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Medicines for the modern world

Lifestyle choices are creating major health problems. But big pharma, and in some instances small biotech, is on the case. Megan Boxall on the companies finding the cure
May 5, 2017

It has been an estimated 200,000 years since modern humans first walked the earth and in all that time the human genome has not changed. But society has. Today we process food, burn fuels and exchange digital messages, all activities to which the human body - designed to roam open plains in search of meat and berries - is not well adapted.

It's therefore perhaps unsurprising that humans - at our cores just the humble homo sapiens of yesteryear - are today at such high risk from lifestyle triggered illnesses. Tobacco use, physical inactivity, pollution, alcohol and unhealthy diets are all proven to increase the risk of contracting chronic diseases, including cancer, diabetes and cardiovascular or respiratory complaints. In turn, these illnesses contribute 70 per cent to the global annual death rate.

And patient numbers are rising. In the UK the prevalence of obesity among adults rose from 15 per cent to 27 per cent between 1993 and 2015. Rising carbon emissions have increased pollution by 2 per cent every year since 1971, which has contributed to the rise in unhealthy lungs. Meanwhile in China and other emerging markets the incidence of lifestyle-related illnesses is growing alongside the accumulation of wealth.

For pharmaceutical companies, these large and growing patient populations are very attractive, as drugs to treat these illnesses are prescribed in vast numbers. For example, statins - used to lower blood cholesterol - are the most used type of drug globally, while inhalers are carried by an estimated 5.4m asthma sufferers in the UK alone.

The league table of all-time top-selling medicines is therefore crowned by drugs to treat lifestyle diseases. At their peak, statins Lipitor and Crestor made $13bn (£10m) and $7bn a year for Pfizer (US: PFE) and AstraZeneca (AZN) respectively. Sanofi's (FR:SAN) heart attack busting drug Plavix made $74bn between 1997 and 2012. And inhaler Advair has contributed at least a tenth of GlaxoSmithKline's (GSK) overall revenue for the past six years.

 

Peak annual sales from the 10 top-selling drugs of all time

DrugCompanyIllnessPeak year sales ($m)Peak year (to date)
LipitorPfizerHigh cholesterol12,8862006
HumiraAbbVieArthritis10,6592013
AdvairGlaxoSmithKlineAsthma/COPD6,8612010
CrestorAstraZenecaHigh cholesterol6,6222011
LosecAstraZenecaGastrointestinal6,3002000
RituxanRocheCancer6,0052011
RemicadeJohnson & JohnsonAutoimmune5,4922011
EnebrelAmgenArthritis3,5342010
AbilifyBristol-Myers SquibbSchizophrenia2,7582011
PlavixSanofiHeart disease2,2702010

Source: Data collected from company annual reports

 

That said, recently the golden era of big-selling lifestyle drugs has hit a roadblock. Many large pharma groups have lost exclusivity on their former blockbuster drugs, but have failed to launch new ones to plug the gap in sales. The problem is that respiratory and cardiovascular illnesses are very well understood. Their treatments are therefore pretty much as good as it is possible for them to be, meaning launching a new drug and persuading physicians to prescribe it is no mean feat.

That's not to say that pharma companies aren't up for the challenge. Respiratory and cardiovascular remain crucial divisions of big pharma groups. Plus, there is a growing class of small-cap pharma attempting to outperform the giants and tackle specific sub divisions of these big patient populations.

Finding a cure for illnesses caused by lifestyle choices should be simple. An overweight person can lower their chances of obesity-related illnesses by eating a balanced diet and participating in regular exercise. A smoker can reduce the probability of contracting lung cancer by quitting, as can an alcoholic whose liver is looking unhealthy. But that's not realistic, and for pharmaceutical companies and their investors, however, it is perhaps beneficial that humans are likely to continue to indulge in things that are bad for their bodies. While these illnesses may not carry the potential blockbuster status of cancer cures or solutions for rare diseases, their large population sizes ensure healthy returns, making them a high-reward area of investment. So which are the companies helping us alleviate the burden of our bad habits?

