Io­n­is/Akcea's Pfiz­er-part­nered an­ti­sense drug shows promise in study, with im­pli­ca­tions for Ar­row­head RNAi as­set — an­a­lysts

Pfiz­er forked over $250 mil­lion up­front to li­cense an an­ti­sense as­set from Akcea and its sis­ter com­pa­ny Io­n­is last year. On Wednes­day, the large US drug­mak­er got a taste of what it has in­vest­ed in.

The two de­vel­op­ers said the drug — AKCEA-ANGPTL3-LRx — met the main goal of sig­nif­i­cant­ly low­er­ing triglyc­eride lev­els in pa­tients with hy­per­triglyc­eridemia, type 2 di­a­betes and non-al­co­holic fat­ty liv­er dis­ease (NAFLD).

An­ti­sense drugs are en­gi­neered to in­ter­rupt the pro­duc­tion of dis­ease-caus­ing pro­teins by tar­get­ing the spe­cif­ic cor­re­spond­ing mes­sen­ger RNA (mR­NA) that en­codes that pro­tein, there­by ma­nip­u­lat­ing pro­tein pro­duc­tion. AKCEA-ANGPTL3-LRx is de­signed to re­duce the pro­duc­tion of an­giopoi­etin-like 3 pro­tein (ANGPTL3) in the liv­er, a key reg­u­la­tor of triglyc­erides, cho­les­terol, glu­cose and en­er­gy me­tab­o­lism.

The 105-pa­tient, place­bo-con­trolled mid-stage study al­so showed the ther­a­py in­duced dose-de­pen­dent re­duc­tions in ANGPTL3, apoC-III (a pro­tein made by the liv­er that plays a key role in the reg­u­la­tion of serum triglyc­erides), very low-den­si­ty lipopro­tein, bad cho­les­terol and to­tal cho­les­terol.

“Fi­nal­ly, and per­haps equal­ly im­pact­ful re­gard­ing the fu­ture di­rec­tion of the pro­gram, no re­duc­tions in liv­er fat or de­creas­es in A1C were ob­served, ren­der­ing it less like­ly that the med­i­cine is po­si­tioned for NAFLD or type 2 di­a­betes (each were ini­tial­ly laid out as pos­si­bil­i­ties when the PFE deal was struck),” Stifel’s Paul Mat­teis wrote in a note.

“We be­lieve full da­ta will be en­light­en­ing re­gard­ing how this drug stacks up against oth­ers in the Io­n­is/Akcea pipeline and more broad­ly in the CV space; man­age­ment views the drug as dif­fer­en­ti­at­ed from APOC­I­I­IL­Rx, which may be­come clear when we see more de­tails re­gard­ing spe­cif­ic lipid changes.”

On­ly days ago, Akcea and Io­n­is un­veiled Phase II da­ta on AKCEA-APOC­I­II-LRx, an­oth­er ex­per­i­men­tal an­ti­sense drug, which No­var­tis had an op­tion on. The high dose of the ther­a­py sur­passed the place­bo’s im­pact in sig­nif­i­cant­ly re­duc­ing triglyc­erides; in ad­di­tion, it al­so slashed apoC-III, very low-den­si­ty lipopro­tein and rem­nant cho­les­terol while boost­ing good cho­les­terol lev­els.

In De­cem­ber, No­var­tis de­cid­ed to walk away from AKCEA-APOC­I­II-LRx — about a month af­ter the Swiss drug­mak­er struck a $9.7 bil­lion deal to swal­low The Med­i­cines Com­pa­ny. The New Jer­sey-based com­pa­ny’s PC­SK9 drug in­clisir­an is pow­ered by Al­ny­lam’s RNAi tech­nol­o­gy that al­lows for high ef­fi­ca­cy in low­er­ing LDL with in­fre­quent dos­es — and is be­ing po­si­tioned as a for­mi­da­ble ri­val to the ex­ist­ing PC­SK9 ther­a­pies from Am­gen and Re­gen­eron/Sanofi.

But ear­ly in 2019, No­var­tis did elect to take over the late-stage de­vel­op­ment of Akcea/Io­n­is’ as­set — AKCEA-APO(a)-L — months af­ter they re­vealed the ther­a­py could slash lipopro­tein (a) lev­els sig­nif­i­cant­ly in at-risk car­dio pa­tients in a Phase II study.

Pfiz­er tied up with Akcea/Io­n­is in Oc­to­ber in a deal that made the two drug­mak­ers el­i­gi­ble to re­ceive up to $1.3 bil­lion in mile­stone pay­ments, in ad­di­tion to dou­ble-dig­it roy­al­ties.

De­tailed da­ta on the AKCEA-ANGPTL3-LRx pro­gram will be un­veiled by Pfiz­er some­time lat­er in 2020, Akcea said on Wednes­day.

Since the pre­lim­i­nary Akcea/Io­n­is da­ta makes it un­like­ly AKCEA-ANGPTL3-LRx will work for type 2 di­a­betes and NAFLD, the da­ta could have an im­pact on com­peti­tor Ar­row­head Phar­ma­ceu­ti­cals RNAi drug, ARO-ANG3, an­a­lysts said.

“For com­peti­tor AR­WR – still in ear­ly-stage stud­ies – this ev­i­dence of lim­it­ed ap­plic­a­bil­i­ty of ANGPTL3 nar­rows the op­por­tu­ni­ty for ARO-ANG3 to dys­lipi­demia – an over­lap­ping tar­get pop­u­la­tion with its oth­er ear­ly-stage as­sets – in the face of large phar­ma com­peti­tors with a mul­ti-year head start,” SVB Leerink’s Mani Foroohar said.

