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 * Reading Now RNA editing: emerging from CRISPR’s shadow By: Ben Fidler,
   Gwendolyn Wu
 * Reading Now Wave sees RNA editing validation in early trial results By: Ben
   Fidler, Ned Pagliarulo
 * Reading Now RNAi’s future the focus of new startup led by John Maraganore By:
   Ned Pagliarulo
 * Reading Now Judo Bio debuts a plan to take RNA drugs to the kidney By:
   Gwendolyn Wu
 * Reading Now Exsilio pitches a ‘leap’ forward for genetic medicine By:
   Gwendolyn Wu
 * Reading Now Orna, a circular RNA specialist, acquires a buzzy startup By:
   Jacob Bell
 * Reading Now Drugging RNA with pills: small molecules for a big frontier By:
   Gwendolyn Wu
 * Reading Now Ipsen, Skyhawk deal the latest example of pharma’s turn to
   RNA-targeting pills By: Delilah Alvarado



Trendline


THE EXPANDING WORLD OF RNA THERAPIES


luismmolina via Getty Images

NOTE FROM THE EDITOR

Genetic messenger molecules power the COVID-19 vaccines developed by Pfizer,
BioNTech and Moderna, training the body’s immune system to detect and defend
against disease and infection.

Known as messenger RNA, these molecules have for many years been the focus of
intense research and development efforts by drugmakers, drawing attention well
before the heralded arrival of the two mRNA vaccines.

More broadly, RNA, or ribonucleic acid, is squarely in drug developers’ sights
after the clinical success of medicines that block gene expression by disrupting
RNA. RNA-targeting therapies from Alnylam Pharmaceuticals, Ionis
Pharmaceuticals, Dicerna Pharmaceuticals, Biogen and Sarepta Therapeutics are
now approved for several nerve, liver and neuromuscular diseases.

Those drugs all use interfering strands of RNA to do their jobs. Over the past
several years, a number of biotech companies have made strides in constructing
small molecule drugs to target RNA, too — an approach long considered futile.
Their work has led to a flurry of dealmaking, as large pharmaceutical companies
buy into the field and expand their research. And now other approaches are
coming to the fore, led by a handful for firms exploring RNA editing. 

Read on for a look at the expanding world of RNA therapies.

Ned Pagliarulo Lead Editor
 * Reading Now RNA editing: emerging from CRISPR’s shadow By: Ben Fidler,
   Gwendolyn Wu
   
 * Reading Now Wave sees RNA editing validation in early trial results By: Ben
   Fidler, Ned Pagliarulo
   
 * Reading Now RNAi’s future the focus of new startup led by John Maraganore By:
   Ned Pagliarulo
   
 * Reading Now Judo Bio debuts a plan to take RNA drugs to the kidney By:
   Gwendolyn Wu
   
 * Reading Now Exsilio pitches a ‘leap’ forward for genetic medicine By:
   Gwendolyn Wu
   
 * Reading Now Orna, a circular RNA specialist, acquires a buzzy startup By:
   Jacob Bell
   
 * Reading Now Drugging RNA with pills: small molecules for a big frontier By:
   Gwendolyn Wu
   
 * Reading Now Ipsen, Skyhawk deal the latest example of pharma’s turn to
   RNA-targeting pills By: Delilah Alvarado
   




RNA EDITING: EMERGING FROM CRISPR’S SHADOW

Early study data from Wave Life Sciences suggests how editing RNA may yield
viable medicines. Large and small drugmakers say such results are just the
start.

By: Ben Fidler, Gwendolyn Wu • Published Oct. 22, 2024

Thorsten Stafforst remembers being told to stop wasting his time.

It was early last decade and scientists across the world were buzzing over a new
tool, called CRISPR, that could precisely alter human DNA. Working in the German
college town of Tubingen, Stafforst and fellow researchers at the local
university were instead engrossed by the prospect of rewriting RNA, DNA’s
chemical cousin.

“Everybody told me, ‘Why do you want to edit RNA?’” Stafforst said. “You can
edit DNA now; that doesn’t make sense.”

Yet in 2012 they and, shortly afterwards, a group at the University of Puerto
Rico figured out how to use a naturally occurring enzyme to swap out single
“letters” in RNA sequences. Their discovery drew from research into the biology
of octopuses and squids, which are adept at rewriting their own RNA. And as with
CRISPR, the findings pointed to a novel way of treating disease. In a world
newly enchanted by gene editing, however, their papers were met with far less
acclaim.

More than a decade later, RNA editing is a fast growing corner of the
biotechnology sector. About a dozen companies, from privately held startups to
established biotech firms, are pursuing the technology. One already has early,
but promising, clinical trial results. Others could follow soon. And large
pharmaceutical companies, such as Eli Lilly, Roche and Novo Nordisk, have taken
an interest.

RNA editing’s proponents say it may be safer and more flexible than DNA editing.
Those advantages, they contend, will enable RNA editing to address more
diseases, including common conditions that are now beyond genetic medicine’s
reach.

“It has all the features of a technology that could leapfrog other editing
technologies,” said Michael Ehlers, a general partner at Apple Tree Partners and
the CEO of RNA editing startup Ascidian Therapeutics.

But RNA editing is far less tested than CRISPR, never mind other ways drugmakers
already harness RNA to make medicines. Researchers and biotechs in the field
aren’t yet sure whether RNA editing will work as intended, or whether it will
prove as potent in humans as laboratory experiments have suggested. And one of
the technology’s purported strengths may end up a flaw, as the transient nature
of RNA editing’s effects could limit its benefit or force developers to
administer it more often than desired.

