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Should exercise be prescribed for breast cancer survivors?


Being physically active has many health benefits and it may have profound effect in women who had breast cancer. Living an active life seems to protect women from getting breast cancer; similarly it also seems to stop it from coming back in survivors of cancer. Levels of activity go down in women who have had breast cancer or other cancers.

For many of those who have had breast cancer exercise is extremely difficult to do. Even thinking about activity for many fatigued survivors is a challenge. Yet some evidence seems to suggest that it does not have to be strenuous. It may not be necessary to regularly exercise in the gym or play sport. The normal activity of daily living may have protective benefit. So the key may be to be active in some way, as much as can be tolerated, and light exercise such as daily walks may be beneficial.

Being overweight has been implicated in breast cancer incidence and recurrence. A higher blood insulin level in overweight women has been linked to breast cancer.

However, not everyone who is overweight is at increased risk. It depends on when the extra pounds are put on and where the fat accumulates on the body.

Women who are overweight before breast cancer are more at risk of getting it and if you lose weight the risk goes down. Women who undergo weight reduction surgery are less at risk. The Nurses’ health study found that maintaining weight loss for at least 4 years lower the risk of getting breast cancer by 40%. Not only are you more at risk of getting it if you are overweight, but the prognosis is also worse if you get breast cancer as it is associated with decreased overall survival.

The association between weight and breast cancer is not clear cut. If you are overweight as a child and continue to be as an adult then you seem to be less likely to get it than if you gain weight as an adult especially after the menopause. The amount of hormones in fat has been implicated. If you gain weight before the menopause the fat will contain lower concentrations of estrogen. After the menopause, the fat in breasts is more likely to have higher estrogen levels, which means higher risk of breast cancer.

Also where you put on the weight seems to play a role. If you gain weight in the tummy area then the risk is higher than if the weight is gained in the hips or thighs. The type of fat that accumulates in the tummy tends to be more active and dividing; two factors that may be related to an increased risk of cancers.

Being overweight after breast cancer is an important risk factor for recurrence, especially in terms of reducing the risk of it coming back over many years. This is an important health issue as most women with breast cancers get a cure for their cancer – as many as 80% survivor their breast cancer. This means that prevention of the breast cancer recurring is an extremely important health promotion issues. Women survivors of breast cancer need to remain free of recurrence. And weight reduction is an extremely important aspect of this prevention strategy.

Physical activity reduces the risk of breast cancer and the risk of recurrence over and above the simple benefits of weight reduction. However, it is unclear how much is required. Some evidence suggests that if the cancer doctor prescribes exercise that it is of benefit and reduces the risks of relapse. However, it is unclear whether it is the level of the physical exercise or whether the cancer doctor’s encouragement simply gets the patient to move. A study from the Women’s Health Initiative found that walking briskly for 1-3 hours per day reduced the risk of recurrence by 16%. However there is no evidence that walking for 5 hours per day will reduce the risk more.  So the benefit may not correlate with the amount of exercise done and simply doing some activity may reap a good deal of the benefit and reduce the risk of breast cancer recurrence.

Weight loss is extremely important in breast cancer survivors to prevent the cancer from coming back. Physical activity, or perhaps just moving around during the day, is equally if not more important than just losing the pounds.

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Toxicity of Targeted Therapy


Great strides have been made in reducing the toxicity of cancer drugs. The systemic nature of much chemotherapy resulted in a range of general unwanted effects with variable severity, duration and type.

Targeted cancer therapy is more elusive but it does offer improved patient tolerability. Yet even targeted therapy is not without unwanted side-effects, and although they are frequently much milder they can last longer and greatly impede patient quality of life. This is particularly relevant if they are not treated as more than just bothersome.

Chemotherapy although often life-saving has effects that are too general and way too toxic. For chemotherapy the toxicity tends to last for a short time immediately after administration of treatment. If you get chemotherapy it is usual that you feel very badly for a few days to 1 week and then you start to feel better.

In the case of targeted therapy there tends to be more prolonged toxicity and you are often told to live with it and it is often not pleasant and not easy to do this. The toxicity is everyday and the problems can be infections, such as thrush, diarrhoea and fatigue.

In many cases, chemotherapy and targeted therapy are given together. Then the side-effects are additive and in particular in the case of fatigue this can be a serious problem. It is not just a tiredness and a lack of energy, but an inability to do anything and many can’t even stand up or function at all normally.

