New Therapeutic Modalities in Drug Discovery and Development: Insights & Opportunities

15-10-2020

Special issue guest edited by Mafred Kansy and Giulia Caron

NME_apporvals.jpg

Data Source: https://www.fda.gov/drugs/drug-approvals-and-databases/compilation-cder-new-molecular-entity-nme-drug-and-new-biologic-approvals; (Status 10/5/2020)

 

The study of the statistics of new drug registrations over time shows an interesting pattern. At the end of the last century productivity, measured in terms of market launches, was declining and charts as the one above have often been used to highlight potential productivity losses in pharmaceutical R&D [1,2]. This trend seems to have reversed in the last decade. Certainly, the number of launches alone is not a good measure of productivity and other, partly controversially discussed measures, have been applied [3-5].

What might be the reason for this potentially positive trend of increasing numbers of NMEs and Biologics approvals over the last 10 years? 

It is obvious that massive efforts in strategy adjustments, early ADMET optimization and the introduction of new assays, methods and computational techniques by pharmaceutical R & D and academia have had an effect. New disease relevant targets have been identified and potentially improvements in regulatory processes could have been beneficial. Moreover, the introduction of new therapeutic modalities, besides the so-called classical Rule of 5 (Ro5) [6] compliant molecules has had some impact.

Antibodies, antibody-drug conjugates, fusion proteins, neurotoxins, peptides, polymers, small interfering RNA, etc., are reaching the market. Furthermore, the introduction of the so-called "beyond rule of five compounds" (bRo5) indicates that even for some demanding targets larger compounds (MW >> 500) can be designed and optimized to have adequate ADMET characteristics and resulting bioavailability with desired in vivo effect.

Conformational flexibility has been identified as an important parameter to describe the “chameleonic” behavior of some bRo5 compounds, which seems to have an inherent potential to conformationally adjust to the surrounding environment. Intramolecular hydrogen bonds are analyzed to explain the characteristics of some new therapeutic modalities [7,8]. Recently, flexibility descriptors helped to improve computational solubility prediction of bRo5 compounds [9].

Certainly, small molecules still make up the majority of new market introductions, but this cannot be taken for granted in the future.

There is a need to discuss the findings from the discovery and development and analysis of new therapeutic modalities, including bRo5 compounds. Potentially those findings can be used to adjust strategies in Drug Discovery and Development (DDD) overall, from small to large size drug candidates and make Pharma R & D even more successful.

This special issue of ADMET and DMPK is guest-edited by Manfred Kansy, independent consultant, Germany - former F. Hoffmann-La Roche Ltd. employee, and Prof. Giulia Caron, University of Turin, Italy. It will address especially findings, strategies, tools applied in the discovery and development of new therapeutic modalities. The topics of the special issue include but are not limited to:

  • Statistical evaluation of new market introduction regarding ADMET, physicochemical properties, market potential etc.
  • Novel strategies for improving ADMET characteristics of drugs
  • New characterization methods applied in the “New Therapeutic Modality” research with a potential link to physicochemical interpretations
  • Computational methods developed or adapted to deal with new therapeutic modalities and bRo5 drug candidates
  • Case studies, learnings in the discovery and development of new therapeutic modalities and comparison to the so-called small molecule drug space

The special issue is planned for April 2021. The deadline for manuscript submission is March 01, 2021. During article submission please select “New Therapeutic Modalities” as a section.

References:

  1. Cockburn, I. M. (2006). Is the pharmaceutical industry in a productivity crisis? Innovation Policy and the Economy,7, 1–32.
  2. Schuhmacher, O. Grassmann, M. Hinder. Changing R&D models in research-based pharmaceutical companies. J. Transl Med. 2016; 14:105
  3. Pamolli, L. Magazzini, M. Riccaboni. The productivity crisis in pharma R &D. Nature Reviews in Drug Discovery 10, 428-438 (2011)
  4. Yevgeniy Feyman. Is Pharmaceutical Productivity in Decline. Maybe Not. Forbes. April 13, 2015. https://www.forbes.com/sites/theapothecary/2015/04/13/is-pharmaceutical-productivity-in-decline-maybe-not/
  5. Kristopher J. Hult. Economics, 2015. Incremental innovation and pharmaceutical productivity.
  6. Lipinski C, Lombardo F, Dominy B, Feeney P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997;23:3-25 
  7. Rossi Sebastiano, B. C. Doak, M. Backlund, V. Poongavanam, B. Over, G. Ermondi, G. Caron, P. Matsson, and J. Kihlberg. Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5. J. Med. Chem.2018, 61, 9, 4189–4202.
  8. Caron, G. Ermondi. Molecular descriptors for polarity: the need for going beyond polar surface area. Future Med. Chem. 2016, 8(17),2013-2016
  9. Avdeef, M. Kansy. “Flexible-Acceptor” General Solubility Equation for beyond Rule of 5 Drugs. Mol. Pharmaceutics 2020, 17, 10, 3930–3940