Partly as a result, companies are testing out different approaches as they
search for the best formula. “It’s still a very early technology,” Stafforst
said. “We will have to learn how to make the best drugs, and that will take a
while.”

Here’s where things stand:


WHAT IS RNA EDITING, AND HOW DOES IT WORK?

RNA molecules are shifty, versatile chains of nucleotides. While they can take
different forms and hold various functions, their main job is helping cells turn
the genetic information of DNA into proteins.

Sometimes, though, the final protein product looks different than the blueprint
RNA translates. One way this occurs is by the work of enzymes that bind to RNA
and switch one genetic letter for another. Those enzymes are named after what
they do — adenosine deaminase that acts on RNA, or ADAR — and the changes they
make can alter a protein’s shape or function. For instance, squids use ADARs to
rewrite the expression of genes in their central nervous system.

Last decade, Stafforst’s group in Germany and then another led by Joshua
Rosenthal, a senior scientist at the University of Chicago’s Marine Biological
Laboratory, discovered how to co-opt this system. In separate research papers,
they described ways to shepherd ADAR enzymes to a specific spot on messenger RNA
molecules and change the transcription of the associated protein. Stafforst’s
group and a team of Stanford University scientists led by Jin Billy Li followed
up in 2019 with a paper outlining a simpler approach.

Their findings opened up new possibilities for drugmakers. A targeted RNA edit
could correct the effects of a gene mutation that causes the production of a
harmful protein, or boost levels of a protein that’s lacking. It could be used
to mimic helpful genetic variants, break apart troublesome interactions between
proteins or target conditions without a genetic component altogether.

“There’s a whole variety of different applications that are uniquely possible
with RNA editing,” said Kris Elverum, CEO of Airna, a startup co-founded by
Stafforst.

Biotechs are now attempting to prove they can turn that potential into
medicines. Wave Life Sciences, one of the field’s leaders, uses strings of
nucleotides to coax ADAR enzymes into making a specific edit. Its lead drug
candidate, for an inherited disease called alpha-1 antitrypsin deficiency, or
AATD, changes a letter on mRNA molecules, compelling the body to make a missing
protein.

Other companies, like publicly traded ProQr Therapeutics and Korro Bio, as well
as startups Airna, Shape Therapeutics and ADARx Pharmaceuticals, are pursuing
similar ideas. “We’re all trying to get ADAR, this protein that sits inside of
you, to actually make these edits very specifically, very safely, and not hit
other adenosines throughout the RNA,” said Ron Hause, Shape’s senior vice
president and head of AI.

There are differences in their approaches, though, ranging from the tools they
use to screen for molecular guides, the RNAs they choose and the delivery
methods they’re evaluating.

ProQr is trying to use its RNA editing therapies to induce the effect of
variants known to protect against heart disease or to prevent toxic bile acid
buildup in the liver. Korro is targeting AATD, as well as exploring how to
correct for a troublesome genetic mutation in Parkinson’s disease. Shape is
packaging ADAR enzymes into engineered viruses and sending them into the brain,
where they could help treat neurological conditions.

There are other twists to the concept. Rather than try for single-letter
changes, Amber Bio and Ascidian intend to rewrite whole stretches of RNA, akin
to editing words or sentences in one go. Amber is using so-called Cas proteins —
made famous with CRISPR — to make larger RNA edits. Ascidian, meanwhile, is
editing “exons,” the sections of DNA that encode for proteins. It does so by
using engineered molecules to replace a mutated exon with a functional version
when DNA is converted into RNA.

These twists could allow RNA editing to be used for diseases caused by many
different mutations rather than just one, or even broader groups of people with
a particular condition. Ascidian’s first candidate, for a genetic eye condition
called Stargardt disease, replaces more than 20 exons at a time.

Exon editing “really opens the aperture to a much broader patient population in
any given genetic disorder,” said Ascidian Chief Scientific Officer Robert Bell.


Ascidian’s head of research Robert Bell with scientist Savita Matapurkar at the
Ascidian Therapeutics laboratory in Boston, Mass.
Permission granted by Kevin Trimmer/Ascidian Therapeutics
 


WHAT ARE THE ADVANTAGES OVER OTHER TECHNOLOGIES?

Gene editing research spread through biotech like wildfire over the past decade.
A generation of biotech companies formed following the 2012 paper that first
described the potential for CRISPR, a bacterial defense system, to be adapted to
edit human genes. Since then, CRISPR science won a Nobel Prize, and a CRISPR
drug for the blood diseases sickle cell and beta thalassemia reached market.
Newer technologies like “prime” and “base” editing, designed to make more
precise changes to DNA, have emerged, too.

CRISPR and its offshoots work by breaking DNA or rewriting genetic code —
permanent changes that can carry unintended consequences. A wayward edit might
disrupt the function of a healthy gene or, theoretically, turn cells cancerous
down the road. That raises the bar for using gene editing, Stafforst argues.
“You really need to have a fatal disease and a very bad prognosis,” he said.
(Not everyone agrees, however.)

DNA editing therapies may also not be well suited for chronic conditions, or
disorders for which people with the same underlying mutation experience variable
symptoms or disease severity, said Korro CEO Ram Aiyar.

“You don’t know environmental factors. You don’t know what other genetic
manifestations will lead to difference in severity, and you don’t want to find
that out after you treat them with a one-time therapy and find out that it
doesn’t really work,” Aiyar said.

