Editorial update on emerging drugs for cancer cachexia

Abstract

Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and weakness. It affects most patients with advanced cancers, reduces quality of life and accounts for more than 20% of all cancer-related deaths. A number of promising therapies for cancer cachexia are in development, including appetite stimulants, anti-inflammatory drugs and those targeting catabolism. However, the multifactorial pathogenesis indicates strongly that the most effective treatments will come from drug combination approaches. Drug treatments should ideally be combined with exercise training to maximize efficacy and ultimately reduce mortality and enhance the quality of life of patients with cancer cachexia.

Keywords:

• anorexia
• cachexia
• cancer
• skeletal muscle
• tumor
• wasting

1. Background

Cancer cachexia is a complex, multifactorial syndrome characterized by a progressive loss of skeletal muscle mass (with or without loss of fat mass), which cannot be fully reversed by conventional nutritional support and is associated with functional impairments [1]. Cachexia can develop in stages from precachexia to cachexia to refractory cachexia, according to the degree of weight loss and depletion of energy stores [1]. Fat loss usually precedes loss of muscle mass [2], and as a consequence, cachexia is often diagnosed very late in disease progression in overweight and obese patients [3]. The pathophysiology includes a negative protein and energy balance driven by reductions in food intake, severe inflammation and abnormal metabolism [1]. Cachexia is present in up to 80% of patients with advanced cancer, including cancers of the gastrointestinal tract, breast, lung, colon, pancreas, sarcoma and prostate [4]. It is also present early in the progression of gastrointestinal, pancreatic and lung cancers [4]. The consequences of cachexia are devastating and include severe fatigue in more than 70% of cancer patients [4]. Fatigue negatively impacts on physical function and reduces patient quality of life. Cachexia impairs the response to chemo-/radiotherapy, increases the risk of complications associated with surgery and accounts for more than 20% of all cancer-related deaths [1]. Since ∼ 25% of all deaths in developed nations are due to cancer and of these, > 33% will suffer from cachexia and > 20% will die from cachexia, there is a profound need for therapies that can ameliorate cancer cachexia [4].

The best way to treat cancer cachexia is to cure the cancer, although this is rarely achieved, and even when successful, it typically occurs after the cachexia has worsened considerably in the interim. Existing treatments have been focused on treating the anorexia, inflammation and catabolic processes associated with cancer cachexia. There are currently no FDA-approved drugs for treating cancer cachexia per se. This editorial update describes current and future pharmacotherapies for cancer cachexia. It is recommended that interested readers also consult with our initial review [5].

2. Future pharmacological agents

2.1 Appetite stimulants

The most promising appetite stimulants are those targeting the melanocortin-4 receptor (MC-4R) and those stimulating ghrelin. Santhera Pharmaceuticals (Liestal, Switzerland) have developed several orally active MC-4R antagonists for the treatment of cancer cachexia. Oral gavage of SNT207707, SNT209858 and BL-6020/979 has all increased food intake and attenuated the reductions in body mass, lean mass and fat mass in colon-26 (C-26) tumor-bearing mice [5]. Clinical trials have yet to be initiated.

Several drugs have been developed to increase ghrelin levels. Anamorelin (Helsinn Therapeutics, Bridgewater, NJ, USA) is a synthetic orally active ghrelin receptor agonist in Phase III development for treating cachexia/anorexia associated with non-small lung cancer (NSCLC). The randomized, double-blind, placebo-controlled trial aims to enroll up to 477 patients and measure lean body mass and muscle strength. AEZS-130 is an oral peptidomimetic growth hormone (GH) secretagogue developed by Æterna Zentaris, Inc. (Quebec, Quebec, Canada) that is well-tolerated in healthy subjects. A proof-of-concept study in patients with cancer cachexia is expected in 2011. A caveat for the use of ghrelin agonists for treating cancer cachexia is the potential for stimulating tumor growth. Ghrelin and its receptor are expressed in many tumor cells and contribute to tumor progression. Although no clinical study has reported an increased tumor incidence with ghrelin administration, these have been short-term studies only.

