Ob­sE­va makes case for hor­mone sup­pres­sive ther­a­py in uter­ine fi­broid study, but safe­ty qualms vex in­vestors

About a month af­ter the Swiss biotech dis­closed a failed late-stage study in its IVF pro­gram, Ob­sE­va on Mon­day un­veiled pos­i­tive piv­otal da­ta on its ex­per­i­men­tal treat­ment for heavy men­stru­al bleed­ing trig­gered by uter­ine fi­broids, but the ther­a­py’s safe­ty pro­file irked in­vestors.

Ob­sE­va in-li­censed the drug, lin­zagolix, from Japan’s Kis­sei Phar­ma­ceu­ti­cal in 2015. Two dos­es of the drug (100 mg and 200 mg) were test­ed against a place­bo in the 535-pa­tient Phase III study, dubbed PRIM­ROSE 2, in pa­tients who were both on and off hor­mon­al add-back ther­a­py (ABT).

The aim of the ther­a­py was to re­duce the rate of heavy men­stru­al bleed­ing. Pa­tients with men­stru­al blood loss vol­ume of ≤ 80 mL and ≥ 50% re­duc­tion from base­line at 24 weeks were cat­e­go­rized as re­spon­ders.

The re­spon­der rate was 93.9% for women re­ceiv­ing 200 mg of the drug with ABT (p < 0.001), and 56.7% for women re­ceiv­ing 100 mg with­out ABT (p < 0.001), com­pared to 29.4% in the place­bo group. Both dos­es al­so in­duced sta­tis­ti­cal­ly sig­nif­i­cant rates of amen­or­rhea (the ab­sence of men­stru­a­tion), pain re­duc­tion and qual­i­ty of life.

“We be­lieve pos­i­tive da­ta from the low-dose with­out ABT co­hort (40-50% re­sponse rate) could dif­fer­en­ti­ate Lin­zagolix from com­peti­tors, with a com­pet­i­tive mar­ket po­si­tion as a po­ten­tial first-line treat­ment for pa­tients un­able to re­ceive ABT (women pre­dis­posed to high BMI, CV risk and di­a­betes),” BMO Cap­i­tal Mar­ket’s Do Kim wrote in a note last month.

Lin­zagolix is an oral GnRH re­cep­tor an­tag­o­nist, a sub­stance that caus­es the ovaries to stop mak­ing es­tro­gen and prog­es­terone, be­ing de­vel­oped for use in heavy men­stru­al bleed­ing trig­gered by uter­ine fi­broids and pain as­so­ci­at­ed with en­dometrio­sis. GnRH drugs, which typ­i­cal­ly come in the form of in­jec­tions or nasal sprays, have been around for decades and are ad­min­is­tered in tan­dem with ABT to ame­lio­rate the menopausal-type side ef­fects and the thin­ning of bones.

The clin­i­cal im­pact of lin­zagolix at 75 mg and 100 mg dos­es with­out hor­mon­al ABT are be­ing as­sessed in Ob­sE­va’s late-stage en­dometrio­sis (EDEL­WEISS 2/3) tri­als. The drug is al­so be­ing in­ves­ti­gat­ed in a sep­a­rate uter­ine fi­broids tri­al — PRIM­ROSE I — that is set to read out in the sec­ond quar­ter of next year. If da­ta from the oth­er PRIM­ROSE study are al­so pos­i­tive, the com­pa­ny ex­pects to sub­mit a mar­ket­ing ap­pli­ca­tion to the EU by the end of next year and to the FDA by ear­ly 2021, it said.

“A sub­stan­tial amount of da­ta re­leased to date sup­ports use of lin­zagolix with­out ABT in pre-menopausal women with these con­di­tions, avoid­ing known risks of ABT while pro­vid­ing symp­tom re­lief and bone preser­va­tion,” H.C. Wain­wright’s Raghu­ram Sel­vara­ju wrote in a note last week. “In our view, lin­zagolix’s po­ten­tial as an ef­fec­tive GnRH re­cep­tor an­tag­o­nist that can be used with­out ABT could con­fer best-in-class sta­tus with­in this cat­e­go­ry of com­pounds.”