RNA editing developers believe their technology can solve some of those
problems. Mistakes caused by oligonucleotide-mediated editing should be able to
be reversed without causing long-term harm. The transient effects of treatment
would position drugmakers to treat acute conditions or to subtly dial protein
expression up or down by adjusting dosing.

“It’s a class of new medicines that we can open up as a field,” said Wave CEO
Paul Bolno.

Bolno’s company and others will build on the decades of work already done by
makers of RNA-based therapies like antisense oligonucleotides and small
interfering RNAs. Wave and ProQr are following a similar playbook, for example.
Their treatments consist of specially engineered RNAs that enter liver cells
with the help of a sugar molecule, not a microscopic virus or other substance
the body may reject as foreign.

“We can take advantage of that history, but now apply it to the field of
editing,” Bolno said.

Developers hope the end result is drugs with the power of gene editing, but that
more closely resemble “traditional” drugs, said Elverum, Airna’s CEO.

“We’re all much more comfortable with medicines that can help us today, but give
us the flexibility of being able to adjust based on how our health evolves in
the future,” Elverum said. “It’ll take the word ‘editing’ and flip it on its
head.”

Roadblocks remain, of course. Current ADAR-based approaches are only able to
make a specific single-letter change in RNA, limiting their potential to such
diseases that involve those letters. Drugmakers don’t yet know whether the edits
they make will be efficient enough to produce a therapeutic benefit, how long
that might last or if unexpected safety issues will crop up.

“The most important next step will be clinical proof that the modality, in
principle, works,” Stafforst said in August.


WHICH COMPANIES ARE WORKING ON IT?

At least 11 companies are developing therapies that edit RNA in one way or
another.

Wave, which went public in 2015, has spent years working on multiple methods of
RNA drugmaking. But in recent years it’s added RNA editing capabilities to its
mix and formed an alliance with GSK.

ProQr made its Wall Street entry in 2014 and also recently made RNA editing a
focus. The company was developing antisense oligonucleotides for eye diseases,
but changed course after a clinical setback. It has a research partnership in
place with Eli Lilly.

Korro, which was co-founded by Rosenthal, is a newer arrival on public markets.
The company was formed a decade ago and raised more than $200 million from
private investors before going public through a reverse merger in 2023. It’s
working with Novo Nordisk. Beam Therapeutics, an established biotech in gene
editing, is dabbling in RNA editing too.

Joining those companies are a new crop of startups.

Ascidian, which launched in 2022 with the backing of Apple Tree, already has a
collaboration with Roche. It’s one of only a few companies, along with Wave and
South Korea’s Rznomics, to start a clinical trial for an RNA editing drug.

Airna emerged from stealth in 2023 with $30 million in funding led by Arch
Venture Partners. Like Wave and Korro, it is investing in AATD research. New
Enterprise Associates, Decheng Capital and Breton Capital, among others, have
poured nearly $150 million into Shape Therapeutics via two funding rounds. Shape
is working on RNA editing therapies for the brain through a deal with Roche,
according to Hause.

ADARx Pharmaceuticals is making drugs that can either silence or edit messenger
RNA. It has 12 programs in development across genetic, cardiometabolic and
central nervous system diseases, one of which is in clinical testing, according
to its website. It hasn’t yet publicly disclosed an RNA editing program,
however.

The field is still attracting new entrants. Radar Therapeutics emerged earlier
this year with a $13 million seed round. Amber took in a $26 million seed round
in 2023.

“I’m hoping all of us are successful, because we all go at it [from] a different
direction,” said Korro CEO Aiyar. “A rising tide will raise all boats here.”


WHAT IS THE STATUS OF THE TECHNOLOGY?

Wave gave RNA editing companies a boost this fall. On Oct. 16, the company
reported data from two people with AATD who were treated with one of its drugs
in a clinical trial in the U.K. Treatment quickly produced significant amounts
of a type of protein their bodies normally can’t make. The effects kicked in
within days and lasted through about two months of follow-up. Importantly, no
serious side effects were reported.

The findings are preliminary and don’t yet prove whether Wave’s therapy can
safely and effectively treat AATD, an inherited disorder that causes lung and
liver damage. Nonetheless, the data were the first clinical validation of RNA
editing and were lauded by Wall Street analysts and investors as an indication
of the technology’s potential.

“We view this as both a bar-clearing and, more importantly, enabling event for
the ADAR space,” wrote Myles Minter, an analyst at the investment bank William
Blair. Shares of Wave, ProQr and Korro all climbed substantially in response to
the news.

It’s “an important milestone” and “a big win for the field,” said Korro’s Aiyar,
of Wave’s results.

More details are expected later this month. They will be followed next year by
results in people given more than one dose of Wave’s drug.

SELECT RNA EDITING PROGRAMS IN DEVELOPMENT

Company Disease target Status Wave Life Sciences Alpha-1 antitrypsin deficiency
Phase 1: Single-dose data disclosed on Oct. 16, multi-dose data in 2025 Ascidian
Therapeutics ABCA4-related retinopathies Phase 1: Initial efficacy data to be
reported after 12 to 18 months of follow-up Rznomics Hepatocellular carcinoma,
glioblastoma Phase 1 trial underway ProQr Therapeutics Cholestatic disorders,
cardiovascular disease Phase 1 trials expected to begin late 2024 or early 2025
Korro Bio Alpha-1 antitrypsin deficiency, Parkinson’s disease, ALS, pain
Preclinical: Will request start of a Phase 1 trial in AATD by end of 2024 Shape
Therapeutics CNS disorders, Rett syndrome, Alpha-1 antitrypsin deficiency,
Stargardt disease Preclinical Airna Alpha-1 antitrypsin deficiency Preclinical:
Will request start of a Phase 1 trial in 2025

SOURCE: Companies, clinicaltrials.gov

Other important readouts lay ahead. Ascidian should soon give a glimpse of exon
editing’s potential. The company in June began enrolling people with Stargardt
and other so-called ABCA4-related retinopathies in a Phase 1 trial. Ascidian
will assess efficacy 12 to 18 months after dosing, according to a spokesperson,
but isn’t specifying when those results might be available.

