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.

Arrowhead Achieves Robust Alpha-1 Antitrypsin Lowering As Grounds for Trial Termination Still Shrouded in Mystery

Last Friday, Arrowhead Pharmaceuticals presented first data from its phase I study of ARO-AAT being developed for addressing liver disease in people with certain mutations in the alpha-1 antitrypsin gene.  Based on the selective data release, Arrowhead has assumed the lead in this indication as Alnylam struggles to regain its footing following apparent off-target-related liver toxicity almost 2 years ago.

The press release can be found here, the actual presentation here. 

With a mean maximal target gene knockdown of -87% between 6 to 8 weeks following a single subcutaneous injection of 100mg dose of the GalNAc-enabled ARO-AAT, Arrowhead has shattered the previous AAT knockdown record by Alnylam’s ALN-AAT of -80% at a ~4x dose of ARO-AAT.  The dynamics of the knockdown also suggests that infrequent dosing should be feasible with ARO-AAT, although without seeing the multi-dose data from this study, it is difficult to predict whether we are talking about quarterly or semi-annual dosing here.

It will also be interesting to find out whether the variation of knockdown in the 4 patients- ~-70% knockdown at 4 weeks for the 2 weaker responders and ~-90% for the 2 better responders- had to do the polymorphism issues similar to those encountered by Alnylam before.

Safety mystery remains

When Arrowhead announced on June 18 that it would terminate the healthy volunteer trial prematurely given that it had escalated above doses at which maximal knockdown can be observed, I was hesitant in taking it at face value or whether this decision also had something to do with the safety profile of ARO-AAT.

The Alpha-1 National Education Conference update only added to the impression.  Firstly, because Arrowhead must already know the knockdown from the 200mg and perhaps also the 300mg open-label cohorts since at least June 18, why didn’t the company simply show the data?   

Regarding safety, the company chose a cut-off date of June 11, that is a week before the June 18 decision.  By June 11, there were only 2 drug-related injection site reactions among the 32 subjects that had received at least 1 dose of either ARO-AAT (n=20) or placebo (n=12) per slide 17 of the presentation.  Those happened to be in the 2 of 4 100mg open-label subjects, the only subjects for which the knockdown had been reported.  

Confusingly, the company also reported that 44 subjects had received at least 1 dose (at least as of the trial termination decision date of 18/6), meaning that 8 subjects had further received 300mg of ARO-AAT (4 open-label, 4 blinded) and 4 placebo (all blinded).  Adding to the confusion, a company representative emailed me in a response to a tweet of mine on the ISR frequency that the safety update referred to those 40 subjects that had received at least 1 injection as of 11/6, but- as I said- contrary to this statement the table on slide 17 only included 32 subjects.  For all those others, the safety data were missing entirely.

The question now is whether the omission was intended as a teaser for the Liver Meeting presentation in November, a minor math issue, or whether there was something more nefarious to it.  The speed with which the company will move into patients (which already have or are at risk for liver disease) will be an important indication whether liver toxicity or the like has been observed subsequent to June 11.

Arrowhead Cuts Trial Short And The Market Loves It

Yesterday, Arrowhead Pharmaceuticals announced that it is cutting short its phase I study of ARO-AAT as it had observed what appeared to be maximal drug activities at lower than predicted doses.  ARO-AAT is the GalNAc-targeted investigational RNAi agent for the treatment of alpha-1-antitrypsin-related liver disease.  This just 3 months after it had initiated dosing in the (healthy volunteer) study.  

The stock market greeted the announcement, sending shares up another 24% turning it into a 10-bagger in the span of one year!

Interpretation of AAT program status

This is what was said to describe the general results seen so far:

”We have escalated above a dose that we believe achieves maximal activity, and all doses to date appear to be generally well-tolerated.”

And this was the trial design:

AROAAT1001 (NCT03362242) is a Phase 1 single- and multiple-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and effect of ARO-AAT on serum alpha-1 antitrypsin levels in healthy adult volunteers. The study includes 7 cohorts in which 16 subjects receive placebo and 28 subjects receive single or multiple doses of ARO-AAT at doses of 35, 100, 200, or 300 mg. Additional cohorts were planned at a dose of 400 mg, but were deemed unnecessary based on observed activity at lower doses.

The company said that data from the study would be presented at AASLD late this fall.  However, based on the original study design involving single and multiple dose cohorts of 35, 100, 200, 300, and 400mg, we can roughly infer the following from the press statements: single and multiple dose cohorts of the first 3 doses up to 200mg had been completed (= 6 cohorts) and the 300mg single-dose cohort had started when they determined that 300mg is already above where maximal activity is reached.  Although the statement does not exclude the possibility that maximal activity appeared to have been seen already at 100mg, we can conservatively 200mg (~3mg/kg) as the dose with which the company plans to move into patients.

In monkeys, the company reported that AAT expression in the liver was almost completely abolished following 2 doses of 3mg/kg spaced 28 days apart based on last year's AASLD poster.

Moving pipeline and technology speedily along

This fast-tracking of the program is consistent with Arrowhead’s overall rapid-fire execution in bringing new programs into the clinic and then use modern, parallel-cohort trial designs and disease experts to move them rapidly along in the clinical development bowel. 

Its goal- and there is every indication they will make good on it- is to bring around half a dozen clinical candidates into the clinic in just over year.  If that weren’t challenging enough for a small biotech company like Arrowhead, these programs are not limited to being targeted to a single tissue (the liver), but could also involve the lung and cancer.

In a way, the liver pipeline is being moved along in a similar fashion to when Alnylam selected its current late-stage clinical crop of candidates 5 or so years ago in a cook-off between different target genes.  Once the technology is ready for a certain tissue, you focus on populating the pipeline with related candidates.  This allows you to grow your market cap and become an established biotech player.  With a market cap now well above $1B, Arrowhead certainly is close to reaching that dream.  It only needs to add to balance sheet cushion.

Overpromising

On the other hand, claimed breakthroughs not in just one (lung), but two (à cancer) additional tissue types, make me wonder whether Arrowhead has started to overpromise again in a fashion similar to the DPC experience when it and investors chose to whistle over safety signals ('DPC has no side effects').  It is understandable if RNAi companies dangle the carrot of additional tissue types in front of the investor community- investors need dreams to hang their hats on- but the speed in light of the size of the company make me wonder if they are taking a short-cut or two too many and investors choose to ignore red flags again.

How times have changed: a year ago, still overly punished by the markets for the DPC fiasco, an cutting-a-trial-short announcement like yesterday’s would have sent shares down further.  Now, Arrowhead is getting the benefit of the doubt.

Knowing that a statement like ‘all doses to date appear to be generally well-tolerated’ can mean pretty much anything bar a drug-related patient death, I choose to remain neutral with regard to the news and will await the AASLD data until further judgement on the quality of Arrowhead’s approach.