According to global contract manufacturer Cambrex, however, the potential for the small molecule sector is at an all-time high. Dr Matthew Moorcroft, the company’s VP Global Marketing, discusses the research on which this contention is based.
The rise in biological drugs, a greater focus on niche and personalised treatments and the near extinction of the traditional blockbuster model have led some in the industry to suggest that the small molecule drugs sector is in decline. But, research done recently into active pharmaceutical ingredient (API) volume trends by Cambrex, one of the world's largest contract manufacturing organisations (CMO), shows that rumours of the demise of the small molecule have been greatly exaggerated; on the contrary, the company believes that the potential for the small molecule sector is at an all-time high.
A total of 45 new molecular entities (NMEs) — of which 33 were small molecules and 12 were biologics — were approved in the US during 2015, which is the highest number of approvals during the last 16 years (1999–2015). Furthermore, the current number of chemical molecules in every phase of drug development is greater now than at any time since 1999, says Dr Moorcroft (Figure 1).
Figure 1: Number of chemical molecules in development (1995–2015)
He attributes this to the versatility of small molecule drugs, which have been able to transition from global blockbusters to targeted therapies for cancer treatment or orphan indications. ‘Their surprising longevity comes from their unique and enviable ability to be formulated into pills and tablets,’ he states. ‘A few years ago, you’d have been forgiven for thinking that the rise of biologics and monoclonal antibodies a decade ago in oncology meant that small molecule use in this indication was over. In fact, it is far from that.’
‘The rise of new and pioneering drug classes such as protein kinase inhibitors has completely revitalised the existence of small molecule drugs in modern medicine. When compared with biologics, peptides and oligonucleotide-based medicines, small molecules will continue to be the backbone of the pharmaceutical industry in many therapies, driven by patient preference for oral dosing, lower manufacturing costs and ease of transportation,’ he adds.
A closer analysis of the NME approvals in 2015 showed that 21 out of the 45 were approved to treat orphan diseases — rare conditions that affect 200,000 or fewer Americans and for which there are typically few or no drugs available. It was also apparent that expedited review processes are being used more routinely: 27 NMEs were designated in one or more categories of Fast Track, Breakthrough, Priority Review and/or Accelerated Approval.
A third conclusion is that most launches take place in the US; 29 out of 45 of the new drugs were approved by the US FDA before receiving approval in any other country.
To get a more accurate picture of the trends in volume demand for APIs, Cambrex looked in detail at the 408 NCEs launched in the US market during the last 15 years. The figures are based on consumption data rather than on the more usual focus on top-line drug sales.
To create a representative sample, the company chose four sample sets split out by a period of 5 years; it then took the data across two consecutive years to smooth out any anomalies. ‘For example, a particular year might have had an unusually high number of cardiovascular drugs approved, all with high dosages and therefore with huge volumes of API usage associated with them, which might skew the data somewhat,’ Moorcroft explains.
‘When we combined both of these approaches, it gave us a set of 209 small molecules. This was around half the total and, we felt, gave us a healthy number of data points from which to spot any trends that may exist.’
Cambrex also decided to focus the research on NCEs only, without taking into account reformulations, ANDAs or line extensions. Furthermore, because most drugs are launched there first, figures from outside the US were not included. But if the five major European markets and Japan were added in, the resulting demand volumes would be approximately doubled, Moorcroft suggests.
Similarly, the demand from the more populous markets such as India and China was excluded because differences in disease prevalence/epidemiology can result in large uptakes of some products, distorting the results.
The study also took into account the fluctuations in volume demand across the entire lifecycle of the drugs. ‘Pharmaceuticals, like many other goods, follow the classic lifecycle pattern of introduction, growth, maturity and decline,’ Moorcroft explains: ‘But we wanted to just check whether these data showed us the same curves.’
Potential sources of error were also assessed, such as the effects of mature products and of those launched in 2014–2015 that have yet to reach peak volume. Cambrex zeroed in on 16 particular products that it believed would be the greatest source of error and repeated the analysis several times; however, the differences in the data were not significant and the company therefore felt this approach was robust enough to allow any potential trends to be observed.
Results and analysis
The results of the research indicated a number of clear trends that will shape the future strategy of CMOs in the small molecule sector and are already influencing Cambrex’s investment plans. Although the Cambrex study related only to the US market, the company says that these volumes could easily be doubled when demand in the five major EU markets and Japan are factored in.
The first major finding was a clear trend showing that the spread of volumes is narrowing and there is more clustering around the 1–10 metric tonne (mt) range compared with 15 years ago. For the US market, volume data forecasts for 2014–2015 NCEs correspond to a range centred around 10 kg to10 mt of API; by comparison, the range in 1999–2000 was broader at 1kg to 100mt. The data for 2014/15 showed that 12 out of 27 NCEs are expected to reach a peak volume of 1mt in the US. The number of NCEs with a peak volume of more than 100mt and less than 10kg is declining (Figure 2).
‘We believe an effect of this evolution has been a requirement for contract manufacturers to be flexible enough to be able to produce APIs in a range from kilogrammes to hundreds of metric tonnes to satisfy the wide variety of demand,’ says Moorcroft. ‘CMOs need to be monitoring demand and investing in the right capacity to satisfy customer needs as small molecules continue to evolve.’
Orphan focus
The trend towards a narrower range of peak volumes in small molecule APIs also correlated to the well-observed tendency to focus increasingly on orphan diseases; the consequent reduction in overall patient population sizes was the second major trend to emerge from the Cambrex research. ‘Orphan diseases have, by definition, a smaller patient population than traditional drugs,’ says Moorcroft. ‘That said, not all orphan drugs are low volumes; indeed, some are taken in high doses and consumed daily.’
The average patient population targeted in 1999–2000 was 13 million patients, but this had fallen by more than half to 6 million in 2014/15, the data showed (Figure 3).
Figure 3: Average patient population targeted per drug
‘In the period 1999–2000, a significant proportion of drugs were being used in indications with quite large patient populations, such as obesity, diabetes, conjunctivitis, GORD and hyperlipidaemia,’ Moorcroft explains. ‘Fifteen years later, there is a big change in the average patient population size as the drugs are being used for indications such as multiple myeloma, cystic fibrosis and thyroid cancer.’
Cambrex then went on to examine whether the reduction in patient population size was reflected in the therapeutic dose size; that is, whether the APIs were becoming more clinically potent. However, plotting the single patient consumption for each oral solid dose NCE per year revealed that no significant trend emerged during the data period.
The majority of drugs continued to be in the 1–100g per patient per year dosing range, although there was a slight increase in the number of lower dose NCEs below 1g per year. The data also showed little or no change in the size of tablet units. The most frequent size continues to be 10–50mg, although the popularity of the 50–250mg size range is showing a gradual increase.
The research findings considered only final API volumes, Moorcroft stresses, so when other steps in the value chain are taken into account, such as advanced intermediates, the overall volume requirement will be significantly higher, increasing the need for greater and larger-scale assets.
‘It is important for a world-class CMO to be able to offer a range of manufacturing options to cover the lifecycle of the drug on the market — from introduction to maturity — as well as the option to manufacture key late-stage intermediates and starting materials, should security of supply or regulation be a prerequisite,’ he says.
As a result of this, pharmaceutical companies typically aren’t best suited to handle the multiple-scales in manufacturing or dealing with the flexibility and changeover requirements for multiple products, and CMOs will continue to see more outsourcing opportunities as they are better placed to manufacture the coming pipeline of small molecule APIs.
