Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

He­pati­tis delta, al­so known as he­pati­tis D, is a liv­er in­fec­tion caused by the he­pati­tis delta virus (HDV) that re­sults in the most se­vere form of hu­man vi­ral he­pati­tis for which there is no ap­proved ther­a­py.

HDV is a sin­gle-strand­ed, cir­cu­lar RNA virus that re­quires the en­ve­lope pro­tein (HB­sAg) of the he­pati­tis B virus (HBV) for its own as­sem­bly. As a re­sult, he­pati­tis delta virus (HDV) in­fec­tion oc­curs on­ly as a co-in­fec­tion in in­di­vid­u­als in­fect­ed with HBV. How­ev­er, HDV/HBV co-in­fec­tions lead to more se­ri­ous liv­er dis­ease than HBV in­fec­tion alone. HDV is as­so­ci­at­ed with faster pro­gres­sion to liv­er fi­bro­sis (pro­gress­ing to cir­rho­sis in about 80% of in­di­vid­u­als in 5-10 years), in­creased risk of liv­er can­cer, and ear­ly de­com­pen­sat­ed cir­rho­sis and liv­er fail­ure.

HDV is the most se­vere form of vi­ral he­pati­tis with no ap­proved treat­ment.

Ap­proved nu­cle­os(t)ide treat­ments for HBV on­ly sup­press HBV DNA, do not ap­pre­cia­bly im­pact HB­sAg and have no im­pact on HDV. In­ves­ti­ga­tion­al agents in de­vel­op­ment for HBV tar­get mul­ti­ple new mech­a­nisms. As­pi­ra­tions are high, but a func­tion­al cure for HBV has not been achieved nor is one an­tic­i­pat­ed in the forsee­able fu­ture. With­out clear­ance of HB­sAg, an­ti-HBV in­ves­ti­ga­tion­al treat­ments are not ex­pect­ed to im­pact the dead­ly course of HDV in­fec­tion any­time soon.

HDV is a large and grow­ing Or­phan Dis­ease in the west­ern world.

World­wide, an es­ti­mat­ed 15-20 mil­lion peo­ple are in­fect­ed with HDV, ap­prox­i­mate­ly 6% of the HBV-in­fect­ed pop­u­la­tion. HDV is his­tor­i­cal­ly most preva­lent in the Mid­dle East, Asia, and Africa. How­ev­er, mi­gra­tion from re­gions of high preva­lence in the last decade has in­creased HDV preva­lence in the West­ern world, be­com­ing a large health­care con­cern with in­fect­ed in­di­vid­u­als es­ti­mates of ~100,000 in the U.S. and ~200,000 in West­ern Eu­rope. There is no vac­cine for HDV, and once a pa­tient is in­fect­ed with HBV, the he­pati­tis B vac­cine will not pre­vent in­fec­tion with HDV. Ther­a­pies are ur­gent­ly need­ed.

HDV has be­come a tar­get for drug de­vel­op­ers, lead­ing to po­ten­tial ther­a­pies to at­tack the silent killer.

Eiger Bio­Phar­ma­ceu­ti­cals is a late-stage bio­phar­ma­ceu­ti­cal com­pa­ny fo­cused on the de­vel­op­ment and com­mer­cial­iza­tion of treat­ments for se­ri­ous rare and ul­tra-rare dis­eases and is lead­ing the charge in the de­vel­op­ment of treat­ments for HDV.

Eiger is tar­get­ing HDV in­fec­tion with two FDA Break­through Ther­a­py Des­ig­na­tion pro­grams: Lon­a­farnib and Pegin­ter­fer­on lamb­da (Lamb­da).

Lon­a­farnib is the on­ly oral agent in de­vel­op­ment for the treat­ment of HDV.

Lon­a­farnib is a well-char­ac­ter­ized, first-in-class, oral­ly ac­tive in­hibitor of far­ne­syl trans­ferase, an en­zyme which at­tach­es a lipid chain to pro­teins through a host process called preny­la­tion. HDV us­es this host cell process in­side liv­er cells to com­plete a key step in its life cy­cle. Lon­a­farnib in­hibits the preny­la­tion step of HDV repli­ca­tion in­side liv­er cells and blocks a crit­i­cal step in the virus life cy­cle. Lon­a­farnib is cur­rent­ly in Phase 3 for the treat­ment of HDV with a sin­gle, piv­otal, in­ter­na­tion­al tri­al called D-LIVR. The D-LIVR study (n=400, an­tic­i­pat­ed en­roll­ment) is on­go­ing, ac­ti­vat­ing sites and en­rolling pa­tients. D-LIVR is the first-ever glob­al Phase 3 HDV study and will span twen­ty coun­tries with over one hun­dred sites.

