Have we found the cure yet?

Unfortunately, last summer the trial reported negative findings. Five years and several millions of pounds – not to mention the trauma for Tom and the other patients who endured two rounds of brain surgery – had resulted in enormous disappointment.

In complex illnesses such as Parkinson’s Disease the heartache of a failed clinical trial is not uncommon. But the potential rewards for success make those failures worthwhile.

For the research institutions and pharmaceutical companies, the discovery of a novel drug that has the potential to slow or reverse the symptoms of a currently incurable disease would result in enormous financial reward.

For healthcare services around the world, finding such a cure would alleviate the burden of healthcare costs. For patients and their families, the price of finding the cure is beyond measure.

Amid drugs pricing outrage, pressured healthcare systems and the rising prevalence of chronic diseases, the value of discovering a novel drug for an incurable illness has risen enormously. That’s why, over the past few years, the number of clinical trials undertaken by pharmaceutical companies has rocketed. In fact, in the first week of February alone a total of 83 clinical trials reported findings to the US Food and Drug Administration (FDA). Assuming that’s roughly the average rate, in the 75 weeks since our first instalment of ‘Finding the Cure’, 6,225 clinical trial have reported data. But have any of those trials taken us any closer to finding a cure for some of the world’s biggest killers?

Cancer: Leaps and bounds

In 2016 the FDA approved a drug called Keytruda as the first choice of treatment for certain lung cancer patients. It was a momentous occasion in the quest for a cure for cancer, as Keytruda is an immunotherapy (it uses the body’s own immune system to fight cancer) and the first of its kind to be selected as the preferred treatment for newly diagnosed cancer patients.

Until that point, first choice treatments had almost exclusively been chemotherapies – a toxic mix of drugs that are effective in killing cancer cells, thus helping to reduce tumour size. But chemotherapy is brutal and not entirely effective as it seeks to stop the cancer from getting worse, rather than making it better. Immunotherapy, on the other hand, can almost completely eradicate cancer cells. It works by alerting the body’s own natural defence mechanism to the presence of the cancer, encouraging it to launch an attack.

Keytruda - developed by US pharma giant Merck (US:MRK) - specifically targets a protein that appears on the surface of the cancer cells called PD-L1. This protein is cancer’s invisibility cloak: it can bind to a matching protein on the surface of immune cells that stops the immune system from recognising the cancer. Keytruda blocks that binding, allowing the immune system to recognise and destroy the cancer.

In a clinical trial for late-stage lung cancer patients Keytruda proved 40 per cent more effective than chemotherapy in reducing the risk of death. Such efficacy was previously unheard of in such a severely ill population.

But Merck has only tested Keytruda in patients whose cancer exhibits PD-L1 proteins and it is not approved for non-PD-L1 cancers. Its mechanism, therefore, flags up a major problem with immunotherapies: they do not work for all patients.

This was highlighted by fellow PD-L1 drug Opdivo, created by Bristol-Myers Squibb (US:BMS). Between 2014 and 2016 Opdivo attracted a lot of attention as it gained approval for melanoma, leukaemia, kidney and head and neck cancer patients previously treated with chemotherapy. But when BMS tried to get the drug approved as the first choice of treatment it failed its clinical trial. The reason was that BMS had not selected just PD-L1 patients as Merck had done, but trialled Opdivo in all patients. Its failure was a blow for the company and a valuable lesson in the quest for cancer cures: one size does not fit all.

Instead the future lies in combination treatments. Both cancers and immune cells display huge numbers of proteins that play a similar role to PD-L1. By pairing two or more drugs that target different proteins, scientists are hoping these treatments will work for more people.

At present, however, there’s little optimism that combination treatments currently undergoing clinical trials will work. Immediately after Opdivo’s failure, BMS decided to partner it with an older drug, Yervoy. But in January the company said that it had decided not to attempt to gain approval for the treatment via an accelerated regulatory pathway (often used for innovative drugs with good early data at clinical trial), suggesting that BMS has little confidence in the trial.

