Exploring psychotherapeutic issues and agents in clinical practice
The fungus Aspergillus fumigatus, widespread in nature, can cause disease in humans, especially those who are immunocompromised. Amebiasis, a mild to severe gastrointestinal infection caused by the parasite Entamoeba histolytica, is considered a world-wide scourge, causing severe illness in millions of individuals and tens of thousands of deaths in underdeveloped countries. Fumagillin is an antimicrobial compound that was isolated from A. fumigatus in 1949 (Hanson & Eble, 1949). The first human experience with fumagillin, reported in 1952, demonstrated effectiveness against amebiasis and other protozoan parasitic infections (Killough, Magill, & Smith, 1952). Four of 10 patients receiving the highest dose (i.e., 50 mg per day) for 7 to 14 days had a notable loss of appetite without nausea or vomiting. Although the significance of this observation was not apparent at the time, it foreshadowed later serendipitous developments involving chemical analogs of fumagillin and their intriguing use for treating obesity.
Fumagillin and Angiogenesis
Angiogenesis is the process of new blood vessel growth, which is important for development, reproduction, and growth. In 1971, Folkman first proposed the novel and controversial theory that angiogenesis is critically important for tumor growth and that inhibition of angiogenesis might be an effective strategy for treating cancer. This theory led to extensive research efforts to identify angiogenesis factors and find angiogenesis inhibitors that could be used in the treatment of cancer.
In the late 1980s, Folkman’s laboratory group discovered a fungal contamination during routine culturing of capillary endothelial cells used in their angiogenesis research (Ingber et al., 1990). Because the contaminant produced endothelial cell rounding, a characteristic finding with angiogenesis inhibitors, they investigated further and determined it to be A. fumigatus. The active fraction they purified from their fungal culture was identified as fumagillin, which inhibited endothelial cell growth and tumor-induced angiogenesis. Their subsequent studies investigating the effectiveness of fumagillin as an inhibitor of tumor growth also found that it produced unacceptably severe weight loss in mice, which would make it unsuitable for clinical studies in cancer patients.
Because of this problem, the group (together with Takeda Chemical Industries, a Japanese pharmaceutical company) proceeded to synthesize fumagillin analogs that may have anti-angiogenic activity without significant adverse effects. One such analog, AGM-1470 (later known as TNP-470), was found to be a more potent angiogenesis inhibitor than fumagillin and it was not associated with weight loss in their mouse studies. TNP-470 was the first angiogenesis inhibitor drug to be tested in cancer patients and it slowed tumor growth, but its clinical development was discontinued because of dose-related neurotoxicity (Satchi-Fainaro et al., 2004).
Angiogenesis and Obesity
If tumor growth is angiogenesis-dependent, what role does angiogenesis have in normal non-neoplastic tissue growth in the body? Unlike most adult tissues, adipose tissue can grow and regress throughout adulthood, is highly vascularized, and has angiogenic properties (Rupnick et al., 2002). Although Folkman’s group did not find significant weight loss with TNP-470 in their mouse tumor studies (Ingber et al., 1990), they shifted to investigate anti-angiogenic agents in various mice models of obesity (Rupnick et al., 2002). These studies found that treatment with TNP-470 and several other angiogenesis inhibitors resulted in dose-dependent reversible weight reduction and adipose tissue loss, and that favorable metabolic adaptations in appetite, energy expenditure, and fuel use were associated with the weight loss. Animal studies by other research groups have also demonstrated favorable effects of fumagillin and TNP-470 on adiposity (Joharapurkar, Dhanesha, & Jain, 2014; Lijnen, Frederix, & Van Hoef, 2010).
The Advent of Beloranib
Although fumagillin was first discovered in 1949, its molecular mechanism, inhibiting the cellular enzyme methionine aminopeptidase type II (MetAP-2), was not identified until 1997 (Han et al., 2000). Because of interest in angiogenesis inhibition in general, MetAP-2 inhibition in particular, and the neurotoxicity of TNP-470, other fumagillin analogs were designed for further study. Using the known physical and biochemical properties of fumagillin and TNP-470, together with molecular modeling of the MetAP-2 enzyme protein, the drug CKD-732 was synthesized (Chun et al., 2005). CKD-732 had a greater affinity for MetAP-2 and higher efficacy on suppressing tumor growth in preclinical studies than TNP-470. Two phase I studies of CKD-732 in cancer patients have been conducted (Shin et al., 2010, 2012). Although prominent neurotoxicity was not apparent in these studies and CKD-732 showed an effect on disease activity, it is not clear whether it will be further developed as a cancer treatment. No clinical studies using this drug for cancer are listed on the ClinicalTrials.gov website or on the National Cancer Institute clinical trials website.
