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Integrin Antagonists

Vedolizumab and natalizumab, the leading biological drugs (antibodies) that are used to treat IBD, act principally on the a4- integrins; the former targets the integrin α4β7, whereas the latter targets both α4β1 and α4β7 integrins. However, natalizumab is associated with the emergence of progressive multifocal leukoencephalopathy (PML), and is therefore marketed with a black box warning and its use is severely limited. Vedolizumab does not have the PML risk, but it does not completely block T cell homing and has non-responder, and secondary loss of response issues. This suggests thatα4β1-dependent homing can be a compensatory mechanism to evade α4β7 blockade. Nevertheless, both α4β1 and α4β7 integrins are validated, high-value targets and continue to be investigated clinically with the risk of PML in mind. 

 

A newer α4β7-specific antibody, abrilumab (AMG181) has been shown to induce remission and mucosal healing in patients with moderate to severe UC without any incidence of PML. Two orally delivered, selective antagonists of α4β7 are in clinical trials: MORF-057, a small molecule from Morphic Therapeutics has completed a phase I trial; however, it does not inhibit integrin α4β1 and may have the same non-responder, and secondary loss of response issues as vedolizumab. Similarly, PN-943, a peptide from Protagonist Therapeutics is claimed to have better local gut exposure in phase I studies, but the compound is topical in nature and not designed to have systemic exposure. EncycleTherapeutics is developing a drug-like peptide macrocycle that is claimed to be orally available, however no published development has occurred in the past 4 years. Similarly, AJM300 (EA Pharma), an oral α4-inhibiting prodrug, is in clinical trials in UC patients. However, it has the same mechanism of action as natalizumab – it causes stem cell mobilization and lymphocytosis similar in magnitude to natalizumab – and may cause PML.

 

Aviara’s Integrin Antagonist Strategy

Integrin cell adhesion receptors are one of the best examples of long-range conformational changes that results in modulation of the receptors affinity for ligand [31]. Yet, there are no examples of drugs that specifically target these conformational changes. The innovativeness of Aviara’s integrin program is in our approach to target the high affinity conformation of α4-integrins, which recent data suggests may alleviate the risk of developing PML yet maintain efficacy in autoimmune and inflammatory diseases. This makes our approach unique.

 

AVA4746, which is the predecessor molecule to our current leads, is 400X more selective for the high affinity conformation of integrin α4β1 over its low affinity form; however, it has little activity towards α4β7. In animal models of inflammation as well as in a Phase 1 clinical trial, AVA4746 did not induce stem cell mobilization or significant lymphocytosis. Evidence from literature (e.g., vedolizumab) suggests that targeting α4β7 does not induce lymphocytosis. Thus, the lack of mobilization and lymphocytosis induced by AVA4746 does not appear to be due to lack of activity against α4β7. Taken together, this evidence suggests that AVA4746 (and by extension, this family of molecules) likely will not cause PML. Aviara’s newest drug molecules (e.g., AVA7367) target both the α4β7 integrin and the high affinity conformation of integrin α4β1, and are expected not to inducesignificant hematopoietic stem mobilization and lymphocytosis, thus ameliorating the risk of developing PML while still maintaining efficacy in IBDs. These orally available, once-daily, small molecule agents utilizing a dual mechanism of action would provide a distinct marketing advantage over Entyvio®.

 

Ultimately, if successful, our program would lead to a small molecule, once-a-day, oral version of the biologic therapeutic natalizumab that is not associated with the risk of developing PML. We recognize that this hypothesis cannot truly be tested until phase III clinical trials. However, if successful, it could be transformative in the care of IBD patients.

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