2.2 Drugs targeting inflammatory cytokines

The most effective anti-inflammatory drugs have been those targeting TNF-α and IL-6. Recent results for thalidomide (Celgene Corp., Summit, NJ, USA), one of the most well-known TNF-α inhibitors, have been conflicting with some studies reporting beneficial effects for improving lean body mass [6], appetite and quality of life in patients with advanced cancers [7], while others have found no effect on lean body mass and quality of life, and with poor tolerability [8]. Celgene Corp. developed lenalidomide (Revlimid), an FDA-approved derivative of thalidomide for treating myelodysplastic syndromes. A randomized, multicenter Phase II trial is currently being conducted to assess the efficacy of lenalidomide for enhancing lean body mass and grip strength in advanced cancer patients. A humanized monoclonal anti-IL-6 antibody, ALD518 (Alder Biopharmaceuticals, Inc., Bothell, WA, USA), may also benefit cancer cachexia since its administration increased hemoglobin levels and prevented the reduction in lean body mass in patients with advanced NSCLC [9]. Greater benefits may be conferred when TNF-α and IL-6 are targeted simultaneously and Ohr Pharmaceutical, Inc. (New York, NY, USA) have developed the broad-spectrum peptide nucleic acid (PNA) immunomodulator drug, OHR/AVR118, which targets both TNF-α and IL-6, and maintains immune homeostasis. In a Phase II study in advanced cancer patients, 28 days of daily OHR/AVR118 injections not only improved appetite and caused weight stabilization or weight gain in ∼ 65% of patients [10], but also increased time to stand from a sitting position, indicating impaired muscle functional capacity [10]. A Phase IIb trial is currently being conducted to assess the efficacy of OHR/AVR118 for improving appetite and enhancing body mass, lean mass, strength and quality of life in patients with recurring or advanced cancers and is expected to be completed before the end of November 2011.

Since prostaglandins are well-known mediators of inflammation formed by cyclooxygenase (COX)-2 activity, Pfizer Italia (Latina, Italy) developed the COX-2 inhibitor, celecoxib (Celebrex) for treating cancer cachexia. In a nonrandomized, open-label Phase II study, 4 months of daily administration of celecoxib increased lean body mass and improved grip strength and quality-of-life parameters in advanced cancer patients [11]. It is important to note that the dose of celecoxib (300 mg/day) did not increase cardiovascular or gastrointestinal risk and was lower than the ≥ 400 mg/day dose associated with increased risk of cardiovascular complications [11]. A randomized, Phase II trial assessing the feasibility of recruitment and retention of advanced NSCLC patients undertaking a 12-week multimodal intervention of celecoxib, oral nutritional supplements and physical exercise is due for completion by December 2014.

2.3 Anabolic drugs

2.3.1 Selective androgen receptor modulators

GTx (Memphis, TN, USA) has completed eight Phase I and Phase II trials demonstrating the safety and efficacy of the selective androgen receptor modulator (SARM), Ostarine (GTx-024), for improving lean body mass and muscle function in cancer patients [12]. Two randomized, double-blind, placebo-controlled Phase III trials were initiated in July 2011 to investigate whether 12 weeks of Ostarine treatment improved lean body mass and muscle function in patients with NSCLC. Estimated completion for both studies is February 2013. Ligand Pharmaceuticals, Inc. (La Jolla, CA, USA) recently completed a Phase I multi-dose clinical trial demonstrating that oral SARM, LGD-4033, was safe and well-tolerated, and increased lean mass in healthy males. Phase II studies are planned to investigate the efficacy of LGD-4033 in cancer cachexia and other conditions associated with muscle wasting. SARMs are also being developed by Kaken Pharmaceutical Co. Ltd. (Tokyo, Japan), Bristol-Myers-Squibb Co. (New York, NY, USA), Johnston & Johnston (New Brunswick, NJ, USA), Merck (Whitehouse Station, NJ, USA) and GlaxoSmithKline (Brentford, Middlesex, UK).

2.3.2 Myostatin/activin inhibitors

Myostatin and activin are members of the transforming growth factor-β superfamily (TGF-β) and signal via the activin type IIB receptor (ActRIIB) to negatively regulate skeletal muscle mass and function. They achieve this by several mechanisms, including inhibiting myogenesis and the Akt/mTOR pathway involved in muscle protein synthesis and increasing the expression of ubiquitin ligases to increase muscle proteolysis. Much research has focused on the therapeutic potential of inhibiting myostatin, or more recently, inhibiting the ActRIIB for treating cancer cachexia. An inhibitory myostatin antibody (PF-354, Pfizer Global Research and Development, Groton, CT, USA) prevented muscle wasting and weakness in tumor-bearing mice [13], but the increases in muscle mass were not as great as those with an ActRIIB decoy receptor (sActRIIB), indicating greatest hypertrophic effects with simultaneous inhibition of multiple TGF-β ligands [14]. Scientists at Amgen Research (Thousand Oaks, CA, USA) showed that sActRIIB administration not only prevented muscle wasting, but completely reversed prior weight loss and prolonged survival in C-26 tumor-bearing mice [14]. A Phase II trial investigating whether AMG 745 (Amgen Research) can attenuate the muscle wasting with aging was withdrawn prior to patient enrollment and it is unknown whether Amgen will continue developing this compound. Acceleron Pharma, Inc. (Cambridge, MA, USA) is developing the ActRIIB decoy, ACE-031, which was shown to be well tolerated and increased lean mass in healthy postmenopausal women. Despite a Phase II trial in boys with Duchenne muscular dystrophy being terminated because of minor side effects, Acceleron Pharma remains committed to the development of ACE-031.