Staying in bed is not a solution for this kind of fatigue, especially in the case of targeted therapy as it is given long-term, and this is a prolonged period of suffering and there is little quality of life. Chemotherapy and targeted therapy will prolong survivals but attention needs to be paid to what kind of survival and to address problems like fatigue.

Targeted therapy was initially considered to be the ultimate goal as in theory this reduces toxicity generalized side-effects. However, even though the target is identified it does not always work. In some cases, the tumour may express the target but the tumour is resistant to the target therapy. So it is vital to identify those who will benefit from a specific target therapy so that are none on target therapy and getting the side-effects that lower the quality of life without any benefit.

Living with severe fatigue is difficult for anyone, especially in active people who no longer can work, have social activity or play sports like they did before. If targeted therapy does not work for them, then they will have reduced quality of life for no reason.

Side-effects related to targeted therapies should not be ignored. Assessing how the cancer sufferer feels about the impairment of their quality of life, toxicity and most importantly ensuring target therapy works before administration will limit those suffering from more than bothersome side-effects.

Using Bone Cells to Target Pain


Harnessing the remodelling processes in bone is a target for treating pain related to cancer that has spread to the bone. Remodelling is the natural process by which bone recycles and regenerates. Two major cell types drive the remodelling of bone – osteoblasts and osteoclasts.

Osteoclasts recycle bone by creating an acidic environment to dissolve bone, which is a process that can trigger bone pain. In the presence of tumour cells, the number and size of osteoclasts increases in bone tissue. Larger osteoclasts are better at doing their job at forming an acid environment and dissolving bone.

When RANK binds to its receptor (RANK ligand) it activates NF-kB, which promotes the formation of osteoclasts in bone and increases bone resorption, so inhibiting this activation will help preserve bone health. This feature has been exploited in the treatment of osteoporosis.

Osteoprotonegrin acts a decoy receptor for RANK and prevents bone resorption. A monoclonal antibody, denosumab has been developed that mimics this decoy receptor action. In animal models, denosumab reduced pain in half plus preserved bone mass by interfering with osteoclast demineralisation. Bone cancer pain is reduced when the bone is less fragile and the bone is much less likely to fracture, which is a major problem. The drug reduces the pain that bone cancer patients have when they move. It also may slow down the spread of the cancer as weaker bone is more vulnerable to cancer spread.

Cancers that promote bone formation when they spread also cause bone pain. For example, prostate cancer when infiltrates bone causes this type of pain. The nerve growth factor neurotrophin regulates the growth of nerves and what we perceive as painful. Normal activity or movement is often perceived as painful when cancer is causing the pain. TrkA is the receptor for neurotrophin and it switches on and off what we consider painful. The antibody tanezumab binds TrkA and reduces the bone pain associated with types of cancer that increase bone formation.

The influence of hormones on bone cancer pain is unclear, but testosterone clearly could have a role. After castration, bone density decreases. Also in animals lowering testosterone lowers pain thresholds and animals perceive pain at a lower level.

Research into new pain medicines for bone cancers is limited by the risk of reducing pain at the cost of enhancing cancer growth. For example, using VEGF will improve pain of constricted blood impeded by a bone cancer. However, cancers grow using VEGF to promote blood vessel growth and anti-VEGF is a drug to treat cancer.

 

Pain in the CancerBone


 

Neurobiology investigations are leading to the development of new bone pain therapies that may help fight cancers.

Using neurobiology to derive models of bone cancer pain helps to identify the biological mechanisms that drive the bone pain. The aim is to enable the development of new drugs not just for bone cancer, but for other types of cancer as well.

Tumour growth slows down in the bone, and this may be a way tumours evade targeted treatments. So finding the mechanisms involved in tumor-related bone pain will help tackle bone cancers, and provide clues of how to prevent metastasis or spread of other types of cancers as well.

Bone pain occurs in up to 84% of all major cancers. Bone is a common tissue of cancer spread, and primary bone cancer is rare, particularly breast cancer and prostate cancers.

Red cells are made in bone and a number of factors are present in bone that speed up and slow down cell growth. In bone, many cancer cells slow down their growth, and they do not divide as fast.  This has the benefit that it slows down cancer progression and may prolong survivals. However, it also may mean that the cancer evade treatments for this reason. So when the cancer eventually spreads through the bone, and then recurs it can become widespread in the body.