Rznomics’ drug, for liver and brain cancers, is in early-stage testing in South
Korea as well.

By the end of 2024, Korro will apply to start a clinical trial in AATD, and
expects to report interim results in the second half of next year. Its candidate
is delivered via a tiny fatty sphere rather than the sugar molecule Wave uses.
But it demonstrated an “improved preclinical profile” compared to Wave’s drug,
wrote BMO Capital Markets analyst Kostas Biliouris, in a note to investors last
week.

ProQr, meanwhile, plans to advance its first two RNA editing drugs into the
clinic by early 2025.

Outside of its Roche partnership, Shape is advancing programs for Rett syndrome,
Stargardt and AATD, according to Hause. It has a gene therapy-focused
partnership with Otsuka Pharmaceutical, too.

And Airna could file papers to move into clinical testing with an AATD drug next
year, according to Elverum, but hasn’t disclosed what else is in its pipeline.

As with initial efforts by CRISPR biotechs, many of these programs target the
same diseases. And insiders believe the RNA editing field could undergo some of
the same ups and downs as gene editing. Aiyar noted how every new technology
goes through a hype cycle, when exuberance is followed by disillusionment and,
later, a rebound that actually delivers workable products.

“There are folks that still really don’t know where RNA editing fits in the
landscape,” he said.

While initial clinical data may “derisk” RNA editing, afterwards comes the work
of making drugs that last longer, are more powerful and, eventually, solve
thorny health problems. Stafforst, at the University of Tubingen, envisions a
future when RNA editing will be used to adjust signaling cues in metabolism,
opening up its use in treating heart and metabolic conditions.

“There’s still enough to do for the next 20 years,” he said.

Article top image credit: Christoph Burgstedt via Getty Images



WAVE SEES RNA EDITING VALIDATION IN EARLY TRIAL RESULTS

Data from the first two patients treated in a Wave study show successful editing
of messenger RNA and potential for clinical benefit, the company said.

By: Ben Fidler, Ned Pagliarulo • Published Oct. 16, 2024

Clinical trial results released by Wave Life Sciences on Oct. 16 appear to
provide early validation for the company’s newest drugmaking technology as well
as a burgeoning field of genetic medicine, RNA editing.

The data are from just two patients, the first treated in a Wave study of the
biotechnology firm’s medicine for an inherited lung and liver disease called
alpha-1 antitrypsin deficiency, or AATD. Still, Wave claims the data show
convincing evidence its medicine successfully edited the messenger molecules
cells use to turn DNA blueprints into proteins.

According to the company, this kind of effect hasn’t before been demonstrated in
clinical testing. “Achieving the first-ever therapeutic RNA editing in humans is
a significant milestone for our organization, for our GSK collaboration, and for
the entire oligonucleotide field,” said Wave CEO Paul Bolno in a statement.

Wave’s medicine is built from a strand of nucleic acid known as an
oligonucleotide. Delivered into the body’s cells via a type of sugar molecule,
the oligonucleotide recruits enzymes known as ADAR to change single bases on
messenger RNA. This could allow Wave to correct garbled instructions for making
proteins in people with genetic diseases like AATD. In theory, it could also
sidestep some of the risks inherent to permanently altering DNA with drugmaking
approaches like CRISPR gene editing.

The data Wave reported Wednesday indicate that, at least in the first two
patients, the company’s treatment worked as intended. Both patients have a form
of AATD which means their bodies don’t produce wild-type AAT protein. But, after
treatment, researchers measured significant increases in this protein, as early
as the third day following and through about two months of follow-up.

Total AAT protein levels reached, on average, 10.8 micromolars in blood plasma
concentration by day 15 after treatment, which Wave said meets the threshold set
by regulators for approval of AAT augmentation therapies.

There were no serious side effects and all adverse events in this study, as well
as another in healthy volunteers, have been mild to moderate in nature, Wave
said.

While preliminary, Wave’s results look to be a step forward for RNA editing,
which has recently drawn significant investment from biotech and pharmaceutical
companies alike.

Because RNA molecules degrade quickly, the effects of an RNA editing treatment
are temporary. Developers claim this will help avoid the risk of long-term harm
that might result from wayward snips to DNA via gene editing. They also contend
RNA editing allows for more precise tweaking of protein expression and gives
them the ability to administer multiple doses.

“It can address a whole bunch of features” associated with DNA editing, said
Bolno, in a recent interview with BioPharma Dive.

Wave is one of only two companies, along with privately held Ascidian
Therapeutics, with an RNA editing medicine in human trials. Its trial has
therefore been closely watched by investors and analysts as a gauge of how well
the technology might actually work.

Notably, while the two patients only received a single dose of Wave’s drug, the
effects of treatment appeared more potent and durable than analysts had
expected. The findings “provide [a] robust demonstration of ADAR RNA editing in
humans” as well as “clinical validation” of Wave’s technology, wrote Leerink
Partners analyst Joseph Schwartz in a note to clients.

