Risk taking is complicated. In business, ebullient entrepreneurs are lauded for putting their livelihood on the line and taking risks, while serial gamblers who do the same are frowned upon. When it comes to drug discovery, the picture is more nuanced. It is an inherently risky endeavour, but society relies upon new drug discoveries and innovations.

Even so, investors, funding bodies and regulators are increasingly eschewing higher risk discovery projects in favour of lower risk projects. This is a problem because we need a lively and dynamic drug discovery sector if we are to have a hope of developing cures and treatments for the biggest human health challenges facing our society. One solution is building confidence through platform-based discovery, which increases the opportunity for investment as we have seen recently with major pharma looking at a wide range of platform technologies to in-license or acquire.

Neurodegeneration is one of the areas of biggest unmet health need, affecting up to a billion people worldwide according to the World Health Organization. For all the diseases that come under its auspices, there are no treatments that reverse disease, or even genuinely halt progression and hence, patient deterioration. At best, many of the market-‘leading’ medicines are only able to reduce symptoms or slow their advance.

The lesson we can learn from witnessing drug development in neurodegeneration over the last few decades is a simple one: if we want big solutions to complex problems, we need to think big and embrace both risk and complexity.

The holy grail for those of us working in this field revolves around the three Ns: neuroprotection, neuroplasticity and neurorepair. The latter two in particular have had little focus in terms of meaningful drug discovery. Neurorepair refers to the ability of nerve cells and neuronal tissue to regenerate; in essence this refers to the ability to reverse disease. Neuroplasticity refers to the brain’s requirement to change and rewire and is necessary for learning, adapting and creating new memories and abilities.

‘The bigger challenge is ensuring those funding research also recognise the need to embrace risk and complexity’

The development of breakthrough drugs that provide these three Ns is being hindered by inadequate economic incentive structures, system failures and a reduced appetite for risk. It is necessary to understand and accept the complexity of the problem, and therefore the likely complexity of potential solutions. This requires a degree of imaginative, contrarian thinking that those involved in drug discovery and development need to support and fund.

Early-stage biotechnology and drug discovery companies are reliant on a mix of grant, angel (especially high-net worths and family offices) and early-stage venture capital funding. There is a corporate ‘valley of death’ that generally lies after the drug discovery stage. It starts during the preclinical work and becomes acute around early-stage clinical trials, because many investors are only willing to invest in post-successful, early-stage human data. Pharmaceutical innovation is risky and there isn’t a way to sugarcoat it.

The UK government provides minimal assistance for early-stage companies – notably through R&D tax credits. While beneficial, the schemes and policies in place do not recognise the huge social value that biotech companies provide – without them there is no route to innovative treatments or the economic growth many of them could power.

The pension reforms that were announced last year were also very welcome, but the practical implementation is slow, understated and will not make much difference to the bottom line of many early-stage biotech companies for some time.

From an industry point of view, there are built-in incentives to repurpose existing drugs in favour of more predictable outcomes that can be accelerated to market. Programmes of development, while costly, look to find new ways to use existing assets with different modes of action. However, these repurposed drugs are often one-dimensional, single target and not capable of tackling more complex pathways.

They only provide marginal gains in most cases and big pharma tends to struggle to find sufficient financial incentives to develop them, so without a realignment of market dynamics, we are unlikely to see early-stage biotech companies thinking big and investing in designing more novel compounds.

From a regulatory perspective, the way clinical trials are conducted for neurodegenerative diseases needs a rethink. For patients with crippling pain and short life expectancies, it is unethical to require lengthy trials of 24-48 weeks when innovative diagnostic techniques like neurofilament light (NfL) analysis can indicate efficacy after just six weeks.

The regulatory process needs redesigning, particularly for those with rare diseases. The relatively small patient cohorts, combined with impractical trial requirements, mean many large pharmaceutical companies do not invest as much R&D into developing solutions in this area. There is recognition among regulators that this needs to happen; the bigger challenge is ensuring those funding research also recognise the need to embrace risk and complexity.

Drug development is expensive, so it is essential from an ethical and financial point of view that we test fast and fail fast. It is only by rapidly testing new compounds that we can learn more about the chemistry and biochemistry required to produce effective medicines. Investors are understandably concerned about backing high-risk companies, but especially so if they only have ‘one shot’ at success instead of several because of the cost of lengthy trials.

Fixing this issue is one way of helping to tilt the risk appetite in favour of innovation and getting the most potent drugs to market as quickly as possible.

There is a much wider ethical debate to be had in terms of our approach to drug development and the ethical implications of our investment and development choices.  Many neurodegenerative drugs are repurposed versions of existing drugs – these provide a smoother regulatory process and have more predictable outcomes because we understand more about the pathways that control cell function.

‘We need to embrace an entrepreneurial approach to drug discovery and the sensible motto: nothing ventured, nothing gained’

However, this leads to the production of drugs that only address the symptoms of a disease or seek to slow its progression. While these are obviously a positive step forward from the status quo, the scientific community has not developed compounds that demonstrate capacity to perform neurorepair or enhance neuroplasticity. This is because developing novel compounds that do this is a ‘moonshot’ objective – it’s undeniably tough but we have an ethical and scientific duty to try.

Patients with hugely debilitating diseases are being given drugs that extend life, instead of giving them a better quality of life. We need to reconsider what we are trying to achieve and what is desirable, and engage patients and as many different stakeholders as possible when making these decisions. This will provide us with the ‘guiding star’ to help the scientific and pharmaceutical community develop drugs that provide patients with the kinds of outcomes they want to see.

So, what does a preventative approach to neurodegeneration look like?

The development of compounds that indicate potential for increasing neurorepair and neuroplasticity. Doing this is difficult and risky, but the rewards are immense for patients, carers, health services, governments and industry.

We need a rethink in the way we approach clinical trials. We need to adjust the market incentives and dynamics that push life sciences companies down a well-trodden path so that some of them take new paths that may lead to game-changing discoveries instead.

To do these things, we need to embrace an entrepreneurial approach to drug discovery and the sensible motto: nothing ventured, nothing gained.

References are available on request.