 

  

A breath of fresh air

When a person breathes in bad air - whether that be through smoking, or cycling into work behind a bus - toxins enter their lungs. These toxins cause the lungs' walls to stiffen and thicken, which reduces the amount of air that a person can breathe in and out. The damage can eventually lead to the development of chronic obstructive pulmonary disease (COPD), for which there is no cure due to the permanent lung damage caused by unhealthy air.

But COPD patients can manage their illness. Steroids, long-acting beta-agonists and long-acting reliever inhalers - first used in the 1960s to treat asthma - have long been considered effective drugs for reducing the breathing difficulties of COPD patients. They are so efficient that in the past 50 years there has been little need for new drug development, and innovation in the respiratory drugs space is therefore thin on the ground. Instead pharma companies are attempting to make drug usage more efficient by rolling all three types into one inhaler device. GSK was the first company to file its closed triple combination inhaler with the US Food and Drug Administration (FDA) in November 2016, but AstraZeneca and Novartis (CH:NOVN) have competitor products not far behind.

There is also competition afoot in the more innovative arm of the respiratory market: injectable drugs, which target the excessively high levels of white blood cells experienced by certain asthma and COPD patients. GSK also leads the way in this field with its Nucala product, which was approved in November.

But some disagree that the COPD market is well catered for. Jan-Anders Karlson, chief executive of small-cap respiratory company Verona Pharma (VRP), thinks respiratory drug developers have become lazy, and that a lack of innovation has come at a cost to patients. He argues that steroids are not terribly reliable COPD treatments and so merely using asthma inhalers for these patients is not good enough. Verona is aiming to launch the world's first non-steroid long-acting bronchodilator, RPL554. Fellow UK small-cap Mereo BioPharma (MPH) is taking a different approach. Its COPD drug, BCT-197, is an anti-inflammatory used to clear patient airways. Meanwhile Circassia (CIR) - the former allergy specialist recently reborn as a respiratory player - is helping to fund the late-stage US trials of AstraZeneca's novel lung muscle relaxant, Duaklir.

 

Triple combination therapies are a popular area of investment in European pharma

Company Drug Estimated filing 
GlaxoSmithKline (GSK)SymbicortSubmitted
AstraZeneca (AZN)PT0102019
Novartis (CH: NOVN)QAW0392019
Vectura (VEC)VR20762022
Circassia (CIR)'triple combination'2025

Source: Data compiled from company websites

 

One area of the respiratory illness arena where true innovation is firing on all cylinders is lung cancer. Of course, it must be noted, that lung cancer - the single biggest killer in the western world - is not exclusively a lifestyle illness. There are many people inflicted with the disease who have lived their whole life in rural England and never touched a cigarette. Then there are also cases of life-long smokers who are still going strong into their 90s.

But the facts are clear: smoking causes 84 per cent of deaths from lung cancer. When you inhale carcinogen-filled cigarette smoke, changes in the lung tissue begin almost immediately. At first the body may be able to repair this damage. But with each repeated exposure, normal cells that line the lungs are increasingly damaged. Over time, the damage causes cells to act abnormally and eventually cancer may develop.

Small-cell lung cancer - the more aggressive version of the illness - occurs almost exclusively in heavy smokers. It is more aggressive because it moves quickly through the body and, more often than not, the cancer has already spread to vital organs by the time it is discovered. The five-year survival rate is just 5 per cent.

But lung cancer research and drug development is accelerating remarkably quickly, largely thanks to increasing evidence that the body's own immune system can influence recovery. In October 2016, US pharma giant Merck (MRK) became the first company to launch an immunotherapy as the first choice treatment for non-small-cell lung cancer. The drug, Keytruda, works by alerting the immune system to the cancer's presence and stimulating it to launch a response.