So how do cancers cause bone pain? Some cancers produce chemicals that weakens and cracks bone and this leads to pain. However other cancers can also produce chemicals that harden bone, which thus can lose its functional elasticity and this also leads to pain. Also as tumor cells grow, nerve endings also go into the bone and this can cause pain.

Pain in the bone can often be the first sign of cancer and in prostate cancer bone pain manifesting as low back pain may be the presenting sign.

The way that an individual type of cancer impacts on bone and causes pain is variable. For example, prostate cancer generally leads to abnormal bone growth, whereas breast cancer is more likely to cause more bone destruction.

Spread of cancer from the bone tends to be to multiple organs. Understanding the interactions between tumor and bone may help to identify potential targets for chemotherapeutic intervention to halt tumor growth.

If the vertebrae are riddled with tumour cells, treatment is very difficult and irradiating the whole body or half the body if often required. Many patients already have bone marrow suppression making this an not a viable treatment option.

Breakthrough cancer pain is one of the most difficult types of pains to manage. It is not tumour breaking through the bone, but pain is breaking through the analgesic regime that the patient is on to manage their pain. For patients it is a very difficult pain to deal with because it feels as if the bone is breaking. It is a key pain to  target to improve quality of life and functional status.

As pain increases, the patient quality of life deteriorates. Stepwise pain control involves going from a non-opiate adjuvant to mild opiates and then on to strong opiates plus a NSAID  depending on increasing pain severity.

Despite escalating medication  most patients experience some breakthrough pain or end-of-dose pain. Opiates are very useful drugs but have significant side-effects that are more prevalent in the elderly.

 The cancer affects the areas of mechanical stress where there is greatest bone destruction from the tumour. Growth factors embedded in the bone stimulate tumour cells and further destroy the bone.

One of the reasons it is so difficult to treat cancer pain is that there is simply not one type of pain and there may be combinations of tumorigenic, neuropathic and inflammatory pain. In tumorigenic pain, tumour cells are secreting factors which excite the sensory fibres that radiate to the bone and other parts of the body. Much of a tumour mass is composed of inflammatory cells that potentially cause pain. Neuropathic pain occurs as the tumour is driving through the tissue that it is invading and it causes nerves to sprout.

The pain experienced by many cancer patients is probably all three of these types occurring simultaneously. So a therapy is being given to treat neuropathic pain and at the same time the inflammatory or neuropathic pain, as there is probably multiple mechanisms driving the pain.

 

Pharmacogenomics – Hope for Cancer Pain?


Controlling pain – a complex and subjective experience – is critical to care of cancer patients. Managing cancer pain with analgesics is complicated by inter-individual variability in efficacy, side-effects and adverse drug reactions

Pharmacogenomics – how genetic inheritance affects response to medications – may help explain why some of us respond differently to pain treatments. Subjective responses govern cancer pain perception and there is some genetic contribution to variability. Other influences include biological variations (ethnicity, age and gender); environmental factors (smoking status and perhaps the gut microflora); co-morbidity and concomitant medications (potential for drug-drug interactions).

Opiates remain the major treatment choice for cancer pain, but in some patients they fail or side-effects are intolerable. Dosing traditionally involves carefully escalating and adjusting it based on the clinical response and any side effects or adverse drug reactions. Success is getting enough analgesia, while minimizing adverse effects of taking the drug.

Opiate drugs can cause unpleasant side-effects, such as nausea, vomiting, constipation and sedation. But they can also cause some serious side-effects including strong sedation, respiratory depression and even death if the patient is unable or has reduced ability to metabolize opiates.

Morphine is the most common opiate given. At a population level, morphine has a similar safety profile and efficacy to the other opiates. However, individuals vary in morphine response. Non-responders get little pain control despite increasing the dose. So far only two factors predict non-response to morphine – renal impairment and sepsis.

Giving catecholines enhances opiate efficacy. Catechol-0-methyltransferase inactivates catecholamines (dopamine, adrenaline and norepinephrine); variability in the enzyme’s gene causes differences in pain sensitivity and response.

Identifying known variant alleles that affect the pharmacology of opiates will help tailor treatment and select the best dose.  Codeine – the most researched opiate – exerts analgesia when converted to morphine via the action of cytochrome P450 2D6. The enzyme’s marked genetic variability controls the response to codeine. Some patients produce only a little enzyme, so when given codeine, they don’t make much morphine – up to 10% of Caucasians. Others are very fast or extensive metabolizers have increased enzyme activity but get worse side-effects.

