By: Mayuri Mutha, Senior Manager, CMC Development & Project Management
Joseph Sclafani PhD, Director, CMC Development & Project Management
Drug development is a complex, expensive, and multistage process which could take 10 to 15 years to bring a new molecule from discovery to commercialization. Drug repurposing, also known as drug repositioning paves an alternate path for drug development which involves identifying new therapeutic indications or uses for the existing molecules that could have been initially approved for or have clinically failed in a different indication. The success rate for new drugs to reach the market is approximately only 10% whereas about 30% of repurposed drugs get regulatory approval. With advancing data-driven techniques such as Artificial Intelligence (AI) and Machine Learning (ML), the elucidation of new uses for existing molecules is gaining more popularity.
Drug repurposing can be broadly categorized as on-target repurposing in which the pharmacological mechanism of action remains the same as the new and the original indication, and off-target where the pharmacological mechanism of action for the new indication is different from that of the initial indication. Historically, drug repurposing was more serendipitous work but over time, it has become more methodical. Identification may also be spurred by an unprecedented urgent medical need as exemplified by the repurposing of azidothymidine (AZT) for the AIDS epidemic in the 1980’s. More recently the Covid pandemic prompted researchers to revisit Remdesivir, originally shelved as a treatment for the Ebola Virus.
The systematic approaches for drug repurposing are continuously evolving and include but are not limited to:
- Target-centric repositioning is an on-target repurposing involving an indication extension or an adjacent indication within the same therapeutic area.
- Drug-centric repurposing is based on identifying new indications for a drug based on newly identified targets.
- Disease-centric repurposing focuses the on drug-disease relationship of closely related indications. One of the common examples of this approach is developing a combination therapy drug consisting of two or more existing molecules.
In the US, 505(b)(2) applications are popular for regulatory approvals of repurposed drugs already approved for a different indication. 505(b)(2) applications require fewer supporting studies as they rely both on literature and upon the Agency’s finding of safety and effectiveness for a previously approved drug product, resulting in shorter timelines and reduced cost of drug development. A New Drug Application (NDA) can be submitted for regulatory approval of repurposed drugs that are not previously approved once enough evidence of the drug’s safety and effectiveness is established (often in Phase 3 studies).
There are several advantages to repurposing, in addition to the shortened early development timeline. Repurposed commercial drugs also provide the advantage of having many patient years of reported safety data. If commercial, accessibility of cGMP API for proof of concept (POC) studies is much more possible in bulk in the open market, and may already be packaged in a suitable dosage form or strength for human trials. Repurposing also offers an opportunity for smaller companies and universities to address areas of unmet need, which may not be in the competitive space of larger pharmaceutical companies. These indications could fall under the category of Orphan Drug Status and if successful, would be eligible for extended patent protection. Although the IP lifetime could be abbreviated for repurposed drugs, it can provide time for companies to develop second-generation new molecular entities (NMEs) which have improved specificity and bioavailability. An example is Lenalidomide (Revlimid), a second-generation multiple myeloma therapy introduced after Thalidomide.
Nonetheless, drug repurposing carries significant challenges for universities and small companies. In the case of a repurposed shelved drug that formerly failed for its original indication, safety data may be outdated or insufficient for the proposed new indication. The drug development regulatory path is difficult to traverse for universities and startups who are unfamiliar with the preparation of documents for different regulatory agencies. Potential repurposed drugs still carry the stigma of shortened IP protection as the composition of matter patents may have already expired, despite many examples where second-use patents (method of use), have been successfully enforced, satisfied unmet patient need and provided a return on investment. Even though early development is accelerated, late-phase failure rates may be comparable to those observed with NMEs, when clinical data does not provide a clear advantage over current standard of care.
Securing funding for initial POC studies is also challenging for smaller entities seeking to repurpose drugs. However, government grants from the NIH and NCI can provide early funding to perform seminal POC studies, needed to justify later phase trials. In addition, nonprofit agencies such as Cures Within Reach work with universities to specifically provide funding for early studies incorporating repurposed drugs toward new indications.
Syner-G Biopharma has the expertise to aid in developing of repurposed drugs for novel indications. We can provide consultation services to navigate the complex regulatory pathway as well as advise on the development of novel formulations for existing drugs, used towards repurposing. Syner-G can help you identify the right CDMO/CRO and provide technical support for preformulation, preclinical and clinical formulation development of repurposed drugs. We also have extensive experience in medical writing and can help draft documents for regulatory submission to support the approval of repurposed drugs for novel indications.