As­traZeneca, Mer­ck­'s star PARP in­hibitor Lyn­parza ex­pands reach in ovar­i­an can­cer with new US ap­proval

Weeks af­ter GSK widened the mar­ket for PARP in­hibitor Ze­ju­la in pa­tients with ovar­i­an can­cer, ri­val As­traZeneca’s mar­ket-lead­ing Lyn­parza has al­so se­cured ex­pand­ed use in women with the dis­ease.

Lyn­parza, in com­bi­na­tion with Roche’s Avastin, has been ap­proved by the FDA for the main­te­nance treat­ment of adult pa­tients with ad­vanced ep­ithe­lial ovar­i­an, fal­lop­i­an tube or pri­ma­ry peri­toneal can­cer who have ex­pe­ri­enced a com­plete or par­tial re­sponse to first-line plat­inum-based chemother­a­py and whose dis­ease is as­so­ci­at­ed with ho­mol­o­gous re­com­bi­na­tion de­fi­cien­cy (HRD) pos­i­tive sta­tus, de­fined by ei­ther a BR­CA mu­ta­tion and/or ge­nom­ic in­sta­bil­i­ty. Rough­ly one in two women with ad­vanced ovar­i­an can­cer has an HRD+ tu­mor.

Al­though drug de­vel­op­ers have large­ly leaned on BR­CA mu­ta­tions to iden­ti­fy pa­tients who can ben­e­fit from PARP in­hibitors, sci­en­tists have sug­gest­ed that de­fects in oth­er genes in­volved in DNA re­pair — which ren­der cells can­cer­ous — could be prime tar­gets too.

The new Lyn­parza ap­proval is based on the late-stage PAO­LA-1 tri­al, which showed the ad­di­tion of the PARP in­hibitor to Avastin ther­a­py re­duced the risk of dis­ease pro­gres­sion or death by 67%, and that the com­bi­na­tion im­proved pro­gres­sion-free sur­vival (PFS) to a me­di­an of 37.2 months ver­sus 17.7 months in pa­tients with HRD pos­i­tive ad­vanced ovar­i­an can­cer who were on­ly giv­en Avastin.

“We ex­pect grad­ual up­take in the HRD+ set­ting, as ge­net­ic se­quenc­ing be­comes more in­te­grat­ed in­to treat­ment par­a­digms. Be­yond the HRD+ in­di­ca­tion, the PARP class may be more chal­lenged giv­en the su­pe­ri­or ef­fi­ca­cy of Avastin in these pa­tients. How­ev­er, Avastin us­age re­quires in­tra­venous ad­min­is­tra­tion and is as­so­ci­at­ed with a num­ber of side ef­fects that may make oral PARP us­age more de­sir­able, es­pe­cial­ly in the COVID en­vi­ron­ment,” SVB Leerink an­a­lysts said.

The ap­proval will al­so se­cure for As­traZeneca $100 mil­lion in col­lab­o­ra­tion rev­enue from part­ner Mer­ck.

Akin to Lyn­parza, GSK’s Ze­ju­la and Clo­vis’ Rubra­ca are poly ADP-ri­bose poly­merase (PARP) in­hibitors. PARP is a pro­tein used by dam­aged cells to ini­ti­ate re­pair, and by thwart­ing it, the class of drugs is en­gi­neered to pre­vent can­cer cells from re­pair­ing them­selves, there­by cat­alyz­ing their de­struc­tion.

Last Oc­to­ber, Ze­ju­la was ap­proved for use in ovar­i­an can­cer pa­tients with HRD+ tu­mors who have been through (and were sen­si­tive to) at least three rounds of chemother­a­py. But in late April, Ze­ju­la’s use was ex­pand­ed — on the ba­sis of the PRI­MA tri­al — to women with ovar­i­an can­cer who ex­pe­ri­enced a com­plete or par­tial re­sponse to first-line plat­inum-based chemother­a­py — ac­count­ing for ap­prox­i­mate­ly 80% of all ovar­i­an can­cer pa­tients — this ap­proval in­clud­ed in­clud­ing HRD neg­a­tive pa­tients.

“While this does open the door for Ze­ju­la to be the on­ly PARP that has for­mal ap­proval for use in 1L ovar­i­an can­cer pa­tients with­out a mark­er of re­pair de­fi­cien­cy (HRD-), the drug may face com­mer­cial chal­lenges in this HRD- group, giv­en Avastin monother­a­py main­te­nance demon­strat­ed ~2x the ef­fi­ca­cy of PARP monother­a­py main­te­nance based on a com­par­i­son be­tween PAO­LA-1 and PRI­MA tri­al re­sults,” SVB Leerink an­a­lysts wrote in a note.

“We think some clin­i­cians may be re­luc­tant to ad­min­is­ter a PARP with­out de­ter­min­ing HRD sta­tus giv­en that about 2/3 of non-BR­CA+ pa­tients, the HRD- co­hort, may get less ef­fi­ca­cy with a PARP than with Avastin.”

As the sec­ond-to-mar­ket drug in the class, Ze­ju­la gen­er­at­ed ~25% of the rev­enue Lyn­parza did last year — £229 mil­lion ver­sus £921 mil­lion.

Next up on the dock­et for As­traZeneca and Mer­ck’s Lyn­parza is an ap­proval for a sub­set of pa­tients with metasta­t­ic cas­tra­tion-re­sis­tant prostate can­cer, af­ter the com­pa­nies re­port­ed a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in over­all sur­vival.

