OPEN INNOVATION PLATFORM – Beyond the Rule of Five: Scouting for Novel Formulation Approaches to Enable the Subcutaneous Application of Molecules With Poor Drug-Like Properties in Preclinical Research – Facilitated Through opnMe.com
bRo5 (beyond Lipinski’s rule of 5) compounds, like PROTACs, offer novel opportunities for drug discovery to address difficult or previously undruggable targets. Nevertheless, these molecules often have poor drug-like properties, such as low permeability, low aqueous solubility, and are therefore difficult to access via oral administration. Other routes of administration have been explored in preclinical drug discovery to enable the evaluation of a molecule’s PK, efficacy, and safety profile without optimization of the compounds’ properties. The subcutaneous administration route is often chosen as an alternative. Even though the subcutaneous application route has immense potential in the preclinical context, there are only a few well-described formulation options or excipients available.
Based on the success of a recently completed open innovation challenge in drug delivery,1 we have decided to use Boehringer Ingelheim’s portal, opnMe.com, once again: We invite scientists from around the world to submit their innovative and even unconventional ideas to tackle this fundamental challenge.
We are looking for proposals that would provide innovative formulation approaches to facilitate the subcutaneous application of bRo5 molecules in a preclinical setting.2 As an incentive to submit proposals, we provide all selected applicants with access to an unprecedented selection of novel bRo5 compounds. Additionally, successful applicants will have the opportunity to directly interact with scientific experts to establish successful collaborations.
Here, we provide a short overview of the bRo5 compound class from a formulation developer’s perspective. Further, it will provide insights into the opnMe call and how we plan to incentivize innovative drug delivery solutions.
Developed in the 1990s, Lipinski’s rule of five (Ro5) was an attempt to rationalize compound design in preclinical research. The set of rules concerning a molecule’s physicochemical properties state that poor oral absorption or permeability are more likely when a molecule exhibits the following characteristics: >5 hydrogen bond donors, a molecular mass > 500, calculated logP is > 5, and a sum of nitrogen and oxygen atoms greater than ten.3 Today, there is an increasing focus on less druggable targets, such as the disruption of protein-protein interactions (PPI), that offer high potential for the development of new therapeutic agents and may require beyond rule of 5 (bRo5) chemical matter.4 In 2020, 31% of all approved NCEs failed to meet Lipinski’s criteria.5
There is great therapeutic potential in the bRo5 chemical space. PROtelolysis Targeting Chimeras (PROTACS) have attracted great attention both from academia and industry. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the non-enzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors.6 A challenge for preventing PROTACs from realizing their therapeutic potential is their lack of compliance to the Ro5. In vivo studies reported with PROTACs in peer-reviewed literature have typically been performed through parenteral delivery rather than oral administration.7
bRo5 compounds typically have poor physicochemical, drug metabolism, and pharmacokinetic properties, such as high lipophilicity, low solubility, low permeability, and high metabolic clearance. For these molecules, it is a challenge to achieve the desired exposure via the p.o. administration route.8 Other routes of administration have been explored in preclinical drug discovery to enable the evaluation of a molecule’s PK, efficacy, and safety profile. The subcutaneous administration route is often chosen as an alternative as it offers several advantages. Absorption upon subcutaneous administration is normally rapid because the subcutaneous space is richly proliferated with blood vessels. The area is easily accessible, and many sites of injections are available.9,10
The subcutaneous route is amenable to different formulation principles, e.g., suspension and solution formulations, minipumps, or extended-release formulations like PLGA-microparticles.11 The choice of formulation type can play a major role when evaluating the in vivo profile of a compound during drug discovery. Reaching a constant and/or maximum exposure is critical when assessing the pharmacokinetic, pharmacodynamic, and safety profile of a molecule. While subcutaneously applied suspension formulations typically yield an extended-release profile, solution formulations target high compound exposures. The subcutaneous delivery of bRo5 molecules comes with a set of challenges. Due to their lipophilic nature, the development of a solution formulation is difficult. For all preclinical in vivo models, there are tolerability constraints in terms of maximally tolerated amounts of excipients, like co-solvents or complexation agents.
opnMe PLATFORM TO INCENTIVIZE INNOVATION
The prospect of open innovation is to gather out-of-the-box ideas beyond existing networks. The Molecules for Collaboration program on opnMe.com offers the opportunity to initiate joint research projects. One successful example for a recently completed project was launched in October 2020. By the submission deadline on December 17, 2020, 73 scientists worldwide submitted proposals on novel strategies to tackle a major problem in pharmaceutical research, namely poor solubility. Eventually, 20 high-quality projects were selected to obtain access to our unique molecules.1
In our upcoming call, we are looking for suitable subcutaneous formulation approaches that could potentially enable the early phases of drug discovery for bRo5 molecules. We invite researchers and technology developers to submit proposals that would provide innovative formulation approaches for the subcutaneous administration route in a preclinical setting, to enable subcutaneous formulations of bRo5 molecules for preclinical PK, PD, and safety studies.