Ab­b­Vie and Neu­ro­crine Bio­sciences’ twice-dai­ly GnRH ag­o­nist ther­a­py elagolix (brand­ed as Orilis­sa), which was ap­proved last year to treat en­dometrio­sis, is al­so un­der FDA re­view for use in uter­ine fi­broids.

The com­pa­nies have re­port­ed da­ta from two piv­otal six-month stud­ies — in one late-stage study, 68.5% (p<0.001) of elagolix-treat­ed women with uter­ine fi­broids achieved clin­i­cal re­sponse com­pared to place­bo (8.7%), in the sec­ond tri­al 76.2% (p<0.001) did com­pared to place­bo (10.1%). How­ev­er, the drug’s side ef­fect pro­file has caused pause — in ad­di­tion to the loss of bone den­si­ty, some pa­tients al­so ex­pe­ri­enced hot flash­es and night sweats.

Mean­while, Vivek Ra­maswamy’s My­ovant al­so has GnRH ag­o­nist, re­l­u­golix, that has per­formed well in late-stage uter­ine fi­broid stud­ies, and the drug’s safe­ty pro­file ap­pears to be bet­ter than elagolix.

In the Ob­sE­va tri­al, the most fre­quent­ly ob­served ad­verse events, oc­cur­ring in > 5% of pa­tients, were headaches, hot flush­es, and ane­mia. Mean per­cent­age change from base­line in bone min­er­al den­si­ty (BMD) was con­sis­tent with pre­vi­ous clin­i­cal da­ta, it added.

That im­plies BMD re­duc­tions were un­der 2% across all treat­ment groups, Cred­it Su­isse’s Mar­tin Auster said. “(A)nd on­ly 2.5% of women (9/367 with BMD da­ta for all anatom­ic sites) had a >8% BMD de­crease (OB­SV is blind­ed to the da­ta so as­so­ci­at­ed dose arms are not known), an im­por­tant FDA thresh­old. ”

Jef­feris an­a­lyst Biren Amin not­ed that that the “BMD loss ap­pears to be slight­ly high­er than com­peti­tors, (1.31% with high-dose lin­zagolix vs 0.13-0.75% for com­peti­tors).”

The com­pa­ny’s shares $OB­SV closed down more than 29% at $3.23 on Mon­day.

Uter­ine fi­broids are al­most al­ways be­nign tu­mors that emerge in or on the mus­cu­lar walls of the uterus. They can cause symp­toms such as ab­nor­mal uter­ine bleed­ing, heavy or painful pe­ri­ods, ane­mia, ab­dom­i­nal pain, back­ache, in­creased ab­dom­i­nal girth and bloat­ing, uri­nary fre­quen­cy or re­ten­tion, con­sti­pa­tion or painful defe­ca­tion, preg­nan­cy loss, painful in­ter­course and, in some cas­es, in­fer­til­i­ty. Be­tween 20% to 80% of women de­vel­op fi­broids by the time they reach age 50, ac­cord­ing to HHS es­ti­mates.

In No­vem­ber, Ob­sE­va’s oxy­tocin re­cep­tor an­tag­o­nist, no­la­si­ban, failed to dif­fer­en­ti­ate from place­bo in key study, forc­ing the com­pa­ny to aban­don the pro­gram. The drug, in-li­censed from Ger­many’s Mer­ck KGaA, was en­gi­neered to en­hance the re­cep­tiv­i­ty of the en­dometri­um to em­bryo im­plan­ta­tion to aug­ment the chances of a suc­cess­ful preg­nan­cy and live-birth among pa­tients un­der­go­ing em­bryo trans­fer fol­low­ing as­sist­ed re­pro­duc­tive tech­nol­o­gy.

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