“We view this as both a bar-clearing and, more importantly, enabling event for
the ADAR space more broadly,” wrote William Blair analyst Myles Minter in a
separate investor note.

The results lifted shares of Wave by more than 75% on Oct. 16, pushing its
market value above $2 billion. Shares in Korro Bio and ProQR, two other
companies investing in RNA editing, rose by even more.

Korro and another firm, the privately held Airna, are also working on RNA
editing therapies for AATD. Korro has said it intends to ask regulators by the
end of the year to start a trial.

GSK has global rights to Wave’s AATD medicine under a broad partnership the two
companies signed in 2022. The British pharma will take the lead on development
and commercialization after Wave’s current trial wraps up. Wave could receive up
to $525 million in milestone payments from GSK, if all goes well.

Article top image credit: Christoph Burgstedt via Getty Images


RNAI’S FUTURE THE FOCUS OF NEW STARTUP LED BY JOHN MARAGANORE

“The time to re-enter the RNAi revolution is now,” said Robert Nelsen, the
managing director of Arch, which led the Series A funding round for City
Therapeutics.

By: Ned Pagliarulo • Published Oct. 8, 2024

Since stepping down as CEO of Alnylam Pharmaceuticals three years ago, John
Maraganore has lent his talents widely, joining the boards of up-and-coming
biotechnology companies, advising them on strategy and allying with some of the
venture firms that back those young drugmakers.

His latest role returns him to his Alnylam roots. In early October, City
Therapeutics launched with a plan to build the next generation of the “RNA
interference” medicines Alnylam pioneered. Maraganore, who co-founded City with
a group of venture capitalists, scientists and other Alnylam veterans, will
serve as the biotech’s executive chair.

“At Alnylam, we launched the birth of RNAi therapeutics as a new class of
medicines,” Maraganore said in a statement announcing City’s debut. “We see the
potential for RNAi to emerge as the next major category of high-impact
medicines, rivaling if not exceeding the success of monoclonal antibodies.”

“New innovation is needed to realize this future, and we believe City
Therapeutics can lead this next chapter,” he added.

City plans to innovate in several ways, including by tweaking the components of
the biological process by which RNA interference, or RNAi, works. Typically,
RNAi is described as a technique to “silence” genes. It does so via small,
interfering strands of RNA that trigger cleavage of the messenger RNA
instructions cells use to produce proteins.

City aims to design new kinds of RNAi triggers that similarly spark mRNA
cutting, but are smaller and more potent. One example is what City terms
“cleavage-inducing tiny RNAs,” the acronym for which led to the biotech’s name.

The startup also aims to design targeting molecules, or ligands, that enable the
delivery of these engineered RNA strands to more types of cells and tissues.
(The approved RNAi medicines that Alnylam and rival Dicerna Pharmaceuticals have
to date developed are all aimed at the liver.)

To get started, City has $135 million in funding from a large syndicate of
investors that includes Arch Venture Partners, an early investor in Alnylam.
Also backing City are Fidelity Management & Research, Invus and Regeneron
Ventures, along with several other firms.

“The time to re-enter the RNAi revolution is now, and our investment in City
Therapeutics is based on our conviction that RNAi therapeutics will expand as a
major category of breakthrough medicines,” said Robert Nelsen, a managing
director and co-founder of Arch, in a statement.

City didn’t disclose which diseases it will target, but expects to begin
clinical testing for its first program “at or around” the end of 2025. The
company hopes to advance one or two new drugs into the clinic each year after
that.

It’s not the only biotech startup setting out to improve on RNAi medicines. On
Monday, Judo Bio launched with plans to bring RNAi drugs to the kidney by using
what it calls ligand-siRNA conjugates. Maraganore is also on Judo’s advisory
board.

Article top image credit: Permission granted by City Therapeutics



JUDO BIO DEBUTS A PLAN TO TAKE RNA DRUGS TO THE KIDNEY

The Cambridge, Massachusetts-based biotech is using what it calls ligand-siRNA
conjugates to reach drug targets in the kidney, which historically have been
difficult to reach with RNA therapies.

By: Gwendolyn Wu • Published Oct. 7, 2024

A new biotechnology company called Judo Bio is taking a strike at kidney
diseases, armed with $100 million and a RNA drug platform it claims can get to
targets that historically have been challenging for researchers to hit.

Formed three years ago, Judo is backed by a handful of investors that include
Atlas Venture, which incubated the startup and co-led its Series A, as well as
The Column Group and Droia Ventures.

With its technology, Judo is following in the footsteps of Alnylam
Pharmaceuticals, which pioneered use of a biological process called RNA
interference to make a new class of drugs. Unlike Alnylam’s first medicines,
which are directed at the liver, Judo claims it can reliably sneak its RNA
medicines into the kidney.

First discovered in 1998, RNA interference gave drugmakers a tool to silence
genes that encode disease-causing proteins. In the nearly three decades since,
Alnylam has used that tool to develop five approved medicines for a range of
rare and common diseases. (A sixth, from Novo Nordisk-owned Dicerna
Pharmaceuticals, is also approved.)

Those medicines work via what’s known as small interfering RNA, or siRNA, which
can mute messenger RNA and thereby prevent problematic proteins from being made
by a cell.

Judo sees itself as a successor of sorts. Its leadership includes Alnylam
veteran Alfica Sehgal, who now serves as the startup’s chief scientific officer,
while John Maraganore, Alnylam’s former CEO, sits on its advisory board.