In line with obesity research findings using fumagillin and TNP-470, preclinical studies of CKD-732 have demonstrated that it decreases food intake, body weight, fat mass, and the size of adipocytes (Kim et al., 2007). CKD-732 was originally developed by the Chong Kun Dang Pharmaceutical Corporation (CKD Pharm) in South Korea (Kim & Shin, 2005). In a licensing agreement with CKD Pharm, the biopharmaceutical company Zafgen was formed in 2005 to sponsor clinical development of CKD-732 (also known as ZGN-433; ZGN-440; beloranib) outside of Korea as a treatment for obesity and related conditions.
Beloranib and the Treatment of Obesity
Three phase I studies of beloranib for the treatment of obesity have been completed (NCT01028261; NCT01372761; NCT01507077; access http://www.ClinicalTrials.gov). Phase II studies for the treatment of obesity (NCT01666691), obesity associated with Prader-Willi syndrome (NCT01818921), and obesity associated with hypothalamic injury (NCT02063295) have also been completed. A phase II study for the treatment of obesity and type 2 diabetes (NCT02324491) and a phase III study for the treatment of obesity associated with Prader-Willi syndrome (NCT02179151) are currently in progress.
None of the results from completed beloranib studies has been posted on the ClinicalTrials.gov website. Only one study has been published (Hughes et al., 2013); this 4-week phase I study compared three dosages of beloranib to placebo in 31 obese women. The highest dosage resulted in significantly greater weight loss (3.8 kg) compared to placebo (0.6 kg). Beloranib was associated with significant reductions in triglycerides, low-density lipoprotein cholesterol, and hunger. Changes in various metabolic biomarkers suggested the drug stimulated energy expenditure, fat use, and lipid excretion, and was associated with a decrease in total adipose tissue. Beloranib was relatively well-tolerated, and no dose-related toxicities were reported.
The main findings from the other completed studies are described briefly in a series of press releases that can be read in the newsroom section of the Zafgen website (access http://www.zafgen.com/zafgen). Joharapurkar et al. (2014) also described the findings from some of these studies, but the information they present is taken verbatim from the press releases. All of the studies found significant degrees of weight loss and acceptable tolerability for beloranib compared to placebo, justifying further clinical development of the drug for obesity.
Clinical Considerations on the Use of Beloranib
Beloranib is not yet approved by the U.S. Food and Drug Administration, but several issues are relevant to its potential use. Currently, beloranib must be given intravenously or subcutaneously. Although some drugs are marketed for non-oral use (e.g., insulin, exenatide [Byetta®; Bydureon®], liraglutide [Victoza®; Saxenda®] for diabetes), oral drug formulations are preferred by patients. Whether beloranib can be formulated for oral use (e.g., sublingual) or intranasal use would be important to investigate.
The promising efficacy and favorable tolerability found in the phase I and phase II studies must be confirmed in studies with larger groups of patients. The safety of beloranib in particular will need to be evaluated carefully. Angiogenic factors have broad biological functions that are necessary for normal physiological functioning, including formation of the vascular system during embryonic development, neurotrophic and neuroprotective activity, tissue and organ regeneration, maintenance of vascular integrity, and maintenance of vascular fenestrations in endocrine glands (Cao, 2010). Hence, angiogenesis inhibitor drugs used for treating obesity may have many expected and unexpected adverse effects. For example, the drug thalidomide was found to be an angiogenesis inhibitor more than 30 years after it was notoriously associated with major teratogenic effects (D’Amato, Loughnan, Flynn, & Folkman, 1994). Other angiogenesis inhibitor drugs have been associated with bleeding, hypertension, protein-uria, and fatal cardiovascular events, and angiogenesis inhibition may impair wound healing and tissue repair (Cao, 2010). Because dose-related neurotoxicity was seen with TNP-470, neurotoxicity will also need to be evaluated with its chemical analog drug beloranib.
Compared to the general population, individuals with psychiatric illness are more likely to be overweight or obese, have higher rates of weight-related medical conditions, and have greater non-suicide mortality rates (Walker, McGee, & Druss, 2015). Factors associated with overweight and obesity in psychiatric patients not only include unhealthy diet and physical inactivity, but also intrinsic illness-related physiological processes as well as psychotropic drug-related effects. The safety and effectiveness of beloranib would be uncertain when used in a patient population not studied during its clinical development. However, should beloranib be approved as a treatment for obesity, it will surely be used in psychiatric patients and nurses should become familiar with its efficacy, side effects, and unique mechanism. The story behind beloranib also should remind nurses of the importance of careful observation, being familiar with concepts outside of their range of practice, and the role of serendipity in advancing clinical science.
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