Many genes are likely to play a role; each with just a modest association with pain. So we need sample sizes in the thousands to identify genes involved with any certainty. Most studies performed to date were underpowered to detect modest effects, but will detect strong effects. If we measured all the factors influencing the opiate response, we could perhaps model inter-individual variation to morphine response. Also we could stratify patients according to age, disease process and psychological profile.

Using pharmacogenomics to predict pain management in the clinic is for the future. First we need to define a good clinical response to opioids. Perhaps then we will develop a simple blood test to predict the best opiate and dose for individual patients.

Pharmacogenomic approaches in pain management could lead to individualized therapy to best select the appropriate analgesic from the onset to provide sustained efficacy with the lowest side effect profile.

Harnessing the Metabolome


Spotting individual differences is the key to personalised medicine. In the future, identifying individuality using the metabolome – a personal metabolic snapshot at a particular instant – we may categorise patients into intervention responders and non-responders. By determining susceptibility to future disease and intervening early we may prevent disease from occurring.

We usually target specific metabolites when developing drugs. Using metabolomics offers a different approach as it generates a hypothesis, whereas we usually test a hypothesis. But once we generate the hypothesis it can then be tested.

Imaging technology – nuclear magnetic resonance or mass spectrometry – can generate unique signatures based on each individual’s environment and their genome at a particular time. These metabolomic signatures tend to cluster together – rats cluster with rats and humans with other humans. We, humans, eat different types of food and have different environments so we tend to have wider clusters than inbred rats that tend to have similar lifestyles.

By analysing different biofluids the aim is to look for the differences between for example disease and healthy individuals. For example using urine metabolic signatures a difference was found between osteoarthritis patients and controls, and between those with more severe and less severe disease.

In a study of cardiovascular disease, those with diseased arteries clustered in a signature different from those whose arteries were normal. In the future, metabolomic signatures may be more useful to traditional biomarkers such as cholesterol used to target patients for intervention. Perhaps it will help use blood and biofluid measurements in more informed way and predict outliers in disease and treatment response.

Interpreting data is complex and difficult. Signatures generate vast amounts of data and all of the metabolites in a pathway – some of them not yet identified. Looking at specific important molecules in a pathway simplifies the approach and helps separate signal from noise.

Examining the gut microflora offers an opportunity. We might identify specific microflora associated with gastrointestinal diseases, such as irritable bowel disease, and investigate how they affect metabolite profiles.

In population studies, it may be possible to investigate clusters of healthy people and diseased people with similar phenotypes to see if there are differences in their metabolome.

The way to harness the true potential of the metabolome is to predict healthy people who are likely to get ill and to intervene to protect them.

 

Treating Advanced Parkinson’s Disease


In advanced Parkinson’s disease, major motor and non-motor fluctuations increase and reduce quality of life. Long-term oral levodopa worsens involuntary movements – dyskinesia – and wearing off – off time or ‘untreated’ period of time between dose activity when motor fluctuations present.

Disabling motor fluctuations occur in 80% of patients with advanced disease. As Parkinson’s disease progresses the challenge is to stimulate dopamine receptors continuously but avoid unwanted involuntary movements.

Oral Levodopa Treatment Fails

Traditional treatments lose effectiveness later in disease course. Oral levodopa only stimulates dopamine receptors intermittently because of its short plasma half life (1.5-2 hours), and the erratic stomach emptying- seen in Parkinson’s patients –  slows absorption in the intestine.

Treatment induced dyskinesia results from the intermittent and pulsatile supply of levodopa, with variable plasma concentration and insufficient stimulating of dopamine receptors. Frequent reduced, divided dosing of oral levodopa given with catechol-O-methyltransferase inhibitors increases the plasma half life, but does not stabilise fluctuating plasma levels completely. Longer-acting dopamine agonists – eg slow release levodopa/carbidopa combinations – stimulate dopamine receptors continuously with less dyskinesia, but affect symptoms suboptimally.

Treatment Options

Three main choices exist for treating advanced Parkinson’s Disease: enteral infusions of levodopa/carbidopa (duodopa), subcutaneous infusions of apomorphine, and deep brain stimulation (DBS).

