WO2023042158A1

WO2023042158A1 - Methods of determining and providing clinically meaningful improvements on patient reported outcomes in anorexia / cachexia patients

Info

Publication number: WO2023042158A1
Application number: PCT/IB2022/058788
Authority: WO
Inventors: Elena PALMESINO; Salvatore Chessari; Ruben Giorgino
Original assignee: Helsinn Healthcare Sa
Priority date: 2021-09-17
Filing date: 2022-09-16
Publication date: 2023-03-23
Also published as: TW202327596A

Abstract

Uses of anamorelin for improving patient reported outcomes in anorexia / cachexia patients, particularly based on patient populations who benefit from such use, and methods for defining and providing clinically meaningful treatment effects.

Description

METHODS OF DETERMINING AND PROVIDING CLINICALLY MEANINGFUL IMPROVEMENTS ON PATIENT REPORTED OUTCOMES IN ANOREXIA / CACHEXIA PATIENTS

FIELD OF THE INVENTION

The present invention relates to the use of anamorelin for improving patient reported outcomes in anorexia / cachexia patients, particularly based on patient populations who benefit from such use, and particular methods for defining and providing clinically meaningful treatment effects.

BACKGROUND OF THE INVENTION

Weight loss and anorexia are among the symptoms that characterize cancer cachexia, a multifactorial syndrome that occurs in more than 80% of patients with cancer before death. Kumar (2010); von Haehling (2010); Aoyagi (2015). Following the current consensus criteria described in Fearon (2011), cancer cachexia is primarily diagnosed either by recent weight loss > 5% over past 6 months (in absence of simple starvation), or recent weight loss > 2% and body-mass index (“BMI”) < 20 kg/m², or sarcopenia.

Reduced food intake in patients with cancer is caused by primary anorexia and can be compounded by secondary nutrition impact symptoms. According to a number of reports, cancer patients describe weight loss and anorexia symptoms as sources of concern and worry, with significant impacts on their daily lives. Hinsley (2007); Hopkinson (2014); McGrath (2002); Hopkinson (2015); Oberholzer (2013).

To better understand the experiences of weight loss and low BMI in lung cancer patients, Rodriguez et al. conducted an on-line study of ninety-five patients; 35 of them (36.8%) were classified as having considerable weight loss (defined as > 5% loss of body weight in the past 6 months or > 2% for a BMI 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 level and more severe symptoms (including appetite loss). Patients were also asked to identify which weight loss symptoms had the most significant impact on their lives. For these patients the most frequently reported symptoms with significant impacts were changes in food taste (38%), fatigue (38%), and decrease in appetite (33%). Early satiety was also noted as having a significant impact in 14% of the patients surveyed. Rodriguez (2017)

Anorexia is a major contributor to the weight loss in cancer patients. Anorexia in cancer may be characterized as a general loss of appetite, early satiety, altered food preferences, or a combination of these. Molfino (2015). Cancer related anorexia is also a major clinical problem; it adversely influences 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 for survival in advanced NSCLC patients, leading the investigators to conclude that assessment of anorexia and appetite loss is a valuable tool in determining thoracic radiotherapy strategy. Sundstrom (2006).

Reduced dose intensity of chemotherapy and increased toxicity have also been noted in patients with weight loss, which can lead to dose reductions, treatment delays or definitive termination of treatment. Ross (2004); Andreyev (1998). Furthermore, in a study in NSCLC patients comparing non- weight losing patients to weight losing/underweight patients (> 5% weight loss in prior 6 months or > 2% weight loss with BMI < 20 kg/m²), it was 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 the weight losing/underweight patients compared to non-weight losing patients, and that while 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 appetite loss), are common, debilitating, and concerning occurrences for advanced cancer patients. Despite the high prevalence and the association with poor prognosis, there has been a lack of therapeutic advance in managing these symptoms of advanced cancer patients, and pharmacological interventions remain limited.

Anamorelin HC1 is an orally-active selective ghrelin receptor agonist. Ghrelin is the endogenous ligand for the G-protein-coupled ghrelin receptor. Kojima (1999). It is synthesized predominantly in the stomach and has a short circulating half-life (~15 minutes) in both animals and humans, which limits its therapeutic potential since long term efficacy would necessitate continuous infusion. Nevertheless, research into the effects of ghrelin or longer-acting ghrelin mimetics has revealed that ghrelin possesses anabolic, appetite-enhancing, adiposity-increasing, and anti-inflammatory properties (Guillory (2013)), along with prokinetic gastrointestinal activity. Trudel (2002).

In vitro, anamorelin displays high affinity and selective binding to the ghrelin receptor and is a highly potent growth hormone (“GH”) secretagogue by in vitro assay (EC50 = 1.5 nM). In vivo, anamorelin HC1 elicited a robust GH release following oral administration to dogs and a potent appetite enhancing effect in rats following intracerebral administration; increases in food intake and body weight were also noted in animal models. Trudel (2002). In clinical studies, anamorelin treatment is also associated with increases in appetite and body weight, along with gains in lean body mass (“LBM”) and improvements in health-related quality of life (“QoL”) measures. Currow (2014). Nevertheless, in the phase III ROMANA studies undertaken to evaluate the efficacy and safety of anamorelin HC1 for the treatment of anorexia NSCLC patients with cachexia, anamorelin failed to demonstrate a statistically significant improvement in hand-grip strength, one of the two-co-primary endpoints. Temel (2016).

Therefore, the treatment of malignancy associated weight loss and anorexia in cancer patients are an area of unmet medical need.

