Cedric Francois, Apellis CEO

Apel­lis turns up mixed re­sults in close­ly watched eye dis­ease tests. Are the da­ta strong enough for ap­proval?

Look­ing to scuf­fle with rare dis­ease gi­ant and now As­traZeneca sub­sidiary Alex­ion, lit­tle Apel­lis scored a break­through win ear­li­er this sum­mer for its own com­ple­ment fac­tor in­hibitor drug. Apel­lis, though, al­ways had its eyes on big­ger fish, but a first glimpse at piv­otal da­ta for a ma­jor in­di­ca­tion has mud­died the wa­ters.

In two Phase III stud­ies test­ing pegc­eta­coplan in pa­tients with ge­o­graph­ic at­ro­phy, Apel­lis’ drug nailed the pri­ma­ry end­points in one test but flopped the same check­points in a “car­bon copy” study, ac­cord­ing to topline da­ta re­leased Thurs­day.

Ge­o­graph­ic at­ro­phy is an ad­vanced form of dry age-re­lat­ed mac­u­lar de­gen­er­a­tion with no ap­proved ther­a­pies that af­fects around 5 mil­lion pa­tients world­wide — in­clud­ing around 1 mil­lion in the US — and is a lead­ing cause of blind­ness.

An ap­proval here could spell block­buster sales for pegc­eta­coplan, a com­ple­ment C3 in­hibitor now mar­ket­ed as Em­paveli for parox­ys­mal noc­tur­nal he­mo­glo­bin­uria (PNH) — which is ex­act­ly why an­a­lysts and in­vestors have kept such a close eye on these stud­ies. In June, Eval­u­ate Phar­ma pegged the drug’s po­ten­tial mar­ket in GA at $1.2 bil­lion in 2026.

In the Phase III OAKS tri­al, pegc­eta­coplan in­ject­ed in the eye re­duced the rate of GA le­sion growth by 22% (p=0.0003) and 16% (p=0.0052) com­pared with pooled sham in­jec­tion in pa­tients ad­min­is­tered a month­ly and once-every-oth­er-month dose of the drug, re­spec­tive­ly, af­ter a year, Apel­lis said.

Tak­en alone, that’s great news for Apel­lis. But the sec­ond tri­al toplined Thurs­day — the Phase III DER­BY study — paint­ed a murki­er pic­ture of the drug’s ef­fi­ca­cy.

In that tri­al, pegc­eta­coplan failed to sig­nif­i­cant­ly cut le­sion growth rate com­pared with sham in both co­horts, post­ing rates of 12% (p=0.0528, just over the stan­dard bench­mark of p=0.05) and 11% (p=0.075), re­spec­tive­ly. That’s a con­cern since the stud­ies were mir­ror im­ages of one an­oth­er and of­fered con­tra­dict­ing pic­tures of whether Apel­lis’ drug works in this in­di­ca­tion.

In an at­tempt to bridge the gap be­tween the two stud­ies, Apel­lis of­fered re­sults from a pre­spec­i­fied analy­sis com­bin­ing the pri­ma­ry end­points from both stud­ies to de­ter­mine over­all sig­nif­i­cance. The biotech said month­ly dos­es of the drug in both stud­ies cut le­sion growth by 17% over­all (p=<0.0001) and a once-every-oth­er-month dose cut le­sion growth by 14% (p=0.0012) com­pared with sham.

A failed study is a black mark on any drug’s record, but CEO Cedric Fran­cois said the to­tal­i­ty of pegc­eta­coplan’s ef­fi­ca­cy and safe­ty da­ta — which in­cludes re­sults from the Phase II FIL­LY tri­al — could of­fer a com­pelling case for reg­u­la­tors. The com­pa­ny ex­pects to file for ap­proval as soon as the first half of 2022.

“You have to look at these da­ta in terms of the to­tal­i­ty of da­ta that we have as­sem­bled,” he told End­points News. “The en­tire da­ta pack­age that we have presents a very strong case for ap­proval.”

