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.

Reconsidering RNA Editing for Alpha-1-Antitrypsin Disease

Alpha-1-antitrypsin (AAT) is the lead program in the RNA Editing pipeline with Wave Life Sciences recently licensing its candidate to GSK.  It is safe to assume that a number of other companies are working on similarly developing RNA Editing drugs in the AAT area as well.  Developments in the competitive environment using other platforms such as gene knockdown (RNAi, ASO) and genome editing are therefore of high interest.

Arrowhead Pharmaceuticals SEQUOIA data

This week, Arrowhead Pharmaceuticals and partner Takeda revealed that its RNAi candidate for alpha-1-antitrypsin-related liver disease worked as intended in the SEQUOIA phase II study and over time should translate into a measurable benefit in terms of developing severe liver disease.

After 52 weeks of treatment, mutant Z-AAT was knocked down by a solid -94%.  This in turn led to a 2/3 decrease in the more inert aggregated form of alpha-1-antitrypsin.  It is the aggregated AAT that is thought to cause cellular stress, followed by a cycle of apoptosis and hepatocyte regeneration, ultimately leading to inflammation and fibrosis, if not liver failure in ~20% of subjects homozygous for the Z-allele of alpha-1-antitrypin.  

Indeed, ARO-AAT/TAK-999 achieved a striking benefit of reducing portal inflammation (see above graph) which should be highly predictive of a benefit on liver fibrosis progression.  Although a high 50% of trial subjects on ARO-AAT experienced a reduction in fibrosis, this was not statistically significant due to small patient numbers.  A larger and longer (2-4 years) registrational study is therefore planned to confirm the benefit and gain regulatory approval.

RNAi unsurpassed in reducing Z-AAT, but RNA Editing may be more elegant

If the degree of reducing the insulting Z-AAT was all that mattered, RNAi would be difficult to beat. ADAR RNA Editing and genome editing for example would have to overcome the limitation that target sequences are limited to a very specific area around the mutation whereas RNAi has the entire mRNA to play with.

But looking more closely, the name of the game is actually inhibiting aggregation.  It is now that I increasingly appreciate the elegance and power of the RNA Editing approach   which fundamentally rests on the genetic observation that heterozygous carriers of alpha-1-antitrypsin disease have a much reduced risk of developing related liver disease, if an increased risk at all.  These people carry one 'Z' allele and one normal ‘M’ allele. 

I had not paid much attention to this, thinking that mechanistically this is simply due to a concentration effect of 50% less Z-AAT polymerizing less well and having a protective genotype that manifests after decades of life does not necessarily mean that converting a patient already suffering from liver disease to such a genotype will necessarily translate to the fastest possible treatment benefit.  RNAi with its highly potent Z-AAT reduction may be faster.

It is now that it dawns on me that there is likely more to the MZ genotype benefit.  Looking at the Wave Life Sciences mouse preclinical data on its RNA Editing candidate, it always irritated me that whereas the mRNA editing efficiency was ~50%, the increase in circulating AAT was 7x.  Since only ~15% of Z-AAT normally gets out of the liver, this basically means that the 50% of M-AAT allows essentially ALL of the AAT, including Z-AAT to get out of the liver.  This is consistent with the ratio of M-AAT/Z-AAT in circulation reflecting the 50% mRNA editing efficiency in hepatocytes.

It therefore appears that the M-AAT (and potentially non-wildtype variants generated by RNA Editing) functions to poison the Z-AAT aggregation chain reaction, keeps Z-AAT in solution and fit for secretion into circulation.  What is more, unlike RNAi, this has the additional benefit of also addressing the lung manifestations due to insufficient levels of circulating AAT and for which alpha-1-antitrypsin disease is better known.  RNAi by contrast may have to rely on other developments in improving the management of alpha-1 lung disease as it reduces circulating AAT even further.

In light of the above, as a shareholder I am now changing my mind and support ProQR with its industry-leading IP and know-how to enter the exciting alpha-1 race to generate a best-in-class RNA Editing drug.  We should soon find out when ProQR will reveal its line-up of initial pipeline candidates.