David Liu, Broad Institute

Re­ly­ing on an ul­tra-rare vari­ant, David Liu un­veils a new ap­proach to edit­ing sick­le cell

There are now at least five dif­fer­ent ap­proach­es to cur­ing sick­le cell in or near­ing hu­man test­ing from at least eight dif­fer­ent com­pa­nies or aca­d­e­m­ic cen­ters. But re­searchers have not stopped look­ing for im­prove­ments.

David Liu, the co-in­ven­tor of base edit­ing and co-founder of Beam Ther­a­peu­tics, un­veiled in Na­ture Tues­day a new ap­proach for us­ing gene edit­ing to turn pa­tients’ sick­ling he­mo­glo­bin in­to a healthy form of the pro­tein. If it plays out in hu­mans, ex­perts say, the strat­e­gy could of­fer a more di­rect and po­ten­tial­ly safer way of treat­ing the de­bil­i­tat­ing ge­net­ic dis­ease.

“It’s a step for­ward,” said Ste­fano Riv­el­la, who works on gene-based cures for blood dis­or­ders at Chil­dren’s Hos­pi­tal of Philadel­phia and was not in­volved in the study. “It’s very promis­ing and def­i­nite­ly some­thing nov­el com­pared to the oth­er tech­nolo­gies.”

Over the last half-decade, com­pa­nies have large­ly re­lied on two gene-based strate­gies for treat­ing sick­le cell, nei­ther of which ac­tu­al­ly deal with the mu­ta­tion di­rect­ly. Blue­bird bio us­es gene ther­a­py to give pa­tients a func­tion­ing, lab-syn­the­sized copy of the gene. And the var­i­ous CRISPR com­pa­nies — CRISPR Ther­a­peu­tics, Ed­i­tas and In­tel­lia — all use a cre­ative workaround: They shat­ter a gene that stops peo­ple from mak­ing fe­tal he­mo­glo­bin, the form of the pro­tein that most peo­ple stop mak­ing in in­fan­cy. In sick­le cell pa­tients who re­ceive the treat­ment, the fe­tal he­mo­glo­bin turns back on and be­gins fer­ry­ing oxy­gen around the body.

Both ap­proach­es have yield­ed func­tion­al cures in the clin­ic, clear­ing dozens of pa­tients of the dev­as­tat­ing pain crises that are the hall­mark of the dis­ease. But they al­so come with risks that, while not yet seen in hu­mans, have been well es­tab­lished in the lab.

To de­liv­er its gene, blue­bird re­lies on lentivirus, a re-en­gi­neered form of HIV that in­te­grates ran­dom­ly in­to a pa­tients’ DNA and could in­ter­fere with genes that sup­press tu­mors. CRISPR breaks the DNA in half, rais­ing sim­i­lar con­cerns about how the frac­ture could re­ver­ber­ate across the genome.

“I’m def­i­nite­ly con­cerned,” said Hans-Pe­ter Kiem, a gene edit­ing re­searcher at Fred Hutch. “It’s a the­o­ret­i­cal risk, but I’m def­i­nite­ly con­cerned.”

De­spite clin­i­cal suc­cess, those con­cerns have on­ly grown in the last cou­ple of years, as re­searchers spot­light­ed new ways CRISPR cuts could the­o­ret­i­cal­ly man­gle the genome: re­ar­rang­ing chro­mo­somes, for ex­am­ple, or in­ter­act­ing in pre­vi­ous­ly un­fore­seen ways with par­tic­u­lar ge­net­ic vari­ants com­mon in peo­ple with African an­ces­try.

“We have not seen any­thing yet (in the clin­ic),” said Fy­o­dor Urnov, a gene edit­ing re­searcher at UC-Berke­ley. “But this is the clas­sic ex­am­ple of where ab­sence of ev­i­dence is not ev­i­dence of ab­sence.”

Liu and a post­doc, Greg New­by, tried to find a way to fix the mu­ta­tion more di­rect­ly, with­out break­ing any­thing. That’s not a straight­for­ward task. Sick­le cell is caused by a change at a sin­gle base: a switch from A to T. Base edit­ing, the strat­e­gy Liu pi­o­neered in 2016, al­lows re­searchers to swap one base for an­oth­er with­out break­ing the dou­ble-he­lix, but it on­ly works for a frac­tion of com­bi­na­tions. T-A isn’t one of them.

