RNA: From the mes­sen­ger to the med­i­cine

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

In the 1990s, my col­leagues and I were gene hunters. In the years be­fore the hu­man genome was ful­ly se­quenced, we searched tire­less­ly for the ge­net­ic roots of dis­ease. It was a decades-long en­deav­or to first de­fine a syn­drome, then lo­cate the re­spon­si­ble gene, de­ter­mine its se­quence, study its mu­ta­tions and ma­nip­u­late it for ther­a­peu­tic ben­e­fit.

At the time, RNA sci­ence wasn’t be­ing se­ri­ous­ly con­sid­ered. DNA was our star, and RNA was a bit play­er.

It’s a dif­fer­ent sto­ry to­day, now that mR­NA vac­cines that were de­vel­oped in record time are pro­tect­ing mil­lions of peo­ple from a dan­ger­ous ill­ness. There is a dawn­ing aware­ness of the po­ten­tial for RNA-based med­i­cines. The CEO of the Bill & Melin­da Gates Med­ical Re­search In­sti­tute, Pen­ny Heaton, calls mR­NA vac­cines the be­gin­ning of “a new gold­en age of vac­ci­nol­o­gy.”

But she could have been even more op­ti­mistic. Be­cause af­ter decades of re­search in­to this nu­cle­ic acid that was once seen as a hum­ble as­sis­tant to DNA, RNA sci­ence is of­fer­ing new in­sights in­to in­tractable con­di­tions whose caus­es were pre­vi­ous­ly a mys­tery. It’s al­so un­lock­ing pow­er­ful new treat­ments.

Genes tell the body what to do. But if their code is gar­bled or in­com­pre­hen­si­ble, dis­ease will get the up­per hand. RNA—present in every cell in the body—is the mes­sen­ger of these im­por­tant in­struc­tions. These mes­sages (RNA tran­scripts) can be edit­ed to achieve a sub­stan­tial ther­a­peu­tic ef­fect, and this has im­pli­ca­tions in a wide range of de­gen­er­a­tive dis­eases.

It’s hard to be­lieve we ever viewed RNA as a poor re­la­tion to DNA. It’s not just a gold­en age for vac­cines that we have en­tered, it’s the be­gin­ning of a whole new era for med­ical sci­ence.

The op­por­tu­ni­ty

Hun­dreds of dis­eases can be traced to dys­func­tion­al pro­teins in the body. While DNA es­sen­tial­ly in­structs cells to cre­ate or reg­u­late these pro­teins in a way that pro­motes health and sur­vival, there are of­ten mis­prints, ty­pos, dele­tions and oth­er er­rors in DNA’s in­struc­tions. Con­se­quent­ly, the body some­times fails to pro­duce nec­es­sary pro­teins, pro­duces tox­ic pro­teins or fails to prop­er­ly reg­u­late pro­tein pro­duc­tion. This means dis­ease.

It al­so means the po­ten­tial for RNA-based med­i­cines, which seek to cor­rect these er­rors, is vast. And these treat­ments of­fer some­thing that gene ther­a­py or gene edit­ing does not: the abil­i­ty to make changes to cells that are re­versible and will not last a life­time.

Un­like gene ther­a­pies or gene edit­ing, RNA can be made to func­tion the way con­ven­tion­al drugs do. It can achieve a ther­a­peu­tic re­sult with­out mak­ing a per­ma­nent change to the pa­tient’s cells. Gene ther­a­pies or gene edit­ing risk cre­at­ing off-tar­get ef­fects in neigh­bor­ing cells and or­gans, which can be­come per­ma­nent changes. By con­trast, the body can shed an RNA ther­a­py the way it can shed the ef­fects of a drug.

The abil­i­ty of RNA to clar­i­fy DNA in­struc­tions to pro­mote hu­man health, with­out per­ma­nent al­ter­ations to a per­son’s cells, is why the po­ten­tial for RNA-based med­i­cines goes far be­yond de­vel­op­ing the next gen­er­a­tion of vac­cines. Biotech com­pa­nies are ex­plor­ing the many pos­si­bil­i­ties to­day.

One suc­cess­ful com­mon ap­proach in­volves “knock­ing down” dys­func­tion­al pro­teins that can lead to dis­ease, for ex­am­ple de­gen­er­a­tive con­di­tions like amy­otroph­ic lat­er­al scle­ro­sis (ALS) or meta­bol­ic dis­or­ders. Biotech com­pa­nies have been mak­ing in­roads on these con­di­tions by edit­ing RNA in­struc­tions to elim­i­nate a “gain-of-func­tion” pro­tein. In these cas­es, weak­en­ing the pro­duc­tion of cer­tain tox­ic pro­teins lessens the dis­ease im­pact.

