Is Ireland missing out on blockbuster drug discovery?

For decades now, successive governments have courted big pharma and encouraged them to set up in Ireland and manufacture their drugs. This has created industry jobs for scientists, but there has been no appetite to encourage drug discovery – a risky business that demands huge investment at an early stage.

The IDA, which is responsible for the attraction and development of foreign direct investment, has attracted most of the big pharma names and ensured a steady stream of the specialised science and medical graduates they require even as their needs changed.

Interestingly, Ireland is the world's leader in the manufacture of so-called biologic drugs. These are hard to make – far harder than making an aspirin tablet, for example – as they are complex and designed to biologically inhibit the parts of our immune system that can turn against us and cause diseases such as rheumatoid arthritis. The biologics are cash cows for the drug industry, with the global market set to reach an estimated $272 billion (€240 billion) in 2017.

Ireland is, thus, known around the world for the quality of its scientists and ability to make difficult drugs. Yet there must be a question mark over why that kind of scientific talent has not been encouraged to enter into the really valuable field of drug discovery.

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This is a strategic mistake, according to experts such as Luke O'Neill, professor of biochemistry at TCD and founder of Opsona Therapeutics in 2004 and Inflazome in 2016. The aim of Inflazome is to develop new drugs for arthritis, type 2 diabetes, Alzheimer's and Parkinson's.

You have to fund research here because you never know: we might crack it

“Blue skies research is essential,” says O’Neill. “That is where the biggest value is. Ireland has to be participate in this because we could have a guy or a woman who will make the big breakthrough. You have to fund research here because you never know: we might crack it.”

A discovery leading to a new drug could be worth $1 billion or more to the Irish economy. But O’Neill says this won’t happen by funding research that simply changes a nuance here or there.

Lab work

Since at least the 1980s, the crucial initial work that led to the production of new drugs has almost always been done in a university laboratory, first through the identification of drug targets that might alleviate disease. This has been followed by enormous investment by big pharma to get the drug through rigorous clinical trials and onto the market.

A case in point are TNF-inhibiting drugs, which were developed to combat rheumatoid arthritis. In 1986, in work funded by the UK Arthritis Foundation, professors Ravinder Maini and Marc Feldman found that TNF (tumour necrosing factor) was sloshing around in large quantities inside the rheumatoid knee. TNF is a protein made by the body's immune system during infection.

The pharma industry noted their research and funded work to block or inhibit TNF. This led to the manufacture of a drug called Remicade, which cures rheumatoid arthritis in 50 per cent of patients. Remicade acts by slowing down the erosion of joints and the crippling twisting of fingers. The drug is shared by Johnson & Johnson and Merck, and its annual sales value in the US along hovers around $5 billion. It is one of the most valuable drugs of all time, and is now also used to treat Crohn's disease.

No surprise, given the success of Remicade, that there are now six anti-TNF drugs available on prescription, including one called Humira, which is manufactured in Sligo for Abbvie. The firm earns about $6 billion a year on the drug. So all of this value in monetary and human terms come from one discovery.

Taxpayer exposure

Most would agree that the huge risks involved with funding drug discovery, where a multimillion investment can evaporate following adverse results in a clinical trial, is not something that Irish taxpayer should be exposed to. But there is a solid argument for government creating an atmosphere that encourages more private investment in discovery work.

Breakthroughs in Ireland would help offset the huge expense of new drugs such as Orkambi for cystic fibrosis. This is not likely to be a once-off; we are going to see more Orkambi situations as big pharma produces drugs that cure diseases but are hugely expensive.

Another example is the drug sofosbuvir, produced by Gilead against hepatitis C. Many women in Ireland contracted hep C from receiving anti-D during pregnancy in the 1970s and 1980s.

Without treatment, the women became chronically sick, got liver cancer, and died. There was no treatment, but Gilead came up with a vaccine that has a 98 per cent cure rate but costs €45,000-€55,000 per patient.

It is clear why the pharma firms want to develop blockbuster drugs that can bring billions of dollars

The price is justified not only morally but economically, as a person with hep C requires a lot of healthcare resources, while a liver transplant operation costs about €1 million.

