Wave Life Sciences to Focus RNA Editing on Gene Upregulation

Yesterday, oligonucleotide therapeutics developer Wave Life Sciences provided a high-level preview on how it will deploy its RNA Editing technology.  Accordingly, modulating protein-protein interactions and, even more so, increasing gene expression will be the declared mechanisms of action of development candidates following its lead candidate WVE-006 for alpha-1-antitrypsin disease (AATD).

WVE-006 was recently licensed to GSK and should be the first RNA Editing candidate to enter clinical development later this year.  A big milestone for the field.   WVE-006 corrects a common single nucleotide mutation in the alpha-1-antitrypsin gene, Z-AAT, that causes both liver and lung manifestations of AATD. Z-AAT is retained in liver hepatocytes to cause cellular stress instead of being secreted to do its job and protect the lung.  As such, WVE-006 can be considered both a mutation corrector and gene function booster.

 

Mutations often scattered across genes

More often than not, however, mutations causing rare genetic diseases are scattered across a gene and precision genetic medicines targeting small segments of a gene at a time may thus only address a subset of patients.  A prime example is Duchenne Muscular Dystrophy where even exon 51 skipping which is the approach with the largest addressable patients still only serves 11-13% of the overall DMD population.

                                DMD patient segmentation according to skipped exon (from Wave Life Sciences presentation)

A very interesting indication for ADAR RNA Editing is Rett Syndrome (affects 1 in 10000 girls by age 12 in the US).  Here as well are the mutations scattered across the MeCP2 gene.  Almost half of those would be addressable by RNA Editing (including eliminating stop codons), but each individual target would be quite small.

So instead of targeting the specific mutations, ADAR Editing may also be used to screen all adenines in the MeCP2 transcript to identify those that lead to an increase in protein abundance and thus function either by stabilizing the resulting mRNA or by increasing MeCP2 stability.  While this approach would not apply to Rett Syndrome caused by 2 null mutations on the X chromosomes, a say 3x increase in activity of the chromatin CpG-binding protein may be enough to alleviate disease in a large fraction of Rett Syndrome patients with MeCP2 versions having reduced activity.  Or consider mutant CFTR proteins in cystic fibrosis with reduced channel activity. Increase the abundance of those CFTR mutant proteins and it should increase the overall desired activity.

The screening approach would also facilitate finding potent RNA editing oligos due to the flexibility and increase in targeting space as opposed to having to optimize the editing oligo around a small defined target site.

 

mRNA technology

Wave Life Sciences likened the gene upregulation approach as a simpler version of mRNA therapeutic technology.  Simpler, because it does not involve the delivery of long mRNAs which necessitates the use of LNPs and similar larger nanoparticle formulations due to mRNA stability requirements.  By contrast, RNA editing can be mediated by oligos ~30 nucleotides in length, short enough to be amenable to conjugation and oligo chemistry strategies already applied in RNaseH and splice modulation ASO and RNAi.

Smaller also means better tissue penetration and delivery to more target tissues.

Moreover, meaningful expression from an mRNA only occurs in short bursts so that the frequency of repeat administration is dictated by protein half-life.  Meanwhile, the administration frequency for oligo-mediated editing, due to the longer persistence of highly stabilized oligos, can be expected to be in the weeks and months.

It should be noted though that RNA editing would essentially upregulate what is already present in the cell (with the exception of the one editing change), whereas mRNA therapeutics in sensu strictu can generate entirely new proteins.

RNA editing would also not be the first oligonucleotide approach to mRNA upregulation.  RNA activation, the targeting of promoter-proximal regions using RNAi-type double-strand RNAs, and the targeting of upstream 5’ UTR mRNA elements with steric blocking antisense molecules as developed by Ionis Pharmaceuticals are competing approaches.  These, however, have so far either lacked the robustness or the flexibility in terms of sequence choice that AàI editing should afford.  

 

Now more than ever in biotechnology, companies need to carefully tease out the unique, differentiating advantages of a platform technology when selecting an indication.  RNA Editing leaders ProQR and Wave Life Sciences are in the fortunate position that they can apply the new biotech paradigm starting with their first RNA Editing candidates.  Biotech is ripe for a reboot and RNA Editing should have every ambition to be part of it.

