I wrote last year about macrocyclic compounds and their potential as drugs. Now BioCentury has a review of the companies working in this area, and there are more of them than I thought. Ensemble and Aileron are two that come to mind (if you count “stapled peptides” as macrocycles, and I think they should). But there are also Bicycle, Encycle, Lanthio, Oncodesign, Pepscan, PeptiDream, Polyphor, Protagonist, and Tranzyme (update – now merged with Ocera). These companies have a lot of different approaches. Many of them (but not all) are using cyclic peptides, but there are different ways of linking these, different sorts of amino acids you can use in them, and so on. And the non-peptidic approaches have an even wider variety. So I’ve no doubt that there’s room in this area for all these companies – but I also have no doubt that not all these approaches are going to work equally well. And we’re just barely getting to the outer fringes of sorting that out:
While much of the excitement over macrocycles is due to their potential to disrupt intracellular protein-protein interactions, every currently disclosed lead program in the space targets an extracellular protein. This reality reflects the challenge of developing a potent and cell-penetrant macrocyclic compound.
Tranzyme and Polyphor are the only companies with macrocyclic compounds in the clinic. Polyphor’s lead compound is POL6326, a conformationally constrained peptide that antagonizes CXC chemokine receptor 4 (CXCR4; NPY3R). It is in Phase II testing to treat multiple myeloma (MM) using autologous transplantation of hematopoietic stem cells.
Tranzyme’s lead compound is TZP-102, an orally administered ghrelin receptor agonist in Phase IIb testing to treat diabetic gastroparesis.
Two weeks ago, Aileron announced it hopes to start clinical development of its lead internally developed program in 2013. The compound, ALRN-5281, targets the growth hormone-releasing hormone (GHRH) receptor.
Early days, then. It’s understandable that the first attempts in this area will come via extracellular-acting, iv-administered agents – those are the lowest bars to clear for a new technology. But if this area is going to live up to its potential, it’ll have to go much further along than that. We’re going to have to learn a lot more about cellular permeability, which is a very large side effect (a “positive externality”, as the economists say) of pushing the frontiers back like this: you figure these things out because you have to.