Waterstone in-licenses cyclophilin inhibitor SCY-635 for hepatitis C

Waterstone (中美华世通生物医药) has signed a license agreement with Scynexis (NASDAQ: SCYX), obtaining worldwide rights to anti-HCV candidate SCY-635 on November 3. Scynexis will receive an upfront payment and certain milestones and royalties.

SCY-635 is a cyclophilin inhibitor which has completed a phase II trial in patients with hepatitis C. Compared to NS3/4A protease, NS5A and NS5B polymerase, cyclophilin A (CypA) is an anti-HCV target receiving little attention.

CypA also known as peptidylprolyl isomerase A (肽基脯氨基异构酶A), which catalyzes the cis-trans isomerization of peptide bonds at proline residues and facilitates protein folding. A well-known CypA inhibitor is cyclosporine A (CsA), which has been widely used in organ transplantation to prevent rejection.

CypA is also an important host protein involving in the viral life cycles. In 1994, scientists found that the interactions between CypA and HIV-1 Gag polyprotein are critical for HIV-1 replication in human cells[1]. Similarly to HIV-1, the replication of HCV depends on the expression of CypA. The interactions between CypA and HCV NS5B increase the affinity of the polymerase to the viral RNA[2].

Although CsA inhibits HCV in vitro, it isn’t an ideal candidate for hepatitis C due to the potent immunosuppressive properties. Several non-immunosuppressive derivatives of CsA such as NIM 811[3], Debio-025[4] and SCY-635[5] were identified later.

In T cells, the complex of CsA/CypA inhibits calcineurin which is responsible for activating the transcription of IL-2 (also known as T- cell growth factor). Small modification essentially blocks the recognition site of CsA/CypA by calcineurin and thus abolishes the immunosuppressive function associated with CsA.

Scynexis developed SCY-635 as an adjuvant therapy to restore sensitivity to PEG-interferon/RBV therapy in the phase II trial (NCT01265511). However, the novel all-oral, interferon-free, combination therapies have achieved SVR in more than 90% of patients with hepatitis C. Where is the market? Of course, Waterstone may investigate the use of SCY-635 in an all oral regimen. It seems to be late anyway.

[1] Nature. 1994, 372(6504), 359-362.

[2] J Biol Chem. 2009, 284(25), 16998-17005.

[3] Antimicrob Agents Chemother. 2006, 50(9), 2976-2882.

[4] Hepatology. 2006, 43(4), 761-770.

[5] Antimicrob Agents Chemother. 2010, 54(2), 660-672.

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