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.

With little explanation for why Merck’s potential Covid-19 antiviral was less effective in reducing Covid hospitalizations and deaths in a full analysis of a Phase III trial versus an interim look, the FDA’s antimicrobial drugs advisory committee on Tuesday voted 13-10 in favor of the pill’s benefits outweighing the risks for adults within 5 days of developing Covid symptoms.

Molnupiravir will likely be authorized by FDA in the coming days for adults with mild or moderate Covid-19. While Pfizer’s antiviral may prove to be more effective, Merck’s pill will be another weapon in the armamentarium of Covid-19 treatments for countries around the world, adding to the mAb treatments already in use in the outpatient space from Regeneron, Eli Lilly and Vir/GlaxoSmithKline.

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Drugmakers looking to design a new registry or use an existing one to support a regulatory decision on a drug’s effectiveness or safety will need to consult with a new draft guidance released Monday by the FDA.

The agency’s reliance on registry data for regulatory decisions dates back more than two decades, at least, as in 1998 Bayer won approval for its anticoagulant Refludan (withdrawn from the market in 2013 for commercial reasons) based in part on a historical control group pulled from a registry.