Review of Recent RNAi-Related Developments

The last 2 weeks have been busy ones in the lands of RNAi Therapeutics.  Here, I would therefore like to offer my take on the most important developments.

Alnylam’s Primary Hyperoxaluria Drug Breezes Through Clinic

With 20 subjects on Lumasiran, a GalNAc-RNAi targeting glycolate oxidase, for a median of 7 months, the investigational treatment for type I primary hyperoxaluria (PH1) ismore and more looking like a solid drug.  If the data presented last week at a Paediatric meeting in Turkey hold up in another 30 patients, it should fly through approval onto the market by the end of 2019.

While the relatively small numbers in each cohort has caused a bit statistical noise, it seemed like 3mg/kg monthly gives you an advantage over 1mg/kg monthly or 3mg/kg monthly in terms of the key biomarker urinary oxalate.  Interestingly, the company has chosen 3 times 3mg/kg monthly as the loading dose regimen in the now ongoing pivotal ILLUMINATE-A trial to be followed by dosing every 3 months. , the initiation of which the company has just announced.    

The core double-blind portion of the trial runs for only 6 months, so I am a bit puzzled how much the trial can inform on the value of the loading dose regimen and whether quarterly maintenance doses are sufficiently effective.   In any case, the trial design apparently was blessed by the FDA (incl. the urinary oxalate lowering primary endpoint), so surely they will know (e.g. based on preclinical animal data).

Regarding the competition with the primary hyperoxaluria drug candidate from Dicerna, the approximately 2/3 lowering of urinary oxalate and essentially all patients getting into a range considered safe and an unremarkable safety profile sets a high hurdle for the upcoming data presentation of DCR-PHXC at ASN later this month.

Arbutus HBV-RNAi Drug About to Die   

Yesterday, Arbutus provided an update on its LNP-enabled RNAi drug candidate for the treatment of chronic HBV (ARB-1467) and it does not bode well.  Similar to most other drug candidates attempted and barely tried, ARB-1467 should be canned in the not-too-distant future. 

In a combination study testing ARB-1467 in chronic HBV patients on nucleoside reverse transcriptase inhibitor tenofovir, probably only 1 in 6 patients hit a pre-defined criteria in terms of HBsAg lowering that would allow the patient to then receive immune booster PEG-Interferon.  The not very forthcoming revelation and the fact that the data was mentioned even after dropping another shoe that its small molecule HBV RNA destabilizer is also biting the dust makes it clear that not even the company sees much value in ARB-1467.

What an utter disaster this company has been since its inception as a HBV solutions entity.

Arrowhead Early HBV Deal Further Validates

Last week, shareholders in Arrowhead Pharmaceuticals got a lesson in biotech investing as it shares have given up ~1/3 of its value following a nice deal with Johnson&Johnson for the leading HBV knockdown asset in the space, ARO-HBV.

The deal gives Arrowhead a solid $250M in financing, including a $175M upfront fee and a $75M investment in company stock at a premium of ~50% to current trading.  While this avoids an imminent dilutive secondary share issuance- the company had been running low of cash- the ‘up to 15%’ in royalties from future sales of early phase II-stage ARO-HBV is clearly disappointing.  The relatively low royalty despite of it having confirmed strong HBsAg knockdown in patients can be explained with the fact that Arrowhead has avoided bearing the full risk of having to show proof-of-concept of HBV control.  This despite of having earlier paraded results obtained with an earlier DPC-based RNAi candidate (ARC-520) as strong evidence that RNAi can achieve such immune control.

While Arrowhead got punished for playing it safely, it can now focus on commercial home-run indications with highly validated targets and transition to being a broad platform company with a wholly owned attractive lead candidate in ARO-AAT.  Indeed, Arrowhead may emerge as the leading RNAi company as Alnylam, with a market cap ~8x that of Arrowhead, is still burdened by late-stage RNAi drugs with suboptimal specificity.

While humiliating, this serves Alnylam as a good reminder to also value innovation by the direct competition (note: specificity-enhancing technology now adopted by Alnylam has been available for a decade and could have been had for peanuts, e.g. from now defunct RNAi play mdRNA/Nastech).  Fittingly, today long-time archrival Silence Therapeutics issued a press release indicating that Alnylam is playing hard-ball with regard to Silence-owned IP purportedly covering ONPATTRO.

