| NSF Org: |
TI Translational Impacts |
| Recipient: |
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| Initial Amendment Date: | April 2, 2015 |
| Latest Amendment Date: | August 23, 2015 |
| Award Number: | 1456396 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Henry Ahn
hahn@nsf.gov (703)292-7069 TI Translational Impacts TIP Directorate for Technology, Innovation, and Partnerships |
| Start Date: | April 15, 2015 |
| End Date: | September 30, 2017 (Estimated) |
| Total Intended Award Amount: | $750,000.00 |
| Total Awarded Amount to Date: | $885,508.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
4619 WOODLAND AVE PHILADELPHIA PA US 19143-3862 (215)689-1042 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
3624 Market Street, Suite 300 Philadelphia PA US 19104-2614 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | SBIR Phase II |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.084 |
ABSTRACT
The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is very significant. Current peptide-based drugs constitute important tools in human healthcare, and development of new peptide-based drugs represents a growing proportion of the pharmaceutical research effort. Current peptide drugs addressing widespread diseases such as type 2 diabetes (T2DM) and osteoporosis have sales above $1 billion. These drugs must be delivered by injection. This SBIR aims for new drugs with comparable heath benefits that can be taken in pill form, because the convenience of oral delivery, relative to injection, would rapidly capture most of the market. The high stability engendered by our design strategy should enable drug development for diseases that currently cannot be treated. Thus, the commercial potential of this project is high. Orally delivered replacements for injectable drugs would have a substantial broader impact because they would enhance patient compliance. Inadequate treatment of T2DM for example, leads to adverse health consequences that degrade productivity and quality of life for patients. Increased compliance resulting from a general ability to deliver peptide drugs in pill form would vastly improve outcomes for patients, including the specific patients populations targeted by our current programs.
The proposed project is motivated by fundamental questions about the way drug molecules are processed in the human body. Drug candidates cannot address a human disease unless they reach the appropriate sites within the body and then persist in those sites. The proposed research focuses on a particular class of bioactive compounds called "peptides." Peptides can act in powerful and favorable ways within the body, with high specificity of action (which minimizes "side effects"), but they are subject to very rapid destruction after administration. This weakness of peptides requires that they be injected regularly, but peptide drugs would be much more useful if they could be taken orally. This SBIR Phase I project examines unique peptide-like molecules that are designed to retain the favorable pharmaceutical action of peptides themselves but to resist degradation mechanisms within the body that rapidly destroy peptides. The stomach is the most destructive site for peptides, and this project aims to generate peptide-like molecules that are sufficiently robust to survive the stomach and reach the small intestine, where they can be absorbed. Achieving these molecular design goals would have high intellectual merit in addition to advancing drug design.
PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Executive Summary
The purpose of this project was to design a platform for optimizing peptide stability toward proteolytic degradation, to develop an in vitro screening tool that allows for prediction of in vivo oral bioavailability, to establish a comprehensive workflow for screening pharmaceutical excipients, and to identify formulations that are safe and promote the oral bioavailability of peptides. Our most recent results indicate the ability to achieve moderate oral bioavailability (~10%) when compared to subcutaneous delivery. There remains intrinsic variability in these results, which we continue to work to address; however, the infrastructure, workflow process and fundamentally unique peptide scaffold (Hybridtides) appear to allow for oral peptide delivery.
Longevity Biotech produces unique and proprietary synthetic peptides that are both structurally and metabolically stable within a variety of biological environments. Our peptides, called “Hybridtides," contain a blend of natural (α) and non-natural (β) amino acid residues. It is important to note that b-amino acids can mask recognition by proteases when positioned appropriately within a peptide structure. For this reason, Hybridtides can be designed to be highly resistant to various proteases, including the enzymes involved in gastric digestion (pepsin, chymotrypsin and trypsin) without sacrificing biological activity or requiring additional external ‘scaffolding’ that is typically found in macrocycle or ‘stapled’ peptide analogs. Hybridtides gained their name because they are a true hybrid between small molecules and traditional peptides and capture the best aspects of both therapeutic categories (potent, selective and stable).
In order to precisely determine the oral absorption rate of a given Hybridtide, we developed a comprehensive high throughput formulation-screening process. We have designed a new high throughput (HT), 96-well format, oral bioavailability-screening tool (similar to a traditional Ussing chamber) to enable rapid evaluation of a large number of formulation conditions simultaneously. Using this new HT Ussing chamber, we benchmarked apparent Permeability coefficients (Papps) for a variety of small molecule control compounds with fresh intestinal tissue. Using a proprietary process, workflow and the HT Ussing chamber, we were able to identify a variety of formulations that allowed for safe, non-toxic absorption of our Hybridtide peptide candidates.
In this field, there is an undercurrent of inconsistently in terms of experimental conditions. Importantly, for our purposes, manual tissue preparation between Ussing chambers does contribute to variability across experiments, expertise matters. Thankfully, we were able to identify and overcome these issues and using our custom HT Ussing chamber and were able to identify multiple unique and safe formulations that substantially enhanced Hybridtide permeability in vitro.
The best formulations were subsequently administered to rats via intraduodenal catheter (ID) and pharmacokinetic parameters were studied. The rodent subjects received candidate Hybridtides with their accompanying formulations and plasma concentrations were compared between ID and subcutaneous (SC) administration over time. The optimal formulation resulted in a plasma concentration that were approximately 10% of the matching SC dose; i.e. we achieved 10% bioavailability via oral dosing.
In summary, during the course of this project, Longevity Biotech developed an in vitro formulation screening process along with an in vivo validation paradigm for optimizing the oral delivery of our Hybridtides and other therapeutic biologic molecules.
Last Modified: 03/26/2019
Modified by: Scott Shandler
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