In terms of why the stud­ies di­verged so great­ly, Fran­cois didn’t have much to of­fer, say­ing: “If you run the same tri­al 20 times, you’ll get 20 dif­fer­ent re­sults.”

Fran­cois high­light­ed the safe­ty da­ta for pegc­eta­coplan in DER­BY and OAKS, with just 6% of pa­tients re­port­ing ex­u­da­tions from the eye in the month­ly dose co­horts and 4.1% in the every-oth­er-month co­horts. There were two con­firmed cas­es of in­fec­tious en­doph­thalmi­tis and an­oth­er sus­pect­ed case among 6,331 in­jec­tions ad­min­is­tered dur­ing the stud­ies. Mean­while, there were 13 cas­es of in­traoc­u­lar in­flam­ma­tion re­port­ed and no reti­nal vas­culi­tis or reti­nal vein oc­clu­sion re­port­ed.

“We came in­to this pro­gram with a drug that we be­lieved would have to be giv­en every month to pa­tients, where there was con­cern that we may have an in­creased rate of ex­u­da­tion that was go­ing to be a prob­lem,” Fran­cois said. “The safe­ty here is so good that this is a drug that you’ll want to give to all pa­tients with GA.”

An­oth­er po­ten­tial boon to the drug’s case was its ef­fect on what are called ex­trafoveal le­sions, which are ear­ly signs of the dis­ease pri­or to cen­tral vi­sion be­ing af­fect­ed. In a com­bined ex­plorato­ry analy­sis, peg­cep­ta­coplan cut the rate of growth for those le­sions by 26% (p=<0.0001) for the once-month­ly co­horts and 23% (p=0.0002) for the once-every-month co­horts.

So that leaves the ball in the FDA’s court, and it’s un­clear ex­act­ly how reg­u­la­tors will ab­sorb these con­flict­ing re­sults. It wouldn’t be the first time that miss­ing a pri­ma­ry end­point hasn’t tor­pe­doed a drug’s chances, and the un­met clin­i­cal need and strong safe­ty da­ta could be enough to push the drug over the fin­ish line.

If the FDA does co­op­er­ate, it would be the cul­mi­na­tion of Apel­lis’ years­long dri­ve for GA, a dis­ease Fran­cois de­scribed as a “for­est fire” in the eye that has so far con­found­ed drug de­vel­op­ers. Way back in 2017, Roche saw its own chances in GA col­lapse af­ter its an­ti­body lam­pal­izum­ab flopped a key test in GA pa­tients.

But Apel­lis be­lieves com­ple­ment fac­tor in­hi­bi­tion could be key, which ex­plains why Alex­ion — now a part of As­traZeneca — has been dab­bling here with its own C5 in­hibitor fran­chise. Em­pavelis’ ap­proval in PNH in May marked the first ma­jor chal­lenge to Alex­ion’s Soliris, a block­buster drug for which PNH is the sin­gle largest in­di­ca­tion.

Pri­or to its ac­qui­si­tion, Alex­ion was busy switch­ing most of its pa­tients over to fol­low-up drug Ul­tomiris, which sports a match­ing PNH ap­proval and is work­ing to quick­ly ex­pand its la­bel to match the old­er drug.

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His­toric drug pric­ing re­forms pass; Pfiz­er ac­quires GBT; The long search for non-opi­oid pain drugs; 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.

The Endpoints Weekly has officially crossed the 60,000 mark on subscribers — thanks to all of your support. As the editorial team grows, we’ve been able to do a lot more, with many of those on display this week. Be sure to check out Lei Lei Wu’s deep dive on pain R&D. If you missed it, you may also rewatch her companion panel here.

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Gold for adults, sil­ver for in­fants: Pfiz­er's Pre­vnar 2.0 head­ed to FDA months af­ter Mer­ck­'s green light

Pfizer was first to the finish line for the next-gen pneumococcal vaccine in adults, but Merck beat its rival with a jab for children in June.

