Doug Ingram, Sarepta CEO (Sarepta Therapeutics)

Sarep­ta re­veals pos­i­tive re­sults in limb-gir­dle gene ther­a­py tri­al. What does that mean for DMD?

Sarep­ta on Mon­day un­veiled a small batch of pos­i­tive da­ta for one of the gene ther­a­pies it bought out last year, sketch­ing a path to­ward a piv­otal study in 2021 and help­ing bol­ster the com­pa­ny’s broad­er gene ther­a­py am­bi­tions.

The gene ther­a­py, known as SRP-9003, is de­signed to treat a rare de­gen­er­a­tive dis­or­der called limb-gir­dle mus­cu­lar dy­s­tro­phy by boost­ing pro­duc­tion of a pro­tein pa­tients are miss­ing, called be­ta-sarco­gly­can. It was part of a bas­ket of treat­ments Sarep­ta ac­quired in its $165 mil­lion-buy­out of My­onexus last year. The biotech al­ready showed a low dose of the ther­a­py could lead to some in­creased ex­pres­sion of the miss­ing pro­tein and some im­proved mus­cle func­tion in 3 kids, but it was un­clear how long those re­sults would last or if a high­er dose would lead to bet­ter re­sults.

On Mon­day, though, the com­pa­ny an­nounced that their ini­tial 3 pa­tients had con­tin­ued to im­prove. Al­though there was no con­trol group, nat­ur­al his­to­ry stud­ies sug­gest­ed the av­er­age limb-gir­dle pa­tient would de­cline by 4 points on a key mea­sure of mus­cle func­tion, called the North Star As­sess­ment for Dys­fer­linopa­thy. In­stead, the three kids im­proved by 5.6 points. They al­so im­proved on their abil­i­ty to walk long dis­tances and short dis­tances and to stand up.

Louise Rodi­no-Kla­pac

“All three sub­jects at every sin­gle time pe­ri­od have im­proved in every sin­gle one of their func­tion­al scores,” Sarep­ta gene ther­a­py chief Louise Rodi­no-Kla­pac said on a con­fer­ence call with in­vestors. “All in all, very con­sis­tent re­sults that are ex­tend­ing out one year.”

The com­pa­ny was hop­ing that giv­ing a high­er dose of the vi­ral vec­tor that de­liv­ers the miss­ing gene would lead to greater pro­duc­tion of the miss­ing pro­tein. Al­though there were no func­tion­al da­ta for these 3 pa­tients, they showed sub­stan­tial­ly greater pro­tein pro­duc­tion. The av­er­age per­cent­age of mus­cle fibers was 72%, com­pared t0 51% in the first three. The mean in­ten­si­ty was 73% as op­posed to 47%. And the over­all amount of gene ex­pres­sion, as mea­sured by a west­ern blot, was 62%, as op­posed to 36.1%.

Those num­bers in­clud­ed one pa­tient who scored a 97% on the mean in­ten­si­ty met­ric.

“At least one of the chil­dren in the high dose co­hort has lit­er­al­ly maxed the test out,” CEO Doug In­gram said on the call. “It’s hard to be more pleased than that.”

The da­ta are still small and lacked a con­trol group, and the ther­a­py on­ly works on a sliv­er of the larg­er limb-gir­dle pop­u­la­tion.

Still, an­a­lysts were pleased. The safe­ty da­ta — es­sen­tial­ly no se­vere com­pli­ca­tions, save for one case of de­hy­dra­tion-in­duced vom­it­ing — and the im­prove­ment across vir­tu­al­ly every met­ric point­ed not on­ly to the po­ten­tial of the par­tic­u­lar treat­ment, but al­so of Sarep­ta’s oth­er pro­grams, in­clud­ing their Roche-part­nered gene ther­a­py for Duchenne mus­cu­lar dy­s­tro­phy.

“To­day’s re­sults show im­prove­ment in all bio­mark­ers, rel­a­tive to the low dose, with no new safe­ty is­sues,” Baird’s Bri­an Sko­r­ney wrote in a note to in­vestors. “Over­all, this da­ta con­tin­ues to sup­port our view that AAVrh74 [Sarep­ta’s vec­tor] has a unique pro­file rel­a­tive to com­peti­tors in the gene ther­a­py space, and should re­in­force both the DMD and LGMD op­por­tu­ni­ties.”

Al­though Sarep­ta has been an RNA-fo­cused com­pa­ny for the vast ma­jor­i­ty of its 40-year his­to­ry, most re­cent­ly get­ting two mus­cu­lar dy­s­tro­phy drugs ap­proved off that tech­nol­o­gy, it’s in­creas­ing­ly in­vest­ed its fu­ture in gene ther­a­py. Most promi­nent­ly, they de­vel­oped a Duchenne pro­gram that Roche paid $1.15 bil­lion up­front to part­ner on last year. The My­onexus deal, al­though far small­er in size, brought five dif­fer­ent gene ther­a­pies for five dif­fer­ent forms of limb-gir­dle mus­cu­lar dy­s­tro­phy. If all are ap­proved, In­gram said, that would ac­count for 70% of limb-gir­dle pa­tients.

All the com­pa­ny’s gene ther­a­pies use the same vec­tor — a pro­pri­etary form of ade­no-as­so­ci­at­ed virus — al­low­ing an­a­lysts to project the re­sults from this study on­to its oth­er ones, in­clud­ing SRP-9001, the much-an­tic­i­pat­ed Duchenne tri­al due to read out next year.

“We be­lieve the da­ta fur­ther val­i­dates Sarep­ta’s gene ther­a­py plat­form,” Mizuho’s Difei Yang wrote in a note to in­vestors, “and pro­vides an im­por­tant, pos­i­tive read-through to 1) SRP-9001 (mi­crody­s­trophin gene ther­a­py) giv­en the sim­i­lar vec­tor, pro­mot­er, and dose (2e14), and 2) Sarep­ta’s pipeline of five ad­di­tion­al LGMD in­di­ca­tions.”

In­gram said the com­pa­ny will talk to reg­u­la­tors about set­ting up a piv­otal tri­al for next year. The com­pa­ny wouldn’t com­mit to any de­tails, al­though they im­plied that af­ter to­day, some of those de­tails should be ob­vi­ous.

“The fi­nal dose for the reg­is­tra­tion tri­al will be se­lect­ed in Q3,” Rodi­no-Kla­pac said, “but based on the safe­ty and se­lec­tion da­ta we just showed you, I think it’s clear we’ll con­tin­ue on the high dose.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Ciaran McCrickard)

An un­ortho­dox pro­pos­al for Bio­gen's Medicare-man­dat­ed Aduhelm tri­al

Biogen has gone full blitz since Medicare announced it would only cover its new Alzheimer’s drug when used in clinical trials, accusing the agency of discriminating against Alzheimer’s patients and trying to get physicians to change regulators’ minds.  Critics, meanwhile, cheered what they see as a necessary wall protecting payers and patients from an unproven and unsafe drug.

Far less attention, though, has gone to what a Medicare-funded clinical trial would actually look like. Biogen has operated as if it would be a standard late-stage Alzheimer’s trial, enrolling a couple thousand patients and giving half placebo.

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