 

Disclosure: I own both ProQR and Wave Life Sciences shares, though ProQR considerably more. 

A Visit to ProQR

Yesterday, I had the pleasure and privilege to visit ProQR in Leiden (Netherlands).  Thank you, Sarah and Andy from IR, for making it happen! 

The goal of my visit was to see whether the people and the context in which it all happens are conducive to ProQR's delicate quest of growing, leading, and establishing the immensely valuable RNA Editing platform as a new therapeutic modality.  

It takes a special mix of enabled technology, intellectual property, and committed people to make this happen.  Luckily, it has been done before in biotech and is therefore achievable with the careful execution by skilled and highly motivated people. 

In addition to the people aspect, two issues were on top of my mind as they will likely determine shareholder return over the next 3-5 years: 

the editing oligonucleotide chemistry and the pipeline.

 

Chemistry and structure

Historically, ProQR has heavily relied on phosphorothioate (PS) backbone chemistry for their now discontinued cytoplasmic (CFTR) mRNA correction and RNaseH/steric blocking antisense projects.  Publications by ProQR and collaborators similarly reveal their use of this chemistry for ADAR RNA Editing.

While the selective use of the PS modification for editing oligo stabilization purposes should be acceptable similar to what is practiced and proven in the RNAi space, insisting on its broad use can have catastrophic consequences for platform development as Ionis Pharmaceuticals' antisense journey has shown. 

Even their wild success story, splice modulator SPINRAZA which has saved the lives of many babies with the spinal muscular atrophy mutation, suffers from PS-related side effects.   On a side note, the fact that SPINRAZA, but not other intrathecally administered RNAseH mechanism-based PS-ASO so far has proven to be an impactful drug, is partly due to it relying on a gain-of-function approach where low double-digit % target engagement can be sufficient.  And yes, ADAR Editing is primed for similar gain-of-function applications.

Obviously, ProQR could not reveal much about the chemistry and structure of their upcoming EONs for competitive and IP-related reasons. Still, they were able to communicate that they share my concerns and are aiming to minimize chemistry-related tox issues while retaining necessary oligonucleotide stability.  In particular, the 10+ oligo chemistry team that I saw hard at work and the background of their Chief Scientific Officer Gerard Platenburg make me hopeful that ProQR are indeed looking broadly for acceptable backbone chemistries.

On the structural side, again, ProQR could not say much in detail except that they believe the meat of the action in coming up with general EON design and optimization rules is where the oligonucleotide interacts with the ADAR deaminase domain and that there could be differences between different tissues.

When challenged with my observation that in many publications in the space often only 1-2%-type mRNA editing efficiencies are seen whereas I would prefer 10-20% efficiencies, the team was quick to point out their belief that the inherent ADAR editing capability is close to 100%.  I agree as such high ADAR efficiency can be observed in neuronal development and editing efficiencies north of 50% have been demonstrated with optimized candidates for more advanced alpha-1-antitrypsin candidates by ProQR and Wave Life Sciences.

ProQR does not believe it has to screen 1000+ oligos to find candidates of acceptable efficacy (off-targeting is not really a concern with ADAR Editing) as it is now routinely practiced in RNAi and RNaseH antisense drug development.  While this suggests that ProQR are confident about their funneling strategy, I would caution that since screening costs have come down dramatically over the last 2 decades, when it comes to finding the best possible development candidate for an indication you are excited about, this is a place where capital is well spent.

  

The pipeline

CEO Daniel de Boer understands the importance of maintaining momentum following the recent landmark deal with Eli Lilly until first clinical data, possibly in 2024 (my guess) can speak for itself.  Maintaining momentum is of critical importance because a strong currency (=share price) and investor base is instrumental for biotech success.  Providing additional preclinical data and pipeline visibility is also key in getting the attention of the industry for business development.

The next catalyst in the ProQR story is therefore the much anticipated revelation of its clinical pipeline.   Previously, ProQR guided this to occur by either year-end 2022 or early 2023.  Daniel was positive that such an event can be held in Q1 along with preclinical data in support.

In addition to minimizing technical and biology risk, ProQR apparently also understands that market potential matters.  Indeed, RNA Editing is such a unique mechanism that it can either address new, significant markets with no real alternative treatment approaches or go head-to-head with other modalities as the most elegant and promising mechanism, for example alpha-1-antitrypsin or Huntington's disease (my thoughts, not indications ProQR mentioned). 

