In 2018, major news included Abbvie’s Humira, a monoclonal antibody (mAb) approved for the treatment of arthritis and a range of diseases in the inflammation and immunology space, leading the pack of global highest-revenue drugs with sales of around $20 billion. In addition, innovative cell and gene therapies seem ready to revolutionize treatment for diseases from sickle-cell anemia to inherited genetic forms of blindness; the FDA expects to approve 10–20 cell and gene therapy products a year by 2025.
But scratch beneath the surface and you’ll see that biologics are not the only big players in the pharma space. Small molecules continue to play a significant role in the development of innovative treatments that benefit the lives of patients around the world. Specialty medicines are increasingly driving global pharma growth, especially in developed markets, with approximately half of specialty sales attributable to small molecule applications.
The continuing role of small molecules is also visible in recent approval trends and the current pipeline. In 2018, the FDA approved 59 new drugs, 71 percent of which were small molecules (29 percent were biologics). Specialty meds – which can be defined as high-cost, high-complexity medicines – are often associated with biologics and are highly visible in today’s pipeline, but small molecules represent an estimated 60 percent share versus large molecules. We are also seeing the impact of regulatory incentives with regards to orphan medicines specifically, with orphan designations playing an increasing role in both small and large molecule approvals, and accounting for more than half of US and European approvals in 2018.
Small molecules continue to play a role in innovative treatments for the four major indications that account for more than half of global pharma growth: oncology, diabetes, autoimmune, and respiratory diseases. For example, small molecule protein kinase inhibitors, of which the FDA has approved 48, are becoming more important in cancer therapy. Another area of growth entails the use of small and large molecules in combination; antibody drug conjugates (ADC), which couple potent small molecule payloads with the targeting capabilities of monoclonal antibodies, allowing for more precise treatment of cancer (and fewer side effects than standard chemotherapy).
The small molecule landscape is changing in terms of drug product complexity, molecule potency, manufacturing trends, and industry makeup. How the industry responds will shape the next chapter of small molecule drug development. Key trends include:
i) Small molecules and their applications are becoming increasingly complex. The majority of today’s pipeline consists of poorly soluble molecules that require enabling technology to advance to the clinic and beyond. Target product profiles for new drug products are also becoming more challenging, as therapies become more precise. Failing to reach acceptable bioavailability can be the limiting factor in advancing many new chemical entities.
ii) Demand for high-potency APIs is on the rise. Over a quarter of drug products in development contain highly potent APIs (HPAPIs), driven by improved targeting in treatments for cancer, diabetes, autoimmune diseases and other indications. For oncology drugs, the proportion with a HPAPI component is closer to three-quarters. These APIs are highly toxic and require specialized manufacturing and handling capabilities, which many smaller innovator firms may not want to build in-house.
iii) Small companies are driving innovation. The vast majority of small molecule drugs in development are held by small or “emerging” companies with fewer than 100 employees. Our analysis suggests that these companies account for approximately 4,400 candidate compounds – or 70 percent of the small-molecule pipeline. These companies are increasingly bringing successful compounds to commercial production, and typically require access to enabling technologies, development, and manufacturing partners to do so.
iv) The need for speed. Speed has always been important – but today it is more critical than ever because of the rise in specialty drugs, orphan and breakthrough designations, as well as increasing reliance on the FDA’s NDA 505(b)2 pathway. Since smaller companies can be reliant on one or only a few compounds, establishing a clear line of sight to clinical studies and commercialization is imperative. They often need access to phase-appropriate development services, infrastructure, and knowhow to accelerate time to first-in-human studies, through later-phase clinical studies, and for rapid scale-up.
v) One size does not fit all. Flexibility is increasingly important when aligning manufacturing services with more specialized and lower-volume drug products. Forecasts are more challenging for specialty products with finite patient populations, and flexible business models and assets are essential. Flexibility further extends across the drug development cycle where integrated development and commercialization can be of value to certain companies and/or drug programs. CDMOs that offer an end-to-end spectrum of flexible development and manufacturing capabilities, as well as complementary service options such as regulatory expertise and counsel, are natural partners for emerging innovator firms or specific innovator programs. For example, ADC programs supported through integrated payload, monoclonal antibody, and conjugation services can bring significant value to customers.
In short, small molecules are still a big deal – and will be for the foreseeable future. CDMOs with specialized technologies and expertise will continue to help pharma companies advance their compounds. The ability to tailor services to specific customers and drug programs will play an increasingly important role in accelerating patient access to innovative drugs.
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