As an incentive to submit proposals, we provide all selected applicants with access to an unprecedented selection of novel bRo5 compounds, covering a diversity of structural classes (e.g., PROTAC) and potential therapeutic mechanisms. We expect that this collection will provide high value to test your formulation technologies with the most recent and innovative molecules. These structurally diverse molecules also come with additional internal data (Table 1) characterizing the molecules’ physicochemical properties, like lipophilicity (log P/D7.4) and solubility over a wide pH range. Additionally, all criteria are listed that assign a compound to the bRo5 chemical space (number of H-bond donors and acceptors, molecular weight). Each compound exhibits at least one violation to Ro5. Solubility in organic media is often a prerequisite for application of formulation technologies and therefore, is vital information to formulation developers.
All compounds were designed for recent, disease-relevant targets, some of which are highlighted in more detail below:
- ACBI1 causes degradation of the BAF chromatin remodeling complex proteins SMARCA2 and SMARCA4, as well to a lesser degree PBRM1. The compound is a PROTAC (proteolysis-targeting chimera) that induces degradation of its targets via inducing the formation of a triple complex of the target, the PROTAC, and the E3 ligase VHL, resulting in target ubiquitylation and proteasomal degradation.
- HCV NS3 protease is a 180-amino acid chymotrypsin-like serine protease. It is an essential component of HCV replication and infectivity. The NS3 protein contains two functional domains: a serine protease and a helicase domain. Both HCV compounds which are offered as part of this call bind to the active site of NS3 that is located in the shallow and broad protein-protein interaction surface of the protease and the helicase domain of the enzyme and are nanomolar to picomolar inhibitors of protease activity and of viral replication for various HCV genotypes and for resistant mutants D168V and R155K. Boehringer Ingelheim was the first company to establish proof-of-concept in humans for an HCV NS3 protease inhibitor as a treatment of HCV infection.
PROPOSAL SUBMISSION & TERMS FOR COLLABORATION
As part of this latest call for research proposals in the field of formulation research, we are open to all applications if they arrive by July 29, 2021, 11:59 PM PST. Our internal review process will commence in August 2021 and will be finalized until end of September 2021. The winners will then be notified, and collaboration work will commence in Q4 2021 or Q1 2022. Please refer to opnMe.com for more information, including detailed information on the call for proposals and the success criteria.2
As an incentive, selected project teams will be provided with suitable amounts of the molecules to facilitate their research and/or to validate your new proposed technology. We expect to provide quantities, which are typical for early drug discovery phases (up to 200 mg initially) of each drug substance completely free-of-charge. With the provided compounds, we aim to create a new way to help scientists validate their formulation approaches and to publish their data to advance scientific knowledge. Furthermore, we are transparent about the rights and obligations of the researchers who approach the portal to submit their innovative ideas, especially with regard to intellectual property, which will remain with the scientist.
Successful applicants will have the opportunity to directly interact with scientific experts and leaders in drug delivery at Boehringer Ingelheim to share information and to discuss additional guidance or resources needed to maximize the potential of the work. Additional support could include provision of additional molecules, in vitro and in vivo assessments, access to state-of-the-art analytical methods, as well as the possibility of site visits to the Boehringer Ingelheim facility in Biberach, Germany.
bRo5 compounds have a tremendous impact on the treatment of diseases with high unmet medical needs such as cancer. Thus, there has been increased interest in the discovery and development of bRo5 drugs in the pharmaceutical industry. Due to their poor physicochemical properties, such as low solubility and high lipophilicity and their poor permeability, the investigation of bRo5 chemical matter is fraught with risk and uncertainties.4
Already in the early stages of drug discovery, the successful formulation of bRo5 compounds for preclinical studies, such as PK, PD, and safety investigations, is challenging.
Boehringer Ingelheim’s opnMe.com platform incentivizes fundamental research and advances the translation of important new concepts into practical approaches. The current opnMe.com call for proposals is an opportunity for researchers in the field of formulation development to test their innovative ideas and approaches for subcutaneous drug formulation on a unique set of structurally diverse bRo5 structures from current research projects, e.g., a PROTAC.2 Additionally, we hope that this call will facilitate active collaboration and the pragmatic implementation of innovative drug delivery solutions.