SUMMARY OF INVENTION

Cancerous patient populations have been unexpectedly discovered in which anamorelin is surprisingly effective against anorexia and cachexia. In particular, it has been discovered that patients with the worst personal perceptions of anorexia, as determined by a novel symptoms subscale (the 5-IASS) of FAACT, in addition to low scores on the FAACT A/CS, respond remarkably well to anamorelin, even when the patients have a low ECOG performance status (reflecting a healthier patient). The efficacy of treatment is particularly evident when measured on the 5-IASS symptoms subscale using PGIS and PGIC anchor-based methods to evaluate clinical benefit.

Thus, in a first principal embodiment, the invention provides a method of providing a clinically meaningful treatment benefit in a 5-IASS score, optionally based on PGIS and PGIC anchor-based measures of benefit, in a human patient suffering from anorexia and cachexia, comprising once daily administering to the patient a therapeutically effective amount of anamorelin wherein: (a) the patient has a body weight loss > 2% in the previous 6 months; (b) the patient has a body mass index < 20 kg/m²; (c) the patient has a 5-IASS score of < 17 points; and (d) the patient has a 12-item FAACT A/CS score of < 37 points.

The benefits also are particularly evident in terms of a combination of weight gain and 5- IASS scores. Thus, in a second principal embodiment the invention provides a method of providing a clinically meaningful treatment benefit in a 5-IASS score and/or body weight, optionally based on PGIS and PGIC anchor-based measures of benefit, in a human patient suffering from anorexia and cachexia, comprising once daily administering to the patient a therapeutically effective amount of anamorelin wherein: (a) the patient has a body weight loss > 2% in the previous 6 months; (b) the patient has a body mass index < 20 kg/m²; (c) the patient has a 5-IASS score of < 17 points; and (d) the patient has a 12-item FAACT A/CS score of < 37 points. The benefits also are evident in composite clinical response, as that term is specifically defined herein. Thus, in a third principal embodiment the invention provides a method of achieving a composite clinical response in a human patient suffering from anorexia and cachexia comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein, (a) the composite clinical response comprises: (i) increasing body weight of the patient by > 5%; and (ii) improving 5-IASS scores in the patient by

> 2 points; and (b) the patient is characterized by: (i) a body weight loss > 2% in the previous 6 months; (ii) a body mass index < 20 kg/m²; (iii) a 5-IASS score of < 17 points; and (iv) a 12-item FAACT A/CS score of < 37 points. The methods have general applicability to the treatment of patients with cancer cachexia. Thus, in a fourth principal embodiment the invention provides a method of treating cancer cachexia in a cancer cachexia patient comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein the patient optionally has anorexia, and is characterized by: (a) a body weight loss

> 2% in the previous 6 months; (b) a body mass index < 20 kg/m²; (c) a 5-IASS score of < 17 points; and (d) a 12-item FAACT A/CS score of < 37 points.

In a fifth principal embodiment, the invention provides a method of treating cancer cachexia in a cancer cachexia patient comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein the patient optionally has anorexia, and is characterized by: (a) a body weight loss > 2% in the previous 6 months; (b) a body mass index < 20 kg/m²; (c) a 5-IASS score of < 17 points; and, optionally (d) a 12-item FAACT A/CS score of < 37 points.

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

Still further methods relate to the methods used to determine the clinically meaningful treatment benefits for use in the present invention, and the treatment of patients using such methods. Thus, in a seventh principal embodiment the invention provides a method of determining a clinically meaningful 5-IASS improvement threshold in a human patient suffering from anorexia and cachexia comprising the following steps: (a) providing a plurality of patients suffering from anorexia and cachexia characterized by a 12 item FAACT A/CS score of < 37 (cf. Blauwhoff (2016)), a 5-IASS score < 17, and a BMI <20 kg/m² (cf. Fearon (2011 )) with an involuntary weight loss of > 2% in the previous 6 months; (b) providing a within patient clinically meaningful change (CMC) on PGIS-A to enable the determination of a clinically meaningful threshold for anorexia symptoms improvement in the plurality of patients; (c) providing a within patient clinically meaningful change (CMC) on PGIC-A to enable the determination of a clinically meaningful threshold for anorexia symptoms improvement in the plurality of patients; (d) administering to the plurality of patients once daily a therapeutically effective amount of anamorelin for a treatment period; (e) generating a dataset comprising 5-IASS scores, PGIS-A scores, and PGIC-A scores for the plurality of patients from equal timepoints during the treatment period; and (f) determining a 5-IASS improvement threshold that correlates to the PGIS-A CMC and the PGIC-A CMC. Of course, the ultimate goal of the invention is to treat anorexia and cachexia. Thus, the seventh principal embodiment is always preferably practiced by once daily administering to the patient the therapeutically effective amount of anamorelin, in order to achieve these clinically meaningful treatment benefits.

Additional advantages of the invention are set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by 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.

DETAILED DESCRIPTION

Definitions and Use of Terms

As used in the specification and 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 like terms as used herein means any one member of a particular list and also includes any combination of members of that list.

When used herein the term “about” will compensate for variability allowed for in the pharmaceutical industry and inherent in products in this industry, such as differences in product strength due to manufacturing variation and time-induced product degradation, as well as differences due to waters of hydration and different salts. The term also allows for any variation which in the practice of good manufacturing practices would allow the product being evaluated to be considered therapeutically equivalent or bioequivalent in humans to the recited strength of a claimed product. In some embodiments the term allows for any variation within 5% or 10% of the recited specification or standard.

As used in this specification and in the claims which follow, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. When an element is described as comprising one or a plurality of components, steps or conditions, it will be understood that the element can also be described as “consisting of’ or “consisting essentially of’ the component, step or condition, or the plurality of components, steps or conditions.

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

“ECOG” (Eastern Cooperative Oncology Group) Status refers to scales and criteria used by doctors and researchers to assess how a patient’s disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis, as described by Oken (1982). The questionnaire for scoring on the ECOG performance scale is reproduced in Table 1.