Lon­a­farnib has been grant­ed Or­phan Drug Des­ig­na­tion by the U.S. Food and Drug Ad­min­is­tra­tion (FDA) and Eu­ro­pean Med­i­cines Agency (EMA), Fast Track Des­ig­na­tion and Break­through Ther­a­py Des­ig­na­tion by U.S. FDA and PRIME des­ig­na­tion by the EMA. Lon­a­farnib is not ap­proved for any in­di­ca­tion.

Lamb­da may be a bet­ter tol­er­at­ed in­ter­fer­on in de­vel­op­ment for the treat­ment of HDV.

Pegin­ter­fer­on lamb­da (Lamb­da) is a well-char­ac­ter­ized, late-stage, first-in-class, type III in­ter­fer­on (IFN) that stim­u­lates im­mune re­spons­es that are crit­i­cal for the de­vel­op­ment of host pro­tec­tion dur­ing vi­ral in­fec­tions. Lamb­da is be­ing de­vel­oped as a bet­ter tol­er­at­ed in­ter­fer­on with few­er of the typ­i­cal flu-like, de­pres­sion and blood count low­er­ing side ef­fects as­so­ci­at­ed with oth­er in­ter­fer­ons. Lamb­da has pre­vi­ous­ly been ad­min­is­tered to over 3,000 pa­tients in Phase 1, 2, and 3 clin­i­cal tri­als for HBV and HCV, and has a large, well-un­der­stood safe­ty data­base. Eiger has in­ves­ti­gat­ed Lamb­da in over 50 HDV-in­fect­ed pa­tients across in­ter­na­tion­al aca­d­e­m­ic cen­ters in two Phase 2 stud­ies.

Phase 2 LIMT Lamb­da monother­a­py study re­sults demon­strat­ed durable sup­pres­sion of HDV RNA in 36% of pa­tients at 24 weeks post-treat­ment. Phase 2 LIFT Lamb­da / Lon­a­farnib com­bi­na­tion study in­ter­im re­sults were re­cent­ly re­port­ed at The LIV­ER meet­ing (AASLD 2019), with >50% of pa­tients HDV RNA sup­pressed to un­quan­tifi­able lev­els at Week 24 and 95% of pa­tients achiev­ing the pri­ma­ry end­point of > 2 log de­cline in HDV RNA at Week 24. Eiger plans to ad­vance Lamb­da in Phase 3 reg­is­tra­tion for HDV in 2020.

Lamb­da has been grant­ed Or­phan Drug Des­ig­na­tion by the U.S. FDA and EMA, and Break­through Ther­a­py and Fast Track des­ig­na­tion by U.S. FDA. Lamb­da has not yet been ap­proved for any in­di­ca­tion.

Lon­a­farnib and Lamb­da hold promise as fu­ture foun­da­tion­al treat­ments for pa­tients with HDV in­fec­tion.

At­tack­ing the HDV virus with mul­ti­ple ther­a­pies, tar­get­ing dif­fer­ent mech­a­nisms of ac­tion to dis­rupt the virus at dif­fer­ent points in the vi­ral life cy­cle, is ex­pect­ed to yield the most ro­bust re­sults to­ward a fu­ture HDV cure. Lon­a­farnib and Lamb­da are ex­pect­ed to be foun­da­tion­al ther­a­pies for fu­ture treat­ment, alone or in com­bi­na­tion, with oth­er in­ves­ti­ga­tion­al treat­ments for HDV.

HDV Aware­ness and Test­ing

It is im­por­tant that pa­tients with chron­ic HBV get test­ed for HDV. There is now a sim­ple and eas­i­ly ac­ces­si­ble blood test for HDV from Quest Di­ag­nos­tics in the U.S. Test­ing for HDV may help save lives by in­sur­ing co-in­fect­ed in­di­vid­u­als are di­ag­nosed and re­ceive ap­pro­pri­ate med­ical care and treat­ment as ear­ly in the dis­ease course as pos­si­ble.

Eiger is spon­sor­ing a He­pati­tis Delta Test­ing Pro­gram where­by health­care prac­ti­tion­ers are in­vit­ed to sub­mit HBV-pos­i­tive pa­tient blood sam­ples to Quest Di­ag­nos­tics for HDV test­ing. Eiger cov­ers the costs of blood draw, test, and test re­port­ing.