So don’t expect ultra-orphan gene mutation correction programs where patient populations are sliced down to a few hundred applicable patients and less.  The recent fate of numerous gene therapy companies hurtling towards bankruptcy despite having been able to produce promising clinical data for such ultraorphan indications show that at the moment this business model does not work.

In addition to market size and having a unique modality angle, minimizing delivery and biology risks are top selection criteria.  Expect the line-up to come with early biomarker opportunities to make go/no-go decisions as early in clinical development as possible. It therefore would not surprise me if most if not all the first-generation pipeline candidates targeted liver hepatocytes.  And why not, since the unique ADAR Editing mechanism, especially for gain-of-function provides differentiation in an otherwise relatively crowded target tissue.

Having said that, I would not mind an exciting CNS program either to gain some experience with this target organ as long as the pipeline and thus the fate of the company is not dominated by a single program.  Instead, the company should give itself ~3 shots on goal and if any one of them hits the target, the company would be wildly successful.

 

People and culture

It was the late-stage failure of an antisense oligonucleotide-based orphan drug program in ophthalmology that prompted ProQR to shift gears and become 100% committed to ADAR RNA Editing.  Along with it came a considerable reduction in workforce mainly affecting those working on the clinical programs.

The surviving employees and increasingly new additions, numbering 128 now and set to grow to ~150 by mid-2023 are lucky to inhabit a nicely refurbished headquarters that reflect a respect for nature (natural colors and materials, lots of plants) as well as good RNA science and biotech leadership.  It may be news to mRNA pioneer Katalin Kariko that a meeting room is named after her. Of course, the coolest room featuring sauna-type wooden benches is named in honor of the late founder of the orphan drug biotech model and ProQR mentor, Henri Termeer.

The space offers plenty opportunities for flexible work and informal meeting and exchange to help build the cohesion among the workforce and provide the dynamic work environment necessary to overcome the challenges faced by new therapeutic modalities.

One concern that I had before visiting ProQR was that not being in a major biotech hub, a Leiden-based biotech may find it difficult to attract top international talent.  But the ~100 scientists, largely from all over Europe, will feel right at home in this small university town setting where the quality of the coffee and toasties matter more than living close to say an internationally acclaimed opera house.  Being next to Amsterdam and Schiphol airport are equally important in this regard, but also to make it easier for Board members, advisors, and collaborators visiting the company.   

Management seems to get along each other well with almost all of them going back to around the founding in 2012.  To wit, ProQR was born as an initiative by Daniel de Boer in his quest to find a good drug for his child that was diagnosed with a rare disease.  This quest led him to a meeting with fellow Dutchman Henri Termeer- the rest is history.  

While Daniel will have learned a lot in his 10+ years of biotech leadership and has proven to be a very capable businessman, it is good to know that he is supported by a leadership team with deep experience in the biotech business (Rene Beukema, corporate development) and oligonucleotide chemistry and therapeutics  (Gerard Platenburg). 

Bart Klein (SVP Axiomer) deserves a special shout-out for his pioneering role in oligo-guided ADAR RNA Editing. 

I vividly remember an encounter with Bart at a scientific meeting, possibly the 2017 OTS meeting in Bordeaux if not the 2014 ESCDD meeing at a Dutch seaside place.  Anyhow, he excitedly urged me to have a look at ProQR’s cool technology. I unfortunately hesitated and showed myself closed-minded as my view of the company at the time was clouded by their CFTR program that was built on the flawed notion, probably a PCR artefact, of a cytoplasmic mRNA cut-and-paste repair mechanism.  Although this program dominated the valuation and public attention of ProQR at this early time in oligo-guided RNA Editing, it was this little side project that, in truly visionary fashion excited him most.  Today, this belief is the reason why what commanded maybe 20% of the company mindshare up until the early 2022 sepofarsen failure is the reason why ProQR is still alive and kicking and may very well be the foundation of one of those stunning biotech comebacks.

Nothing is certain in biotech, but here is a story with a high probability of success.

Disclosure: I own >2% of the company stock. This blog post is not meant as a stock recommendation, but to provide greater visibility and transparency of ProQR and ADAR RNA Editing.