Table 1. ECOG Performance Status

“FAACT” refers to the Functional Assessment of Anorexia Cachexia Therapy (FAACT) Questionnaire, as described previously by Small (2002). “FAACT A/CS” or “FAACT in the anorexia/cachexia domain” refers to a series of twelve questions described by Ribaudo (2001), which are selected from the FAACT and measure patients’ perception of and concerns related to appetite, food consumption, weight gain/loss, vomiting, and stomach pain, which can be scored from 0-4, for a range of possible scores of 0-48. The questions that make up the FAACT A/CS are reproduced in Table 2.

Table 2. FAACT A/CS

“FAACT total score” refers to the patient’s score on the FACT-G added to his or her score on the FAACT A/CS for a range of possible scores of 0-156. “FACT-G” or “Functional Assessment Cancer Therapy - General Version” is a 27-item compilation of general questions as described previously in Webster (2003). The FACT-G is divided into four primary 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 the primary domains for a range of possible scores of 0-108.

“5-IASS” or “5-Item Anorexia Subscale” refers to the following 5-items from the FAACT A/CS questionnaire: “I have a good appetite,” “Most food tastes unpleasant to me,” “My interest in food drops as soon as I try to eat,” “I have difficulty eating rich or heavy foods,” and “When I eat, I seem to get full quickly.” Gelhorn (2016).

“First line treatment” is a treatment regimen or regimens that are generally accepted by the medical establishment for initial treatment of a given type and stage of cancer. Also called induction therapy, this primary therapy is the first assault of chemotherapy drugs on the malignancy. A “second-line treatment” is one tried when the first line treatment does not work adequately. The management of a cancer case requires regular evaluation of treatment and adjustment as needed. A break with the primary treatment and an adoption of a new regimen signals “second-line treatment.”

“PGIS” and “PGIC”: The PGIS (Patient Global Impression of Severity) is a single-item questionnaire and has a 4-point Likert-type response scale ranging from “do not have” symptoms to “severe” symptoms related to appetite/eating or weight. The PGIC (Patient Global Impression of Change) is also a single-item questionnaire with a 7-point Likert-type response scale ranging from “very much worse” to “very 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 hereto.

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,” “significantly,” or other variations of the 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 upon its statistical significance relative to a baseline such as placebo. In like manner, when a treatment or benefit is described herein, it will be understood that the treatment or benefit preferably shows efficacy to a degree of statistical significance.

“Targeted therapy” is a form of molecular medicine that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy). 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 distinguished from chemotherapy, that is, cytotoxic therapy).

“Therapeutically effective amount” means that amount which, when administered to a human for supporting or affecting a metabolic process, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease or supporting or affecting the metabolic process. In any of the embodiments or subembodiments of this invention, a therapeutically effective amount preferably comprises 100 mg of anamorelin or a pharmaceutically acceptable salt thereof when administered orally 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 stated 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 scoring questionnaires are administered for purposes of evaluating clinical benefit, all negatively worded item responses are reverse coded and summed in accordance with 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 ranges are expressed herein by specifying alternative upper and lower limits of the range, it will be understood that the endpoints can be combined in any manner that is mathematically feasible. Thus, for example, a range of from 50 or 80 to 100 or 70 can alternatively be expressed as a series of ranges of from 50 to 100, from 50 to 70, and from 80 to 100. When a series of upper bounds and lower bounds are related using the phase “and” or “or”, it will be understood that the upper bounds can be unlimited by the lower bounds or combined with the lower bounds, and vice versa. Thus, for example, a range of greater than 40% and/or less than 80% includes ranges of greater than 40%, less than 80%, and greater than 40% but less than 80%. Unless otherwise specified by the term “between,” the boundaries of the range (lower and upper ends of the range) are included in the claimed range, and can be preceded by the term “about.”

When an element of a process or thing is defined by reference to one or more examples, components, properties or characteristics, it will be understood that any one or any combination of those components, properties or characteristics can also be used to define the matter at issue. This might occur, for example, when specific examples of an element are recited in a claim (as in a Markush grouping), or an element is defined by a plurality of characteristics. Thus, for example, if a claimed system comprises element A defined by elements Al, A2 and A3, in combination with element B defined by elements Bl, B2 and B3, the invention will also be understood to cover a system defined by element A without element B, a system in which element A is defined by elements Al and A2 in combination with element B defined by elements B2 and B3, and all other possible permutations.

Methods of Treatment

The invention relates to various methods of treating anorexia and cachexia and affected patient populations that are responsive to anamorelin treatment. Thus, in a first principal embodiment, the invention provides a method of providing a clinically meaningful treatment benefit in a 5 -IASS score, optionally based on a PGIS anchor- based measure of benefit, in a human patient suffering from anorexia and cachexia, comprising once daily administering to the patient a therapeutically effective amount of anamorelin wherein (a) the patient has a body weight loss > 2% in the previous 6 months; (b) the patient has a body mass index < 20 kg/m²; (c) the patient has a 5-IASS score of < 17 points; and (d) the patient has a 12-item FAACT A/CS score of < 37 points.

In a second principal embodiment the invention provides a method of providing a clinically meaningful treatment benefits in a 5-IASS score and/or body weight, optionally based on PGIS anchor-based measures of benefit, in a human patient suffering from anorexia and cachexia, comprising once daily administering to the patient a therapeutically effective amount of anamorelin wherein (a) the patient has a body weight loss > 2% in the previous 6 months; (b) the patient has a body mass index < 20 kg/m²; (c) the patient has a 5-IASS score of < 17 points; and (d) the patient has a 12-item FAACT A/CS score of < 37 points.

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

The methods have general applicability to the treatment of patients with cancer cachexia. Thus, in a fourth principal embodiment the invention provides a method of treating cancer cachexia in a cancer cachexia patient comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein the patient optionally has anorexia, and is characterized by: (a) a body weight loss > 2% in the previous 6 months; (b) a body mass index < 20 kg/m²; (c) a 5-IASS score of < 17 points; and (d) a 12-item FAACT A/CS score of < 37 points.