It is clear why the pharma firms want to develop blockbuster drugs that can bring billions of dollars in sales revenue around the world. What is less clear is why some of them at least want to invest significantly in so-called “orphan drugs” – ones that benefit only small group of patients.

One such orphan disease is Muckle-Wells syndrome, an extremely rare genetic condition that causes the eyes, skin, joints, kidney and liver to become inflamed. About 15 years ago it was found that a gene called NLRP3 is defective in people with this condition.

In 2015 a group of scientists including Prof O’Neill found a drug, MCC950, that could block the damaged gene.

Drug companies are interested in developing MCC950 because the gene is also defective in common conditions such as arthritis. For those with the condition, the drug works but it costs about €200,000 a year.

This example of how a drug is developed for orphan diseases is highly relevant as we move towards a personalised model of medicine, where future drugs might be designed for 1,000 patients, or less.

Scientists understand that the body’s immune system is complex and different for each individual, and finding a broken cog in a system of perhaps 10,000 parts could lead to new drugs in the future.

If Ireland is to finally move into the drug discovery arena, its resident talent must be funded to do the work. This has happened up to now, says O’Neill, as the focus has been on funding applied medical research, which can provide secure, but far less valuable, returns for patients and investors.

“It is like you have a football team and you are investing in the forwards and expecting the other team’s midfield to pass to you,” he says. “If all we invest in is forwards, we’ll never score a goal and that is why we need to invest in basic medical research.”

Clinical trials

The recent upside of medical research in recent years is the increasing number of clinical trials taking place for patients with a range of conditions. For example, under the UCD Clinical Research Centre umbrella there are trials under way led by Prof Glen Doherty into IBD; Prof Fionnuala McAuliffe investigating the role of the microbiome in the health of pregnant women; and Prof Peter Kelly, who is running a trial on stroke.

“The UCD CRC is impacting patient’s lives and helping to transform the Irish healthcare landscape, by ensuring that novel treatments are developed and diffused into routine clinical practice,” says the centre’s director, Dr Peter Doran.

"We have created an environment that is supportive of investigators, recognised by regulators and attractive to patients, an environment which has seen a huge increase in the volume and impact of clinical research being conducted at our partner hospitals – the Mater, St Vincent's and [the National Maternity Hospital at] Holles Street."

Clinical trials advocates – ‘I had no hesitation in taking part’

Fionnuala McAuliffe is professor of obstetrics and gynaecology at the National Maternity Hospital Dublin:
Clinical trials help answer questions that healthcare professionals are not sure of. Which drug is best? Which investigation is best? Do healthy eating and exercise in pregnancy actually reduce pregnancy weight gain, reduce diabetes and normalise the size of the baby at birth?

At the National Maternity Hospital, and in the maternity services in general, women are very open to consider participation in clinical trials as they understand that the intervention and results may well improve the outcome for them and their babies, and for future mothers and infants.

Grace (30), from Northern Ireland, has Crohn's disease. She was teaching in London when she became ill and had to have live-saving surgery. She nearly died and after her surgery moved back to Ireland. She took part in a clinical trial run by Prof Glen Doherty at St Vincent's, and said that it has changed her life and given her new hope for the future:
I don't know whether I was given the medication, or not, as in the trial we are not told, but I certainly felt better after it, and had more good days than bad. I have a rare and severe form of Crohn's, which means I can't work, and I can't socialise so I didn't think too much before saying yes when my consultant suggested that I sign up for a clinical trial in Dublin.

Alex Hosford ( 70), from Cork, was brought to Cork University hospital in August 2015 with a severe case of septicaemia. It was found that the infection had spread to the bone in his shoulder. He later found out the infection was due to multiple myeloma:
I suffer from neuropathy because of the chemotherapy treatment and I was unable to walk for a time because of this. It's something I must live with for the rest of my life, but I have been recovering at a steady pace. I regained a lot of my strength and can walk again.

When I entered the care of Prof Mary Cahill [consultant haematologist ], she suggested the possibility of a trial. Both myself and my family had no hesitation in my taking part – we've always had a very positive experience and outlook on medical trials.

There were two reasons really. I knew I would get the inside track in terms of attention, with access to the best doctors and treatment. Then there was the other part of me that knew that, on the long course of events, I was going to help someone, somewhere down the road, by taking part in the trial.