Q J Med 1999; 92:1–4
`
`Editorial
`
`Peptides as drugs
`
`We are on the brink of a therapeutic revolution. There
`has been a rapid expansion in the use of peptides as
`drugs over the last decade, and this is likely to con-
`tinue. Peptides regulate most physiological processes,
`acting at some sites as endocrine or paracrine signals
`and at others as neurotransmitters or growth factors.
`They are already being used therapeutically in
`such diverse areas as neurology, endocrinology and
`haematology.
`Most peptides cannot be administered orally as
`they are rapidly inactivated by gastrointestinal
`enzymes, so that subcutaneous or intravenous admin-
`istration is required. Therefore, research is focussing
`on alternative routes of delivery, including inhaled,
`buccal, intranasal and transdermal routes, as well as
`novel delivery systems such as the use of protective
`liposomes. Neuropeptide systems in the brain are
`being examined as potential targets for therapeutics,
`providing an exciting future development area. The
`dual problems of
`local
`targeted delivery and the
`blood-brain barrier, prevent administered peptides
`from readily gaining access to the required site of
`action, although as we will discuss, solutions are on
`the horizon.
`Peptides act by binding to specific cell surface
`receptors. The perfect therapeutic agent would be a
`small-molecular-mass chemical mimic of the recep-
`tor ligand, which would be cheap to manufacture
`and could get to the site of action after oral adminis-
`tration. However, receptors are large with many bind-
`ing sites, and peptides have a complex tertiary
`structure, both of which improve specificity as well
`as affording protection from simple invading molec-
`ules, like bacterial toxins. Consequently, production
`of successful peptide mimics using chemical libraries
`is largely unsuccessful and we still rely on the native
`peptide for therapeutics.
`The list of peptides as potential drugs is huge;
`space does not permit discussion of them all. It is
`beyond the scope of this article to focus on older
`peptide therapies
`such as
`luteinizing-hormone-
`releasing hormone, growth hormone, arginine vaso-
`pressin or the very interesting peptide, cyclosporin.
`We will instead highlight some exciting new areas of
`
`© Association of Physicians 1999
`
`QJM
`
`research as well as recent developments in the use of
`more established peptide therapies.
`Insulin was the first peptide to be isolated and
`administered therapeutically, and is still
`the most
`commonly prescribed peptide, having been used for
`over half a century. We have yet to find a chemical
`mimic; however, there is still ongoing research into
`novel analogues and methods of administration.
`Manipulation of the insulin molecule has allowed the
`development of shorter-acting insulins, such as Lispro
`insulin. This is rapidly absorbed, readily dissociates
`into insulin monomers, and produces plasma levels
`that more closely mimic the normal postprandial
`insulin profile. Thus, Lispro can be injected immedi-
`ately prior to a meal, unlike conventional short-acting
`insulins that should be injected half an hour earlier.1
`A recent development is the use of non-injectable
`forms of insulin. Daily injections up to four times per
`day,
`is a major source of distress in the diabetic
`population, for example children or the elderly. It
`comes as no surprise that inhaled, intranasal, buccal,
`rectal and sub-lingual preparations of insulin have all
`been investigated. Precise insulin dosage is critical
`for ‘brittle’ type 1 diabetics. However, for some, e.g.
`people with type 2 diabetes who have significant
`residual endogenous insulin secretion, less accurate
`forms of administration may be adequate. Results pre-
`sented at the 1998 American Diabetes Association
`meeting, showed that inhaled insulin provided glyca-
`emic control equivalent to the subcutaneous route,
`whilst allowing insulin to be taken immediately
`before a meal. Thus, the future seems to be more
`hopeful for the ‘multiply-punctured diabetic’.