The company’s platform is built around so-called ligand-siRNA conjugates, which
pair the gene silencing nucleic acid with a targeting molecule. Judo’s ligands
shuttle the RNA payload to specific types of kidney cells, where they bind to a
receptor known as megalin that helps cells absorb vitamins and solutes.

Bound to megalin, Judo’s drug is ingested by the cell and, once inside, works to
silence mRNA expression of solute carrier proteins. These proteins typically act
as transporters and their dysfunction is linked to a range of diseases.

According to Rajiv Patni, Judo’s CEO, using a “proven” mechanism like siRNA
allowed the company to pursue more challenging drug targets like those in the
kidney.

“The kidney is a huge risk — in part but not entirely — because of its
complexity,” Patni said. “As a drug developer, you’re always thinking about a
tissue target that is the holy grail.”

The kidney’s complexity is also why Judo chose to focus on the organ. It’s where
blood is filtered and, while other drugs can reach the organ, they’re typically
excreted without any helpful effect.

The company has not disclosed disease targets, but Patni says Judo is looking at
systemic diseases such as diabetes and hypertension, as well as kidney-specific
conditions.

Judo shares its name with the form of martial arts known for taking a weakness
and turning it into a strength, said Sehgal, the Alnylam vet. One of Judo’s
primary moves, a strike, is also the acronym for the company’s platform, which
is being developed to knock down certain genes via the kidney.

Article top image credit: Permission granted by Judo Bio


EXSILIO PITCHES A ‘LEAP’ FORWARD FOR GENETIC MEDICINE

Led by former Moderna executive Tal Zaks, the company aims to develop gene-based
therapies that can be administered more than once.

By: Gwendolyn Wu • Published June 25, 2024

Exsilio Therapeutics, a biotechnology startup led by a former Moderna executive,
emerged from stealth in June 2024 with an approach it claims can solve some of
the shortcomings of genetic medicines.

The Boston-based company is debuting with $82 million from a group of investors
that include Novartis’ venture arm and the gene editing biotech CRISPR
Therapeutics. It’s led by interim CEO Tal Zaks, who was Moderna’s chief medical
officer when the company successfully developed a messenger RNA-based vaccine
for COVID-19.

According to Zaks, Exsilio is taking a page from that endeavor. It aims to use
mRNA, as well as other tools, to make medicines that can effectively paste
entire genes into cells and be administered more than once. The goal is to
broaden the reach of gene-based drugs in a scalable and more efficient way.

“We are leveraging what Moderna has demonstrated to work and extending the
payload of what can be therapeutically accomplished with the flexibility of mRNA
as a new class of medicine,” Zaks wrote in an email to BioPharma Dive.

Exsilio, which is Latin for “leap,” aims to do so by turning to so-called
genetic elements, encoded in mRNA and delivered into the body via fatty bubbles
known as lipid nanoparticles. These genetic elements, Exsilio says, would be
programmed to then insert new DNA into cells’ genomes at “safe harbor” sites
that wouldn’t cause unintended harm.

Exsilio believes this approach could allow it to treat a disease regardless of
the specific genetic mutation that caused it. Such flexibility would be
valuable, as some inherited conditions are linked to many different mutations.
The effects of Exsilio’s medicines would durable, the company claims, because
the inserted genes would be integrated into a cell’s genome, rather than
transiently expressed.


Tal Zaks, the former chief medical officer of Moderna, is interim CEO of
Exsilio.
Permission granted by Exsilio
 

The company pitches its method as a way to sidestep the limitations of viral
delivery systems that are commonly used for gene replacement therapy. For
example, adeno-associated viruses are too small to contain some large genes and
can trigger the body’s defenses, leading to side effects or compromising
treatment. Some people already have immunity to certain AAVs, too, or develop it
after receiving an AAV-based therapy, making retreatment riskier.

By contrast, Exsilio says its therapies will be able to be given more than once.
“We should be able to dose patients regardless of their pre-existing immunity as
well as repeatedly until the desired therapeutic gene dosage is obtained,” Zaks
wrote.

Exsilio is targeting genetic conditions, cancer and autoimmune diseases. The
financing will help the company progress to the point of selecting its lead
candidates, though it didn’t say when it expects to bring a prospect into human
testing.

Novartis Venture Fund and Delos Capital co-led the Series A round, which
involved other investors such as OrbiMed and a J.P. Morgan division’s new life
sciences fund. The company was founded in 2022 and seeded by OrbiMed.

“We were captivated by Exsilio’s genomic medicines approach that stands to
enable large-gene integration in a safe and redosable manner,” said Aaron
Nelson, a managing director of Novartis’ venture fund, in a statement.

Exsilio is one of many biotechs working to broaden the scope of genetic
medicines with the help of newer approaches. In recent years, well-funded
companies like Prime Medicine, Tessera Therapeutics and Tome Biosciences have
launched with similarly large ambitions.

“It is difficult to compare very early technology — the proof will be in the
medicines that companies are able to develop for patients,” Zaks wrote.

Article top image credit: Olena_T via Getty Images



ORNA, A CIRCULAR RNA SPECIALIST, ACQUIRES A BUZZY STARTUP

After laying off staff in late 2023, Orna is now expanding through the purchase
of ReNAgade Therapeutics, which was built around technology designed to more
effectively deliver RNA-based medicines.

By: Jacob Bell • Published May 23, 2024

Orna Therapeutics, a young biotechnology company focused on a flashy area of
genetic research, in May 2024 expanded through the acquisition of another
well-funded startup.

