Starting Early is Key to De-Risking Drug Development

The pharmaceutical industry is under tremendous pressure to make drug development faster and cheaper. “There is a need for better treatments that show real-world efficacy, but the price has to be acceptable to payers and at the same time offer good returns to the developing company,” says Will Downie, Catalent’s senior vice-president of Global Sales & Marketing. “However, R&D budgets are tight and failures are costly.” He further points out that the majority of molecules in the pipeline are increasingly complex, thus presenting development challenges. 

“There are a number of pitfalls in drug development that can stall, stop, or require you to rework your program,” observes Julien Meissonnier, vice-president of Science & Technology at Catalent. “More than 40% of new chemical entities in late-stage discovery are insoluble in water (1). Only one in 10 new molecules in active clinical development are readily bioavailable (2). The rate of attrition is high, with many drugs failing between first toxicity study and Phase I, and the likelihood of approval for Phase I candidates is 9.6% (3),” he says, highlighting the need for early formulation and dose form design. Downie explains that applying the right formulation strategy using structured and rigorous science can help avoid costly failures and re-starts, but it’s important to start from an early stage. The key, according to Meissonnier, is to select an appropriate formulation technology and dose form based on the needs of the molecule in development. 

Stephen Tindal, director of Science & Technology & Technical Support for Catalent’s OptiForm Solution Suite, US, notes that the transition from high throughput screening (HTS) to traditional formulation development requires a significant amount of expertise. “Early on, it is useful to be able to screen thousands of samples at very small scale, to narrow down the sample set to the best few. Whether that can be done effectively will of course depend on the API sample set in question, on the validity/variability of the analytical method, and the screening criteria that are applied, and the ability to manage the amount of data generated,” he says. “Done well, HTS can deliver a small set of ‘most viable’ samples for further evaluation using laboratory techniques at a higher scale, with better validity and less variability. Optimistically, it may even be possible to develop software that performs in-silico predictions to reduce the laboratory work further.”

Tindal observes that the screening criteria can vary from company to company. “At Catalent, during a first meeting with a customer, we see very few molecules for which sufficient data has been collected to make an informed decision on which formulation development technology to use,” he says. “Most companies pursue simpler formulation options, which are often appropriate only for drugs with good solubility. This is inconsistent given what we know about the prevalence of poorly soluble molecules in development pipelines.” According to Tindal, Catalent’s OptiForm Solution Suite platform helps address this issue. “We evaluate the API’s challenges and consider the technologies that are needed for improving the API profile. We consider salt form, conventional technologies (e.g., powder in capsule), and enabling technologies such as amorphous dispersion, lipid-based formulation, and micronization in parallel, depending on solubility and other data. This saves time and money, and gives a higher chance of success for the estimated 90% of drugs in development where solubility is a problem,” he says. 

In July 2017, Catalent announced the expansion of its OptiForm Solution Suite platform to include support at an earlier stage of drug development. The expanded service includes in silico and formulation screening tools to select the most viable candidate; molecule characterization to identify development challenges, parallel screening to determine the feasibility of multiple bioavailability-enhancing technologies; formulation development for good laboratory practice (GLP) toxicity studies; and a dosage form strategy and cGMP materials for Phase I studies (4). 

“To optimize early-stage development of oral doses, it is necessary to select the best few viable candidate API forms that have been identified during early R&D,” explains Ronak Savla, scientific affairs manager at Catalent. “A comparison of the APIs’ properties needs to be undertaken, and those with poor chemistry eliminated, before looking to achieve a reasonable level of oral bioavailability in animals to study drug metabolism and pharmacokinetic (DMPK) properties,” he says. “Where a drug is poorly soluble, there are opportunities to enhance its solubility. It is also necessary to characterize available polymorphic forms to select the most stable form. At this stage, doses are formulated as liquids rather than finished dose units.” 

Savla observes that early API characterization and solid-state optimization is typically undertaken by an API supplier and/or preformulation services supplier, and then transitioned to a contract development and manufacturing organization for formulation development activities. “But animal dosing of poorly soluble APIs poses unique challenges requiring a fast, flexible, and cost-effective service, so it’s our belief that companies with broad capabilities are better placed to do this work,” he says.

Reliance on formulation to solve suboptimal pharmacokinetics of Development Classification System (DCS) Class IIb lead compounds-where the main challenge is the solubility of molecules-has been shown to increase timelines by approximately two years (5). “Instead of pursuing a powder-in-capsule formulation for Phase I, screening for other potential options that maximize a molecule’s bioavailability and solubility profile should be investigated if delays in later development are to be avoided,” Tindal explains. 

Catalent’s OptiForm Solution Suite platform was used to assist in the formulation of a drug candidate developed by a London-based pharmaceutical company, Trio Medicines. “The compound, TML-001, had undergone initial clinical trials that indicated poor bioavailability,” Tindal says. “An acetylated prodrug was developed, and screening showed that it falls into the Biopharmaceutics Classification System (BCS) class IIa category, where the molecule’s dissolution rate was more of a problem than its solubility. Further tests suggested issues with permeability.” 

Catalent presented Trio with four alternative candidate formulations: a micronized form, a lipid-based formulation, and two amorphous dispersions created by hot-melt extrusion. “The most promising was the micronized API, which was simple to manufacture and showed good chemical and physical stability,” says Tindal. “The amorphous dispersions were ranked as the riskiest because they showed greater degradation, possibly as a result of thermal action during processing. In addition to being relatively difficult to process, a crossover study in healthy humans showed that the solid dispersions offered no improvement over the original formulation, and were, therefore, dismissed. In contrast, the other formulations demonstrated enhanced performance, marking a good starting point for further trials, which could be further adjusted to offer improvements to bioavailability later in development.”

“Catalent’s OptiForm Solution Suite has been designed to help drug developers start early and start smart. It provides a fast and efficient path from candidate selection to Phase I by selecting the right candidate, presented in the right API form, delivered in the right formulation and right dosage form,” Meissonnier sums up. 

References

1. K.T. Savjani, A.K. Gajjar, and J.K. Savjani, ISRN Pharm, online doi: 10.5402/2012/195727, Jul. 5, 2012. www.ncbi.nlm.nih.gov/pmc/articles/PMC3399483/
2. R. Lipp, Am. Pharm. Rev., 16 (3) 10–16 (2013).
3. D. Thomas, “Clinical Development Success Rates 2006–2015,” presentation at BIO International Convention (San Francisco, CA June 2016).
4. “Catalent Launches New OptiForm Solution Suite,” Press Release, July 17, 2017.  
5. M.M. Hann and G.M. Keseru, Nat. Rev. Drug Discov., 11, 355-65 (2012).

Article DetailsPharmaceutical Technology
Vol. 41, No. 10
Page: 24

Citation
When referring to this article, please cite it as A. Siew, “Starting Early is Key to De-Risking Drug Development,” sidebar to “Formulation Strategies in Early-Stage Drug Development," Pharmaceutical Technology 41 (10) 24 (2017).