`A number of other peptides have been investigated
`for the treatment of diabetes. For example, peptides
`that delay gastric emptying may be valuable in the
`treatment of both type 1 and type 2 diabetes.2 If
`patients with glucose intolerance or early diabetes,
`ate small amounts of food frequently, decreasing the
`flux in intestinal glucose absorption,
`this would
`diminish beta-cell work, and may therefore slow the
`progression of the disease. Islet amyloid was origin-
`ally noted to be present in the islets of patients with
`type 2 diabetes, and its precursor amylin is secreted
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`ith insulin. A proposed action of amylin to improve
`insulin sensitivity was not confirmed3 but
`it was
`found to be a potent inhibitor of gastric emptying.2
`Recent studies of pramlintide, a stable amylin ana-
`logue which does not form amyloid, indicate poten-
`tial for the approach of delaying gastric emptying,4
`and it is undergoing phase 3 clinical trials.
`Another peptide in which there is currently much
`interest is the endogenous hormone, glucagon-like
`peptide–1 (GLP–1).5 This not only has
`insulin-
`releasing properties, but also suppresses glucagon
`levels, and delays gastric emptying. The insu-
`linotropic action of GLP–1 is glucose-dependent,
`thus, it acts more potently after a meal than in the
`fasting state, protecting against hypoglycaemia.
`GLP–1 has been reported to increase peripheral glu-
`cose disposal, another desirable effect in diabetes,
`and a target for non-peptide treatments such as the
`thiazolidinediones. GLP–1 has been shown to
`decrease appetite in the rat,6 and more recently in
`man,7 particularly relevant for the 85% of patients
`with NIDDM who are overweight. The results of a
`recent small double-blind placebo-controlled cross-
`over study using subcutaneous injections of GLP–1
`for three weeks, has demonstrated therapeutic prom-
`ise in early type 2 diabetes.8 Indeed, development of
`a novel buccal tablet,9 with good bioavailability has
`ensured at least two pharmaceutical companies are
`exploring the possible use of GLP–1 as therapy.
`Longer-acting peptide agonists of the GLP–1 receptor
`are also under clinical trial.
`In 1980, 8% of the population in Britain were
`clinically obese (body mass index >30); by 1994
`this had increased to 15%. Obesity is a major risk
`factor
`for
`ischaemic heart disease, diabetes and
`stroke. As all those who see obese patients know,
`exercise and dieting does not work for the majority.
`The recent withdrawal from the market of phenterm-
`ine and fenfluramine, indicates the difficulty in find-
`ing a safe and effective therapy. The number of new
`obesity treatments recently licensed demonstrates the
`magnitude of the need and the desperate desire for
`an effective medical treatment.
`The discovery of the adipose tissue peptide hor-
`mone, leptin,10 has opened a new chapter in the
`search for an anti-obesity agent. Leptin, a signal of
`the degree of body adipose tissue mass, decreases
`appetite and increase metabolic rate in animal
`models. Exogenous administration of
`this peptide
`could treat obesity. Conversely an antagonist could
`treat anorexia. In obese humans, leptin levels are
`high, yet they keep eating. This may reflect the fact
`that
`the transport system into the central nervous
`system is saturable, producing functional leptin resist-
`ance.11 However, it is still believed by many that
`exogenous administration of leptin will cause weight
`loss. The first clinical evaluation of daily injection of
`
`Editorial
`
`recombinant methionyl leptin in obese volunteers,
`treated for 6 months, demonstrated an 8 kg loss in
`weight. This occurred with minimal side-effects. We
`await with interest to see whether this weight loss
`continues on further treatment. Certainly patients
`with the rare condition of obesity due to genetically
`absent leptin,12 respond well.
`The discovery of one adipose tissue hormone that
`regulates body weight may lead to the identification
`of others. These may hold greater therapeutic hope.
`With over 100 million obese people globally, and the
`incidence of obesity climbing, this is an area which
`will continue to be a major focus for research.
`The long acting stable analogue of somatostatin,
`octreotide, has a number of therapeutic indications.
`Octreotide is very effective at treating acromegaly as
`well as the symptoms from gastro-enteropancreatic
`endocrine tumours, particularly from carcinoid syn-
`drome, Zollinger-Ellison syndrome and VIPomas.
