Community Research and Development Information Service - CORDIS

FP7

SADEL Report Summary

Project ID: 278042
Funded under: FP7-HEALTH
Country: Italy

Periodic Report Summary 3 - SADEL (Scaffolds for alternative delivery)

Project Context and Objectives:
The SADEL consortium, which stands for “Scaffolds for Alternative DELivery”, initiated a collaboration to develop oral-formulation of a Nanofitin®-based drug in Inflammatory Bowel Diseases (IBD). The two main phenotypes of IBD, Crohn’s Disease (CD) and Ulcerative Colitis (UC), are chronically relapsing intestinal inflammatory conditions with a typical onset in young adulthood and with an unpredictable disease course that may lead to debilitating complications. The clinically validated target chosen by the Consortium is TNFα, a cytokine considered a key regulator of immune cells and involved in systemic inflammation. The objective of the SADEL project is to advance existing Nanofitins® hits against TNFα towards the preparation of Phase I Clinical trials in UC.
Nanofitins® constitute a new class of non-antibody affinity ligands able to selectively bind a wide range of targets. As an addition to their antibody-like properties, Nanofitins® have a small size (optimal tissue penetration), pH resistance (favorable stomach passage), resistance to human intestinal fluids (long half-life in digestive track) and high affinity (low effective concentration needed). They also demonstrate strong potential for optimizing pharmacological properties, including reducing immunogenicity.
Consequently, the SADEL project is designed to address unmet technical challenges by making optimal use of the Nanofitins® protein scaffold. The Nanofitins®-based drugs will progress through routes not travelled by antibodies while interacting with targets not modulated by chemical compounds. They will be administered orally, reducing the systemic exposure and avoiding the safety issues reported with systemic administration of antibodies. This requires large quantities of proteins for frequent administration, which is compatible with Nanofitins® manufacturing in bacterial systems, broadly adopted in the industry with a low cost of goods.

Project Results:
Since the beginning of the project, the consortium has been driven by the goal of developing an oral formulation of an anti-TNFα Nanofitin for the treatment of Inflammatory Bowel Disease. From the nearly 30 anti-TNFα Nanofitin candidates involved in the project, 3 were identified as lead compounds based on their in vivo intrarectal efficacy in mouse models of colitis and biochemical characterization studies. The performance of these 3 leads were beyond the consortium’s expectancies, as they have reached a level of efficacy similar to the positive commercial control in the gold standard evaluation animal model, still on a non-optimized format. Further investigations allowed to demonstrate their efficacy as much in preventive as in curative setups, regardless of the mode of administration (Oral VS. Intrarectal). Taken together, these data have provided a first in vivo proof of concept of the oral efficacy of anti-TNFα Nanofitins for the treatment of IBD. Efforts within the consortium were then oriented so as to make anti-TNFα Nanofitin a commercially relevant product:
- A fairly elevated optimal dosage (100 mg/kg) of the lead Nanofitin, determined over a dose escalation study, was initially required to achieve high efficacy. A maturation effort provided a second generation lead with a similar efficacy at a 10 fold lower dosage, which fall into the acceptable dosage range for an oral drug.
- The manufacturing process was adapted to deliver GMP-like batches of untagged Nanofitins, while keeping a similar yield. Fine and systematic analytical investigation allowed the identification of one sensitive hotspot prone to heterogeneity in the sequence of Nanofitins, which was optimized accordingly.
- The mechanism of interaction (MoI) of the lead was elucidated and found to be different from the one of commercial antibodies which, beside the excitement of developing a highly innovative compound, could complicate the overall development potential of the molecule. In addition to a thorough characterization of the MoI of the current lead, the consortium allocated resources to find novel hits mimicking the mAbs MoI, which will streamline the regulatory pathway.

Potential Impact:
Globally, SADEL has made very significant progress in developing an orally available anti-TNF compound to treat Inflammatory Bowel Diseases. A significant amount of work is still to be carried out, the first hurdles have been successfully crossed in due time, outperforming the set milestones. The starting Fourth period will consist in consolidating the data obtained so far especially by modelling the mode of action of the Nanofitin leads and by mapping their safety profile. The resolution of the structure of the Nanofitin-TNFα complex should also bring significant insight. The final expected outcome is to compile the data obtained in the project, in preparation for an IMPD submission for a first-in-man clinical study after the project is terminated. After the 60 months allotted to SADEL, the clinical development of the lead compound has already been considered through an agreement with a European Industrial partner. It will ensure that a successful product will seamlessly progress along the drug development pathway, and will ultimately be available to patients, in particular in Europe. The consortium has indeed made a commitment to deliver, beyond excellent research, a first-in-class, patient-friendly treatment for Inflammatory Bowel Diseases.

List of Websites:
www.sadelproject.eu

Related information

Contact

Ilaria Bonetti, (European Project Manager)
Tel.: +39 02 85155364
Fax: +39 02 85155308
E-mail

Subjects

Life Sciences
Record Number: 189868 / Last updated on: 2016-10-13
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