But novel small-cell lung cancer treatments are still lacking, and it has been 17 years since the last new drug approval for this strain of the illness. Keytruda recently reported 35 per cent efficacy in an early-stage small-cell lung cancer population, and Bristol-Myers Squibb's (BMY) drug, Opdivo, achieved similar rates when used in combination with a traditional chemotherapy. Both of these drugs are still a long way from small-cell cancer approval, though.

The most promising developments in small-cell treatment are genetic therapies. IMMU-132 - being developed by a little-known US company, Immunomedics (US:IMMU) - is an antibody drug mixture, wherein the antibody binds to a protein and then stimulates the active part of the drug to launch an attack. More than half of patients in an early-stage trial recently responded well to the treatment. Meanwhile, PM1183 - another early-stage drug being developed by PharmaMar - used in combination with chemotherapy managed to stimulate a response from all the patients in an early-stage trial. Such a result had been previously unheard of in a small-cell lung cancer patient population.

But because of small-cell cancer's quick progression, improvements in diagnostics are arguably even more important in prolonging survival than finding a cure. A recent Cancer Research study reported that a simple blood test could detect the recurrence of lung cancer up to a year before symptoms are spotted. The test examines the genetic strains in the blood sample to predict the likelihood of the cancer returning. According to the study, a high level of genetic reshuffling indicates tumours that have the greatest chance of a comeback.

Aim-traded Oncimmune (ONC) is currently trialling a similar blood test on 12,000 smokers in Scotland. The group's EarlyCDT diagnostic kit also examines the DNA profile of a blood sample for early warning signs of cancer. Management thinks that the device can uncover cancer in a high-risk population up to four years before symptoms are revealed.

 

A weighty problem

Western life promotes obesity. Food is produced in vast quantities, processed for easier storage and sweetened to taste better. We work behind a desk, travel in a car and relax in front of the television. In fact, it is incredibly easy to consume more calories than we burn every day: the process that leads to weight gain.

Unfortunately our genetics make the problem far worse. Our ancestors adapted to sporadic food consumption and therefore stored energy very efficiently. As we share those genetic traits, we too are very good at extracting the energy from the food we eat and storing it as fat. Genetics is an incredibly complex area and it is increasingly thought to play a role in an individual's ability to gain and lose weight.

To understand this we need to rewind a few years to the human genome project. In the early 1970s when the project began, scientists assumed that the human genome would be far more complex than that of other species. So when early findings revealed that in fact we have a genome which is 50 per cent identical to that of a banana, scientists were astonished. How can we possibly be such a complex species if the humble banana shares half of our genetic code?

The answer lies in the second part of the genome, the non-coding DNA. Put simply, DNA - the building blocks that make up an individual's genetics - is either coding or non-coding. The coding part is the bit that is 50 per cent the same as a banana and it is our non-coding DNA that makes us such a complex species and gives us the power of speech, emotion and creativity.

Non-coding DNA can also be altered by lifestyle changes. If we are inactive or prone to consuming large quantities of cake, our non-coding DNA can alter to match that lifestyle. We then pass down that DNA to our children, which makes them more likely to share the same traits. But non-coding DNA can change indefinitely. An overweight person with overweight parents - although genetically more likely to struggle to lose weight - can turn off the weight carrying genes by increasing activity and eating healthily.

And today it is becoming easier to make such positive changes. Going to the gym can be cheap and easy, thanks to the availability of 24-hour gyms such as Gym Group (GYM) and Anytime Fitness. Fitness trackers such as the Fitbit (US:FIT) or Apple's (US:APPL) smart watch motivate people to take more steps every day. The price of sportswear is plummeting thanks to the likes of JD Sports (JD.), Sports Direct (SPD) and Amazon (US: AMZN). Meanwhile food producers including Ireland-based Kerry Group (KYGA) are reporting strong demand for their nutrition-focused ranges.

 

 

Drugs companies, on the other hand, are working on cures for the complications associated with obesity, such as high cholesterol - a problem almost exclusively caused by the build-up of excess fat. Cholesterol lines the walls of the body's blood vessels, making them narrower and causing high blood pressure. This puts undue strain on the heart, which leaves high-cholesterol patients at much higher risk of a heart attack.

