EXECUTIVE INTERVIEW - Lonza Small Molecules: Facing Up to the Challenges of Drug Development

In recent years, there has been a significant growth in the proportion of the pharmaceutical development pipeline that originated in small and emerging companies. These businesses rarely have their own capabilities for scale-up and manufacture, and adding to the challenges they face is the increasing likelihood they will retain the assets in-house until the later stages of clinical development. CDMOs such as Lonza are therefore key partners for emerging companies in the pharma-biotech sector as they look to progress their promising molecules through the development pipeline and on to the market. As an integrated CDMO, Lonza is also well placed to assist in overcoming a wide range of issues that might arise, from complexity to capacity. Drug Development & Delivery recently interviewed Jan Vertommen, Lonza’s Head of Commercial Development (Small Molecules), to discuss some of the challenges facing the sector and how his company is looking to address them.

Q: It’s no secret CDMOs working in the pharma/biotech sector are facing multiple challenges, whether from the molecules they are asked to make or the wider business environment. Let’s start with the molecules. What’s getting harder?

A: It all boils down to increasing complexity, in all of its forms. With so many of the “easy wins” having already being met in terms of therapeutic targets, pharma and biotech companies are increasingly working on targets that are more difficult to address, if not previously thought undruggable. As a result, the molecules now entering their development pipelines are more likely to be difficult to make, difficult to formulate, or both.

The difficult-to-make aspect might be that the molecule itself is complicated; it might also mean the synthetic route to make it is long-winded. On the formulation side, in recent years, the molecules heading into the clinic have become increasingly likely to be insoluble, with knock-on effects on their bioavailability. All of these challenges can usually be overcome, but it takes expertise – and experience.

Q: What are you doing to try and address these complexities?

A: One way Lonza Small Molecules is trying to address the difficult-to-make problem is by applying artificial intelligence (AI) to find shorter, more efficient synthetic routes. The lab-scale routes used to make drugs entering the pipeline are getting ever longer, but the more steps a synthesis has, the more likely it is to have a low overall yield, and take longer to complete, not to mention generate more waste. Our new Route Scouting offering combines our in-house database of reactions, reagents, and raw materials with AI tools that suggest potential synthetic routes, and these can be tested in an automated system. It provides a great support for our process chemists as it is able to evaluate and check a route far more quickly than they could do on their own.

The likelihood of a molecule being deemed highly potent is also increasing, not least because of the continuing interest in antibody drug conjugate (ADC) molecules that combine a targeting antibody with a highly potent API. These require very careful handling, and the right equipment must be in place to ensure both plant operators and the wider environment are effectively protected from these drugs, as they have pharmacological effects in extremely small doses. The ongoing growth in this market means we have made strategic investments in capabilities and capacity to ensure we can keep up with demand.

We’ve also made significant investments in our solid form services. The right tactic varies from one molecule to the next, clearly, but it may involve finding a more stable crystal form. To tackle the solubility challenge, spray drying to create an amorphous form often comes into the picture.

Q: Away from the nuts and bolts of manufacturing, the Covid-19 pandemic caused significant disruption to our lives and businesses, and the world is still recovering from its impacts. How is it continuing to affect pharma?

A: One notable way is the decline in biotech funding that we’ve seen over the past couple of years. Funding – rightly – spiked very significantly in 2020 and 2021, as the world searched for drugs to treat and vaccines to prevent Covid-19 infections. Venture capital investments, financing rounds, and IPOs hit record levels in 2021 as a result.

However, since these huge peaks, funding availability has now declined once more, returning far closer to the levels we saw before Covid-19 turned our lives upside down. And, as a result, small and emerging biotech businesses are feeling the squeeze. Significant funding is only likely to be available if a company has an exceptionally promising pipeline, backed up by a sound business model and an experienced, proven management team.

Unsurprisingly, this has led to companies being far more careful in their spending decisions. Companies are becoming far more selective in their progression decisions as they look to ensure only the most likely to succeed are pushed forward.

Equally unsurprisingly, this is having a knock-on effect on the CDMO world. Existing customers, we have found, are starting fewer new projects, although we have seen an increase in new customers committing their business to us.

Q: What sort of impact is this having on project timelines?

A: It is clear companies are now more likely to delay the start of a manufacturing campaign rather than risk resources being wasted on a project that might not progress after all. In the past, in the interests of speed, they might press on with the next part of a manufacturing campaign after a positive signal was seen in a trial. This financial risk might be avoided by waiting until the trial’s full results are available, albeit with the knock-on risk the timeline might be pushed back as a result. It’s a real balancing act.

There is another knock-on effect for CDMOs here, too – capacity availability is currently significantly better than it has been in recent years because fewer projects are competing for it. Biotechs may believe they don’t need to rush to tie down capacity well in advance, believing that it’s likely to be available when they actually need it. It remains to be seen how capacity availability will trend in the coming years. It all goes back to the availability of funding, and if that spikes upward again, there will likely be an uptick in demand for manufacturing capacity.