Duodopa Treatment

Duodopa is delivered continuously via a portable pump and provides smoother plasma levels than oral levodopa. Less motor fluctuations occur with off time reduced by 70-90%. Infusing duodopa into the duodenum  improves global functioning, walking, and lessens off time and motor fluctuations. It reduces the daily dose of levodopa required and eliminates delay due to gastric or absorbing the drug in the intestine. Keeping levodopa plasma levels constant limits severe fluctuations between extreme stiffness and involuntary movements. Most problems encountered occur when inserting the device. Contraindications include patients unfit for abdominal surgery, pronounced dementia, and inadequate patient compliance or support.

Apomorphine Pumps

Infusing apomorphine continuously into the skin via a pump reduces off time and is a viable alternative for some patients with advanced disease. Apomorphine contraindications include presence of dementia, hallucinations and the lack of compliance or support.

Deep Brain Stimulation

Stimulating specific regions of the brain electrically – deep brain stimulation – reduces symptoms in many patients. For deep brain stimulation, a surgeon places the stimulating device under the skin and attaches electrodes to the areas of the brain that control motor function. The device stimulates these areas and blocks the abnormal signals for tremor. Contraindications include patients over 70 years of age or unfit for brain surgery, presence of dementia, depression or anxiety.

Pump treatments and deep brain stimulation are best for motor and non-motor symptoms in advanced disease. In the future, the aim is to developing more physiological dopaminergic agents and even better forms of brain stimulation.

Managing Severe Psoriasis


Psoriasis is a common inflammatory and proliferative skin disorder with marked tender plaques topped with a silvery scale. Psoriasis is common, with a prevalence of 1.5-3% in most ethnicities; it is a chronic, persistent condition of variable severity with a relapsing-remitting course. The exact cause of psoriasis is unknown, but it may be a T-cell mediated autoimmune disease.

Assessing severity involves measuring the physical extent of the disease and level of disability – both practical and psychological suffered. Discordance often exists between the patient’s clinical symptoms and level of distress. Psoriasis patients report decreased quality of life similar to cancer and other chronic diseases.

No psoriasis cure exists; treatments include phototherapy; photosensitive drugs plus phototherapy; and systemic treatments – including biologics. Tailoring treatment depends on individual symptoms and level of disability, and aims to improve quality of life.

Phototherapy – ultraviolet B or photochemotherapy using ultraviolet A – alters the immune response. The main adverse effect of ultraviolet B irradiation is redness of the skin; reports remain unproven of an increased incidence of skin cancers. PUVA – a photosensitising agent (psoralens) plus ultraviolet A irradiation- induces complete or partial control of symptoms in 70% or more patients. Two methoxy-psoralen compounds are given – 8-MOP and 5-MOP – either taken orally or by bathing the plaques. 8-MOP is used more often; it the patient suffers nausea it is substituted by 5-MOP.

PUVA is not given long-term because of an associated increased risk of skin cancer; only ten courses of treatment are recommended. Protective glasses are worn for a day after taking psoralen treatment to prevent eye damage.

Low-dose methotrexate is a cheap and effective treatment for sever psoriasis. Nausea is the most common adverse event, but this can be prevented by also giving folic acid. Liver and bone marrow damage can occur, so careful monitoring of the patient’s blood profile is required. If the patient is taking certain antibiotics or has kidney damage while on methotrexate, then bone marrow damage can be acute. Women taking methotrexate should not conceive because of the risk of foetal damage.

Ciclosporin is a fast and effective treatment, but it can cause hypertension and kidney damage.Ciclosporin suppresses the immune response and may increase risk of cancer. Women on ciclosporin should undergo regular cervical smears. Limiting UV exposure is recommended; as are regular dental checks for gingival hyperplasia.

Low doses of acitretin – a second-generation retinoid – is a esafe, effective treatment for psoriasis and well tolerated. Damage to the skin and mucous membranes is common, including conjunctivitis, hair loss and inflammation of the lips. Retinoids affect liver enzymes and blood lipids; toxic reactions are rare. Pregnant women should not take retinoids and women advised not to conceive until two years after stopping treatment.

Retinoids and PUVA act in concert, and are given together to reduce the dose of ultraviolet A irradiation required.

Hydroxyurea inhibits DNA synthesis in proliferating cells and is reported to be effective in treating psoriasis. It is very slow to act and given as a trial for at least 8 weeks.