The methods of treatment can further be understood with reference to various subembodiments which can modify any of the first through sixth principal embodiments. It will be understood that these subembodiments can be combined in any manner that is both mathematically and physically possible to create additional subembodiments, which in turn can modify any of the principal 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 can be further defined based on recent involuntary weight loss and body mass index (“BMI”). As with all instances herein wherein a patient is characterized by a criterion, it will be understood that such characterization applies when the drug therapy is commenced, and that the characteristic can be determined by testing shortly before the method commences. Thus, in one subembodiment, the patient has a body weight loss greater than 2% in the previous 6 months and a body mass index less than 20 kg/m². As an alternative, the patient can be characterized based on a body weight loss greater than 2%, 4%, 5%, 8%, or 10% in the previous 6 months. As another alternative, the patient can have a body mass index less than 19, 18, 17, or 16 kg/m². In one particular subembodiment, the patient has a body weight loss greater than 5% in the previous 6 months and a body mass index less than 20 kg/m².

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

The patient can be characterized by any of the defining parameters set forth herein, or any combination of parameters. In one embodiment the patient is characterized as having a 5-IASS score of < 10 points and a body weight loss greater than 2% in the previous 6 months. In another embodiment the patient is characterized as having a 5-IASS score of < 10 points, a body weight loss greater than 2% in the previous 6 months, and a 12-item FAACT A/CS score of < 28 points. In still another embodiment the patient is characterized as having a 5-IASS score of < 10 points, a body weight loss greater than 2% in the previous 6 months, and either second line or third line treatment.

Still 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 also can be characterized based on a disease state. Thus, in one subembodiment, the patient has cancer. In another subembodiment, the patient has unresectable NSCLC. In still another subembodiment, the patient has gastrointestinal cancer, optionally selected from colorectal, gastric, or pancreatic cancer.

The patient also can be characterized by concomitant therapies. Thus, in any of the embodiments or subembodiments of the present invention, the patient is not receiving systemic anti- cancer treatment. Alternatively, the patient is receiving systemic anti- cancer treatment. When the patient is receiving systemic anti-cancer treatment, it can be, for example, first, second, or third treatment line treatment, and it can be chemotherapy, radiation therapy, immunotherapy, or targeted therapy, or a combination of these.

The methods of the present invention also can be characterized by the associated outcome or benefit. Thus, in any of the embodiments or subembodiments of the present invention, the treatment effect may comprise 1, 2, 3, 6, 9, or 12 weeks. In other subembodiments, the treatment additionally or alternatively increases the 5-IASS score of the patient by greater than or equal to 2, 3, or 4 points. Alternatively or in addition, the method might increase the body weight of the patient by greater than or equal to 2, 3, 4, or 5%, or increase the patient’s FAACT total score by greater than or equal to 15, 20, 25, 30, or 35 points.

In any of the methods of treatment of the present invention, the clinically meaningful treatment benefit in 5-IASS can also be defined as equaling or exceeding the 5-IASS improvement threshold determined by the method of the seventh principal embodiment, or any of its subembodiments / parameters. In like manner, the clinically meaningful treatment benefit in body weight can be defined to equal or exceed the body weight improvement threshold determined by the methods of the seventh principal embodiment.

Methods for Determining Improvement Thresholds

The invention also provides methods of determining improvement thresholds on 5-IASS and weight gain that correspond to clinically meaningful improvements in the patient’s health status, based on patient reported improvements in disease severity and condition. In preferred embodiments, these thresholds correspond to the clinically meaningful benefits that define the methods of treatment of the current invention. Thus, in a seventh principal embodiment the invention provides a method of determining a clinically meaningful 5-IASS improvement threshold in a human patient suffering from anorexia and cachexia comprising the following steps: (a) providing a plurality of patients suffering from anorexia and cachexia characterized by a 12 item FAACT A/CS score of < 37, a 5-IASS score < 17, and a BMI < 20 kg/m² with an involuntary weight loss of > 2% in the previous 6 months; (b) providing a within patient clinically meaningful change (CMC) on PGIS-A to enable the determination of a clinically meaningful threshold for anorexia symptoms improvement in the plurality of patients; (c) providing a within patient clinically meaningful change (CMC) on PGIC- A to enable the determination of a clinically meaningful threshold for anorexia symptoms improvement in the plurality of patients; (d) administering to the plurality of patients once daily a therapeutically effective amount of anamorelin for a treatment period; (e) generating a dataset comprising 5-IASS scores PGIS-A scores, and PGIC-A scores for the plurality of patients from equal timepoints during the treatment period; and (f) determining a 5-IASS improvement threshold that correlates to the PGIS-A CMC and the PGIC-A CMC.

The methods of determining a 5-IASS improvement threshold according to the seventh principal embodiment can further be characterized by various subembodiments or parameters. In one particular subembodiment, the methods are also used to determine a clinically meaningful body 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 within patient clinically meaningful change (CMC) on PGIS-W to enable the determination of a clinically meaningful threshold for body weight improvement in the plurality of patients; (b) providing a within patient clinically meaningful change (CMC) on PGIC-W to enable the determination of a clinically meaningful threshold for body weight improvement in the plurality of patients; (c) generating a dataset comprising body weight scores, PGIS-W scores, and PGIC-W scores for the plurality of patients from equal timepoints during the treatment period; and (d) determining a body weight improvement threshold that correlates to the PGIS-W CMC and the PGIC-W CMC. The term “body weight score” refers to an increase or decrease in body weight on a kilogram basis observed from baseline (i.e. initiation of treatment).

