Page 61 - Read Online

Page 8 of 15 Zanello et al. Rare Dis Orphan Drugs J 2023;2:9 https://dx.doi.org/10.20517/rdodj.2023.04

Generation of additional knowledge is often needed and should not be underestimated
There is a common misbelief that repurposing does not require the extensive generation of new knowledge
because there is a huge amount of data that can be re-used from past investigations, clinical studies, and
post-authorization generated data.

Not repeating the issue exposed in “Learning lessons from failures and building on past findings”, where the
information might exist but the investigator has no access to it, we shall consider two distinct situations: on-
target (where the pathophysiological mechanism is known) and off-target (where the mechanism is being
discovered) repurposing approaches. The latter offers fewer opportunities to re-use previously generated
findings.

Without distinguishing one or the other situations, the interviewees have reported that they had to perform
one or more of the following steps: toxicology testing (especially if the new indication is for the pediatric
population while the initial one was in adults); non-clinical pharmacology testing (i.e., use of animal
models); in vivo non-clinical proof of concept; development of new clinical endpoints and outcome
measures, e.g., Patient Relevant Outcomes Measures, Patient Reported Outcomes, and Health-Related
Quality of Life Studies.

The conduct of non-clinical research studies and clinical trials is often cited as one of the main challenges.
In any case, the generation of additional knowledge is a step that should be factored into the development
plan and should not be underestimated.

Repurposing is not always an easy journey, it is a true therapeutic development
To follow on from the previous item, the respondents said that being able to conduct an abbreviated
program in the case of a repurposing approach is not granted. In many cases, it was not possible. It is not
exceptional to have to do a Phase 1 trial and even develop an animal model.

The development of a new formulation is also often cited. A new formulation is required when reaching a
new population (e.g., pediatric versus adult or targeting a specific organ), when a different dosage is needed
or when a novel route of administration is explored.

On top of that, repurposing approaches encompass the need for GMP supply and pharmacovigilance
follow-up (compared to compounded formulations, for example), which makes it a complete cycle and
significantly increases the costs and complexity of the development estimated at first glance.

Hence a repurposing approach should not be underestimated. It is not necessarily always going to be faster
than any other type of therapeutic development, and while the length can be reduced due to a certain
number of factors (e.g., patient involvement, rigorous planning, extrapolation of data), this is not a given.
This finding has been reported by several interviewees.

Defining industrial property strategies require strong expertise and knowledge
IP strategies must be established at the time of the discovery-based first on the patentability of the
repurposed drug in its new application and then eventually on the “freedom-to-operate” analysis. The
patentability analysis aims at looking into state of the art, meaning any published documents related to the
invention including active, abandoned and expired patents besides the scientific literature. Once the
patentability of the discovery is established, the path to developing the repurposed drug remains a fine line.
Unlike the on-target approach where the pathophysiological mechanism is known, the off-target approach