Immunosuppression occurs as bone marrow cells are suppressed and immune cells in the blood are depleted. Anaemia is uncommon. Blood cell counts are monitored and if levels fall too low the treatment changed. Advise women to wait until six weeks after stopping treatment to conceive.

Half of patients taking fumaric acid esters achieve a 75% improvement in psoriasis in four months. Over 60% of treated patients experience gastrointestinal problems, including abdominal pain, nausea and diarrhoea. Flushing occurs in one-third and can last from minutes to hours. Monitoring blood cell counts, renal function and liver chemistry is recommended.

Two classes of biologic agent are currently in use for treating psoriasis – those that alter cytokine production – TNFα inhibitors – and those that target T cells – efalizumab.

TNFα plays a key pro-inflammatory role in psoriasis. Membrane bound receptors – p55 and p75 – mediate TNFα activity. When released into the circulation,they bind excess TNFα and limit the inflammatory response.

Etanercept – a fusion protein of human immunoglobulin and two soluble p75 receptors – binds circulating TNFα. Given etanercept, 49% of patients achieve a 75% improvement in twelve weeks. Injection site reactions, occur in one third of patients, are usually mild, occur early in treatment and resolve with repeated injections.

Infliximab – a monoclonal antibody (a chimera of human constant and mouse variable regions) – forms stable complexes with soluble and membrane-bound TNFα.Infliximab is rapid-acting and highly effective; 87% of patients get a 75% improvement at 10 weeks. The presence of murine sequences can provoke antibodies causing infusion reactions and reduced efficacy.

Adalimumab – a fully humanised monoclonal antibody – binds  to both soluble and membrane-bound TNFα. On adalimumab, 80% of patients achieve a 75% improvement in 12 weeks.

All three anti-TNFs increased risk of infection (especially TB), exacerbate heart failure, and worsen multiple sclerosis and hepatitis. Antinuclear antibodies and a lupus-like syndrome can develop.

Efalizumab – a recombinant human monoclonal to lymphocyte function associated antigen-1 –  blocks T cell activation, trafficking and adhesion. Efalizumab is less effective than anti-TNFs. Headaches, flu-like symptoms, skin rashes and thrombocytopenia can occur. Disease can flare when treatment is withdrawn. Efalizumab does not increase the risk of infection or malignancy.

Treating severe psoriasis effectively involves choosing the best treatment for individual patients,. In the future, improved understanding of the processes involved in psoriasis may result in new medicines.

Why are New Drugs so Expensive?


New drugs can be prohibitively expensive. Patients may miss out on the best treatment in this age of increasinge economic restraint.

So are pharmaceutical companies ripping off the most vulnerable consumers or does their perceived greed have a logic to it? Should the pharmaceutical industry change practices to make medicines more available to those who really need them? Or is protecting us the real reason that new drugs are so costly?

Understanding the processes involved in drug discovery helps explain why pharma charges so much for some products and not others.

An Arduous Discovery Processi

Getting a new drug product to market takes considerable time, a huge amount of effort and significant investment. It costs an estimated 4 billion euros to bring a brand new medicine to market, so stakes are high.

Pharma expects to have a minimal success rate.  Five thousand candidates may start a drug development cycle; only 10 will be given to humans in clinical trials.  Then only one of them might make it to market – a huge attrition rate.

Developing a truly innovative product is an extremely laborious and expensive process. But these blockbusters – even if rare – can be game changers when they come along as they give a company huge financial.

Role of the Regulatory Authority

The regulatory authorities – the FDA in the US and the EMEA in Europe – govern the drug discovery product cycle. Pharma companies employ big legal teams and regulatory experts to satisfy the requirements of these regulatory agencies. The company must satisfy specific requirements at each step along the discovery process.  The correct documentation must be submitted to the authority and on time. Errors during the submission process will be time consuming and extremely costly for pharma. New technology has greatly reduced the time taken to review drug applications after they have been submitted to the regulatory authority.

A fast track process means some drugs are expedited, with an accelerated time for development review. This occurs for orphan drugs and for some biologics.

The “Me too” Approach

Producing an innovative medicine is the ideal for the pharma industry, but in reality most companies take a pragmatic approach. As a result of this, 70% of drugs are not completely innovative, but are “me too” drugs directed against pre-validated targets.