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

The 5-IASS improvement threshold can be determined by calculating the improvement in 5-IASS scores needed to achieve the PGIS-A CMC and PGIC-A CMC. In like manner, the body weight improvement threshold can be determined by calculating the improvement in body weight scores needed to achieve the PGIS-W CMC and PGIC-W CMC.

Dosage Forms / Routes of Administration

Pharmaceutical compositions for preventing and/or treating a subject are further provided comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients. A “pharmaceutically acceptable” excipient is one that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects or interacting in a deleterious 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 of skill 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 to such a route, and in a dose effective for the treatment or prevention intended. The active compounds and compositions, for example, can be administered orally, rectally, parenterally, ocularly, inhalationaly, or topically. In particular, administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, vaginal, intravaginal, transvaginal, ocular, intraocular, transocular, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural, intravitreal, etc.

The pharmaceutical composition can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The pharmaceutical composition and other ingredients can also be enclosed in a hard or soft-shell gelatin capsule, compressed into tablets, or incorporated directly into the individual's diet. For oral therapeutic administration, the pharmaceutical composition can 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 active compound. The percentage of the compositions and preparations can, of course, be varied and can conveniently be between about 5% to about 80% of the weight of the unit.

The tablets, troches, pills, capsules, and the like can also contain the following: a binder, such as gum gragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid, and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin, or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar, or both. A syrup or elixir can contain the agent, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic/biocompatible in the amounts employed. In addition, the pharmaceutical composition can be incorporated into sustained-release preparations and formulations.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein, refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of pharmaceutical composition is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are related to the characteristics of the pharmaceutical composition and the particular therapeutic effect to be achieved.

The therapeutically effective amount of anamorelin can vary across a range of suitable doses depending on the health of the subject, the desired response, the dosage form and the route of administration. In a preferred subembodiment when administration is oral, the therapeutically effective amount is from about 10 to about 500 mg/day of anamorelin, preferably from 25 to 300 mg/day, more preferably 50 to 150 mg/day, and most preferably 100 mg/day. The dose is administered as a single administration once per day, preferably before the first meal of the day. The most preferred form of the compound is anamorelin HC1, and the foregoing doses are preferably based on the weight of the salt.

EXAMPLES

In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. The following examples are put forth 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 and are intended to be purely exemplary 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, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ANAMORELIN FOR THE TREATMENT OF MALIGNANCY ASSOCIATED WEIGHT LOSS AND ANOREXIA IN ADULT PATIENTS WITH ADVANCED NON- SMALL CELL LUNG CANCER

This is a phase III multi-center, randomized, double-blind, parallel-group, placebo- controlled study to evaluate the efficacy and safety of anamorelin HC1. Approximately 316 patients with advanced NSCLC and cachexia will be randomized 1 : 1 to anamorelin HC1 100 mg or placebo, taken orally once daily (QD) for a total of 24 weeks. Patients will be instructed to take the study drug at least 1 hour before their first meal of the day.

The target study population is advanced NSCLC adult patients with a body mass index < 20 kg/m² with involuntary weight loss of >2% within 6 months prior to screening and anorexia. Significant inclusion and exclusion criteria include:

Inclusion Criteria

• Female or male >18 years of age.

• Documented histologic or cytologic diagnosis of American Joint Committee on Cancer (AJCC) Stage III or IV NSCLC. Stage III patients must have unresectable disease. • Body mass index < 20 kg/m² with involuntary weight loss of > 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 on the 5-IASS and < 37 points on the 12-item FAACT A/CS.

• Patients receiving or not receiving systemic anti-cancer treatment at the time of screening are eligible to participate. Systemic anti-cancer treatment includes first, second, third treatment line with chemotherapy/radiation therapy, immunotherapy, or targeted therapy.

• ECOG performance status 0, 1 or 2 at screening.

Exclusion Criteria

• Patient with other forms of lung cancer (e.g., small cell, neuroendocrine tumors).

• Woman who is pregnant or breast-feeding.

• Reversible causes of reduced food intake. These causes may include but are not limited to: o NCI CTCAE Grade 3 or 4 oral mucositis, o NCI CTCAE Grade 3 or 4 GI disorders (nausea, vomiting, diarrhea, and constipation), o mechanical obstructions making patient unable to eat, or o severe depression.

• Patient undergoing major surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization.

• Patient currently taking androgenic compounds including but not limited to testosterone, testosterone- like agents, oxandrolone, megestrol acetate, corticosteroids, olanzapine, mirtazapine, dronabinol, marijuana (cannabis), or any other prescription medication or off-label products intended to increase appetite or treat unintentional weight loss.

The co-primary efficacy endpoints are:

Co-primary Efficacy Endpoints

Duration of clinically meaningful treatment benefit in weight until Week 12. • Duration of clinically meaningful treatment benefit in 5-IASS until Week 12.

The duration of treatment benefit is measured as the duration for which the patient observes a change from baseline superior or equal to the predefined threshold of clinical meaningfulness. For the purpose of computation it will be assumed a linear evolution between two measurements. The secondary efficacy endpoints are:

Secondary Efficacy Endpoints

• Mean change in body weight from baseline up to Week 12.

• Mean change in 5-IASS up to Week 12.

• Mean change in FAACT total score from baseline up to Week 12.

A partial flow chart for the study is given in Table 3.

Table 3. Study Flow Chart

EXAMPLE 2: DETERMINATION OF IMPROVEMENT THRESHOLD ON THE 5-IASS

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 PGIS and PGIC determined through patient interviews, according to principles described in Pokrzy winski (2018), Revicki (2008) and FDA guidance documents. The PGIS and PGIC consist of a single question each to assess the severity and change in appetite/eating-related symptoms. The PGIS is a single-item questionnaire and has a 4-point Likert- type response scale ranging from “do not have” symptoms to “severe” symptoms related to appetite/eating. The PGIC is also a single-item questionnaire with a 7-point Likert-type response scale ranging from ‘ ‘very much worse’ ’ to ‘ ‘very much improved. ’ ’ The PGIS will be administered at baseline, Week 6 and Week 9, and the PGIC will be administered at Week 6 and Week 9.

