Sekar Kathiresan (Verve)

Look­ing to leapfrog an­ti­bod­ies and RNAi, Sekar Kathire­san says gene edit­ing ap­proach to cut PC­SK9 looks durable

JP Mor­gan isn’t typ­i­cal­ly a da­ta con­fer­ence. But there are al­ways ex­cep­tions for da­ta that could make or break a com­pa­ny, piquing the in­ter­est of po­ten­tial in­vestors and part­ners alike.

Da­ta, for in­stance, like what Sekar Kathire­san is bring­ing to the vir­tu­al con­fer­ence, show­ing that a one-time treat­ment with Verve Ther­a­peu­tics’ base ed­i­tor can keep PC­SK9 lev­els low — there­by low­er­ing LDL cho­les­terol, aka the bad kind — out to 6 months. In non-hu­man pri­mates.

The two take­away fig­ures are 61% LDL cho­les­terol re­duc­tion and 89% cut in av­er­age blood PC­SK9 pro­tein lev­el. That’s the same lev­el of re­duc­tion for PC­SK9 as the treat­ment reg­is­tered at 2 weeks, when the re­searchers doc­u­ment­ed a 59% drop in LDL-C.

“What you are see­ing is durable low­er­ing of cho­les­terol and con­sis­tent low­er­ing of LDL cho­les­terol 6 months af­ter ad­min­is­tra­tion of the gene edit­ing treat­ment,” Kathire­san told End­points News in a pre­view.

While pre­clin­i­cal, the re­sults mark a sig­nif­i­cant step for the in vi­vo use of the next-gen­er­a­tion gene edit­ing tool known as base edit­ing. Where­as the first gen­er­a­tion of CRISPR gene edit­ing mol­e­cules would snip the DNA se­quence and let it re­pair on its own, base edit­ing works by con­vert­ing one let­ter on the genome to an­oth­er.

In this case the con­struct, VERVE-101, made a sin­gle change from A to G in the ge­net­ic se­quence of the PC­SK9 gene in the liv­er, with an aim to in­ac­ti­vate the gene for good.

As liv­er cells turn over rough­ly every 200 days, Kathire­san added, 6-month dura­bil­i­ty da­ta of­fer rea­son­able con­fi­dence that the changes are there to stay.

“The fun­da­men­tal prob­lem with coro­nary heart dis­ease is cu­mu­la­tive ex­po­sure to LDL over time, OK? And the fun­da­men­tal treat­ment is to low­er that cu­mu­la­tive ex­po­sure as much as pos­si­ble,” said the CEO, who left be­hind an aca­d­e­m­ic ca­reer and a di­rec­tor­ship at Mass Gen­er­al’s Cen­ter for Ge­nom­ic Med­i­cine to steer the biotech. “The way to think about this is kind of the area un­der the curve analy­sis, you know? You want to keep the LDL down and con­sis­tent­ly down for as long a pe­ri­od as pos­si­ble.”

VERVE-101 rides on the phar­ma­co­log­ic val­i­da­tion of­fered by mon­o­clon­al an­ti­bod­ies and siR­NA ther­a­pies that tar­get PC­SK9 but does away with the need for chron­ic treat­ment. Each of which he sees pre­sent­ing its own com­pli­ance is­sues that could lead to in­suf­fi­cient pro­tec­tion.

With tox­i­col­o­gy stud­ies un­der­way, Verve ex­pects to dose its first pa­tient some time in 2022. By tar­get­ing the ini­tial clin­i­cal in­di­ca­tion of het­erozy­gous fa­mil­ial hy­per­c­ho­les­terolemia, the com­pa­ny will be de­vel­op­ing “a ge­net­ic treat­ment for a ge­net­ic dis­ease” be­fore turn­ing to “gar­den va­ri­ety coro­nary heart dis­ease.”

PC­SK9 will just be a start. Kathire­san has iden­ti­fied sev­en oth­er genes that, as he’s dis­cov­ered over years of stud­ies in pop­u­la­tion ge­net­ics, har­bor pro­tec­tive mu­ta­tions — one of them be­ing ANGPTL3, for which Verve has al­so pre­sent­ed 2-week pre­clin­i­cal da­ta. All eight tar­gets fall in­to one of three path­ways: LDL-C, triglyc­erides or lipopro­tein(a).

“Each of those path­ways are kind of com­ple­men­tary in terms of risk for a pa­tient,” he said. “So a med­i­cine tar­get­ing each of those path­ways should be ad­di­tive in terms of ben­e­fit.”

5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
Biotech is now seen by investors as a growth space as well as a safe haven, fuelling the recent IPO boom.

Janet Woodcock (AP Images)

End­points poll: Janet Wood­cock takes the (in­ter­im) helm at the FDA. And a large ma­jor­i­ty of our read­ers want her to stay there

It’s official: Janet Woodcock is now the acting chief of the FDA.