As its name suggests, the startup, ReNAgade Therapeutics, was built around
technology designed to more effectively deliver RNA-based medicines to specific
parts of the body. ReNAgade launched in 2023, with $300 million in funding and
an industry veteran, Amit Munshi, at its helm. The company had also created a
joint venture to apply its technology to Orna’s “circular RNA” research.

As a result of the deal, Orna absorbed ReNAgade and made Munshi the CEO of the
combined company.

“RNA-centric approaches are poised to eclipse traditional cell therapy-based
methods and reshape the future of medicine,” Munshi said in a May 2024
statement. “This strategic acquisition unifies Orna’s and ReNAgade’s strengths
and capabilities under one roof, expanding technological synergies and
multiplying the companies’ depth and breadth of expertise to drive a unique RNA
therapeutic-focused R&D engine.”

Thrust into the spotlight during the coronavirus pandemic, RNA-based medicines
have the potential to treat a wide variety of illnesses. But this area of drug
development presents certain difficulties. For example, RNA molecules are
typically linear and easy to break down, which can limit their effects.

However, some of these molecules form closed-looped structures that scientists
say make them more stable. Orna and another high-profile startup, Laronde, were
formed to study these circular RNAs and find ways to turn them into therapies.
Notably, Laronde came from Flagship Pioneering, the same biotech incubator that
founded Moderna Therapeutics.

Though they attracted considerable investment, both Orna and Laronde have dealt
with challenges, too. Orna turned to layoffs late in 2023, whereas Laronde
suffered from a data integrity scandal and has since merged with another
Flagship startup to form a new company, Sail Biomedicines.

The new Orna plans to advance so-called panCAR medicines for cancer and
autoimmune diseases. These medicines are meant to modify immune cells without
the need to harvest patients’ own cells or have them undergo “lymphodepletion.”

Article top image credit: Artur Plawgo via Getty Images


DRUGGING RNA WITH PILLS: SMALL MOLECULES FOR A BIG FRONTIER

Can biotechnology startups turn what were once accidental discoveries into a
purposeful way to hit hard-to-reach disease targets?

By: Gwendolyn Wu • Published Sept. 6, 2022

Infused or injectable medicines that interfere with RNA, the messenger molecules
that turn genetic instructions into proteins, have taken the spotlight in recent
years, winning approvals for several rare diseases. A group of biotechnology
startups are trying to find similar success by targeting RNA with pills instead.

History shows they face a daunting task. It’s long been considered futile to use
chemical-based compounds to go after RNA because of its shifty nature. When
scientists have succeeded, it’s typically been by accident. Last decade, for
instance, Merck & Co. discovered an experimental antibiotic it was developing
blocked a type of bacterial RNA. Pfizer inadvertently found one of its drug
prospects affected translation of a protein that regulates cholesterol.

Now, drugmakers are doing it intentionally. Helped by better sequencing
technologies, screening methods and a broader understanding of RNA, researchers
can more easily capture how the information molecules look and design drugs that
attach to them.

If successful, they could help unlock disease targets that small molecules can’t
currently reach, bringing forward new ways to treat neurodegenerative disorders,
cancer and other diseases.

At least eight startups are developing small molecules that target RNA. Large
pharmaceutical companies including Sanofi, AstraZeneca, Amgen and Roche have
shown interest in their research, promising hundreds of millions of dollars in a
string of deals. Here’s where things stand.


WHAT ARE RNA-TARGETING SMALL MOLECULES, AND HOW DO THEY WORK?

Small molecules are chemical-based drugs that usually target proteins and block
or change the way they work.

Due to their size, they can reach most tissues in the human body, slip into
cells and bind to the craggy parts of their targets. They are the bedrock of the
pharmaceutical industry, making up a large majority of drugs on the market.

But small molecules have limited reach. About 3,000 of the roughly 20,000 known
genes are considered “druggable,” meaning they can be targeted by a medicine. Of
the proteins they produce, only a few hundred are targeted by available drugs.
Many of the others don’t have the well-defined pockets that small molecules can
nestle into, making them more challenging to reach.

Targeting the RNA molecules that help make disease-associated proteins could
give drugmakers an alternate route. In theory, such a drug could stop production
of a potentially harmful protein, or make more of a helpful one.

For example, Arrakis Therapeutics is working on a medicine that would block the
body from making a well-known, but long thought “undruggable,” cancer protein
called Myc. An experimental Expansion Therapeutics drug destroys RNA implicated
in a type of muscular dystrophy. Accent Therapeutics and Storm Therapeutics,
meanwhile, aim to target the special proteins involved in transcribing and
modifying RNA.

They and others in the field face significant challenges, such as finding the
right RNA sequences and, within them, the correct locations to target. They also
need to ensure their small molecules only stick to their intended targets and
not other RNA, which could lead to side effects or other health risks.


WHAT ADVANTAGES WOULD RNA-TARGETING SMALL MOLECULES HAVE OVER EXISTING
TECHNOLOGIES?

Drugs that interfere with RNA have proven to be powerfully effective tools to
treat a range of diseases.

One method, pioneered by Alnylam Pharmaceuticals and known as RNA interference,
involves using small, synthetic RNA molecules to “silence” genes and prevent
them from creating harmful proteins. Another, similar method, used by Ionis
Pharmaceuticals and others, uses strips of nucleic acid called antisense
oligonucleotides to adjust or shut off protein production.

Both have advanced RNA drug research, leading to medicines for rare genetic
diseases such as spinal muscular atrophy and transthyretin amyloidosis, as well
as more common conditions like high cholesterol. The effects of the medicines
can last up to months at a time.

