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Fetro. Rare Dis Orphan Drugs J 2023;2:7 https://dx.doi.org/10.20517/rdodj.2023.06 Page 9 of 16

guarantee of successful achievement.

IP has expired
In this case, the drug is off-patent or generic and widely available at a low price. Propranolol is an example
of a successful academia-industry DR collaboration in this category leading to a new treatment for patients
[Figure 2].

Propranolol, a non-selective beta-blocker patented in 1962, was granted FDA approval in 1967 as an
antihypertensive drug. When the Léauté-Labrèze team from the Bordeaux University Hospital showed its
antiangiogenic therapeutic properties in 11 cases of infantile hemangioma (IH) in 2008, it was available as a
generic . 4.5% of birth have infantile hemangioma. Most infantile hemangiomas resolve spontaneously, but
[30]
[31]
12% are complex and severe forms with functional and even life-threatening complications, such as
breathing difficulties and requiring systemic treatment. Following this serendipitous discovery by the Léauté
-Labrèze team, Pierre Fabre Dermatologie Laboratories and the University of Bordeaux formed a
partnership in 2008 to co-develop and launch Hemangiol® in Europe and Hemangeol® (a different brand
name for the same oral formulation) in the United States in 2014 for the treatment of proliferating infantile
hemangioma requiring systemic therapy. For information, the brand name Hemangiol® was changed into
Hemangeol® in the United States in accordance with FDA’s best practices in developing proprietary names
[32]
guidance, according to which “io” is used as an infix to suggest a high iodine content . In terms of
organization and assignment of tasks, resources, and operational skills, the company took charge of the
regulatory dossier, including the development of a pediatric formulation and a pivotal study performed on
460 babies between five weeks and five months of age at treatment initiation. The objective of the study was
to select the right dosage and confirm the efficacy and tolerance of propranolol in infants with proliferating
IH requiring systemic therapy. The clinicians of Bordeaux University Hospital were involved in the study
design and management as well as the drafting and publication of the manuscript .
[33]
Pharmaceutical companies may be reluctant to initiate collaborations with academia to repurpose off-patent
drugs. Once drugs lose patent protection, generics can be allowed for sale, leading to off-label use and
commercial risks. As it was possible to dissolve commercially available propranolol tablets or to use a non-
approved preparation of liquid propranolol made up by the hospital pharmacy, off-label use was a big
[34]
challenge with risks of inappropriate dose and use of excipients non-recommended for infants, since the
therapy was adapted from adult dosage to pediatric populations without an appropriate formulation for
young children. However, different actions may be put in place to protect companies.

Patents are the first step. For propranolol in IH, new patents were granted to academia (second medical use
patent in 2008) and industry partners (formulation patent in 2010), offering protection for 20 years until
2028 and 2030, respectively.

In addition to patent protection, regulatory agencies are offering incentives for the development of orphan
and pediatric drugs for rare diseases, such as Pediatric-Use Marketing Authorization (PUMA) in Europe
and Orphan Drug Designation (ODD) in the United States.

Thanks to PUMA, drugs can benefit from ten years of market protection, including 8 years of data
[35]
exclusivity plus an additional two years of market exclusivity .

An Orphan Drug Designation is a status delivered by the FDA in the United States or the EMA in Europe to
medicines developed for rare diseases; it may be requested by sponsors for a previously unapproved drug or