And — according to an Endpoints poll — most industry readers would like her to stay there, although a significant minority is strongly opposed.

To recap: Joe Biden is reportedly choosing between Woodcock and former deputy FDA commissioner Joshua Sharfstein as his nominee for the permanent position. Given their respective track records, the decision is set to determine the agency’s lodestar for years to come.

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An Endpoints Zoom meeting; and the email header employees will see if your company is a Premium subscriber

What’s next for End­points — and how to sup­port our in­de­pen­dent bio­phar­ma news mis­sion

The firehose of biopharma news is gushing these days.

That’s why broader and deeper is the theme for 2021 at Endpoints. You can expect new coverage outside our core R&D focus, with deeper reporting in some key areas. When John Carroll and I launched Endpoints nearly five years ago, we were wading in waist-high waters. Now we’re a team of 25 full-time staffers (and growing) with plans to cover the flood of biopharma news, Endpoints-style.

Eli Lil­ly's an­ti­body cuts risk of Covid-19 by up to 80% among the most vul­ner­a­ble — but will it have a place next to vac­cines?

Eli Lilly says bamlanivimab lowered the risk of contracting symptomatic Covid-19 in a first-of-its-kind trial involving nursing home residents and staff, paving the way for a new option to protect against the virus.

But how big of an impact it might have, and what role it will play, at a time vaccines are being rolled out to the exact population it is targeting still remains unclear.

Among 965 participants in the study — all of whom tested negative for the coronavirus at baseline — the number of symptomatic cases reported in the bamlanivimab arm was 57% lower than that in the placebo arm (odds ratio 0.43, p=0.00021). In addition to that primary endpoint, all secondary endpoints reached statistical significance.

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Hal Barron, GSK R&D chief (GSK via YouTube)

Glax­o­SmithK­line's $4B bis­pe­cif­ic can­cer drug al­liance with Mer­ck KGaA hit by big set­back with a PhI­II fail­ure on NSCLC

Close to 2 years ago, GSK’s R&D team eagerly agreed to pay up to $4 billion-plus to ally itself with Merck KGaA on a mid-stage bispecific called bintrafusp alfa, which intrigued them with the combination of a TGF-β trap with the anti-PD-L1 mechanism in one fusion protein.

But today the German pharma company says that their lead study on lung cancer was a bust, as independent monitors said there was no reason to believe that the experimental drug — targeting PD-L1/TGF-Beta — could beat Keytruda.

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Northway Biotech's new manufacturing facility in Greater Boston

North­way Biotech sets up shop in Boston hub, look­ing to court more cus­tomers with bi­o­log­ics-fo­cused plant

Getting a foot in the door in Boston’s bustling biopharma hub is a rite of passage for many companies, but it comes with a steep price tag. Lithuanian CDMO Northway — now with a new moniker — will set up a new plant in close proximity, and it’s hoping its biologics focus will find a willing customer base.

Northway Biotech (formerly Northway Biotechpharma) on Wednesday held a virtual grand opening ceremony for its $40 million Waltham, MA facility — a 30,000 square-foot cGMP manufacturing and process development plant that will widely expand on the company’s previous capabilities.

News brief­ing: Five pub­lic biotechs, over 2 days, raise $883M from fresh of­fer­ings; Bel­gian biotech ex­pands Se­ries B fund­ing

The wave of biotech IPOs we’ve been seeing in the last few days underscores that the public markets remain one of the key channels for fresh investments in drug R&D. And that trend was in full view this week as a slate of biotechs nailed down hundreds of millions of dollars in fresh funds.

One of the big winners of the week is Editas $EDIT, which nailed $231 million to back its pioneering work on a gene editing platform. The biotech sold 3.5 million shares at $66 each.

With patent con­cerns loom­ing, Roche gets a new pri­or­i­ty re­view on block­buster IPF drug

Seven years after the FDA first approved Esbriet, the blockbuster Roche IPF drug is getting an expedited review for a second indication.

On Thursday, the agency gave Esbriet priority review for unclassified interstitial lung diseases, or forms of pulmonary inflammation and scarring that don’t fit easily into the over 200 known types of ILD. The move comes 10 months after Esbriet received breakthrough designation and sets Roche up for a decision by May.

Michelle McMurry-Heath, BIO CEO (BIO via YouTube)

BIO looks to re­struc­ture, lay­ing off staff amid chal­lenge to the trade org's nor­mal face-to-face style

The biopharma industry, on the whole, had a red-letter year in 2020 amid Covid-19, with fundraising at an all-time high and major players speeding vaccines ahead to approval. But for BIO, the industry’s leading trade organization, the pandemic has prompted a reconsideration of the game plan.

BIO will pivot to digital as the Covid-19 pandemic continues to rage, making “some staff reductions” as it looks to bring its roughly 37,000 in-person meetings each year to the web, the organization said Thursday.

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