While significant progress has been made in delivering these kinds of RNA
therapies into the body, they’re still largely restricted to disease targets in
the liver, meaning there are many diseases they can’t yet treat.

Research has also noted their propensity to trigger immune responses and, in
some cases, difficulty in crossing the blood-brain barrier or entering cells.

Small molecules could help solve these problems. They’re a better known quantity
to drugmakers, easier to deliver than nucleic acid-based therapies and, because
they’re taken orally, are more convenient for patients.

Small molecules might also be better at permeating cell walls and are more
easily absorbed and taken up by the body. They’re cheaper to manufacture, too.


WHICH COMPANIES ARE WORKING ON SMALL MOLECULES THAT TARGET RNA?

A handful of startups have formed to develop oral RNA-targeting drugs.Some have
already caught the eye of bigger pharmaceutical companies looking to invest in
the field.

The most richly funded, Skyhawk Therapeutics, has raised more than $500 million
in private funding and upfront cash from partnerships, according to the company.
In July 2022, Sanofi partnered with Skyhawk to develop drugs for cancer and
research programs for oncology and immune diseases. Skyhawk also has deals in
place with Merck, Biogen and Vertex Pharmaceuticals.

Arrakis, launched in 2015 by a team of Biogen veterans, has drawn the attention
of first Roche and then Amgen, which handed the company a combined $265 million
through deals to develop medicines aimed at a variety of disease targets.

Accent has also been successful in luring big pharma, having signed partnerships
with AstraZeneca and Ipsen.

Remix Therapeutics joined the field more recently, launching late in 2020 with
$81 million in funding. The company added another $70 million in May 2022, a few
months after it teamed up with Johnson & Johnson.

SELECT, PRIVATE COMPANIES DEVELOPING RNA-TARGETING SMALL MOLECULES

Company Top Investors Accent Therapeutics EcoR1 Capital, Atlas Venture, The
Column Group Arrakis Therapeutics Canaan Partners, venBio Partners, NexTech
Invest Expansion Therapeutics 5AM Ventures, Cormorant Asset Management Gotham
Therapeutics (now 858 Therapeutics) Versant Ventures, Forbion, S.R. One Remix
Therapeutics Foresite Capital Skyhawk Therapeutics Fidelity Management and
Research, Alexandria Venture Storm Therapeutics Cambridge Innovation Capital,
Pfizer Ventures, Merck Ventures Twentyeight-seven MPM Capital, Sofinnova
Partners, Novartis Venture Fund

SOURCE: Company press releases

Article top image credit: libre de droit via Getty Images



IPSEN, SKYHAWK DEAL THE LATEST EXAMPLE OF PHARMA’S TURN TO RNA-TARGETING PILLS

Centered on rare brain diseases, the collaboration involves small molecule drugs
that can modify RNA.

By: Delilah Alvarado • Published April 22, 2024

French pharmaceutical company Ipsen is working with privately held biotechnology
company Skyhawk Therapeutics to make small molecule drugs that modify RNA.

Through a collaboration announced in April 2024, Ipsen and Skyhawk plan to
develop multiple RNA-targeting medicines for rare neurological diseases. Ipsen
has an option to acquire two for an undisclosed sum and could pay Skyhawk as
much as $1.8 billion if certain milestones are met.

The alliance is the latest industry collaboration focused on RNA-targeting
pills, an increasingly popular area of drug research. Several startups,
including Skyhawk, say the approach can help access disease targets previously
thought to be “undruggable,” though much of their work remains early.

Nearly all drugs that target RNA are administered through injections or
infusions, rather than the chemical-based pills that are the bedrock of the
pharmaceutical industry.

Skyhawk is among the biotechs looking to change that by developing small
molecule drugs that target RNA to treat disease. Historically, RNA-targeting
pills have mostly been stumbled on accidentally. Skyhawk and its peers, like
Accent Therapeutics, Arrakis Therapeutics and Remix Therapeutics, aim to develop
such medicines purposefully, with the goal of getting to disease targets small
molecules currently can’t reach.

That pursuit has a unique set of challenges and remains in its early stages.
Many of the field’s players don’t yet have prospects in clinical testing;
Skyhawk’s most advanced prospect, for Huntington’s disease, entered human trials
last year. Nonetheless, several have drawn the interest of large pharmaceutical
companies.

Ipsen, for instance, formed a partnership with Accent Therapeutics in 2021
develop a drug for acute myeloid leukemia. Since 2020, Arrakis has signed deals
with Roche and Amgen. Remix is aligned with Roche and Johnson & Johnson.

Skyhawk has several collaborations under its belt, too. Prior to joining forces
with Ipsen, the biotech started alliances with Sanofi, Merck & Co. and Vertex
Pharmaceuticals. The company has raised more than $180 million in private
funding as well.

Article top image credit: Courtesy of Ipsen




THE EXPANDING WORLD OF RNA THERAPIES

Over the past several years, a number of biotech companies have made strides in
constructing small molecule drugs to target RNA. Now genetic messenger molecules
power the coronavirus vaccines developed by BioNTech and Moderna, training the
body’s immune system to detect and defend against disease and infection.

INCLUDED IN THIS TRENDLINE

 * RNAi’s future the focus of new startup led by John Maraganore
 * Judo Bio debuts a plan to take RNA drugs to the kidney
 * Exsilio pitches a ‘leap’ forward for genetic medicine

Our Trendlines go deep on the biggest trends. These special reports, produced by
our team of award-winning journalists, help business leaders understand how
their industries are changing.
Davide Savenije Editor-in-Chief at Industry Dive.