Now, two months after Merck’s 15-valent Vaxneuvance won the FDA stamp of approval for kids, Pfizer is out with some late-stage data on its 20-valent shot for infants.

Known as Prevnar 20 for adults, Pfizer’s 20vPnC will head to the FDA by the end of this year for an approval request in infants, the Big Pharma said Friday morning. Discussions with the FDA will occur first and more late-stage pediatric trials are expected to read out soon, informing the regulatory pathway in other countries and regions.

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No­var­tis re­ports two pa­tient deaths af­ter treat­ment with Zol­gens­ma

Two children with spinal muscular atrophy have died after receiving Novartis’ Zolgensma, a gene therapy designed as a one-time treatment for the rare fatal disease.

The deaths, which resulted from acute liver failure, occurred in Russia and Kazakhstan, Novartis confirmed in a statement to Endpoints News. Having notified health authorities across all the markets where Zolgensma is available, it will update the drug label “to specify that fatal acute liver failure has been reported,” a spokesperson wrote.

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House pass­es his­toric drug pric­ing re­forms, lin­ing up decades-in-the-mak­ing win for Biden and De­moc­rats

The US House of Representatives today voted along party lines (all Dems voted for it), 220-207 to pass new, wide-ranging legislation that will allow Medicare drug price negotiations for the first time ever, and cap seniors’ drug expenses to $2,000 per year and seniors’ insulin costs at $35 per month.

Setting up a major victory for President Joe Biden, representatives returned from their summer recess to pass the Inflation Reduction Act, even as many noted the bill would only modestly reduce inflation.

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Senate Finance Committee Chair Ron Wyden (D-OR) (Francis Chung/E&E News/POLITICO via AP Images)

Sen­ate Fi­nance chair con­tin­ues his in­ves­ti­ga­tion in­to phar­ma tax­es with re­quests for Am­gen

Amgen is the latest pharma company to appear on the radar of Senate Finance Committee Chair Ron Wyden (D-OR), who is investigating the way pharma companies are using subsidiaries in low- or zero-tax countries to lower their tax bills.

Like its peers Merck, AbbVie and Bristol Myers Squibb, Wyden notes how Amgen uses its Puerto Rico operations to consistently pay tax rates that are substantially lower than the U.S. corporate tax rate of 21%, with an effective tax rate of 10.7% in 2020 and 12.1% in 2021.

FDA ap­proves sec­ond in­di­ca­tion for As­traZeneca and Dai­ichi's En­her­tu in less than a week

AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate Enhertu scored its second approval in less than a week, this time for a subset of lung cancer patients.

Enhertu received accelerated approval on Thursday to treat adults with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, and who have already received a prior systemic therapy.

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J&J to re­move talc prod­ucts from shelves world­wide, re­plac­ing with corn­starch-based port­fo­lio

After controversially spinning out its talc liabilities and filing for bankruptcy in an attempt to settle 38,000 lawsuits, Johnson & Johnson is now changing up the formula for its baby powder products.

J&J is beginning the transition to an all cornstarch-based baby powder portfolio, the pharma giant announced on Thursday — just months after a federal judge ruled in favor of its “Texas two-step” bankruptcy to settle allegations that its talc products contained asbestos and caused cancer. An appeals court has since agreed to revisit that case.

CSL is gathering its four business units under a unified brand identity strategy (Credit: CSL company site)

CSL brings Se­qirus, Vi­for un­der par­ent um­brel­la brand in iden­ti­ty re­vamp

CSL is gathering its brands under the family name umbrella, renaming its vaccine and newly acquired nephrology specialty businesses with the parent initials.

CSL Seqirus and CSL Vifor join CSL Plasma and CSL Behring as the four now uniformly branded business units of the global biopharma. The Seqirus vaccine division was formed in 2015 with the combination of bioCSL and its purchase of Novartis’ flu vaccine business. CSL picked up Vifor Pharma late last year in an $11.7 billion deal for the nephrology, iron deficiency and cardio-renal drug developer.

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