`Octreotide has also been used as a therapy for a
`variety of other disorders including upper gastrointes-
`tinal bleeding, acute pancreatitis, dumping syn-
`drome,
`gastrointestinal
`fistulae
`and
`secretory
`diarrhoea. Recently, two new analogues and delivery
`systems making octreotide more stable and thus
`longer-acting have been licensed, such that subcuta-
`neous injections are only necessary every 2 weeks
`(Lanreotide) or 4 weeks (Sandostatin LAR), providing
`an improvement in the quality of life of these patients.
`Interestingly, an oral preparation of somatostatin
`demonstrated good bioactivity,13 however, it has not
`yet been developed commercially.
`Interest has focussed on the use of radiolabelled
`octreotide for imaging, and its potential therapeutic
`use. Expression of particular somatostatin receptors
`on certain tumours allows imaging of these tissues,
`and specific binding and internalization of higher
`dose 111In-pentetreotide, produces cell death and
`tumour regression.14 111In-pentetreotide therapy is in
`its infancy and has only been used in a few patients,
`but has resulted in good objective evidence of tumour
`response. Longer-term studies are required to assess
`the exact usefulness of
`this novel weapon in our
`therapeutic armament. Hopefully it will lead the way
`for other such peptides to allow specific targeting of
`a cytotoxic dose of radioactivity.
`When the interferons were discovered they were
`hailed as a panacea for many conditions, but this has
`not proven to be the case. Recombinant interferon
`beta–1b has been licensed for use in relapsing-
`remitting multiple sclerosis following the results of a
`large multicentre randomized, placebo-controlled
`trial in 1993.15 This showed a 34% decrease in the
`annual rate of exacerbations as well as a decrease in
`their severity after 2 years therapy with interferon
`beta–1b (8 MIU subcutaneously every second day).
`Unfortunately, there was no evidence for any effect
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`Editorial
`
`3
`
`on the level of disability. Interferon beta–1a, being
`glycosylated, is closer to natural interferon. This has
`also been shown to reduce relapse rate but, in addi-
`tion, demonstrated a delay in progression of disabil-
`ity.16 Since the introduction of these drugs, a highly
`charged argument has waged on the cost-benefit ratio
`for such expensive treatments with relatively little
`evidence of long-term benefit.
`Copolymer 1 (Cop–1) is a mixture of synthetic
`peptides composed of the amino acids alanine, glu-
`tamic acid,
`lysine and tyrosine.
`It was originally
`designed to mimic myelin basic protein, one of the
`components of myelin, which is now thought to have
`only a minor role in the pathogenesis of multiple
`sclerosis. Despite this, Cop–1 injections have been
`shown to reduce relapse rate by a similar degree to
`beta-interferon and may be better tolerated.17 Cop–1
`appears to work via a different mechanism to inter-
`feron, making dual
`therapy a likely future devel-
`opment.
`Peptide neurotrophic factors such as nerve growth
`factor (NGF), have been suggested to be valuable in
`the therapy of neurodegenerative disorders such as
`Parkinson’s disease and Alzheimer’s disease. NGF is
`hypothesized to rescue dying neurons and stimulate
`nerve terminal outgrowth. Direct infusion of NGF
`into the putamen has produced some benefit when
`used as a support to autografts of adrenal medulla in
`Parkinson’s disease. Infusion of NGF into the third
`cerebral ventricle of patients with Alzheimer’s disease
`for 3 months resulted in cognitive improvement as
`well as increased cerebral blood flow and EEG
`changes.18 Obviously these methods of drug delivery
`are only appropriate for a very select patient group.
`However, the studies do point to another potential
`use for peptides as drugs in the future, and linking a
`neurotrophin to a carrier molecule to facilitate trans-
`port across the blood-brain barrier may allow intra-
`venous usage.