But Baird’s Mad­hu Ku­mar was more op­ti­mistic, sug­gest­ing ARO-ANG3 will like­ly prove su­pe­ri­or to the Akcea/Io­n­is an­ti­sense drug.

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

Stéphane Bancel, Moderna CEO

'This is not go­ing to be good': Mod­er­na CEO Ban­cel warns of a 'ma­te­r­i­al drop' in vac­cine ef­fi­ca­cy as Omi­cron spreads

Even as public health officials remain guarded about their comments on the likelihood Omicron will escape the reach of the currently approved Covid-19 vaccines, there’s growing scientific consensus that we’re facing a variant that threatens to overwhelm the vaccine barricades that have been erected.

Stéphane Bancel, the CEO of Moderna, one of the leading mRNA players whose quick vault into the markets with a highly effective vaccine created an instant multibillion-dollar market, added his voice to the rising chorus early Tuesday. According to Bancel, there will be a significant drop in efficacy when the average immune system is confronted by Omicron. The only question now is: How much?

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Philip Dormitzer, new GSK global head of vaccines R&D

Glax­o­SmithK­line poach­es Pfiz­er's vi­ral vac­cines lead in rush to cap­i­tal­ize on fu­ture of mR­NA

GlaxoSmithKline has appointed Philip Dormitzer, formerly chief scientific officer of Pfizer’s viral vaccines unit, as its newest global head of vaccines R&D, looking to leverage one of the leading minds behind Pfizer and BioNTech’s RNA collaboration that led to Covid-19 jab Comirnaty, the British drug giant said Tuesday.

Dormitzer had been with Pfizer for a little more than six years, joining up after a seven-year stint with Novartis, where he reached the role of US head of research and head of global virology for the company’s vaccines and diagnostics unit.

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In­tro­duc­ing End­points Stu­dio, a new way to ad­ver­tise with End­points-craft­ed brand­ing cam­paigns

Since our start in 2016, Endpoints has grown fast while executing our mission to cover biopharma’s most critical developments for industry pros worldwide. As readership has grown, our advertising business has too. Endpoints advertising partners support the mission and engage their desired audiences through announcements on our email and web platforms, brand recognition in our event coverage and sponsorships of Endpoints daily and weekly reports.

Reshma Kewalramani, Vertex CEO (Vertex via YouTube)

Bat­tling a line­up of skep­tics, Ver­tex claims an­oth­er ear­ly clin­i­cal win — this time in kid­ney dis­ease

Vertex claimed its second early-stage win of the fall Wednesday, announcing positive results in a small study on a genetically defined form of kidney disease.

The 16-patient, Phase II trial focused on patients with focal segmental glomerulosclerosis, a rare disease where kidneys are unable to filter blood properly. Over 13 weeks on an experimental pill, the level of protein in the patients’ urine fell by an average of 47.6%.

With on­ly burns to show in gene ther­a­py, Astel­las inks deal with AAV spe­cial­ist Dyno in push for a bet­ter cap­sid

On the hunt for a better AAV capsid for gene therapy, Eric Kelsic’s Dyno Therapeutics has set itself apart with its focus on machine learning to help speed discovery. Now, Japanese drugmaker Astellas — fresh off a slate of gene therapy burns — is taking a bet on Dyno as it looks to the future.

Astellas and Dyno will work together as part of an R&D pact to develop next-gen AAV vectors for gene therapy using Dyno’s CapsidMap platform directed at skeletal and cardiac muscle, the companies said Wednesday. Under the terms of the deal, Dyno will design AAV capsids for gene therapy, while Astellas will be responsible for conducting preclinical, clinical and commercialization activities for gene therapy product candidates using the capsids.

As first Omi­cron case in US crops up, re­searchers won­der: which an­ti­bod­ies, vac­cines will hold up?

As Covid-19 drug and vaccine developers race to figure out which of their products might be hampered by the new variant, the CDC on Wednesday afternoon announced the first confirmed case of the Omicron variant (B.1.1.529) in the US, found in San Francisco.

The unidentified individual was a traveler who returned from South Africa on Nov. 22, 2021, was fully vaccinated, and had mild symptoms that the CDC described as improving. All close contacts have been contacted and have tested negative, the centers said.

As lead drug runs in­to a wall, De­ci­phera slims down its pipeline, puts 140 jobs on the chop­ping block

Barely a month after disappointing data shattered hopes for a major label expansion for the GI tumor drug Qinlock, Deciphera is making a major pivot — scrapping development plans for that drug and discarding another while it hunkers down and focuses on two remaining drugs in the pipeline.

As a result, 140 of its staffers will be laid off.

The restructuring, which claims the equivalent of 35% of its total workforce, will take place across all departments including commercial, R&D as well as general and administrative support functions, Deciphera said, as it looks to streamline Qinlock-related commercial operations in the US while concentrating only on a “select number of key European markets.”

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How to use reg­istry da­ta to sup­port FDA de­ci­sion mak­ing: Agency ex­plains in new guid­ance

Drugmakers looking to design a new registry or use an existing one to support a regulatory decision on a drug’s effectiveness or safety will need to consult with a new draft guidance released Monday by the FDA.

The agency’s reliance on registry data for regulatory decisions dates back more than two decades, at least, as in 1998 Bayer won approval for its anticoagulant Refludan (withdrawn from the market in 2013 for commercial reasons) based in part on a historical control group pulled from a registry.