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

Table 4. Patient Global Impression of Severity - Anorexia (PGIS-A)

Table 5. Patient Global Impression of Change - Anorexia (PGIC-A)

Clinically meaningful change (“CMC”) will be determined as per standard practice for these anchors and supported by distribution-based methods. Pokrzywinski (2018); Norman (2003); Revicki (2008). The 5-IASS improvement threshold will be determined as the smallest difference or change in score from baseline that is considered important to the patient (i.e., those improving on the PGIS and on the PGIC). As such, the difference in scores on the PGIS from baseline to Week 6 and Week 9 will be determined, and an improvement on the PGIS will be used to define meaningful change based on mean values of the 5-IASS. Similarly, mean values of the 5-IASS among patients who indicate that their appetite/eating symptoms have improved since starting treatment (based on the PGIC) will be calculated; this value will be used to aid in defining a meaningful change in the symptom measure.

The results of these anchor-based methods will be supported by distribution-based methods calculating a 0.2 standard deviation (SD), 0.3 SD, and 0.5 SD, whereby the 0.5 SD estimate can be considered to provide an upper boundary for what would constitute a meaningful change, while 0.2 SD provides a lower boundary. Revicki (2008). Both 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 more weight than the supportive distribution-based methods. A cumulative distribution of response curve for the 5-item Anorexia Symptom Subscale, one for the treatment group and one for the placebo group, will also be generated to allow a variety of response thresholds to be examined simultaneously and collectively, encompassing all available data.

EXAMPLE 3. DETERMINATION OF IMPROVEMENT THRESHOLD FOR WEIGHT CHANGE _

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

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

Table 6. Patient Global Impression of Severity - Weight (PGIS-W)

Table 7. Patient Global Impression of Change - Weight (PGIC-W)

As with the anorexia anchors, clinically meaningful change will be determined as per standard practice for these anchors and supported by distribution-based methods. Norman (2003); Revicki (2008). Weight change improvement threshold will be determined as the smallest difference or change in score from baseline that is considered important to the patient (i.e., those improving on the PGIS and on the PGIC). As such, the difference in scores on the PGIS from baseline to Week 6 and Week 9 will be determined, and an improvement on the PGIS will be used to define meaningful change based on mean values of weight change in kg. Similarly, mean values of weight change in percentage among patients who indicate that their weight concerns have improved since starting treatment (based on the PGIC) will be calculated; this value will be used to aid in defining a meaningful change in the concerns measure. The results of these anchor-based methods will be supported by distribution-based methods calculating a 0.2 standard deviation (SD), 0.3 SD, and 0.5 SD, whereby the 0.5 SD estimate can be considered to provide an upper boundary for what would constitute a meaningful change, while 0.2 SD provides a lower boundary. Revicki (2008). Both 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 more weight than the supportive distribution-based methods. A cumulative distribution of response curve for the weight change in percentage, one for the treatment group and one for the placebo group, will also be generated to allow a variety of response thresholds to be examined simultaneously and collectively, encompassing all available data.

EXAMPLE 4. EFFICACY AND SAFETY OF ANAMORELIN IN LOW BODY MASS INDEX, CACHECTIC PATIENTS WITH 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 <20 kg/m²).

Inclusion Criteria

Patients with advanced cancer (non-small cell lung cancer, colorectal cancer, gastric cancer, or pancreatic cancer) were eligible for this study if they met the following criteria: unsuitable for radical resection/radical radiation therapy or postoperative recurrence, BMI <20 kg/m² and involuntary weight loss of >2% in the last 6 months, cancer-associated anorexia, performance status of 0-2 (0-1 for pancreatic cancer). Cancer-associated anorexia was defined as a FAACT- 5IASS score of <17 points and FAACT anorexia/cachexia-specific subscale score of <37 points.

Intervention

Following a screening/observation period of up to 4 weeks, eligible patients entered a 24- week treatment period in which they were administered 100 mg anamorelin, once daily, 1 h before breakfast. After 24 weeks, patients entered a 2-week follow-up period. Patients were prohibited from using any drugs or treatments for anorexia, such as systemic corticosteroids, growth hormone and androgen preparations, medroxyprogesterone and megestrol, Kampo medicines, and tube feeding. Adjuvant use of corticosteroids was allowed for up to 5 consecutive days in chemotherapy or radiotherapy regimens.

Endpoints and assessments

The primary endpoint was a composite clinical response (CCR) at 9 weeks, defined as a proportion of patients meeting the following three outcomes: 1) increase in body weight of >5% from baseline, 2) an increase in the FAACT-5IASS score of >2, and 3) alive. Secondary endpoints were the changes in body weight and FAACT-5IASS score at 9 weeks. Exploratory endpoints included QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD), and patient’ global impression of change (PGIC).

FAACT (version 4) and QOL-ACD were completed by the patients every 3 weeks during treatment. For QOL-ACD, we evaluated the changes for items 8, 9, and 11, which cover appetite- related questions: ‘Did you have a good appetite,’ ‘Did you enjoy your meals’, and ‘Did you lose any weight’. These items are scored on a 5-point scale, where 1 represents the worst perception and 5 the best perception.

PGICs were also used to evaluate the patient’s perception of changes in disease/symptom severity over time, including cancer-related symptoms. The patients were asked at 6 and 9 weeks to rate whether their appetite/symptoms related to eating improved after starting treatment, and how their general condition changed. Both questions comprised seven possible responses: Very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse.

