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 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.

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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.

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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.

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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.

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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.

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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.”

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

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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.

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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.

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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.

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Kelly Martin, Radius Health CEO

VC firms take os­teo­poro­sis drug­mak­er Ra­dius Health pri­vate for al­most $900M

After attacks from activist investors and disappointing returns on share prices, Radius Health has now agreed to new ownership, a direction resulting in leaving the Nasdaq.

Radius Health, a biotech out of Massachusetts with one approved product in its arsenal, announced Thursday morning that it agreed to be acquired by two VC firms: Gurnet Point Capital and Patient Square Capital. The deal, worth around $890 million, will include debt assumption and the payout of $1 CVR per share for investors. And on top of that, OrbiMed is providing debt financing.