That's why a doctor is likely to prescribe statins - which block the action of the chemical necessary for making cholesterol - for patients with high blood pressure. Statins have been the gold standard blood thinner for many years, but a new class of drug is currently a hot topic of research in big pharma. PCSK9 inhibitors target a different enzyme to traditional statins and it is thought these drugs could be more effective, not only in reducing cholesterol, but also in lowering the likelihood of a heart attack or stroke. PCSK9 inhibitor Repatha, made by Amgen (US:AMGN), and Praulent, created by Sanofi and Regeneron (US:REGN), are currently approved for lowering blood cholesterol and their owners are now performing follow-up trials to assess whether they are also effective in lowering the risk of a coronary event. If clinical trials are successful these PCSK9 inhibitors are likely to displace statins as the top choice drug for patients with high cholesterol.

An even more novel area of the market is reducing high cholesterol via changes to the human microbiome. The microbiome refers to the huge population of bacteria that live and thrive in the human body. Some of these bacteria help the body by breaking down ingested fibre for easier absorption, but in an unhealthy body can encourage the build-up of cholesterol.

Aim-traded OptiBiotix (OPTI) is on the cusp of launching its cholesterol-lowering food supplements, which use the power of the microbiome. Opti discovered a strain of bacteria found naturally in the human body that has the capacity to lower cholesterol and high blood pressure. The group is planning to launch its own range of food supplements, marketed as 'cholesterol lowering', in which this bacterial strain is a key ingredient.

 

Many global big pharma companies are testing whether their drug can reduce the risk of heart attack

Company Drug Type of DrugPhase of development 
Amgen (US: AMGN) RepathaCholesterol reducerPhase 3 follow up*
Sanofi (FR: SAN)/Regenron (US: REG) PraulentCholesterol reducerPhase 3 follow up*
AstraZeneca (AZN)BrilintaBlood thinnerLaunched
Novartis (CH: NOVN)EnestroHeart failure risk reducerLaunched
Bayer (US: BAY)FinerenoneHeart failure risk reducerFiled
*Already approved as a cholesterol lowerer

Source: Data compiled from company websites

 

An obese person is also at high risk of developing type 2 diabetes. Excess stomach fat reduces the efficiency of insulin - the enzyme used to break down the carbohydrates in food - and so, to compensate the body produces more insulin than it needs. But this causes damage to the cells required to produce insulin which, over time, begin to fail. When insulin is no longer being produced normally, a person has type 2 diabetes.

But this illness can be treated. Patients whose inability to produce insulin has become dangerous will have to inject themselves with insulin shots. Others are prescribed drugs that improve the sensitivity of the body tissues to insulin so that the insulin can be used more effectively. Metformin has long been the gold standard of this type of treatment, created by US giant Bristol-Myers Squibb.

But many scientists have argued that the safety profile for this type of drug is not good enough and ingesting them can cause further damage to the digestive system. Glucagon-like peptide-1 (GPL-1) drugs may provide the answer to this problem. These medications - which have a much stronger safety profile than metformin - work by slowing digestion, which helps lower blood sugar levels. GSK has a GPL-1 drug, Tanzeum, launched in the US in 2016, and Astra has two drugs in the final stages of development: daily treatment Byetta and weekly Bydureon.

But, like obesity itself, drugs are not the only answer to type 2 diabetes. Lifestyle changes have the potential to cure the disease. Michael Moseley, a scientist and BBC presenter, says: "I was diagnosed as a type 2 diabetic." But instead of taking the metformin prescribed "I decided to start a 5:2 diet". This diet involves eating normally five days a week and cutting the daily calorie intake to just 600 calories on the other two (the normal recommended daily calorie intake for an adult male is 2500 calories). This diet reversed Dr Moseley's diabetes. And he is not the only patient to have seen dramatic improvements: a study from Newcastle University found that losing 10 to 15 per cent of body fat can reverse type 2 diabetes in 84 per cent of recently diagnosed diabetics.