2.3.3 Eicosapentaenoic acid

Although early clinical trials reported little benefit of eicosapentaenoic acid (EPA) supplementation for treating cancer cachexia, recent trials with improved compliance and reduced contamination between treatments have reported beneficial effects of EPA supplementation for lean body mass in newly-diagnosed cancer patients [15]. A recent review concluded that patients should be offered a choice of supplementation format (capsules or liquid) to enhance compliance and that endpoint outcomes should be normalized to phospholipid EPA levels due to individual variability in EPA phospholipid, Inc. [15]. As for studies on tumor-bearing mice, clinical trials should also investigate whether the beneficial effects of EPA supplementation can be enhanced by combining it with exercise training [16]. Exercise reduces inflammation, increases muscle protein synthesis and has orexigenic effects, with several studies reporting beneficial effects of exercise for enhancing muscle mass and strength in cancer patients and tumor-bearing rodents [17].

2.3.4 β-adrenoceptor agonists

The hypertrophic effects of β₂-adrenoceptor agonists, such as formoterol, in cachectic tumor-bearing rodents are well established [18]. APD209 (Acacia Pharma Ltd., Harston Mill, U.K.) is an oral fixed-dose combination of formoterol and megestrol, a derivative of progesterone, and a Phase IIa study investigating the effects of 8 weeks of treatment in 13 cachectic cancer patients was completed recently. Six of the seven patients who completed the treatment period demonstrated improved muscle size and strength, and three patients had increased levels of daily physical activity. Few patients reported side effects such as muscle tremor or tachycardia. Acacia Pharma is currently planning larger, randomized trials.

MT-102 (PsiOxus Therapeutics, Ltd., Billericay, U.K.) is an anabolic/catabolic transforming agent with properties including nonspecific β₁- and β₂-adrenergic receptor antagonism, intrinsic sympathomimetic activity and 5-HT_1a receptor antagonism. MT-102 increased food intake, body mass, fat and lean muscle mass, physical activity levels and increased survival in cachectic tumor-bearing rats [19]. A multicenter, randomized, double-blind Phase II clinical trial was initiated in April 2011 to investigate whether up to 16 weeks of MT-102 treatment improved the rate of body mass change compared with placebo in at least 132 patients with cachexia related to stage III and IV NSCLC and colorectal cancer [20]. Estimated study completion date is August 2012 and participants who complete the 16-week treatment period still taking randomized, double-blind trial medication will be offered the opportunity to join in a subsequent trial with a separate primary endpoint.

2.3.5 Other drugs in clinical trial

BYM338 is a human antibody being developed by Novartis Pharmaceuticals to treat cancer cachexia. In August 2011, a multicenter, randomized, double-blind, placebo-controlled Phase II trial was initiated to investigate whether BYM338 can attenuate the loss of body mass in cachectic patients with stage IV NSCLC or stage III/IV pancreatic cancer. The primary outcome is an increase in thigh muscle volume and trial completion is expected in September 2012. The exact targets of BYM338 are not currently available to the public and it is hoped that this information is released at trial completion.

2.4 Combination therapy

Due to the multifactorial nature of cancer cachexia and the limited efficacy of single therapies, a multi-targeted approach may be the most effective treatment. In this regard, a randomized Phase III clinical trial involving 332 patients with cancer cachexia compared the efficacy of 4 months of treatment with megestrol acetate, EPA, l-carnitine, thalidomide or a combination of all four treatments [6]. This treatment approach resulted in the greatest improvements in lean body mass, physical activity levels and fatigability [6].

3. Expert opinion

A number of promising therapies for cancer cachexia are in development but because of the multifactorial pathogenesis of the condition, it is likely that the most beneficial treatment will come from combination drug therapies. The combination that currently appears most promising includes appetite stimulants such as MC-4R antagonists or ghrelin stimulants, anti-inflammatory drugs such as OHR/AVR118, which targets both TNF-α and IL-6, and anti-catabolic drugs such as ActRIIB decoy receptors that may also enhance survival. Drugs manipulating β-adrenoceptor signaling, such as APD209 and MT-102, are also showing promise in clinical trials especially when administered in combination with appetite stimulants. The multi-targeted approach should also include exercise training in order to maximize efficacy. The recent randomized Phase III clinical trial of five different treatments, including a combination of four treatments [6], should be considered to be a template for future approaches. The clearly defined and appropriate endpoints employed in that study should be used as a reference for future trials, with primary endpoints including lean body mass, resting energy expenditure and fatigue and secondary endpoints including muscle strength, anorexia, physical activity levels, quality of life, survival and levels of pro-inflammatory cytokines. Finally, it is critical that therapeutic potential be evaluated at each stage of cancer cachexia since the pathogenesis will vary between stages and not all patients will progress through the entire spectrum. It is especially important to test therapies at the stage of precachexia in order to prevent or delay the development of cachexia and, therefore, improve quality of life as well and survival.

Declaration of interest

The Basic and Clinical Myology Laboratory gratefully acknowledges the generous research funding received from the Victorian Cancer Agency (Australia). KT Murphy holds a Career Development Fellowship from the National Health and Medical Research Council (Australia). The authors declare that they have no competing interests.