Nov­el he­pati­tis B virus nu­cle­o­cap­sid for­ma­tion in­hibitor CB-HBV-001 demon­strates ex­cel­lent an­ti-HBV ac­tiv­i­ty

Spon­sored — This post rec­om­mend­ed by Pharm­cube.

Al­though it’s pos­si­ble to pre­vent HBV in­fec­tion with the HBV vac­cine, the glob­al pop­u­la­tion of in­fect­ed pa­tients still ex­ceeds 250 mil­lion, with more than 60 mil­lion of those at risk for cir­rho­sis and liv­er can­cer. There­fore, vi­ral he­pati­tis B has be­come one of the sig­nif­i­cant threats fac­ing glob­al pub­lic health.

The cure for pa­tients in­fect­ed with he­pati­tis C virus has al­ready been achieved, but un­like HCV’s sin­gle strand­ed RNA struc­ture, HBV is a DNA virus that ex­ists in the nu­cle­us of cells, with a more sta­ble struc­ture and more com­plex func­tion. It is thus more dif­fi­cult to elim­i­nate. In the repli­ca­tion process of HBV, the vi­ral DNA en­ters the host’s cell nu­cle­us and forms a su­per­coil co­va­lent­ly closed cir­cu­lar DNA (cc­cD­NA) — the source for HBV prog­e­ny RNAs. The com­mon be­lief is that on­ly by re­mov­ing the HBV cc­cD­NA with­in the cell nu­cle­us can we erad­i­cate the vi­ral car­ri­er sta­tus of pa­tients. This was al­so the goal of an­ti-HBV ther­a­pies.

HBV cap­sid pro­tein (al­so known as core pro­tein) plays mul­ti­ple func­tions in the repli­ca­tion and sta­bil­i­ty of the virus. Through in­hibit­ing HBV vi­ral as­sem­bly, dis­as­sem­bly, and tran­scrip­tion, cap­sid in­hibitors in­ter­fere with the repli­ca­tion of the virus. That pre­vents new in­fec­tion in liv­er cells, re­duc­ing and even­tu­al­ly elim­i­nat­ing in­fect­ed cells, thus rais­ing cure rates.

Endpoint News

All of the news, delivered with full-text to your inbox. For professionals discovering, developing, and marketing biopharmaceutical drugs.

On No­vem­ber 9, 2018, at the an­nu­al meet­ing of the Amer­i­can As­so­ci­a­tion for the Study of Liv­er Dis­eases in San Fran­cis­co, Shang­hai Zhi­meng Bio­phar­ma Com­pa­ny show­cased an HBV nu­cle­o­cap­sid for­ma­tion in­hibitor with a nov­el chem­i­cal struc­ture, CB-HBV-001. The cur­rent HBV cap­sid pro­tein in­hibitors un­der de­vel­op­ment glob­al­ly can be di­vid­ed in­to two big groups ac­cord­ing to their chem­i­cal struc­ture: het­eroaryldihy­dropy­rim­i­dine (HAP, rep­re­sent­ed by clin­i­cal com­pounds from Roche and HEC Pharm) and sul­fon­amide (rep­re­sent­ed by John­son’s clin­i­cal com­pound). Mean­while, CB-HBV-001 is a pyra­zole with a nov­el struc­ture.

As Zhi­meng Bio­phar­ma’s da­ta show, com­pared to HAPs and sul­fon­amides, CB-HBV-001 pos­sess­es fa­vor­able an­ti-HBV ac­tiv­i­ty (EC50=12nM, test­ed in pri­ma­ry hu­man liv­er cells) and ex­cel­lent phar­ma­co­ki­net­ics and safe­ty pro­files (mice NOAEL: 800mg/kg/day, mice MTD >2000mg/kg). Fur­ther­more, CB-HBV-001 al­so demon­strates fa­vor­able an­tivi­ral ac­tiv­i­ty against virus­es that show re­sis­tance to nu­cle­o­side drugs in the clin­ic. When used in com­bi­na­tion with nu­cle­o­sides and in­ter­fer­on, CB-HBV-001 demon­strates fa­vor­able ad­di­tive ef­fect in in­hibit­ing both HBV DNA and HB­sAg, sug­gest­ing that CB-HBV-001 has po­ten­tial in over­com­ing re­sis­tance to nu­cle­o­sides and achiev­ing bet­ter ther­a­peu­tic ef­fect when used in com­bi­na­tion with ex­ist­ing HBV treat­ments.

Worth not­ing is that CB-HBV-001 demon­strates strong an­tivi­ral ac­tiv­i­ty against dif­fer­ent vari­ants car­ry­ing mu­ta­tions in HBV cap­sid pro­tein — in par­tic­u­lar the T33Q and I105F mu­ta­tions, which are re­sis­tant to both HAPs het­eroaryldihy­dropy­rim­idines and sul­fon­amides, the oth­er types of nu­cle­o­cap­sid in­hibitors.

Zhi­meng Bio­phar­ma is cur­rent­ly con­duct­ing pre-IND re­search on CB-HBV-001. It plans to sub­mit an IND in the sec­ond-half of 2019 and launch clin­i­cal stud­ies in ear­ly 2020.

An­ti-HBV drugs main­ly in­clude im­munomod­u­la­tors and nu­cle­o­side ana­logues. Com­mon im­munomod­u­la­tors in­clude in­ter­fer­ons (IFN); nu­cle­o­sides in­clude lamivu­dine, tel­bivu­dine, en­te­cavir and teno­fovir diso­prox­il. Al­though these drugs can ef­fec­tive­ly in­hib­it the repli­ca­tion of the virus, they have ob­vi­ous lim­i­ta­tions. For in­stance, among im­munomod­u­la­tors, long act­ing poly­eth­yl­ene gly­col-in­ter­fer­on-α are ef­fec­tive for on­ly 30% of hep B pa­tients, and its cure rate is around 7% to 8%. Its flaws are al­so pro­nounced: It re­quires in­jec­tions, is ex­pen­sive, and leads to side ef­fects like flu-like syn­drome and in­som­nia. On the oth­er hand, nu­cle­o­sides don’t pos­sess a mech­a­nism to erad­i­cate the virus, so once pa­tients stop tak­ing the drugs they re­lapse rapid­ly, but sus­tained dos­ing could lead to prob­lems like re­sis­tance.

Since cur­rent ther­a­peu­tic ap­proach­es are clear­ly in­ad­e­quate to ad­dress the clin­i­cal need for hep B ther­a­peu­tics, the re­search and de­vel­op­ment of new an­ti-HBV drugs have be­come a ma­jor re­search di­rec­tion for mul­ti­ple big phar­ma­ceu­ti­cal com­pa­nies. Nu­cle­o­cap­sid for­ma­tion in­hibitors, im­munomod­u­la­tors, siR­NA, and ther­a­peu­tic vac­cines have all be­come ways to ex­plore the goal of cur­ing hep B.

Dr. Huan­ming Chen, founder of Zhi­meng Bio­phar­ma, said: “Dis­cov­er­ing new tar­gets and de­vel­op­ing drugs with new mech­a­nisms of ac­tion are the pre­req­ui­sites of achiev­ing a cure for hep B. But it is very dif­fi­cult to erad­i­cate a virus with a monother­a­py. Com­bi­na­tion treat­ment is more wide­ly en­dorsed in the in­dus­try as a strat­e­gy in achiev­ing a hep B cure.”