Small and emerging pharma and biotech companies are developing the lion’s share of new drug products being approved by the FDA. But these firms face a range of challenges, including more complex molecules, more specialized and precise target product profiles and accelerated clinical milestones, often tied to funding. They also often have unique hurdles on account of their size and scale.

What options are available to biopharma leaders to meet these often-intertwined challenges? We interviewed Christian Dowdeswell, vice president and head of commercial development for small molecules at Lonza, for insights on how contract development and manufacturing organizations (CDMOs) can help small and emerging biotech companies overcome challenges and continue developing drug products that help patients and save lives.

Contract Pharma: What are the most important challenges in the small molecule development space today?

Christian Dowdeswell: High potency remains a growth driver, with oncology being one of the therapeutic areas contributing to demand for highly potent API (HPAPI), along with antidiabetics and autoimmune therapies. These three therapy classes are the primary growth drivers globally for pharmaceutical, as well as HPAPI, consumption globally. Therapies for oncology in particular tend to target small patient populations initially, and we see many therapies being expanded into larger patient populations with related indications following the initial launch. This, coupled with extended progression-free survival, means longer periods of treatment for patients, requiring CDMOs that operate in this area to have a breadth of capabilities to ensure continued supply of product as demand fluctuates.

Another, somewhat related area is the continued prevalence of molecules with bioavailability challenges. An estimated 90% of clinical candidates have low, poor or inconsistent solubility and dissolution.
Dosing up is not always an option, which results in innovators looking to solution providers to equip them with enabling technologies to address poor solubility for increasingly complex molecules and target product profiles. Processing challenges can include contained particle engineering when working with HPAPI, and specialized processing parameters to accommodate higher dose loads or effectively address practically insoluble molecules.

Additionally, the average number of chemical steps used to manufacture an NCE is estimated to have doubled in the last 10 years. The complex nature of API is demanding not only for the formulator, but also for chemical synthesis. New classes of small molecules to address previously “undruggable” targets continue to emerge, which will drive complexity further still for drug substance synthesis and the development of viable dosage forms.

Complexity is not limited to the drug substance. It is also driving innovation in oral dosage form. For example, we are seeing inhalation formulation development across an ever-broader range of molecule classes from small molecules through to large proteins.

CP: What role are smaller and emerging companies playing in terms of developing innovative drug products?

Dowdeswell: The trend of innovation being driven by smaller companies is continuing, tied to the ongoing growth in specialty medicines. These medicines are driving industry growth, with a compound annual growth rate (CAGR) of over 10%. Small companies, which hold two-thirds of the early-stage pipeline, are increasingly filing their molecules rather than selling these assets to big pharma during clinical development. The number of approvals by the FDA for small firms was 62% in 2020, roughly doubling since 2011. Funding for biotechnology companies reached record levels in 2020, and this increased access to funds is believed to be one of the drivers for small and emerging companies to take products all the way to launch. The tendency to develop therapies for niche indications with small patient populations (~67% of FDA approvals in 2020) is undoubtedly a factor here as well.

CP: How do the needs of smaller biopharma firms differ from those of larger ones?

Dowdeswell: Small and emerging companies are typically very lean organizations, with a high focus on subject matter expertise, and business models heavily reliant on service providers. The lean organization enables companies to be very nimble and agile, it helps drive innovation and is a common attribute of many small biopharma companies. This means, however, that smaller companies have the challenge of managing service providers who have expertise and capability to support the mechanics of bringing a drug through the clinical process. In short, outsourcing behavior is frequently different. And, with an increasing number of drug programs on accelerated regulatory approval tracks, integrated services across drug substance and drug product may be considered to speed timelines as well as reduce the complexity of managing multiple vendors.

Large companies may use service providers for a specific need where they have insufficient capability, capacity or technology gaps. On the other hand, smaller companies may look to outsource “soup to nuts,” including everything from synthesis of an API from first principles, development of a dosage form, solubility enhancement, packaging and supply to clinical sites, along with CMC support and regulatory support. Often these companies look to their service providers to guide them through some of the nuances of the clinical process in a consultative capacity.