`Recombinant human erythropoietin (EPO) was first
`licensed as a therapeutic agent in 1988, remarkably
`within 5 years of cloning of the human gene.19 It was
`an immediate success in treating the anaemia of
`chronic renal
`failure. At present,
`subcutaneous
`administration is the route of choice in Europe.
`Erythropoietin is one of a number of drugs, including
`insulin and interferon, for which encapsulation in
`liposomes to allow oral delivery has been investi-
`gated.20 Pharmacological availability is extremely
`variable (0.74–31%), dependent on liposome com-
`position and particle size, however, such studies indi-
`cate potential for this delivery system. Therapy with
`EPO has also been considered for the anaemia associ-
`ated with many disorders including cancer, multiple
`myeloma, myelodysplasia, HIV infection and chemo-
`therapy. It seems to be relatively free of side-effects,
`aside from a significant increase in blood pressure in
`
`about one third of patients in one study of renal
`patients, all but one being controlled with further
`anti-hypertensive treatment.21 Indeed, it has become
`a drug of abuse amongst athletes who derive benefit
`from the increased oxygen carrying capacity of the
`resultant polycythaemia—time will tell as to the real
`prevalence of this problem.
`Recombinant human growth factors such as gran-
`ulocyte-colony stimulating factor (G-CSF) and gran-
`ulocyte macrophage-colony
`stimulating
`factor
`(GM-CSF) stimulate the production of neutrophils or
`granulocytes and monocytes. They reduce the sever-
`ity of chemotherapy induced neutropenia and accel-
`erate haematopoietic recovery,22 and have also been
`used for neutropenia associated with other disorders.
`A number of studies have demonstrated a significant
`reduction in infections with these treatments given in
`the form of subcutaneous injections. They are now
`frequently used as part of the therapeutic protocol for
`a number of haematological malignancies. In particu-
`lar, combination with EPO seems to improve its effi-
`cacy, at least in myelodysplastic syndromes.23 After
`development of peptides to increase red-cell and
`white-cell numbers,
`it comes as no surprise that
`thrombopoietin is the latest
`replacement peptide
`being investigated as a treatment
`for thrombocy-
`topenia.
`Peptide antibiotics have been under investigation
`for a number of years. In this country there are cur-
`rently two antibiotic peptides licensed,
`the poly-
`myxins, polymyxin B and colistin (polymyxin E).
`Colistin is occasionally given by injection to treat
`Pseudomonas aeruginosa in patients with cystic fib-
`rosis, though more frequently aerosol preparations
`have been used.24 It is also used orally in bowel
`sterilization regimens for neutropenic patients, as it is
`not absorbed. Polymyxin B is just used as a topical
`preparation for local eye and ear infections. Both
`antibiotics are prescribable for local skin infections.
`Several classes of other antibiotic peptides including
`defensins, protegrins, magainins, tachyplesins, cecro-
`pins, mutacins and clavanins are under investigation.
`They are isolated from animal or bacterial sources as
`diverse as Xenopus skin, mudfish and streptococci.
`The inability of present non-peptide antibiotics to kill
`certain bacteria, make it likely that antibiotic peptides
`will form an important part of our fight to defeat
`multi-resistance in the twenty-first century.
`We have described some of the present diversity of
`uses for peptide therapies and future potential devel-
`opment. Manipulation of the structure of some of
`these peptides has allowed development of receptor
`ligands with longer action. Peptides active via non-
`injected routes are beginning to appear. Gene
`therapy is likely to provide the basis for novel delivery
`systems in the future. Production of orally active pre-
`parations is more likely with the encapsulation of
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`4
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`Editorial
`
`peptides in liposomes or polymers allowing protec-
`tion from digestion. This is an active area of research
`with much therapeutic potential; the ‘holy grail’ of
`orally active peptides will soon be realized, and with
`it a rapid expansion of peptide therapy will ensue.
`C.M.B. Edwards
`M.A. Cohen
`S.R. Bloom
`ICSM Endocrine Unit
`Hammersmith Hospital
`London
`
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