Aduhelm OK 'bit­ter­sweet' for ALS ad­vo­cates; Con­trast­ing Covid-19 vac­cine read­outs; GSK joins TIG­IT bat­tle; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

With the busiest days of June now behind us, we’re starting to think seriously about the second half of the year. In August, we have scheduled a special report where Endpoints will compile a list of the 20 most influential R&D executives in biopharma. Know a luminary who should definitely be included? Nominate them now.

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In­side Track: Be­hind the Scenes of a Ma­jor Biotech SPAC

Dr. David Hung and Michelle Doig are no strangers to the SPAC phenomenon. As Founder and CEO of Nuvation Bio, a biotech company tackling some of the greatest unmet needs in oncology, Dr. Hung recently took the company public in one of this year’s biggest SPAC related deals. And as Partner at Omega Funds, Doig not only led and syndicated Nuvation Bio’s Series A, but is now also President of the newly formed, Omega-sponsored, Omega Alpha SPAC (Nasdaq: OMEG; oversubscribed $138m IPO priced January 6, 2021).

Who are the lu­mi­nar­ies dri­ving the biggest ad­vances in bio­phar­ma R&D? End­points News is ask­ing for your nom­i­na­tions for a spe­cial re­port

In biopharma, driving a drug to market is the ultimate goal — but none of that happens without a strong research and development program. At the most successful companies, those R&D efforts are spearheaded by true innovators in the field who are always looking for that next novel mechanism of action or breakthrough safety profile.

Now, Endpoints News is asking you to tell us who those guiding lights are.

Bris­tol My­ers breaks the bank on Ei­sai's fo­late re­cep­tor ADC drug, lay­ing out more than $3B+ for rights

For years, innovation in oncology has been a crapshoot with Big Pharma — the whales at the table — dropping the big bucks for the key to the next generation of tumor fighters. Bristol Myers Squibb hasn’t exactly made a name for being an innovator in the space, but that doesn’t mean it won’t splash in when it sees a potential winner.

Now, with a massive check in hand, the drugmaker is willing to put its intuition to the test.

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Michael Chambers (L) and John Ballantyne

Dana­her strikes deal to buy boom­ing next-gen man­u­fac­tur­er Alde­vron for $9.6B

Life sciences conglomerate Danaher Corp. $DHR has struck a deal to buy the fast-growing Aldevron, one of the world’s top manufacturers of hotly sought-after plasmid DNA, mRNA and recombinant proteins for the burgeoning world of vaccine and drugmakers pushing some game-changing technologies.

Buyout talks set the stage for Danaher to settle on a $9.6 billion cash pact to acquire the private Fargo, ND-based company — a key supplier for a disruptive new Covid vaccine as well as a host of gene and cell therapy and CRISPR gene editing players — founded by Michael Chambers and CSO John Ballantyne as a crew of 2 back in 1998.

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Med­ic­aid com­mis­sion to Con­gress: In­crease re­bates for ac­cel­er­at­ed ap­proval drugs

As the FDA continues to approve more new drugs under its accelerated approval pathway, the non-partisan Medicaid and CHIP Payment and Access Commission (MACPAC) is telling Congress to increase the statutory Medicaid rebates for such drugs until their clinical benefits have been verified.

Higher rebates for drugs with accelerated approvals, a move opposed by the biopharma industry, would mean lower net prices, lessening their financial burden on the health care system while incentivizing the companies to speed the verification of the drugs’ clinical benefits in confirmatory trials. Once those benefits are confirmed, the companies would return to the lower rebates when the accelerated approval is converted into a full approval, MACPAC suggests.

FDA's con­tro­ver­sial Aduhelm de­ci­sion leaves ALS pa­tients feel­ing spurned

The FDA’s controversial approval of Biogen’s Aduhelm drug for Alzheimer’s disease has been met with fierce resistance from all corners of the biopharma industry, but few seem to be as upset with the decision as ALS patients and advocacy groups.

For all that’s already been written and discussed about the agency’s announcement, from the drug’s exorbitantly high price of $56,000 per year to criticism over lowered standards, ALS patients see something more. ALS patients and associations say they largely regarded Aduhelm’s approval as a bittersweet double standard: happy that those with Alzheimer’s have a new drug available, but questioning how the FDA evaluated Biogen’s drug compared to the experimental programs being studied for their own disease.

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Spring reg­u­la­to­ry agen­da: What’s com­ing soon-ish from the FDA

The FDA’s lack of a permanent commissioner does not seem to be halting its progress to propose and finalize dozens of new regulations, with the latest batch covering everything from adverse event reporting to supplemental application submissions to annual reports for INDs.

Overall, FDA expects to release more than 40 new proposed regulations and finalize another 24 in the coming months and years.

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As drug­mak­ers spend $6B an­nu­al­ly on DTC ads, sen­a­tors re­vive bill to in­clude list prices in ads

A new GAO report on biopharma companies’ $6 billion annual spending on direct-to-consumer advertising is pushing US Senate Majority Whip Dick Durbin (D-IL) and Sen. Chuck Grassley (R-IA) to reintroduce legislation that would require price disclosures in the ads.

The GAO found that drugmakers spent almost half—$8.2 billion of the $17.8 billion from 2016 to 2018—on DTC ads for drugs in three therapeutic categories, including inflammatory conditions (e.g., arthritis, gout), endocrine and metabolic disorders (e.g., type 2 diabetes, hypothyroidism), and conditions affecting the central nervous system (e.g., depression, multiple sclerosis), according to the new report.