CP: How important is it for biopharma innovators to advance drug candidates to first in human trials quickly?

Dowdeswell: An increasing number of programs are on an enhanced timeline; it has almost become the new norm. There are multiple drivers here. First, successful phase I trials can impact funding for a particular molecule while failing quickly enables a company to focus on candidates more likely to succeed. On top of that, few indications have only one company working to find a therapy and being first to market brings benefits to an innovator and their investors. There is also a strong patient component, particularly where there is an unmet clinical need. The need to run quickly places further complexity on small and emerging companies that must manage outsourced partners, cost and program risk. These factors often lead these companies to look for integrated program solutions such as those offered by Lonza. 

CP: How should pharma and biotech companies approach accelerating candidate molecules from concept to clinic and to market?

Dowdeswell: There are a number of areas to explore here. Typically, small and emerging companies rely on their service providers to supply materials to clinic. Here the nature of the relationship with service providers is important, and a few questions help define it. What business model do the organizations employ? How quickly can services be accessed? How agile is their partner to respond to inevitable changes in the program?

Viable dosage form is often a consideration early on. Here there is a fine balance to be achieved in quickly getting through the clinical process versus time needed to develop a patient-viable dosage form. CDMOs and service providers should be able to offer services that support getting this balance right.

Speed to clinic and market is further exacerbated by the increased chemical complexity seen in many APIs being developed now. Shorter timelines through clinic mean less time to develop efficient chemical synthesis and a less well-defined manufacturing process for an increased number of chemical steps. The same is true for drug product, with nimble CDMOs able to balance phase-appropriate approaches with scalability and minimizing downstream reformulation requirements.

Sophisticated CDMOs may respond to these challenges with new ways of working with customers. Mindset is critical in dealing with small and emerging companies, whose limited number of molecules is their lifeblood. Each work plan must be tailored to a specific molecule, program and client need. 

CP: Can an integrated approach, holistically incorporating drug substance and drug product, help speed product development?

Dowdeswell: Undoubtedly, having a team from a single supplier working on a program removes any delay that would be related to commercial frameworks and competitive concerns versus using multiple CDMOs. Changes can be more simply planned for with a single provider than with multiple. The technical relationship between different aspects of a program can be more openly and easily addressed, be it a need to tweak the synthetic process to adapt to a new solid form, adapt an enhanced drug product intermediate to reflect the needs of a new dosage form (or vice versa) or compare different dosage forms through a single lens. So, the principles are well established that a single provider is advantageous.

However, what we hear from our customers is that this isn’t necessarily what they find in the marketplace and that assembling disconnected sites under a single banner doesn’t make for an integrated service. True integration of such sites into an efficient network requires much work “behind the scenes,” such as processing equipment, project management, quality management systems and ERP systems and data management. It’s a holistic effort that we continually focus on making a reality. Lonza ran over 50 programs in 2020 that utilized more than one of our sites and are leveraging that experience to make our offering stronger (watch this space). One of our key learnings is that there is not a one-size-fits-all solution. Some of our customers are extremely happy having a single point of contact that manages the interactions between different sites for them; others prefer to have that control themselves.

As an example, Lonza has a suite of solutions that cover First-in-Human clinical supply (SimpliFiH) of packaged drug product to clinic and encompassing phase appropriate options around synthesis of API, solid form services, bioavailability enhancement and drug product manufacture and supported by CMC and regulatory services. We knew that the launch of this service package was simply part of the journey and that it would be refined based on ongoing customer feedback. For example, we have recently upgraded our solid form services capabilities based on our continued evaluation of the needs of our small and emerging customer base which, consistent with the market, represent the vast majority of our First-in-Human programs. 

Our customers use some or all of these services, specific to their needs and using simplified commercial terms to ensure that we start work in a timely fashion and advance molecules to clinic—and beyond—as quickly as possible.