My guess is that Alnylam would rather risk an injunction and deprive patients of a very good medicine than to submit to what appear to me legitimate demands of a competitor.

Akcea’s antisense drug for TTR amyloidosis gets FDA nod

Last Friday, Akcea’s TTR drug TEGSEDI (licensed from Ionis) finally got FDA marketing approval for patients suffering from TTR-related polyneuropathy.  As expected from the delay in the approval process, TEGSEDI’s approval is accompanied by hefty black box warnings highlighting thrombocytopenia and renal risks of the (non-GalNAc) phosphorothioate oligonucleotide.  

Furthermore, the REMS program calls for frequent blood monitoring, essentially negating the claimed at-your-home convenience advantage over competing RNAi drug ONPATTRO.  Add to the poor safety profile clear efficacy disadvantages and pricing at parity with ONPATTRO, ONPATTRO should clearly win out in the marketplace.

Having said that, the TTR community is relatively small and key opinion leaders with relationships to a given drug company tend to support the drugs from the same company.

HBV RNAi 2.0

Gene knockdown, in particular RNAi and RNaseH antisense, holds great promise in the treatment of hepatitis B viral infection.  It is currently the only practical means to potently inhibit all viral gene products*.  It therefore is poised to become a cornerstone of future treatment regimens aiming at functionally curing HBV, an infection predisposing more than 200 million patients worldwide currently to liver failure and cancer.

Arrowhead- lessons learned

Unfortunately, the field took a big hit last year when HBV RNAi trailblazer Arrowhead Pharmaceuticals had to abandon its efforts due to preclinical toxicity resulting from its particular approach to releasing the RNAi triggers into the target cell cytoplasm (monkey deaths due to the DPC).

Nonetheless, after more than a dozen trials in WoMan, the company had learned a great deal about HBV and how to best tackle it by RNAi.  Chief among those lessons were the observations that RNAi can suppress viral genes, most notably the surface antigens HBsAg by sometimes more than 2-3 logs.  Moreover, in HBe-antigen negative and those HBe-antigen positive patients previously exposed to polymerase inhibitors (‘nukes’), Arrowhead painfully found that most HBsAg is derived from host genomically integrated HBV.  Consequently, RNAi trigger target sites placed downstream of the HBsAg ORF may be lost and RNAi rendered futile (ARC520àARC521 transition). 

Finally, consistent with the experience with nukes and interferons, it appears that RNAi treatment success (functional cure) should follow complex viral and host immune dynamics and while intriguing changes were observed in the clinic with ARC520/1 (e.g. new lower baselines following treatment cessation), it remains unclear how long an RNAi agent would have to be given.  This has implications for whether intravenous routes of administrations are practical or not.

The competition

Arrowhead Pharmaceuticals, however, has not been the only RNAi game in town developing HBV therapeutics.  Its main competitor in terms of scientific prowess has been Arbutus Biopharma (renamed from Tekmira after biotech wonder boy Vivek Ramaswamy of Axovant fame spectacularly raided the company in 2015).  Its lead RNAi candidate ARB-1467 comprises of 3 RNAi triggers which are formulated in lipids (LNP) and is given intravenously alongside steroids.

While I like the 3-trigger strategy for pangenotypic coverage and for minimizing the risk of the virus developing drug resistance (including by genomic integration), the more cumbersome intravenous route of administration- now reduced to short 2-week intervals in an effort to increase potency- and the steroids makes ARB-1467 uncompetitive in a world of more potent and less frequent simple subcutaneous competition.  The use of immune suppressive steroids, of course, in HBV patients is a dicey proposition and would also seem to run counter to the ultimate aim of achieving immune control of the virus.

Unless it turns out to promote a functional cure along with other agents in short order, say less than 6-12 months, ARB-1467 will likely end up as a science project without much clinical impact.