These medications get quicker to market, which considerably reduces development costs. The downside is that they have to compete with similars in the market. They only improve treatment to a certain extent or improve safety and tolerability compared with another medication. Thus they increase patient compliance. These drugs are hard sells to the payer, unless the improvements are significant or they are cheaper.

Why Drugs Fail?

The development process is always expensive and companies need to recoup investment costs. Big pharma is a high risk and high gain business. Most drug candidates fail; it is cheaper if they fail early. The major reasons why drugs fail early are because they fail to meet specific efficacy and dosing criteria, or are proven unsafe in animals. Late failers usually occur because of side-effect profiles or safety in humans. The FDA or EMEA will not to approve a drug if safety criteria are not met.

Selecting a Drug Candidate

Developing new drugs first involves understanding the disease area and defining a clinical target. Researchers examine the literature and analyse the existing medicines carefully for a potential medical niche they feel they can explore.

Pharma companies aim to develop a drug that is a first in class with a new indication. Also a better return on investment is more likely from a drug for a chronic rather than an acute condition. More profits will be generated from a drug that tackles an unmet clinical need, but this frequently involves higher investment and development costs.

If the condition targeted already has treatment options, the approach is to develop a best in class drug. Research and data will be available on the condition, the competitor drugs and their strengths and weaknesses of these medications and the niche. A common approach is to target a specific aspect of the current medications to improve. These can be related to bioavailability, mechanism of action, or tolerability and safety profile. This approach means patients will already be on a medication. A strong argument is needed to make doctors accept a new medication or for patients to come off a medication they are on and to go a new one. This requires superior evidence over the existing options on the market.

So some major advantage of the new medication needs to be proven, otherwise it will be a much harder sell. If the market is already saturated with choices, then a best in class medication will not make much money. For example, a new cholesterol lowering agent or statin is not likely to have a significant impact on profits unless the efficacy is significant.

Improving the Process

Drug discovery in the traditional sense is wasteful. Some pharma companies reduce costs by focusing on developing specific types of drugs or on specific disease areas. They develop a niche expertise.

For example, one company has targeted diabetes and plans to ‘own the disease’. It is debatable whether this kind of disease monopoly is desirable or not from a consumer perspective, but it reduce expenses of bringing medicines to market. This company are also in the area of diabetes diagnostics and medical devices.

To avoid failures, drug development should be based on solid pharmacology and the drug potency should meet and exceed gold standards. The drug should also ideally be orally administered, have good periodic and linear dosing, be very selective for the clinical target, show good efficacy in animal models with good metabolism and speed of action, with no drug-drug interactions and exhibit robust efficacy.

All studies and evidence collated should meet regulatory requirements and avoid resubmissions. Early stage research requires due diligence. Drugs that fail early in the development process cost much less than if they fail later when up to 500-700m has already been spent.

Proper communication and collaboration within a company will integrate skills, but also identify early any issues with design protocols and regulatory requirements. External communication with regulatory and the understanding of what is required legally will circumvent costly oversights.

If a me too drug is developed, the intellectual property should be structurally unique and not infringe another company’s copyright.

Collaborating with other companies will reduce costs in the drug development and this draws on external expertise and reduces risk burden.

External collaboration to license an intellectual property offers an opportunity for a company to make money with limited investment. If there is a new indication outside the company’s disease portfolio, collaborating with another company with a royalty agreement is a viable way forward. A startup with a new drug may partner with big pharma to complete discovery and market the drug.

Virtual Approaches

Adopting certain approaches to drug discovery is less expensive and time consuming. By simulating binding of new targets virtually expenditure is limited. By identifying drug candidates using molecular data to mine drug space and modelling drug action before going to the lab to test them overall costs are reduced.

We now understand more complex biological systems and this has improved drug discovery. Understanding how medications impact a disease will help develop more effective drugs. But instead of investigating single clinical targets it opens up the opportunity to understand the networks affected by a particular medication and how individuals vary in their response.

Bioinformatics and system biology involve the collation of huge amounts of biological data and its manipulation.  DNA sequence banks, protein banks, and biological sample banks are becoming increasingly open and available.

The use of virtual drug discovery will reduce costs open up new pathways of discovery. Modelling the non-selective binding effects of drugs will identify characteristics that cause side-effects or impair tolerability. A more personalised approach to treatment will evolve and modification of products to increase specificity or reduce unwanted effects .

