Bio­Marin isn’t go­ing to let a ri­val’s suc­cess over the week­end get in the way of mak­ing a bee-line to the FDA with an im­per­fect, but pre­sentable, gene ther­a­py for he­mo­phil­ia A.

On Mon­day the biotech $BM­RN re­port­ed that its talks with the FDA and the EMA con­vinced ex­ecs to make a leap for an ac­cel­er­at­ed ap­proval with da­ta on just a hand­ful of pa­tients. And they’re hand­ing over Phase I/II and in­ter­im Phase III re­sults in Q4 to make their case.

That de­ci­sion was made de­spite a con­sid­er­able back­lash against the lat­est snap­shot of the da­ta, with wors­en­ing ef­fi­ca­cy over time and a low­er ini­tial re­sponse in their piv­otal tri­al — but ex­cel­lent bleed rates, so far. Bio­Marin says that with a break­through drug des­ig­na­tion in the USA and Eu­rope’s prime sta­tus, they have good rea­son to be­lieve they are on track to field the world’s first gene ther­a­py.

In­vestors ap­pear some­what skep­ti­cal though, with Bio­Marin shares down 2.4% in Mon­day af­ter­noon trad­ing.

Here’s the bet they’re mak­ing, out­lined in their lat­est state­ment:

Fac­tor VI­II lev­els sus­tained over a three-year pe­ri­od were suf­fi­cient to achieve strik­ing he­mo­sta­t­ic ef­fi­ca­cy. Fac­tor VI­II ex­pres­sion has en­tered a plateau phase where the rate of de­cline has sub­stan­tial­ly slowed, which could be in­dica­tive of durable, long-term ex­pres­sion.

Leerink’s Joseph Schwartz of­fers a bull­ish as­sess­ment of Bio­Marin’s gam­ble:

Based on BM­RN’s Ph.3 da­ta, the com­pa­ny met their pre-spec­i­fied cri­te­ria for ac­cel­er­at­ed ap­proval – 8 pts achiev­ing mean fac­tor VI­II/FVI­II lev­els above 40 IU/dL. With on­ly 17 pts (out of 20 pts) eval­u­at­ed so far, it is pos­si­ble that the re­main­ing 3 could pro­vide more con­fi­dence in Val­rox al­though it is not re­quired for ac­cel­er­at­ed ap­proval since BM­RN has al­ready met the bar. The com­pa­ny is fo­cused on get­ting Val­rox to mar­ket as soon as pos­si­ble by sub­mit­ting their fil­ing in 4Q19 based on their Ph.3 in­ter­im analy­sis and aims to com­plete GEN­Er8-1 (6E13 vg/kg) en­roll­ment in ear­ly fall 2019. As­sum­ing BM­RN could in­crease and op­ti­mize ef­fi­ca­cy — re­call, chro­mogenic mea­sures were high­er in Ph.1/2 at weeks 23-26 than Ph.3 (68 IU/dL mean/57 IU/dL me­di­an in Ph.1/2 vs 36 IU/dL mean/33 IU/dL me­di­an Ph.3) — we be­lieve that po­ten­tial stud­ies BM­RN may con­duct lat­er could fur­ther boost sales and in­crease Val­rox’s at­trac­tive­ness among he­mo­phil­ia A pts, es­pe­cial­ly as com­pet­ing pro­grams (i.e., SG­MO/PFE) ap­pear to be de­liv­er­ing com­pet­i­tive ef­fi­ca­cy.

Spark Ther­a­peu­tics $ONCE is wide­ly viewed as the run­ner up for now, while Roche strug­gles to com­plete its $4.3 bil­lion buy­out as soon as pos­si­ble. But Sang­amo/Pfiz­er gar­nered some care­ful sec­ond looks a few days ago as they post­ed bet­ter ef­fi­ca­cy and a fast re­sponse among 4 evalu­able pa­tients. That team al­so out­lined plans to make a leap for­ward on an ac­cel­er­at­ed path­way as they sought to catch up with the two fron­trun­ners.

Any stum­ble at this point could prove a set­back, but if they stay on track Sang­amo and Pfiz­er may set up a sit­u­a­tion where pa­tients can choose an im­per­fect gene ther­a­py or wait for a bet­ter one. And Bio­Marin has out­lined plans to charge in the range of $2 mil­lion to $3 mil­lion per treat­ment — with the ca­pa­bil­i­ty of earn­ing $10 bil­lion to $15 bil­lion a year — adding stick­er shock for pay­ers to the list of chal­lenges.

Harith Rajagopalan compared the way type 2 diabetes is managed to sticking your fingers in a dam that’s leaking from a number of places.

You can take drugs to lower your blood sugar, cholesterol, or blood pressure, but you’re not addressing what he says is the core issue — the metabolic abnormality that causes the disease.

“We’re so busy plugging the holes in the dam, we don’t have time to see that the whole infrastructure is at risk,” he said. “That infrastructure is a full-body systemic metabolic abnormality called metabolic syndrome, that we’re ignoring while we’re so busy trying to treat all of the individual symptoms of the condition.”

Forbion laid out its case for a next-generation gene therapy approach when it took the wraps off VectorY Therapeutics and its vectorized antibody tech in February. Now, the Dutch VC has tapped an experienced hand at cell and gene therapy manufacturing to steer the ship — and pulled a marquee syndicate for a €31 million ($37.6 million) seed round.

Alexander Vos, the new CEO, is a venture partner at BioGeneration Ventures and jumps immediately from VarmX, a BGV portfolio company developing an anticoagulant. But before that, he had led Dutch CDMO PharmaCell for eight years until it was bought out by Lonza.