RNAi powerhouse Alnylam Pharmaceuticals meanwhile is the third RNAi company that has begun clinical development of an HBV RNAi agent.  Importantly, it has been the first company using a simple subcutaneous GalNAc-conjugate format, therefore positioning it to be useful even when more prolonged treatment will turn out to be necessary.

After review of the program, however, it appears that the company prematurely rushed the single trigger ALN-HBV into the clinic without thinking too much about resistance issues.  To start with, ~2% of tested HBV genotypes have mismatches with the trigger that mitigate targeting efficiency.  As a single trigger candidate, ALN-HBV will also have to be given alongside highly potent replication inhibitors (nukes) as one can easily see how ALN-HBV resistant genotypes would otherwise eventually take over.

ALN-HBV moreover targets a site downstream of the HBsAg ORF, around the DR2 repeat element with marks the integration hotspot that has bedeviled ARC-520 before.  While Alnylam has been going around claiming ALN-HBV doesn’t suffer from ARC-520-type issues, I would challenge them with two points:

1)     under selection pressure by ALN-HBV to maintain HBsAg expression and thus evade host immune detection, the virus may ‘choose’ to break up upstream the ALN-HBV target site without affecting the HBsAg ORF; 

2)      more troublesome, closer inspection of the very paper Alnylam points to for making its claim (Jiang et al. Genome Research 22: 593) and which analyzes HBV integration hotspots, shows that ~40% of DNA break points appear to be upstream of the ALN-HBV target site (compare ‘position 1600’ below).      

One can therefore easily see why the project leader behind ALN-HBV, Laura Sepp-Lorenzino, has recently left the company to join Vertex Pharmaceuticals.  One has to get the impression that ALN-HBV, just like ALN-GO1 have only been rushed to the fore as a front in order to keep a lid on their competition by creating doubt about the ability of Arrowhead Pharmaceuticals and Dicerna, respectively, to compete with juggernaut Alnylam. 

Thrilled to join @VertexPharma as Head of Nucleic Acid Therapies!!!

— Laura Sepp-Lorenzino (@LauraSepplore) September 23, 2017

 

It is yet another lesson that in drug development, a detailed understanding of the disease is as important as the technology used to tackle it.  Half-hearted side projects typically lead nowhere.

Lastly, I would be remiss if I did not mention the RNaseH antisense efforts by Ionis along with partner GSK, and those of Roche.  Ionis/GSK are not only developing an unconjugated fully phosphorothioated antisense molecule, which I believe has little chance of competing in the market due to predictable safety and potency issues, but also a more interesting GalNAc-conjugate version (IONIS-HBV-LRx).  Although I currently see RNAi ahead of antisense in gene knockdown in hepatocytes (potency, frequency of administration, and safety), the GalNAc-conjugate version potentially has the advantage of also being able to access the pregenomic RNA directly, while direct pgRNA cleavage by RNAi of this non-mRNA remains to be shown.  My prediction is that  while RNAi can to some degree access pgRNA, this is not as effective compared to its cleaving mRNA.  What all of this means biologically remains to be seen.

Arrowhead HBV RNAi 2.0

Therefore, after all the drama and competitive noise, Arrowhead is poised to recapture the HBV RNAi lead with its new GalNAc-based candidate.  ARO-HBV is poised to enter the clinic in the first half of 2018.   It is subcutaneously administered and involves 2 RNAi triggers that are claimed to cover the viral resistance bases, including HBsAg derived from genomically integrated HBV.

The company expects the agent to be used once a month or less frequently, an attribute valuable should functional cures take longer to emerge.

Given knowledge leadership in HBV gene knockdown and prior practical experience, Arrowhead should also be able to navigate through the HBV clinical development maze faster than its competition.  As can be seen from its resurging stock price, this view is also shared by an increasing number of investors. 

Arrowhead has paid for taking some short-cuts when it was compelled to push ARC-520 into the clinic to give it a shot of becoming a serious player in RNAi before it ran out of capital.  It took some risks and failed, but that failure could well be the soil from which future success will emerge. 

Disclosure: long Arrowhead Pharmaceuticals

 

 

 

 

 

 

* it is unclear whether RNAi can directly cleave pregenomic RNA, whereas RNaseH antisense should be able to do that.