In April, Australian biotech AdAlta announced major improvements to the design of its preclinical i-body therapy for lung fibrosis, AD-114, significantly enhancing the drug’s potency and extending its half-life. Company CEO Sam Cobb has stated AdAlta's intentions to progress AD-214 into a Phase I clinical trial in the second half of 2019, and, accordingly, the Company will prioritize development of AD-214 and halt further expenditure on manufacturing the current AD-114 molecule.
Rare Disease Report
sat down with Cobb to discuss the impetus for the drug's redesign, and what it means for those in the idopathic pulmonary fibrosis (IPF) community.
What kind of research was conducted in the creation of AD-214, and what was the impetus for the development of the drug?
AD-214 is a new version of our existing i-body AD-114. Both have incredible specificity to the receptor CXCR4, which is expressed at increased levels in fibrosis.
AD-214 is an Fc-Fusion protein that contains two AD-114 i-body molecules at the front end and an Fc Fragment at the back end. Because AD-214 has the same binding front end as AD-114 – but now with 2 i-bodies instead of one, it binds to CXCR4 with improved potency. Increased potency is expected to result in less dosing being required for patients. As a fusion protein with the Fc-Fragment, AD-214 is also expected to have extended half life like existing Fc-Fusion products on the market – which range from 5 days to 25 days in humans. With the Fc binding domain at the back end, the new molecule AD-214 has an increased half-life, or time in the body. This is expected to result in significantly less dosing and, therefore, a more desirable and acceptable outcome for patients.
There are 11 Fc-Fusion drugs approved by the U.S. FDA (Food and Drug Administration), including abatacept (Orencia), developed by AdAlta Director Robert Peach; aflibercept (Eylea); and etanercept (Enbrel). There is a clear pathway forward for the development of an Fc-Fusion.
The impetus for the development of AD-214 was feedback from potential pharma and biotech partners that an improved half-life of AD-114 would make it a more commercially viable product. This, along with input from our SAB and Board, together with our existing data package, provided a strong scientific rationale to progress with AD-214.
At what point did AdAlta know that AD-214 was ready to be tested in a Phase 1?
The scientific data package was really the deciding factor for AdAlta to progress with AD-214. This included data in a number of models to confirm we had the same mechanism of action – that is that it was able to bind to CXCR4, but with higher potency.
What is the current standard of care for IPF? How is AD-214 expected to change that?
The current standard of care for IPF are the small molecule drugs perfinidone (Esbriet) and nintedanib (Ofev). Both drugs were approved for treatment of IPF in 2014. About 30% of patients respond to these drugs and they have significant side effects. With these 2 drugs, the average life expectancy from diagnosis is 3.8 years.
How strong is the existing data package for AD-214?
With increased potency and increased half life we believe we are providing a superior product for patients. We have been able to leverage all the work done to date on AD-114 in the development of AD-214. So AD-214 has broad anti-fibrotic and anti-inflammatory activity in several models of fibrosis including the lung, liver, kidney, eye and skin. In the lung we also have additional data with human IPF tissue demonstrating an advantage to pirfenidone, which didnt have any effect on IPF tissues, and nintedanib, which had the same effect on both IPF and normal tissue. Our drug only had effects on IPF diseased tissue and had no effect on normal tissue.
What is the anticipated timeline as the drug moves through the pipeline?
AD-214 will be progressed now through manufacturing over the next 9 months; our GLP toxicology study will be conducted in the first half of 2019, and AD-214 will be ready for Phase I studies in healthy volunteers in the second half of 2019.
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