcmillan Dc, Anderson JR, Angerson WJ, Stuart RC. The relationship between quality of life (EORT QLQ-C30) and survival in patients with gastroesophageal cancer. Br J Cancer. 2008; 98:888-893.
・ Molfino A, Muscaritoli M, Rossi Fanelli F. Anorexia assessment in patients with cancer: a crucial issue to improve the outcome. J Clin Oncol. 2015 May 1;33(13):1513.
・ Montazeri A. Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008. Health Qual Life Outcomes. 2009;7:102.
・ Norman GR, Sloan JA, Wyrwich KW. Interpretation of Changes in Health-related Quality of Life The Remarkable University of Half a Standard Deviation. Medical Care. May, 2003. 41 (5) 582-592.
・ Oberholzer R, Hopkinson JB, Baumann K, Omlin A, Kaasa S, Fearon KC, Strasser F. Psychosocial effects of cancer cachexia: a systematic literature search and qualitative analysis. J Pain Symptom Manage. 2013;46:77-95.
・Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-555, 1982.
・ Pokrzywinski R, Speck R. Meaningful Treatment Benefit from the Patient's Perspective. Evidera.com. The Evidence Forum. Fall 2018.
・ Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol. Feb 2008; 61:102-109.
・Ribaudo JM, Cella D, Hahn EA, et al. Re-validation and shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Qual Life Res. 2001;9:1137-1146.
・ Rodriguez AM, Braverman J, Aggarwal D, Friend J, Duus E. The experience of weight loss and its associated burden in patients with non-small cell lung cancer: results of an online survey. Journal of Cachexia, Sarcopenia and Muscle- Clinical Reports. 2017; Volume 2 Issue 2 e00018.
・ Ross P, Ashley S, Norton A, Priest K, Waters JS, Eisen T, et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 2004 May;90:1905-11.
・Small W, Carrara R, Danford L, Logemann J, and Cella D. Quality of Life and Nutrition in the Patient with Cancer by ACCC's “Integrating Nutrition Into Your Cancer Program, pages 13-14, published March/April 2002.
・ Sullivan P, Nelson JB, Mulani PM, Sleep D. Quality of life as potential predictor morbidity and mortality in patients with metastastic hormone-refractory prostate cancer. Qual Life Res. 2006; 15:1297-1306.
・ Sundstrom S, Bremnes RM, Brunsvig P, Aasebo U, Kaasa S, Norwegian Lung Cancer Study Group. Palliative thoracic radiotherapy in locally advanced non-small cell lung cancer: can quality-of life assessments help in selection of patients for short- or long course radiotherapy? J Thorac Oncol. 2006; 1:816-824.
・ Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon KC. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomized, double-blind, phase 3 trials. Lancet Oncol. 2016 Apr;17(4):519-31.
・ Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P, Poitras P. Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. Am J Physiol Gastrointest Liver Physiol. 2002 Jun;282(6):G948-52.
・ von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle. 2010 Sep;1(1):1-5.
・ Webster K, Cella D, and Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health and Quality of Life Outcomes, volume 1, published 2003.
・ Yavuzsen T, Davis MP, Walsh D, LeGrand S, Lagman R. Systematic review of the treatment of cancer-associated anorexia and weight loss. J Clin Oncol. 2005;23:8500-8511.
・Yeo W, Mo FK, Koh J, Chan AT, Leung T, Hui P, et al. Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma. Ann Oncol. 2006; 17:1083-1089.