An open science approach where pharma shares all of its drug data is utopian and unlikely, as barriers to this include economic, IP protection and privacy issues. But there is plenty of data that can be shared

Are Generics Better?

Generic drugs can be made by anyone, so they are much cheaper. They are basically copy drugs with no innovative IP and few if any advantages in terms of action over existing drugs on the market. The big advantage is price.

A generic has a very similar structure and action to a specific prescription drug on the market. The company that produces a generic has no development costs so they can sell it cheaper. Sometimes, however, the generic may have a different formulation. Non-active ingredients may delay the action of the drug or its absorbtion.

Conclusion

Healthcare is expensive. The availability of generic brands offers better value for money but at a price.

Using technology during the development process and virtual modelling help reduce drug development costs.

Streamlining regulatory requirements and shortening review makes it lesscostly and gets medicines to the clinic faster. The price to pay to get new medicines faster and cheaper must not circumvent safety issues, which remain paramount.

Scaffold Hopping for Drug Discovery


Designing new drugs is expensive. Using virtual drug design software to produce novel medicines circumvents some of the considerable costs of developing drugs using traditional approaches.

Many potential new drugs fail to progress through rigorous regulation requirements and clinical trials. The recent steady decline in the number of new drugs making it to market has resulted in use of non-traditional routes to discovery.

A lot of compounds can be synthesised and then screened, but it is a very labour intensive and expensive process. The more economical way – in terms of cost and time – to do this is virtually on a computer. The aim is to take compounds and make virtual molecules. Then to treat them in ways that approximate reality, and recreate in a virtual format the physiological state.

Using a chemical approach and exploiting virtual computational techniques – scaffold hopping – helps reduce expensive pitfalls. It offers the potential to develop novel compounds, different to those identified using traditional approaches.

Ligand Approach

Virtual drug discovery exploits biological action as a driver of investigation. This involves looking at biologically relevant receptor-ligand interactions. The starting point for the development of a new drug is screening for similar biological activity to that of an existing medication. Then the structure is manipulated to improve certain specific properties of the molecule, such as cost of production, improved action, limiting side-effects and increased bioavailability.

The ‘lock and key’ approach leads to making a virtual protein model and using it to try and find out what specific ligands fit inside it. Ligands only have a certain number of conformations, and molecules usually adopt a structure that is low energy, so this helps.

When assessing a protein-ligand interaction, a docking programme computationally reinserts the molecule over and over again in slightly different conformations. The big challenge is if there is a big hole and small molecules, so that they fit in lots of different directions and conformations. Then it is hard to find the orientation that fits best.

Various modifications are made to these compounds to improve efficacy as long as ligand efficiency is preserved.

Chemical Structure Approach

Looking specifically at the chemical structure is an alternative approach to computational drug discovery. This involves using pharmacophores – molecular elements of the compound that makes it active. A minimum number of structural chemical features are required in three-dimensional space to have activity.

Using molecular scaffolds to create molecules that look completely different involves mining drug space containing molecules with biological activity for novel pharmacophores that might make new drugs. Candidate molecules may sit outside of the traditional small medicinal chemistry space.

Pharmacophores are selected from large compound libraries, and then those with undesirable physicochemical properties or moieties are eliminated. The researchers filter through the virtual molecular space to look for subsets of molecules with similar properties. They might have the same kind of polarity, a similar ionisation potential, make a certain hydrogen bond, or have similar molecular weight. After filtering the number of pharmacophores, a number of end candidate drugs are tested.

Combination Approach

It is best to combine use of both structure-based and ligand-based approaches.  The two pathways are different, but the interphase may include a collection of similar molecules that are putatively suggested to be active. This will lead to the accumulation of a group of potential candidates for future research both in vitro and, if successful, in vivo studies.

Looking at Cancer

The ideal cancer drug is a compound available as a once a day oral tablet. The drug needs to obey Lipinski’s rule of 5s – a set of physical properties that govern absorption, distribution, metabolism and excretion. This means the candidate drug will have a molecular weight of less than 500, be lipophilic, and have a limited number of H-bond donors or acceptors.

When a candidate drug is identified and tested in vitro and found to behave as predicted from a computational point of view and this translates into efficacy at a cellular level, the next step is to test it in vivo first in a non-human model and then in humans.

Computational approaches are valid for developing new drugs and an effective alternative to traditional methods. It is target and biology informed.

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