In­stead, Liu and New­by de­signed a base ed­i­tor that would turn the T in­to a C, mim­ic­k­ing an ul­tra-rare he­mo­glo­bin vari­ant first iden­ti­fied in Makas­sar, In­done­sia. De­spite the mu­ta­tion, peo­ple make func­tion­al he­mo­glo­bin and live healthy lives.

“It’s sim­ply a sim­pler and more di­rect way,” Liu said. They’re “con­vert­ing a gene vari­ant that caus­es the dis­ease to one that we know ex­ists in peo­ple who are healthy.”

Work­ing with Mitchell Weiss’ lab at St. Jude, Liu and Win­ters used an elec­tric cur­rent to get ed­i­tor in­to stem cells from hu­man donors, suc­cess­ful­ly cor­rect­ing 80% of them. They did the same with mice — re­mov­ing, edit­ing and trans­plant­i­ng stem cells back in­to mice, where they per­sist­ed and were func­tion­al for 16 weeks. They then took stem cells from those mice and trans­plant­ed them in­to new mice — a way of prov­ing that the edit­ed cells had tru­ly sup­plant­ed them. Even the mice who had un­der­gone “sec­ondary trans­plan­ta­tion” pro­duced 70% edit­ed he­mo­glo­bin.

The ap­proach is high­ly sim­i­lar to one Beam Ther­a­peu­tics un­veiled in late April, when the com­pa­ny showed da­ta on edit­ing the Makas­sar mu­ta­tion in­to cell lines. Beam CSO Giuseppe Cia­ramel­la said they would take their own ap­proach in­to the clin­ic, but that Liu’s pro­vid­ed a proof-of-con­cept in an­i­mals.

“It demon­strates that this Makas­sar pro­tein is like the nor­mal and func­tion­al­ly cures the dis­ease,” he said.

Cia­ramel­la said Beam planned to de­vel­op both the Makas­sar ap­proach and their own base-edit­ed fe­tal he­mo­glo­bin ap­proach and, af­ter ear­ly stud­ies, de­cide which one to bring in­to a piv­otal tri­al. The fe­tal he­mo­glo­bin strat­e­gy, called Beam-101, should en­ter the clin­ic this year, he said, with the Makas­sar not far be­hind.

The hope is that the Makas­sar can pro­vide more ben­e­fits than just safe­ty. Cia­ramel­la not­ed that al­though fe­tal he­mo­glo­bin has been proven to ef­fec­tive­ly elim­i­nate pa­tients’ pain crises, many of the dis­ease’s worst ef­fects – in­clud­ing life ex­pectan­cy in the mid-40s — come not from crises, but from or­gan dam­age that builds up over time.

Pa­tients who re­ceive gene edit­ing ther­a­py to pro­duc­ing fe­tal he­mo­glo­bin con­tin­ue to al­so pro­duce sick­ling he­mo­glo­bin. It’s pos­si­ble that elim­i­nat­ing sick­ling he­mo­glo­bin — or at least as much sick­ling he­mo­glo­bin as pos­si­ble — could fur­ther re­duce the risk of dam­age.

“The da­ta for el­e­vat­ing fe­tal he­mo­glo­bin look very im­pres­sive, but they’re re­cent,” said Urnov, who is al­so de­vel­op­ing a CRISPR-based strat­e­gy for di­rect­ly cor­rect­ing he­mo­glo­bin. “The gene ther­a­py da­ta look very im­pres­sive. They’re al­so very re­cent.”

Urnov added that com­pa­nies and the med­ical world had an oblig­a­tion to bring as many op­tions for­ward as pos­si­ble for sick­le cell, a dis­ease that pri­mar­i­ly af­fects African Amer­i­cans and where pa­tients have long been ig­nored by drug de­vel­op­ers and faced sys­temic dis­crim­i­na­tion when try­ing to seek treat­ment.

Liu’s strat­e­gy, though, doesn’t solve all the prob­lems with the first gen­er­a­tion of sick­le cell gene ther­a­pies. Riv­el­la not­ed that, while their strat­e­gy re­duces off-tar­get ed­its, it doesn’t elim­i­nate them en­tire­ly.

It al­so doesn’t get at the biggest risk that’s al­ready shown it­self in hu­mans: The in­ten­sive con­di­tion­ing that pa­tients in every tri­al have to go through be­fore re­ceiv­ing their edit­ed cells. The chemother­a­py used, busul­fan, has been linked in the past to can­cers and ex­perts now sus­pect it may al­so have helped trig­ger the cas­es of leukemia and myelodys­plas­tic syn­drome blue­bird re­cent­ly saw in its sick­le cell tri­als.