Patients

102 patients were scheduled to start treatment with anamorelin and were included in the intention to treat analysis set. However, one patient met a criterion for study withdrawal (development of poorly controlled pleural effusion or pericardial effusion) and did not start treatment; this patient was excluded from the safety analysis set, which comprised 101 patients. The mean age, weight, and 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. There were 81 patients with NSCLC and 21 with gastrointestinal cancers, including 10 with colorectal, five with gastric and six with pancreatic cancers. The disease status was primary in 74.5% and recurrent in 25.5% of patients. About half of the patients had received one prior anticancer regimen, and most (87.3%) were receiving concomitant cancer therapies, including immunotherapies. Twenty-four patients died due to disease progression during the study.

Composite clinical response

Among 102 patients in the intention-to-treat analysis set, 26 met all three CCR criteria at 9 weeks (25.9%; 95% CI 18.3%-35.3%). The lower 95% CI exceeded the predetermined threshold efficacy rate of 8.0%, meeting the primary endpoint. The percentage of responders ranged from 20.6% to 33.6% during the 24- week treatment period. By cancer type, 23 of 81 patients with NSCLC (29.0%; 95% CI 20.1%-39.7%) and 3 of 21 patients with GI cancers (14.3%; 95% CI 5.0%-34.6%) achieved a CCR at 9 weeks. The percentage of patients with an increase in body weight of >5% was 43.2% at week 9, with percentages exceeding 37% throughout the 24-week study period. The percentage of patients with an increase in the FAACT-5IASS score of >2 point was 61.0% at week 9 and remained >45% throughout the 24-week study period.

Body weight

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

Appetite

FAACT: The FAACT-5IASS score increased by a mean ± SD of 3.9 ± 4.8 at 9 weeks, from a score of 9.2 ± 4.1 at baseline. This increase predominantly occurred by 3 weeks (4.0 ± 4.7 from the baseline value), and the increase was maintained over 24 weeks. Increases in FAACT- 5IASS scores from baseline were observed in patients with NSCLC or GI cancers.

QOL-ACD: As exploratory endpoints, we also determined the changes in mean scores for QOL-ACD items 8, 9, and 11, which relate to appetite. For all three items, there were increases in mean scores by approximately 1 point relative to baseline scores that were apparent at 3 weeks and remained broadly stable thereafter. Patient global impression

Overall, 76 (74.5%) patients reported some improvement (minimal, much, or very much) in their appetite/eating-r elated symptoms at 6 and 9 weeks from baseline. Four patients at 6 weeks and three patients at 9 weeks reported worsening appetite/eating-related symptoms. In terms of their overall condition, 67 (65.7%) patients reported an improvement at 6 weeks and 66 (64.7%) did so at 9 weeks. The overall condition was reported as worse by 12 (11.8%) patients at 6 weeks and six (5.9%) patients at 9 weeks. Data for both PGIC outcomes were missing for nine and 15 patients at 6 and 9 weeks, respectively. Results were comparable between patients with NSCLC and patients with GI cancers.

Conclusions

This study provides further evidence showing the clinical efficacy and safety of anamorelin to manage cancer cachexia. The study met the primary endpoint, with a CCR of 25.9%, accompanied by improvements in body 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 low BMI patients.

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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 a true scope and spirit of the invention being indicated by the following claims.