The authors would like to express their sincere gratitude to Joachim Schäfer, Thomas Trieselmann, Marc Grundl, Florian Montel, and all others involved in supporting opnMe.com.
- K. Horspool, S. Chen, M. Koester, Incentivizing Drug Delivery Research Using an Open Sharing Platform, Drug Development & Delivery 21(3) (2021).
- How would you propose to formulate molecules with poor drug like properties for subcutaneous application in preclinical studies? https://bit.ly/2QvWPoe
- M.-Q. Zhang, B. Wilkinson, Drug discovery beyond the ‘rule-of-five’, Current Opinion in Biotechnology 18(6) (2007) 478-488.
- D.A. DeGoey, H.-J. Chen, P.B. Cox, M.D. Wendt, Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection, Journal of Medicinal Chemistry 61(7) (2018) 2636-2651.
- S. Pathania, P.K. Singh, Analyzing FDA-approved drugs for compliance of pharmacokinetic principles: should there be a critical screening parameter in drug designing protocols?, Expert Opinion on Drug Metabolism & Toxicology (2020) 1-4.
- X. Sun, H. Gao, Y. Yang, M. He, Y. Wu, Y. Song, Y. Tong, Y. Rao, PROTACs: great opportunities for academia and industry, Signal Transduction and Targeted Therapy 4(1) (2019) 64.
- S.D. Edmondson, B. Yang, C. Fallan, Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges, Bioorganic & Medicinal Chemistry Letters 29(13) (2019) 1555-1564.
- Bradley C. Doak, B. Over, F. Giordanetto, J. Kihlberg, Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates, Chemistry & Biology 21(9) (2014) 1115-1142.
- S. Neervannan, Preclinical formulations for discovery and toxicology: physicochemical challenges, Expert Opinion on Drug Metabolism & Toxicology 2(5) (2006) 715-731.
- P.C. Chiang, K. Nagapudi, P.W. Fan, J. Liu, Investigation of Drug Delivery in Rats via Subcutaneous Injection: Case Study of Pharmacokinetic Modeling of Suspension Formulations, Journal of Pharmaceutical Sciences 108(1) (2019) 109-119.
- P. Strack, Külzer, R., Sommer, F., Bretschneider, T., Merkel, O.M., Grube, A., A smart approach to enable preclinical studies in pharmaceutical industry: PLGA-based extended release formulation platform for subcutaneous applications, Drug Development and Industrial Pharmacy 46(4) (2020) 635-645.
Dr. Ines Truebenbach is a Head of Laboratory in the Drug Discovery Sciences (DDS) CMC group in Research at Boehringer Ingelheim. She is currently responsible for the delivery of high-quality and innovative formulations for preclinical PK and PD studies, which enable tailor-made exposure studies for various applications. Her areas of expertise include formulation development for new molecular entities (NMEs), like peptides, oligonucleotides, or bRo5 molecules (PROTACs). She joined Boehringer Ingelheim in 2019 after earning her PhD in Pharmaceutical Biotechnology.
Dr. Menorca Chaturvedi is a Senior Scientific and Digital Manager at Boehringer Ingelheim. She is currently responsible for the scientific alliance management activities for opnMe.com. opnMe collaborates with Boehringer Ingelheim scientists across different therapeutic areas and countries, to present innovative scientific challenges via the opn2EXPERTS and Molecules for Collaboration programs. Prior to joining Boehringer Ingelheim in 2021, she worked on different research and digital projects across academic and non-profit organizations.
Dr. Markus Koester is a Director of Discovery Research Coordination Germany at Boehringer Ingelheim. He leads the global digital communication and portal activity of Boehringer Ingelheim’s open innovation platform, opnMe.com. opnMe was launched in 2017 with a Molecules to Order initiative. It now offers 57 molecules to order and received more than 1,000 orders from 60 countries around the world. In addition, with its two collaboration programs, Boehringer Ingelheim has received more than 1,000 research proposals by now. Prior to joining the company, he worked for Merck KGaA and two biotech start-ups. Overall, he gained more than 20 years of pharma experience in roles ranging from R&D to commercial.
Dr. Achim Grube is a Director of Drug Discovery Sciences (DDS) at Boehringer Ingelheim and leads the DDS-CMC group. The core mission of the group is the physicochemical characterization, solid form finding, and preclinical formulation development and manufacturing of new chemical entities from the early research phase to start of development. He has worked at Boehringer Ingelheim for more than 10 years with experience managing analytical and product development, drug delivery, and preformulation. He has diverse experience with a broad range of delivery systems and various routes of delivery.
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