There has also been apparent uncertainty at AstraZeneca (AZN), which is trialling a similar combination therapy in a trial called MYSTIC. In October last year the group expanded its trial to test ‘overall survival’ of patients rather than just ‘progression free survival’. Doubters have queried why Astra would make a big change to a trial at such a late stage. The company’s recent share price movements suggest investors are not holding out much hope for the results when they are presented in mid-2017.

But there are those who remain convinced that combination therapy will work. Aim-traded group Hutchison China Meditech (HCM) specifically targets drug candidates that it knows will work well in conjunction with other drugs either already on the market or in development. For example, its lung cancer drug, Savolitinib, is currently being trialled with AstraZeneca's drug Tagrisso. Bernstein analyst Tim Anderson agrees that this is the way forward for cancer care and it is in combination therapies that pharma companies will make their real fortunes.

Alzheimer's: As elusive as ever

Alzheimer’s was first described by Dr Alois Alzheimer in 1906 when a patient experienced memory loss, paranoia and psychological changes accompanied by shrinkage in the nerve cells in their brain. It would be another 87 years before the first treatment for this debilitating disease became commercially available.

The reason for this time lag between discovery and treatment is that Alzheimer’s is a complex disease. Without any clear understanding of its causes, researchers were unable to find how to make patients better.

But more recently scientists have uncovered at least part of the answer to the Alzheimer’s mystery. It is thought to be caused by the abnormal activity of amyloid or tau proteins, which occur naturally in the brain but can build up and prevent normal cognitive function in Alzheimer’s patients. Dr Rosa Sancho, head of Alzheimer’s Research UK, thinks that there has also been a change in attitude and “less stigma that this is just something that [inevitably] happens to old people”. The result is that today Alzheimer’s disease attracts more funding and research than almost any other illness. And that research is no longer merely looking to alleviate symptoms – scientists are now trying to find a cure.

But there have been many disappointments. In November Eli Lilly's (US:LLY) amyloid-busting drug Solanezumab failed a high-profile clinical trial. Patients with mild Alzheimer’s who had tested the drug did not display any slowing in cognitive decline compared with those who had taken a placebo. Eli Lilly was not the first to suffer such a setback. Pfizer's (US:PFE) Bapineuzumab and Roche’s (SWI:ROG) Gantenerumab also failed to show any link between reducing amyloid plaques and slowing the progression of Alzheimer’s.

This list of disappointments has led some scientists to start doubting the amyloid theory. Amyloid deposits may merely be a trigger for other pathologies in the brain and become irrelevant once those mechanisms come into play. But Emer MacSweeney, chief executive of charity Re: Cognition Health, which funds clinical trials, remains “cautiously optimistic”. There are still a lot of amyloid studies in progress that could yet report positive results. Eli Lilly itself is trialling Solanezumab in even earlier-stage Alzheimer’s patients. It is also working in partnership with AstraZeneca to develop AZD3293, which acts by stopping the conversion of safe amyloid proteins into dangerous plaques. Axovant (US:AXON) also remains confident about its two amyloid drugs, the first of which is due to announce trial results this year. But the US group has suffered a massive share price decline since Lilly reported its failure.

And there may yet be hope for amyloid drugs that have already reported failures. Recent studies have revealed that Alzheimer’s disease can begin 20 years before symptoms present themselves and so taking drugs early is crucial to their success. In the same way that physicians prescribe high-risk heart disease patients with statins to reduce their cholesterol, an effective Alzheimer’s treatment could work by reducing the build-up of amyloid plaques in the brain.

But the complexity of the brain means that a single chemical or biological drug may never result in a cure for Alzheimer’s. Gerald Dunstan, principle in life sciences at Oliver Wyman consultants, thinks that a combination of drugs and lifestyle changes may be the answer. In 2015 the Finnish Geriatric Intervention Study (colloquially known as the Finger study) concluded that older adults who follow a healthy eating plan and undertake regular exercise and brain-training have enhanced memory performance over those who don’t. Adding a drug such as Solanezumab into a similar long-term lifestyle trial could result in success. Mr Dunstan thinks that pharmaceutical companies are coming around to the idea that Alzheimer’s treatment needs to examine the bigger picture rather than just one specific drug, but “now they need to get the regulators on board”.