Kiem said he could en­vi­sion us­ing Liu’s strat­e­gy with the in-vi­vo ap­proach he is try­ing to de­vel­op, which would elim­i­nate the need for any kind of con­di­tion­ing. And oth­er com­pa­nies are try­ing to de­vel­op gen­tler al­ter­na­tives busul­fan. The ef­forts, though, re­main ear­ly stage.

“As long as peo­ple use busul­fan,” Riv­el­la said. “It doesn’t mat­ter if you use gene ad­di­tion, gene edit­ing, or base edit­ing. The prob­lem will be there.”

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

15 LGBTQ lead­ers in bio­phar­ma; Paul Stof­fels’ Gala­pa­gos re­vamp; As­traZeneca catch­es up in AT­TR; 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.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.

AstraZeneca's new Evusheld direct to consumer campaign aims to reach more immunocompromised patients.

As­traZeneca de­buts first con­sumer cam­paign for its Covid-19 pro­phy­lac­tic Evusheld — and a first for EUA drugs

AstraZeneca’s first consumer ad for Evusheld is also a first for drugs that have been granted emergency use authorizations during the pandemic.

The first DTC ad for a medicine under emergency approval, the Evusheld campaign launching this week aims to raise awareness among immunocompromised patients — and spur more use.

Evusheld nabbed emergency authorization in December, however, despite millions of immunocompromised people looking for a solution and now more widespread availability of the drug.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.

De­spite a slow start to the year for deals, PwC pre­dicts a flur­ry of ac­tiv­i­ty com­ing up

Despite whispers of a busy year for M&A, deal activity in the pharma space is actually down 30% on a semi-annualized basis, according to PwC’s latest report on deal activity. But don’t rule out larger deals in the second half of the year, the consultants said.

PwC pharmaceutical and life sciences consulting solutions leader Glenn Hunzinger expects to see Big Pharma companies picking up earlier stage companies to try and fill pipeline gaps ahead of a slew of big patent cliffs. Though a bear market continues to maul the biotech sector, Hunzinger said recent deals indicate that pharma companies are still paying above current trading prices.

Abortion-rights protesters regroup and protest following Supreme Court's decision to overturn Roe v. Wade. (AP Photo/Gemunu Amarasinghe)

Fol­low­ing SCO­TUS de­ci­sion to over­turn abor­tion pro­tec­tions, AG Gar­land says states can't ban the abor­tion pill

Following the Supreme Court’s historic decision on Friday to overturn Americans’ constitutional right to an abortion after almost 50 years, Attorney General Merrick Garland sought to somewhat reassure women that states will not be able to ban the prescription drug sometimes used for abortions.

Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

GSK says its drug for chron­ic hep B could ‘lead to a func­tion­al cure’ — but will it be alone or in com­bi­na­tion?

GSK, newly branded and soon-to-be demerged, shared interim results from its Phase II trial on its chronic hepatitis B treatment, one that it says has the “potential to lead to a functional cure.”

At a presentation at the EASL International Liver Congress, GSK shared that in around 450 patients who received its hep B drug bepirovirsen for 24 weeks, just under 30% had hepatitis B surface antigen and viral DNA levels that were too low to detect.

FDA un­veils new draft guid­ance to help with oligonu­cleotide ther­a­peu­tics de­vel­op­ment

While oligonucleotides, a wide variety of synthetically modified RNA or RNA/DNA hybrids that bind to a target RNA sequence to alter RNA and/or protein expression, have been winning approvals in recent years (e.g. Novartis’ cholesterol drug Leqvio), the regulatory agency is offering new draft guidance for those looking to follow a similar path.

The non-binding guidance, titled “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics Guidance for Industry” deals with pharmacokinetic, pharmacodynamic, and safety assessments required as part of oligonucleotide therapeutics R&D.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

The story of Amryt Pharma’s candidate for the genetic skin condition epidermolysis bullosa, or EB, will soon enter another chapter.

After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

Sen. Thom Tillis (R-NC) (J. Scott Applewhite/AP Images)

Phar­ma-friend­ly sen­a­tor calls on FDA for a third time to show patent pro­tec­tions should­n't be blamed for high drug prices

North Carolina Republican Sen. Thom Tillis made a name for himself in the 2020 election cycle as the darling of the pharma industry, accepting hundreds of thousands in campaign contributions, even from the likes of Pfizer CEO Albert Bourla.

Those contributions have led Tillis to attempt to re-write patent laws in pharma’s favor, a move which failed to gain steam in 2019, and request for a third time since January that the FDA should help stop “the false narrative that patent protections are to blame for high drug prices.”