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Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims (42)

1. A method of providing a clinically meaningful treatment benefit in a 5-IASS score, based on a PGIS anchor-based and a PGIC anchor-based benefit scale, in a human patient suffering from anorexia and cachexia, comprising administering to said patient a therapeutically effective amount of anamorelin once daily;
a) the patient has had a weight loss of more than 2% in the previous 6 months;
b) the patient has a body mass index of less than 20 kg/ ^m2 ;
c) said patient has a 5-IASS score of 17 points or less; and d) said patient has a 12-item FAACT A/CS score of 37 points or less. 1. A method of providing a clinically meaningful treatment benefit in 5-IASS score and body weight, where appropriate based on PGIS anchor-based and PGIC anchor-based benefit scales, in a human patient suffering from anorexia and cachexia, comprising administering a therapeutically effective amount of anamorelin to said patient once daily;
a) the patient has had a weight loss of more than 2% in the previous 6 months;
b) the patient has a body mass index of less than 20 kg/ ^m2 ;
c) said patient has a 5-IASS score of 17 points or less; and d) said patient has a 12-item FAACT A/CS score of 37 points or less. 1. A method of achieving a combined clinical response in a human patient suffering from anorexia and cachexia, comprising administering to said patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period of time;
a) the composite clinical response is:
i) increasing the patient's body weight by 5% or more; and/or ii) improving the 5-IASS score in the patient by 2 points or more; and b) the patient:
i) weight loss of more than 2% in the previous 6 months;
ii) a body mass index of less than 20 kg/ ^m2 ;
iii) a 5-IASS score of 17 points or less; and iv) a 12-item FAACT A/CS score of 37 points or less. 1. A method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein said patient:
a) weight loss of more than 2% in the previous 6 months;
b) a body mass index of less than 20 kg/ ^m2 ;
c) a 5-IASS score of 17 points or less; and d) a 12-item FAACT A/CS score of 37 points or less. 1. A method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein said patient:
a) weight loss of more than 2% in the previous 6 months;
b) a body mass index of less than 20 kg/ ^m2 ;
c) a 5-IASS score of 17 points or less, and optionally d) a 12-item FAACT A/CS score of 37 points or less. 1. A method of treating cancer cachexia in a cancer cachexia patient, comprising administering a therapeutically effective amount of anamorelin to said patient once daily for a therapeutically effective period of time, wherein said patient:
The method is characterized by: a) a 5-IASS score of 17 points or less, and optionally b) a 12-item FAACT A/CS score of 37 points or less. The method of claim 1 or claim 2, wherein the clinically meaningful treatment benefit is based on PGIS anchor-based and PGIC anchor-based benefit measures. The method of any one of claims 4, 5 and 6, wherein the patient has anorexia. The method of any of the preceding claims, wherein the patient suffers from weight loss and general loss of appetite, early satiety, altered food preferences, or a combination thereof. The method of any of the preceding claims, wherein the patient has an ECOG performance status of 2 or less. The method of any of the preceding claims, wherein the patient has an ECOG performance status of 0, 1 or 2. The method of any of the preceding claims, wherein the patient has cancer. The method of any of the preceding claims, wherein the patient has unresectable NSCLC. The method according to any one of claims 1 to 12, wherein the patient has gastrointestinal cancer. The method according to any one of claims 1 to 12, wherein the patient has a gastrointestinal cancer selected from colorectal cancer, gastric cancer, and pancreatic cancer. The method of any of the preceding claims, wherein the patient is receiving a systemic anti-cancer treatment selected from a first-line treatment, a second-line treatment, or a third-line treatment. The method of any of the preceding claims, wherein the patient is receiving chemotherapy, radiation therapy, immunotherapy, targeted therapy, or a combination thereof. The method according to any one of claims 1 to 15, wherein the patient has not received systemic anti-cancer treatment. The method of any of the preceding claims, wherein the patient suffers from a generalized loss of appetite, early satiety, altered food preferences, or a combination thereof. The method of any of the preceding claims, wherein the patient has a 5-IASS score of 16 points or less, 14 points or less, 12 points or less, 10 points or less, or 8 points or less. The method of any of the preceding claims, wherein the patient has a 5-IASS score of 10 points or less, or a 5-IASS score of more than 10 points but not more than 17 points. The method of any of the preceding claims, wherein the patient has a 12-item FAACT A/CS score of 35 points or less, 30 points or less, 28 points or less, 26 points or less, 24 points or