Ionis Widens Its Modality Horizons

Over the weekend, blue chip antisense oligonucleotide company Ionis and genome editing competitor Intellia presented data on targeting prekallikrein (PKK) for treating hereditary hemeangioedema (Ionis donidalorsen here, Intellia NTLA-2002 here).

Using CRISPR Cas9 endonucleolytic disruption of the KLKB1 gene coding for PKK following LNP delivery, Intellia came out as the apparent winner in this showdown.  Not only did they demonstrate more pronounced PKK inhibition, but also more consistent elimination of debilitating attacks characteristic of the disease.  Moreover, by exploring less frequent antisense oligonucleotide administrations despite suboptimal low -60% knockdown, Ionis indicates that it is worried about the safety and tolerability profile of donidalorsen. 

Whether reversible approaches like antisense and RNAi or irreversible approaches like CRISPR gene disruption will ultimately prevail in the HAE race remains to be seen and will likely be decided by the safety of suppressing PKK expression over the long-term. If there is an overshoot of CRISPR-mediated gene disruption that would e.g. result in blood clotting abnormalities, even for a subset of patients, the field would be wide open for reversible methods.  

Ionis invests in genome editing

But whether that will be antisense remains to be seen.  Especially for targets in the liver, RNAi currently clearly rules the land for gene knockdown: highly potent, titratable and reversible knockdown with 5 years counting without a notable setback, especially related to off-target toxicity.  By contrast, Ionis is being held back by persistent safety issues as it has been beating a dead horse with its phosphorothioate-based backbone chemistry although it appears to be finally weaning itself off with chemistries such as the Mspa backbone.

So it is probably the hope of leap-frogging the RNAi competition by adopting genome editing as Ionis today announced that it was partnering with CRISPR genome editing company Metagenomi.  The HAE data comparison could not have come at a more opportune time.  

One declared aim of the investment in genome editing is life-cycle management of existing franchises.  In the liver, these franchises (TTR amyloidosis, ApoC3, PCSK9 etc) are currently and in the foreseeable future being dominated by RNAi despite Ionis’ heavy investments, so it clearly makes sense to amortize its investments in disease-specific market research, commercial infrastructure and clinical trial experience to accelerate the success of a more promising approach. 

TTR amyloidosis is a great example where even GalNAc-conjugated follow-on antisense compounds are unlikely to challenge Alnylam’s suite of RNAi triggers.  Also due to this dominance, it makes less sense for Ionis to develop an RNAi competitor drug despite its access and now actual adoption of this modality for targets in the muscle.  But as TTR shows, other genome editing companies are already competing for some of these targets so it won’t be all that simple trying to leap-frog RNAi and Alnylam like that.

 

The rise of the multi-modality oligonucleotide therapeutics companies

After straight-forward antisense for gene knockdown and then splice modulation, with the recent adoption of RNAi and genome editing, Ionis is rapidly expanding its oligonucleotide modality toolbox.

In fact, it is becoming a little bit like smaller competitor Wave Life Sciences which has been practicing all types of antisense (knockdown, splice modulation, more recently RNA editing) and RNAi using a bewildering mix of chemistries.  Not only are they burning through cash as if there was no recession and inflation problem, I never liked that because clinical failure after failure (esp. minute target engagements at best) suggest that the company is stretching itself too thin.

By comparison, Ionis, with $2 billion in cash and a more experienced and bigger operation is a different beast altogether and may be able to pull it off, at least on a technical level.  However, instead of spending $80M in upfront alone on a modality that is somewhat further removed from its traditional chemistries (longer mRNAs, LNP delivery for CRISPR), it could have much more synergistically leveraged its investments in chemistry and delivery by investing that same amount in the ripe-for-the-picking RNA editing.  Accordingly, $80M is more than the market cap of my currently favourite RNA editing investment, ProQR.

I’m sure the opportunity to expand druggable targets and indications by applying existing delivery technologies and chemistry know-how by adopting RNA editing is not lost on RNAi players such as Alnylam and especially Arrowhead Pharmaceuticals.  Arrowhead in particular, having scooped up the RNAi assets of Novartis and Roche for peanuts has demonstrated an ability to recognize and act on similar opportunities.

RNA Editing Emerging as a Broadly Applicable Oligonucleotide Therapeutics Modality

This feels like RNAi all over again. 20 Years after my life-altering journey in RNAi Therapeutics started, I can’t shake a similar sensation for the almost boundless therapeutic opportunities around RNA Editing.

