Still reel­ing from re­jec­tion, Bio­Marin re­ports a glimpse of those 2-year val­rox da­ta FDA was look­ing for — but is it enough to change reg­u­la­tors' minds?

Bio­Marin now has the Phase III da­ta it needs to re­file val­rox, its gene ther­a­py for he­mo­phil­ia A, at the EMA — and pos­si­bly con­vince the FDA to re­con­sid­er its re­quire­ment.

Pulling from a to­tal of 134 pa­tients who had been fol­lowed up for a mean of 71.6 weeks, the biotech ze­roed in on a sub­group that was rolled over from a non-in­ter­ven­tion­al study. Among those 112 pa­tients, the an­nu­al­ized bleed­ing rate was re­duced by 84% com­pared to pro­phy­lac­tic Fac­tor VI­II re­place­ment. The one-time in­jec­tion of val­rox al­so cut mean an­nu­al­ized Fac­tor VI­II in­fu­sion by 99% (p <0.0001).

While an in­ves­ti­ga­tor hailed it as “the first sta­tis­ti­cal ev­i­dence demon­strat­ing ABR su­pe­ri­or­i­ty in a gene ther­a­py tri­al,” an­a­lysts not­ed the re­sults are rough­ly in line with in­vestor ex­pec­ta­tions.

For them, a dif­fer­ent num­ber from an­oth­er, small­er sub­group might mat­ter more for the drug’s fu­ture: Fac­tor VI­II lev­els af­ter two years.

Two-year safe­ty and ef­fi­ca­cy fol­low-up, af­ter all, was the da­ta that FDA reg­u­la­tors were look­ing for as they slapped a re­jec­tion on Bio­Marin’s first BLA. So far, 17 pa­tients who had been di­rect­ly en­rolled in­to the Phase III GEN­Er8-1 tri­al with­out go­ing through the ob­ser­va­tion pe­ri­od had reached that mark.

On av­er­age, Fac­tor VI­II ac­tiv­i­ty was 42.2 IU/dL at one-year and de­clined to 24.4 IU/dL at 2 years. The me­di­an lev­els were low­er (14.7 IUdL at Year 2), re­flect­ing wide sta­tis­ti­cal dis­tri­b­u­tion.

The com­pa­ny not­ed that the ex­pres­sion re­mained in the range that pro­vides ef­fi­ca­cy, with a mean an­nu­al­ized bleed­ing rate of 0.9 (and me­di­an 0.0) episodes per year. Bio­Marin said it will sub­mit the da­ta to the EMA, whose re­quest for a full year’s worth of da­ta spurred it to with­draw its ini­tial ap­pli­ca­tion, in the sec­ond quar­ter of 2021 as planned while ask­ing the FDA to “re­view two-year da­ta re­quest.”

But an­a­lysts are skep­ti­cal.

“(W)hile the pace of F8 de­cline here looks mod­er­ate­ly bet­ter than the ph1/2, the dropoff in ex­pres­sion from year 1 to 2 is still mean­ing­ful, and we still be­lieve that clin­i­cal dura­bil­i­ty (the ques­tion of how long will it last) will re­main top of mind for clin­i­cians, es­pe­cial­ly giv­en that there are oth­er good treat­ment op­tions for He­mo­phil­ia A,” Stifel’s Paul Mat­teis wrote, adding that the FDA had giv­en writ­ten feed­back rec­om­mend­ing two-year da­ta from all pa­tients. “Thus, while you nev­er know, it’s hard for us to see why specif­i­cal­ly these da­ta would move the agency from their con­ser­v­a­tive stance.”

Be­sides, Joseph Schwartz of SVB Leerink not­ed, the prod­uct pro­file and re­spon­der rates re­main un­clear. More da­ta might be need­ed, for in­stance, to clar­i­fy what role steroids might play in the reg­i­men as the cur­rent re­sults sug­gest their proac­tive ad­min­is­tra­tion does not seem to im­prove Fac­tor VI­II ac­tiv­i­ty.

“Al­though the da­ta are top-line, there are many stand­ing ques­tions such as how steroids will be im­ple­ment­ed in the re­al world, as­sum­ing ap­proval, and how much ex­pres­sion vari­abil­i­ty is there/are there enough ad­e­quate re­spon­ders to Roc­ta­vian,” he wrote.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Mene Pangalos (AstraZeneca via YouTube)

As­traZeneca shuts the PhI­II door for Ion­is' PC­SK9 drug de­spite pos­i­tive PhI­Ib

When Ionis and AstraZeneca unveiled the first round of mid-stage data for their antisense PCSK9 drug, Mene Pangalos, AstraZeneca’s EVP of biopharmaceuticals R&D, underscored the drug’s “potential best-in-class efficacy profile.”

But now that the second batch is in, it appears AZD8233 isn’t hitting the mark after all.

Ionis announced Friday morning that although the candidate, also dubbed ION449, met the primary endpoint in the Phase IIb SOLANO trial, its partners at AstraZeneca have decided not to move it into Phase III studies because the “results did not achieve pre-specified efficacy criteria.”

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Up­dat­ed: Bio­gen throws it­self back in­to mud­dled da­ta ar­gu­ments with more de­tails on its an­ti­sense ALS drug

With a highly watched FDA decision deadline coming in late January, Biogen and Ionis dropped the full data on the Phase III study of their ALS drug tofersen in the New England Journal of Medicine on Wednesday.

Biogen is looking for approval for tofersen in a very small subset of ALS patients — some 2%, according to the paper — who have a SOD1 gene mutation, which has previously been linked to ALS. Tofersen is meant to reduce levels of mutant SOD1 proteins.

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As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

Phil Sharp, Nobel Prize laureate (L), and John Carroll, Endpoints News co-CEO (via Michael Last)

The End­points 11: Fire­side chat with No­bel Prize lau­re­ate Phil Sharp

On Thursday evening in Boston I had the great good fortune to talk about the creation of the biotech industry with Nobel Prize-winning scientist Phil Sharp. I learned quite a bit about the early days of Genentech, Biogen and Alnylam, which all helped birth this unusual drug development ecosystem. And that’s why we can do things like the Endpoints 11. Here’s my talk with Phil Sharp, which you can either watch or read below.

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