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.

Da­ta Lit­er­a­cy: The Foun­da­tion for Mod­ern Tri­al Ex­e­cu­tion

In 2016, the International Council for Harmonisation (ICH) updated their “Guidelines for Good Clinical Practice.” One key shift was a mandate to implement a risk-based quality management system throughout all stages of a clinical trial, and to take a systematic, prioritized, risk-based approach to clinical trial monitoring—on-site monitoring, remote monitoring, or any combination thereof.

Pfiz­er's big block­buster Xel­janz flunks its post-mar­ket­ing safe­ty study, re­new­ing harsh ques­tions for JAK class

When the FDA approved Pfizer’s JAK inhibitor Xeljanz for rheumatoid arthritis in 2012, they slapped on a black box warning for a laundry list of adverse events and required the New York drugmaker to run a long-term safety study.

That study has since become a consistent headache for Pfizer and their blockbuster molecule. Last year, Pfizer dropped the entire high dose cohort after an independent monitoring board found more patients died in that group than in the low dose arm or a control arm of patients who received one of two TNF inhibitors, Enbrel or Humira.

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Top gene ther­a­py deals, M&A pacts in 2020 high­light an­oth­er big year in one of the hottest fields in bio­phar­ma

Chris Dokomajilar at DealForma has been crunching the numbers on gene therapy deals over the last 2 years and came away with a few key observations.

Both the upfront cash and deal totals last year backed off a bit from the record high hit in 2019, but the totals are still running well ahead of anything we’ve seen in the years prior to 2019/2020.
2020 R&D partnerships came in at 23 deals, with $1.1 billion in disclosed upfront cash and equity and more than $8.5 billion in total deal value. Looking at 2019-2020 M&A, Dokomajilar found: 9 Acquisitions, with over $11.1 billion in disclosed upfront cash and equity and more than $13.4 billion in total M&A value.

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Steve Harr (L) and Hans Bishop

One of the most am­bi­tious start­up teams in biotech just out­lined plans for a $400M IPO and a val­u­a­tion of about $4B

The executive team at Sana Biotechnology has sketched out more details about the full scope of its ambitions as the new unicorn to watch. They amended their S-1 today to include a price range of $20 to $23 a share — which puts them in reach of pulling in around $400 million on the high end with a market value starting right around $4 billion.

That’s not bad for a preclinical biotech with no drugs yet in human studies, but it squares with its ambitions to remake the cell therapy field with a slate of in-house platforms. The biotech raised $705 million — primarily from ARCH (44 million shares) and Flagship (34.2 million shares) — to get to this stage.

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Bob Nelsen (Michael Kovac/Getty Images)

ARCH an­nounces largest fund yet, rais­ing $1.85B to back men­tal health, cell and gene edit­ing ap­proach­es

Nearly a year ago, as the pandemic encroached and the stock market cratered, Flagship and ARCH Venture announced three mega-funds worth a combined $2.6 billion. They wanted, ARCH’s Bob Nelsen said, to restore confidence “that there was money out there and a lot of it” to invest in biotech.

Since then, the stock market has returned — almost frighteningly so — and Nelsen has kept raising and spending cash. On Thursday, he announced a new fund, worth $1.85 billion. It’s the largest pot yet for a VC famous for its deep pockets.

Glax­o­SmithK­line moves malar­ia vac­cine pro­duc­tion to In­dia; Nevakar bags Eu­ro­pean part­ner and nine-fig­ure deal

GSK is shifting production of its malaria vaccine to a Covid-19 vaccine developer in India.

Wednesday’s move to Bharat Biotech was made as part of efforts to battle the deadly fever, as GSK’s vaccine is the first to prove effective in combating the disease. Bharat will take over manufacturing of the protein part of the vaccine while GSK continues developing the adjuvant portion of the shot.

The vaccine is currently being piloted in regions of Ghana, Kenya and Malawi under the Malaria Vaccine Implementation Program. More than 500,000 children have received the first dose since the pilots were initiated by the three countries in 2019.

Lil­ly at­tempts to re­vive an old idea for tack­ling pain, li­cens­ing PhI pro­gram from Japan’s Asahi Ka­sei Phar­ma

Eli Lilly is fronting some new cash in a space they’re quite familiar with.

The company is partnering with Japan’s Asahi Kasei Pharma on an experimental drug for chronic pain, acquiring the rights for the P2X7 receptor antagonist program dubbed AK1780. Lilly will shell out a pretty penny for the program, promising up to $410 million total should each milestone payment come to pass.

Asahi Kasei will receive an upfront sum of $20 million for the candidate. In addition, Lilly is on the hook for up to $210 million in development and regulatory milestones and another potential $180 million in sales milestones. Asahi Kasei can also obtain royalties ranging from the mid-single to low-double digits should an approved product come out of the deal.

Covid-19 roundup: EU and As­traZeneca trade blows over slow­downs; Un­usu­al unions pop up to test an­ti­bod­ies, vac­cines

After coming under fire for manufacturing delays last week, AstraZeneca’s feud with the European Union has spilled into the open.

The bloc accused the pharma giant on Wednesday of pulling out of a meeting to discuss cuts to its vaccine supplies, the AP reported. AstraZeneca denied the reports, saying it still planned on attending the discussion.

Early Wednesday, an EU Commission spokeswoman said that “the representative of AstraZeneca had announced this morning, had informed us this morning that their participation is not confirmed, is not happening.” But an AstraZeneca spokesperson later called the reports “not accurate.”

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Ther­mo Fish­er plat­form seeks to ex­pe­dite donor cell cul­ti­va­tion for al­lo­gene­ic cell ther­a­pies

One of the world’s leading CDMOs has launched a new technology it says will expedite a quickly-growing sect of biotech drug development: off-the-shelf, allogeneic cell therapies.

It’s been nearly a decade since the FDA approved the first use of the method that uses healthy donor cells to create a master cell bank, which is then used for specific therapies — a cord blood allogeneic treatment called Hemacord. In the years since, the use of allogeneic cells has taken off in research circles, most notably in the use of T cell therapies to target solid tumor cancers.