RNA Editing in our context refers to the directed change from Adenine (A) to Inosine (I) in an RNA molecule with ‘I’ being read as a ‘G’ by the molecular machineries inside a cell.  This process harnesses endogenous ADAR enzymes (Adenine Deaminases Acting on RNA) which recognize certain double-stranded RNA features upon which nearby ‘A’s are converted to ‘I’s.  These recruiting features can be created in a sequence-directed manner through the interaction of exogenously applied oligonucleotides with complementarity to cellular target RNA, typically mRNA.

Other types of RNA editing, for example ‘C’ to ‘U’ are also being explored, but as a readily sequence adaptable platform, ‘A’ to ‘I’ excites me the most right now and appears ready for prime time.

 

Boundless therapeutic opportunities

When I was first pitched with the concept of RNA Editing, I was skeptical.  I merely saw it as a gene therapy alternative for ultra orphan applications aiming to revert pathogenic ‘A’s into wildtype or less pathogenic ‘G’s. 

Even fairly common genetic diseases like Duchenne muscular dystrophy and cystic fibrosis for example can be caused by hundreds of different point mutations and it would seem overly cumbersome to develop different oligos to address unique mutations of individual patients.

Also, how would it compete here with genome editing technologies like CRISPR that aim for one-time treatments to achieve the same?

It was during a recent trip back to Stanford when I voiced such concerns as Billy Li remarked in passing that RNA Editing was not limited to such genetic therapies in the traditional sense, but could also be used more widely to modulate wildtype mRNAs to influence processes such as signaling pathways for diseases involving much larger target populations.

Billy Li is an associate professor at Stanford University and a leading researcher on ADAR molecular biology and genetics.

To influence signaling pathways, you may for example target RNA Editing to abolish phosphorylation sites or other amino acids critical for protein-protein interaction.  Often, this will have gain-of-function effects such that editing only a fraction of the target RNAs may result in dramatic upregulation of a pathway.

Tunability and temporary modulation as opposed to the binary nature of genome editing is another attraction of RNA Editing.  You can easily see for example that having a signaling pathway permanently fully switched ON could pose a safety issue.

In addition to changing the coding potential of a target mRNA, RNA Editing can also be used for altering RNA processing sites, especially those regulating splicing, RNA stability and transport.

 

Ready to shine

While it has taken RNAi Therapeutics roughly 15 years from the early start-up phase to having its first drug approved for clinical use, the timeline for realizing the therapeutic potential of RNA Editing should be shortened. 

In particular, much has been learned about the delivery of oligonucleotides such that related oligonucleotide stabilization and conjugation chemistries can be rapidly translated to RNA Editing.  First clinical trials will likely be for applications in the liver and CNS, followed by the eye and lung.   

Similarly, the modification toolbox and the dramatically lowered cost of large-scale oligo synthesis and screening can be exploited to improve targeting specificity and to identify highly active RNA Editing oligos.

   

Investment opportunities

I get my adrenaline kick when science and the stock market come together.  After seeing RNAi Therapeutics mature into a widely accepted therapeutic modality, I had increasingly turned my stock market trading to biotech in general.  While this allowed me to learn much about the regulatory and late-stage aspects of drug development and marketing, I have come to miss the passion I felt while diving into the molecular biology and competitive dynamics of RNAi as it was still developing.

I know many of you are biotech investors and feel the same.  So while RNA Editing investment opportunities are not limited to the stock market, this blog will shine particular light on publicly traded biotechs in the field. 

For full disclosure, I have started a position in ProQR (ticker: PRQR; market cap: $62M), to my knowledge the only public pure-play RNA Editing biotech.  After a failed trial involving antisense oligo-mediated splice modulation it now trades at ~50% below cash suggesting that all that was left is an empty biotech shell.  It couldn't be further from the truth as ProQRians have been working on RNA Editing for almost a decade and now find themselves leading the charge of a hot new biotech platform.  Along the way, ProQR has been working on potentially critical IP and it is also for this reason that Eli Lilly has partnered with it on up to 5 RNA editing programs.  ProQR has been in a quiet period.  The next catalyst will be the announcement of more concrete development timelines and programs.  While we are waiting, the projected 2026 cash runway and partnering potential provides the company and investors with a nice cushion in these turbulent times.

Wave Life Sciences (ticker WVE; market cap: $320M) may be first into the clinic with alpha-1-antitrypsin, but as a most diverse oligonucleotide therapeutics company it is burning through its cash much more rapidly, spending it on less promising antisense knockdown and exon skipping programs.  For RNA Editing, I like it for their deep expertise in oligonucleotide chemistry and their editing efficiencies appear leading.

Stoke Therapeutics (ticker STOK; market cap $520M) is another ticker to watch as it uses oligonucleotides in more general for gain-of-function purposes.