 

An allergic reaction

With summer fast approaching, many will be rolling out the barbecue and stocking up on Pimm's. Others, however, will be ensuring an adequate supply of Beconase and dreading the moment someone mentions the word picnic. It is estimated that 8 per cent of people in western societies suffer from hay fever - an allergic response to an airborne substance such as pollen.

It is unclear exactly when hay fever first started to affect humans, although scientists are fairly certain that our earliest ancestors did not suffer reactions from exposure to pollen or dust. Instead there is a growing body of evidence to suggest that inter-species breeding between the first homo sapiens and their burly neanderthal cousins may have left modern people more prone to allergies. There are three known genes that are present in neanderthals but not in early humans, which are thought to play a role in allergies. These genes heighten a person's immune system, which makes them more likely to react to non-threatening substances. An allergic reaction occurs when the immune system mistakes a harmless airborne substance as a threat and launches an immune response.

But, despite the large and growing population sizes, allergy is a largely underserved part of the pharmaceuticals market. Treatment options currently include antihistamines such as Claritin, steroids such as Beconase, or eye drops. But these are all over-the-counter medicines, used for alleviating symptoms, not tackling the underlying causes of the illness.

Immunotherapy, however, can provide long-term relief for many people suffering from allergies. It works by gradually de-sensitising the patient's immune system to the allergens that trigger symptoms. Immunotherapy can eventually lead to lasting remission from allergy symptoms and may even play a preventative role in the development of other allergies.

But while allergy immunotherapy is not a new concept (it was first discovered in 1911), it is not widely used for allergy sufferers. One of the problems is that it involves exposing a patient to allergens over a long period of time, which is both time-consuming and uncomfortable. Allergy Therapeutics (AGY) is attempting to revolutionise the immunotherapy market with the launch of its four-dose injection treatments and, eventually, its orally administered vaccines. The group expects results from its final-phase study into its Pollinex Quattro product for birch allergies in 2018. Launch soon after would make Allergy Therapeutics the first company globally to launch an aluminium-free, four-dose vaccination against any kind of allergy.

 

Over-dosed

Drug use - and abuse - is a growing problem worldwide. In Britain almost a third of people have taken illegal drugs, and the proportion of the nation who have ever taken drugs is increasing over time. Alcoholism is also rising and in the US it is estimated that 15 per cent of the population are 'problem drinkers'.

That said, according to a 2014 survey of UK drug use, we Brits do not consider ourselves addicted. Only a fifth of those who have ever taken drugs would do so continually and just 13 per cent consider themselves to have a problem. The US and much of Europe is a similar story, where drug use is rising but not to the level where it is becoming a massive problem in society.

At the individual level, however, repeated drug use can alter the way the brain functions. Taking a recreational drug causes a rush of the hormone dopamine into the brain, which triggers a feeling of pleasure. The brain remembers these feelings and wants them repeated. For an addict, changes in the brain alter a person's ability to think clearly and rationalise drug use and breaking out of the cycle can seem a mammoth task.

The market for drug addiction treatments is growing rapidly, particularly in the US, where recent legislative changes means many more doctors are now certified to treat drug addiction. Indivior (INDV) recently reported good sales growth for its opioid addiction treatment, Suboxone, due to the expansion of the market.

For alcoholics, liver damage is often a more pressing problem than addiction. More often than not, liver cancer is caused by the spread of cancer from other parts of the body. But, in the rare instances that cancer originates in the liver, excess alcohol consumption is often to blame. Kidney diseases, including cancers, can also be caused by alcoholism. With both of these illnesses claiming high population figures, most novel cancer treatments are being trialled in these organs. One of the most promising treatments is Hutchison China Meditech (HCM) and AstraZeneca's joint effort, Savolitinib, which has already been approved for use in non-small-cell lung cancer and has recently begun pivotal clinical trials in kidney cancer. Approval would make Savolitinib the first immunotherapy approved for cancer of the kidneys.