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.

Big Phar­ma's Twit­ter ex­o­dus; Mer­ck wa­gers $1.35B on buy­out; $3.5M gene ther­a­py; and more

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Paul Perreault, CSL Behring CEO

CSL lands FDA ap­proval for he­mo­phil­ia B gene ther­a­py, sets $3.5M list price

The FDA has approved the world’s first gene therapy for hemophilia B, ushering into the market a treatment that’s historic in both what it promises to do and how much it will cost.

CSL will be marketing the drug, Hemgenix, at a list price of $3.5 million — which sets a new record for the most expensive single-use gene therapy in the US.

In a statement provided to Endpoints News, the Australian company noted that the current costs of treating people with moderate to severe hemophilia B can be significant over a lifetime. By some estimates, healthcare systems could spend more than $20 million per person.

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Image: Shutterstock

MIT re­searchers re­veal DNA "Paste" tech be­hind lat­est gene edit­ing start­up

MIT scientists have developed a tool that they say can insert large gene sequences where they want in the genome.

In a paper published Thursday in Nature Biotechnology, MIT fellows Omar Abudayyeh, Jonathan Gootenberg and colleagues detail a technology they call PASTE, which they say can potentially be used to insert long strands of DNA and treat genetic diseases caused by many different mutations, such as cystic fibrosis and Leber congenital amaurosis, a rare eye disorder that causes blindness.

Elon Musk (GDA via AP Images)

Biggest drug com­pa­nies halt­ed Twit­ter ad buys af­ter Lil­ly in­sulin spoof

Almost all of the drug industry’s biggest advertisers cut their spending on Twitter to zero or near-zero over the last two weeks amid worries about impersonation of their brands by pranksters and the future of the social media company.

Among 18 of the biggest pharmaceutical advertisers in the US market, 12 cut their Twitter ad spending to nothing for the week beginning Nov. 14, according to Pathmatics, which tracks data on prescription drug ad spending as well as general corporate advertising. The list of drugmakers cutting spending to zero includes Merck, AstraZeneca, Eli Lilly, Novartis, Pfizer and others.

Rob Davis, Merck CEO

Up­dat­ed: No Seagen here: 'Do more' means a small $1.35B pur­chase of Ima­go for Mer­ck

Merck is making an acquisition, the Big Pharma announced before Monday’s opening bell. No, Seagen is not entering the fold, as had been speculated for quarters.

Folding under Merck’s wings will be Pfizer-backed Imago BioSciences. For nearly a year, Merck CEO Rob Davis has been saying the pharma giant needs to “do more” on the business development front after its 2021 $11.5 billion acquisition of Acceleron.

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J&J's Spra­va­to pulls a PhI­II win against Sero­quel XR in treat­ment-re­sis­tant de­pres­sion

A day before Thanksgiving, J&J’s Janssen has a new cut of Phase III Spravato data to be grateful for.

The pharma giant announced on Wednesday that its nasal spray, also known as esketamine, beat extended-release quetiapine, previously sold by AstraZeneca as Seroquel XR, in treatment-resistant depression (TRD). Of 676 adults, a significantly higher number of patients on Spravato were able to achieve remission and avoid relapse after 32 weeks, according to J&J.

Isao Teshirogi, Shionogi president and CEO (Kyodo via AP Images)

Sh­ionogi's Covid an­tivi­ral lands first ap­proval in Japan's new emer­gency ap­proval path­way

Japanese regulators on Tuesday signed off on Shionogi’s homegrown antiviral for Covid-19, known as Xocova (ensitrelvir), making it the first approval under Japan’s emergency regulatory approval system.

The emergency approval, following a back-and-forth with regulators since last February, is based on a safety profile with more than 2,000 patients who have accessed the pill, and clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors or vaccination status, and during the Omicron-dominant phase of the pandemic.

Karen Aiach, Lysogene CEO (RE(ACT) Discovery Institute)

Gene ther­a­py flunks PhII/III study, but for­mer Sarep­ta part­ner sees a path for­ward — if it can find the cash

The development path for Lysogene’s gene therapy for MPS IIIA has been a rocky one. After the FDA slapped a partial clinical hold on a Phase II/III study, a patient already dosed in the trial died, although it was deemed unrelated to treatment. Then earlier this year, Sarepta pulled out of their three-year partnership due to disagreements on who will handle commercial supply.

And now, Lysogene reported the trial has failed its primary endpoint.

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Dermavant Sciences' first consumer TV ad for its Vtama psoriasis med shows people ready for a new topical treatment.

Roivant’s Der­ma­vant de­buts first-ever TV com­mer­cial for pso­ri­a­sis cream Vta­ma

Dermavant Sciences has been marketing its first product, psoriasis med Vtama, to dermatologists for months, but on Tuesday it rolled out its first consumer campaign. The debut DTC effort including a streaming TV commercial encourages patients to a “Topical Uprising” in a nod to Vtama being a topical cream.

In the new commercial, a swell of people discards scarves and jacket coverings, gathering in the street to converge on a pharmacy to demand a steroid-free prescription. A moment of levity follows when a pharmacist says, “You know you can just talk to your doctor, right?” The gathered crowds collectively says, “Oh.”

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