Antibiotics: a reversal of fortunes

Since 1928 when Alexander Fleming discovered penicillin, humans have been able to cure infectious diseases caused by bacteria. But in August last year a 70-year-old woman from Nevada returned from a long stay in India with a swelling in her right hip. All 26 of the antibiotics available in America were given to try to fight the infection, but none were effective. She died in September.

Antibiotics resistance is not a surprise. When Fleming won the Nobel Prize for discovering penicillin he made a stark warning: “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug, make them resistant.”

For too long we ignored these warnings and used antibiotics inexpertly, as Fleming had feared. But now with an estimated 70 per cent of the world’s bacteria resistant to antibiotics, global governments have leapt into action. Last year the UN deemed antibiotics resistance one of the biggest threats to human life. In the UK, a report written by Lord Jim O’Neil called for more research into the discovery of new antibiotics and for heavier penalties for drugs companies not investing in fighting the superbug.

But big pharma remains uninspiring. Not since Eli Lilly discovered daptomycin in 1984 has the industry come up with a completely novel antibiotic. During that time, all but a few big pharma companies have shuttered their bacterial research units and in 2016 AstraZeneca became the latest company to pull out of anti-bacterial drug development when it sold its antibiotics business to Pfizer. GlaxoSmithKline (GSK)is one of the few big players that’s kept at it, sinking about $1bn into anti-bacterial research over the past decade, but to little avail. Progress at smaller companies has also been negligible. Motif Bio (MTFB) - which owns a novel antibiotic called iclaprim – has faced major funding difficulties, causing a delay in late-stage clinical trials. Redx Pharma (REDX) and Summit Therapeutics (SUMM)

have antibiotics in the early stage of development, but both companies also have other projects in more exciting areas of medicine: investment in antibiotics has rather taken a back seat.

Flying the flag for novel antibiotics development – at least in terms of UK public companies - is Eco Animal Health (EAH). The group’s Aivlosin product contains the antibiotic tylvalosin and treats respiratory and intestinal diseases in pigs and poultry. Demand is soaring for the drug because its low dosage rate and ability to move quickly through animals’ systems (before the meat enters the food chain) reduces fears about microbial resistance.

But for humans, the lack of new antibiotics that work against common bacteria is immensely worrying. Until pharma companies make a breakthrough, it’s up to doctors to prescribe antibiotics sensibly and patients to ensure they finish a full course of treatment.

Rare diseases: exciting progress

Accelerated regulatory pathways for orphan drugs mean that treatments for rare diseases can often gain approval faster than those for common illnesses. But in 2016 a speedy approval for a Duchenne muscular dystrophy (DMD) drug, Exondys 51, caused much controversy.

DMD is a rare disease that causes severe muscle wasting, mainly in young boys. Until recently, it has not only been incurable, but also untreatable. In September 2016, Dr Janet Woodcock, head of the FDA’s pharmaceuticals division, ordered the approval of Exondys, a drug made by Sarepta Therapeutics (US:SRPT), even though it had failed multiple clinical trials. The FDA had come under considerable pressure from a group of patients and their families to make the drug commercially available, as it had reported success in a small patient population.

At the approval hearing, there were more than 1,000 attendees and more than four hours of comments from patients, families, advocates, scientists and legislators. According to external FDA expert Aaron Kesselheim, who advised against the approval: “The public presentations were frequently emotional [but] the advisory committee was generally unimpressed with the efficacy data.”

Since then DMD has attracted a lot of attention. Other companies operating in the area have seen their share prices soar as investors speculate that they too will benefit from drug approval without the need for a positive clinical trial result. One of those is the UK’s Summit Therapeutics, which is now working in collaboration with Sarepta to bring its drug, Ezutromid, to market. Ezutromid not only has the potential to treat 100 per cent of DMD patients – Exondys only works for 13 per cent – but has the potential to rectify the underlying cause of DMD, an exciting development in the quest for a cure.