Oth­er com­pa­nies are aim­ing not to elim­i­nate pro­teins but sim­ply al­ter their pro­duc­tion by splic­ing the pre-mR­NA that pro­vides their in­struc­tion guide and di­rec­tions for reg­u­la­tion. This is the case at Sarep­ta, where I pre­vi­ous­ly served as CEO and chief med­ical of­fi­cer.

The com­pa­ny I lead now, Stoke Ther­a­peu­tics, is pi­o­neer­ing a whole dif­fer­ent RNA ap­proach. Stoke is fo­cused on hap­loin­suf­fi­cien­cies or dis­eases like Dravet syn­drome (a se­vere and pro­gres­sive ge­net­ic epilep­sy) and au­to­so­mal dom­i­nant op­tic at­ro­phy that are caused by “loss of func­tion” mu­ta­tions in one copy of a gene, which re­sult in in­suf­fi­cient pro­tein lev­els that are es­sen­tial to hu­man health. Rather than knock­ing down the dys­func­tion­al gene, as oth­er com­pa­nies seek to do, Stoke is de­sign­ing RNA-based med­i­cines to in­crease ex­pres­sion of the prop­er­ly func­tion­ing gene in the pair, “up-reg­u­lat­ing” its pro­tein pro­duc­tion and there­by com­pen­sat­ing for the non-func­tion­al copy of the gene. By se­lec­tive­ly restor­ing, or “stok­ing”, the pro­duc­tion of the nat­u­ral­ly oc­cur­ring pro­tein, Stoke’s TAN­GO (Tar­get­ed Aug­men­ta­tion of Nu­clear Gene Out­put) ap­proach has the po­ten­tial to ad­dress the un­der­ly­ing ge­net­ic cause of hap­loin­suf­fi­cient dis­eases.

RNA sci­ence is even carv­ing out a pres­ence in di­ag­nos­tics, with RNA analy­sis of liq­uid biop­sy for can­cer en­abling ear­li­er di­ag­no­sis.

Vac­cines did not ush­er in a whole new era of RNA-based med­i­cine. But they shined a light on this area, which has been de­vel­op­ing steadi­ly for two decades, and which is open­ing the door to a seem­ing­ly end­less ar­ray of ap­pli­ca­tions, dis­ease states and treat­ment path­ways that, once ex­plored, will al­ter how we un­der­stand and treat ge­net­ic dis­eases.

The need

Be­fore I took the helm at biotech­nol­o­gy com­pa­nies, I treat­ed pa­tients at the point of care. Most of my pa­tients were chil­dren with rare dis­eases.

I have seen what ge­net­ic dis­eases can do, and I know the frus­tra­tion that comes with talk­ing to par­ents about id­io­path­ic con­di­tions that de­grade their chil­dren’s qual­i­ty of life – or worse. Id­io­path­ic means we just can’t shed much light on the cause of dis­ease, even when its ef­fects are all too vis­i­ble. For a doc­tor, the frus­tra­tion that came with di­ag­no­sis and treat­ment of id­io­path­ic con­di­tions was too in­tense to de­scribe.

One of the great things about this new era of ge­net­ic med­i­cine we are liv­ing in is that we now know far more about the caus­es of dis­ease. Many con­di­tions are in­her­it­ed.

But too of­ten, un­der­stand­ing the cause has not led to a cure or even a less­en­ing of the con­di­tion. Gene ther­a­py and gene edit­ing have shown ini­tial promise, but we need ad­di­tion­al strate­gies if we are to trans­late ful­ly our in­creased un­der­stand­ing of dis­ease in­to pow­er­ful treat­ments.

RNA is the next leg of this ex­cit­ing jour­ney. As DNA’s tran­scriber and mes­sen­ger, its use in med­i­cine brings us clos­er to stop­ping dis­eases of all kinds right at their source.

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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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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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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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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Troy Wilson, Kura CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.

A Sen­ate bill wants to even an 'un­lev­el play­ing field' for do­mes­tic, for­eign in­spec­tion drop-ins amid back­log

Amid geopolitical tensions between the US and China, two Republican senators are calling for a bill that would aim to strike a balance on domestic and foreign inspection requirements from the FDA.

Sens. Mike Braun (R-IN) and Joni Ernst (R-IA) have penned a bill called the Creating Efficiency in Foreign Inspections Act. It contains a bit of rhetoric, highlighting “communist China” not once, but twice in the release, but states that the goal is to even the playing field between foreign and American manufacturers.

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