less, 22 points or less, or 20 points or less. The method of any of the preceding claims, wherein the patient has a 12-item FAACT A/CS score of 28 points or less, or a 12-item FAACT A/CS score of more than 28 points and less than or equal to 37 points. The method of any of the preceding claims, wherein the patient has had a weight loss of more than 4%, more than 5%, more than 6%, more than 8%, or more than 10% in the preceding 6 months. The method of any of the preceding claims, wherein the patient has a 5-IASS score of 10 points or less. The method of any of the preceding claims, wherein the patient has a 5-IASS score of 10 points or less and a 12-item FAACT A/CS score of 28 points or less. The method of any of the preceding claims, wherein the patient has a 5-IASS score of 10 points or less and is on either a second-line treatment or a third-line treatment. 20. The method of any preceding claim, wherein the patient has a body mass index of less ^than 19 kg/m2, less than 18 kg/ ^m2 , less than 17 kg/ ^m2 , or less than 16 kg/ ^m2 . The method of any preceding claim, including the benefit occurring within 3 weeks, 6 weeks, 9 weeks, or 12 weeks. A method according to any preceding claim, comprising increasing the patient's body weight by 5% or more. The method of any of the preceding claims, comprising improving the 5-IASS score in the patient by 2 or more points. 20. The method of any preceding claim, comprising: a) increasing said patient's body weight by 5% or more; and b) improving said patient's 5-IASS score by 2 or more points. The method of any preceding claim, comprising increasing the patient's 5-IASS score by 2 or more points, 3 or more points, or 4 or more points. The method of any preceding claim, comprising increasing the patient's body weight by 2% or more, 3% or more, 4% or more, or 5% or more. The method of any of the preceding claims, further comprising increasing the patient's FAACT total score by 15 points or more, 20 points or more, 25 points or more, 30 points or more, or 35 points or more. The method of any of the preceding claims, wherein the anamorelin is administered in a fasted state prior to the first meal of the day. The method of any preceding claim, wherein the therapeutically effective amount comprises 100 mg of anamorelin HCl by weight of the salt. 1. A method for determining a clinically meaningful 5-IASS improvement threshold in a human patient suffering from anorexia and cachexia, comprising the steps of:
a) providing a plurality of patients suffering from anorexia and cachexia, characterized by a 12-item FAACT A/CS score of 37 or less, a 5-IASS score of 17 or less, and a BMI of less than 20 kg/m2 with more than 2% involuntary weight loss in the preceding 6 months;
b) providing a within-patient clinically meaningful change (CMC) on PGIS-A to enable determination of a clinically meaningful threshold for anorexia symptom improvement in said plurality of patients;
c) providing a within-patient clinically meaningful change (CMC) for PGIC-A to enable determination of a clinically meaningful threshold for anorexia symptom improvement in said plurality of patients;
d) administering a therapeutically effective amount of anamorelin to said plurality of patients once daily for a treatment period;
e) generating a dataset comprising 5-IASS scores, PGIS-A scores, and PGIC-A scores for said plurality of patients obtained from equal time points during said treatment period; and f) determining a 5-IASS improvement threshold that correlates to said PGIS-A CMC and said PGIC-A CMC. A clinically meaningful weight improvement threshold in a human patient suffering from anorexia and cachexia can be determined by the following additional steps:
a) providing a within-patient clinically meaningful change (CMC) on PGIS-W to enable determination of a clinically meaningful threshold for weight improvement in said plurality of patients;
b) providing a within-patient clinically meaningful change (CMC) for PGIC-W to enable determination of a clinically meaningful threshold for weight improvement in said plurality of patients;
c) generating a dataset comprising weight scores, PGIS-W scores, and PGIC-W scores for the plurality of patients obtained from equal time points during the treatment period; and d) determining a weight improvement threshold that correlates to the PGIS-W CMC and the PGIC-W CMC. The method of claim 38 or 39, wherein the plurality of patients is further characterized by an ECOG PS of 2 or less. The method according to any one of claims 1, 2, and 9 to 37, wherein the clinically meaningful benefit in the 5-IASS score is equal to or greater than the 5-IASS score improvement threshold determined according to any one of claims 38 to 40. The method of any of claims 2 to 29, wherein a) the clinically meaningful benefit in 5-IASS score is equal to or greater than the 5-IASS score improvement threshold determined according to any of the methods of claims 38 to 40, and b) the clinically meaningful benefit in body weight is equal to or greater than the body weight improvement threshold determined according to any of the methods of claims 39 and 40.