Claims

CLAIMS ) A method of providing a clinically meaningful treatment benefit in a 5-IASS score, optionally based on PGIS and PGIC anchor-based measures of benefit, in a human patient suffering from anorexia and cachexia, comprising once daily administering to the patient a therapeutically effective amount of anamorelin wherein: a) the patient has a body weight loss > 2% in the previous 6 months; b) the patient has a body mass index < 20 kg/m²; c) the patient has a 5-IASS score of < 17 points; and d) the patient has a 12-item FAACT A/CS score of < 37 points. ) A method of providing a clinically meaningful treatment benefit in a 5-IASS score and body weight, optionally based on PGIS and PGIC anchor-based measures of benefit, of a human patient suffering from anorexia and cachexia, comprising once daily administering to the patient a therapeutically effective amount of anamorelin wherein: a) the patient has a body weight loss > 2% in the previous 6 months; b) the patient has a body mass index < 20 kg/m²; c) the patient has a 5-IASS score of < 17 points; and d) the patient has a 12-item FAACT A/CS score of < 37 points. ) A method of achieving a composite clinical response in a human patient suffering from anorexia and cachexia comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein, a) the composite clinical response comprises: i) increasing body weight of the patient by > 5%; and/or ii) improving 5-IASS scores in the patient by > 2 points; and b) the patient is characterized by: i) a body weight loss > 2% in the previous 6 months; ii) a body mass index < 20 kg/m²; iii) a 5-IASS score of < 17 points; and iv) a 12-item FAACT A/CS score of < 37 points. ) A method of treating cancer cachexia in a cancer cachexia patient comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein the patient is characterized by: a) a body weight loss > 2% in the previous 6 months; b) a body mass index < 20 kg/m²; c) a 5-IASS score of < 17 points; and d) a 12-item FAACT A/CS score of < 37 points. ) A method of treating cancer cachexia in a cancer cachexia patient comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein the patient is characterized by: a) a body weight loss > 2% in the previous 6 months; b) a body mass index < 20 kg/m²; c) a 5-IASS score of < 17 points; and, optionally d) a 12-item FAACT A/CS score of < 37 points. ) A method of treating cancer cachexia in a cancer cachexia patient comprising administering to the patient a therapeutically effective amount of anamorelin once daily for a therapeutically effective period, wherein the patient is characterized by: a) a 5-IASS score of < 17 points and, optionally, b) a 12-item FAACT A/CS score of < 37 points. ) The method of claim 1 or 2, wherein the clinically meaningful treatment benefit it based on PGIS and PGIC anchor-based measures of benefit. ) The method of any of claims 4, 5, and 6, wherein the patient has anorexia. ) The method of any of the foregoing claims wherein the patient is suffering from weight loss and a general loss of appetite, early satiety, altered food preferences, or a combination thereof. 0) The method of any of the foregoing claims wherein the patient has an ECOG performance status of < 2; 1) The method of any of the foregoing claims wherein the patient has an ECOG performance status of 0, 1 or 2. 2) The method of any of the foregoing claims wherein the patient has cancer. 3) The method of any of the foregoing claims wherein the patient has unresectable NSCLC. 4) The method of any of claims 1-12 wherein the patient has gastrointestinal cancer. 5) The method of any of claims 1-12 wherein the patient has gastrointestinal cancer selected from colorectal, gastric, and pancreatic cancer. ) The method of any of the foregoing claims wherein the patient is receiving systemic anticancer treatment selected from first line treatment, second line treatment, or third line treatment. ) The method of any of the foregoing claims wherein the patient is receiving chemotherapy, radiation therapy, immunotherapy, targeted therapy, or a combination thereof. ) The method of any of claims 1-15 wherein the patient is not receiving systemic anti-cancer treatment. ) The method of any of the foregoing claims wherein the patient suffers from a general loss of appetite, early satiety, altered food preferences, or a combination thereof. ) The method of any of the foregoing claims wherein the patient has a 5-IASS score of less than or equal to 16, 14, 12, 10, or 8 points. ) The method of any of the foregoing claims wherein the patient has a 5-IASS score of < 10 points or > 10 points and < 17 points. ) The method of any of the foregoing claims wherein the patient has a 12-item FAACT A/CS score of less than or equal to 35, 30, 28, 26, 24, 22, or 20 points. ) The method of any of the foregoing claims wherein the patient has a 12-item FAACT A/CS score of < 28 points or > 28 points and < 37 points. ) The method of any of the foregoing claims wherein the patient has a body weight loss greater than 4%, 5%, 6%, 8%, or 10% in the previous 6 months. ) The method of any of the foregoing claims wherein the patient has a 5-IASS score of < 10 points. ) The method of any of the foregoing claims wherein the patient has a 5-IASS score of < 10 points, and a 12-item FAACT A/CS score of < 28 points. ) The method of any of the foregoing claims wherein the patient has a 5-IASS score of < 10 points, and either second line or third line treatment. ) The method of any of the foregoing claims wherein the patient has a body mass index less than 19, 18, 17, or 16 kg/m². ) The method of any of the foregoing claims, wherein the benefit comprises 3, 6, 9, or 12 weeks. ) The method of any of the foregoing claims comprising increasing body weight of the patient by > 5%. ) The method of any of the foregoing claims comprising improving 5-IASS scores in the patient by > 2 points. ) The method of any of the foregoing claims comprising: a) increasing body weight of the patient by > 5%; and b) improving 5-IASS scores in the patient by > 2 points. ) The method of any of the foregoing claims comprising increasing the 5-IASS score of the patient by greater than or equal to 2, 3, or 4 points. ) The method of any of the foregoing claims comprising increasing the body weight of the patient by greater than or equal to 2, 3, 4, or 5%. ) The method of any of the foregoing claims further comprising increasing the patient’s FAACT total score by greater than or equal to 15, 20, 25, 30, or 35 points. ) The method of any of the foregoing claims wherein the anamorelin is administered in a fasted state before the first meal of the day. ) The method of any of the foregoing claims wherein the therapeutically effective amount comprises 100 mg of anamorelin HC1 based on the weight of the salt. ) A method of determining a clinically meaningful 5-IASS improvement threshold in a human patient suffering from anorexia and cachexia comprising the following steps: a) providing a plurality of patients suffering from anorexia and cachexia characterized by a 12 item FAACT A/CS score of < 37, a 5-IASS score < 17, and a BMI <20 kg/m2 with an involuntary weight loss of > 2% in the previous 6 months; b) providing a within patient clinically meaningful change (CMC) on PGIS-A to enable the determination of a clinically meaningful threshold for anorexia symptoms improvement in the plurality of patients; c) providing a within patient clinically meaningful change (CMC) on PGIC-A to enable the determination of a clinically meaningful threshold for anorexia symptoms improvement in the plurality of patients; d) administering to the plurality of patients once daily a therapeutically effective amount of anamorelin for a treatment period; e) generating a dataset comprising 5-IASS scores PGIS-A scores, and PGIC-A scores for the plurality of patients from equal timepoints during the treatment period; and f) determining a 5-IASS improvement threshold that correlates to the PGIS-A CMC and the PGIC-A CMC. ) The method of claim 38, further comprising determining a clinically meaningful body weight improvement threshold in a human patient suffering from anorexia and cachexia by the following additional steps: a) providing a within patient clinically meaningful change (CMC) on PGIS-W to enable the determination of a clinically meaningful threshold for body weight improvement in the plurality of patients; b) providing a within patient clinically meaningful change (CMC) on PGIC-W to enable the determination of a clinically meaningful threshold for body weight improvement in the plurality of patients; c) generating a dataset comprising body weight scores, PGIS-W scores, and PGIC-W scores for the plurality of patients from equal timepoints during the treatment period; and d) determining a body 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 are further characterized by an ECOG PS of < 2. ) The method of any of claims 1, 2, and 9-37, wherein the clinically meaningful benefit in a 5-IASS scores score equals or exceeds the 5-IASS scores improvement threshold determined according to any of claims 38-40. ) The method of any of claims 2-29, wherein: a) the clinically meaningful benefit in a 5-IASS scores score equals or exceeds the 5- IASS scores improvement threshold determined according to any of the methods of claims 38 to 40; and b) the clinically meaningful benefit in body weight equals or exceeds the body weight improvement threshold determined according to any of the methods of claims 39 and 40.