Arrowhead Pharmaceuticals, Inc. (ARWR)

Wanted to show some info about Aro-enac and compare to Ionis IONIS-ENAC-2.5. It is not a direct comparison but you can get an Idea about the potency and dosing where if things hold true Aro-Enac RNAi (RNA interference) out performs any ASO (antisense oligonucleotide) technologies.

IONIS Mouse data to compare to Arrowheads Rat and sheep data, Also we will look at LPA data to get a comparison on potency and duration. If you are unaware, Ionis presented Data back in Oct 2020 with their data on IONIS-ENAC-2.5 Rx where it showed the primary endpoint of the study was evaluation of safety and pharmacokinetics of IONIS-ENAC-2.5Rx delivered via a Pari eFlow mesh nebulizer.

In the single escalating dose study, 32 subjects in four cohorts received a single dose of 3, 10, 37.5, or 100 mg and were followed for 30 days. In the multiple ascending dose study, 24 subjects in three cohorts received four doses of 10, 37.5, or 75 mg once weekly, with an additional dose administered during the first week. An additional cohort of eight subjects received a 37.5 mg dose given thrice weekly for 10 doses. Subjects were followed for 13 weeks after dosing.

Fiberoptic bronchoscopy including bronchial brushings and bronchoalveolar lavage was performed during screening and after completion of dosing in the MAD cohorts. Quantitative RT-PCR was performed from the bronchial cell brushings to evaluate ENaC mRNA levels.. IONIS-ENAC-2.5Rx demonstrated a significant decrease in the expression of epithelial sodium channel (ENaC) in healthy volunteers. The study showed a mean 55.6 percent decrease (p<0.05) in ENaC mRNA expression at the 75 mg dose in the multidose segment of the trial. The study represents the first time an antisense medicine delivered directly to the lung via a nebulizer has shown a significant reduction in ENaC messenger RNA levels. In preclinical studies, ENaC mRNA reductions of 40 percent or more resulted in significant improvement in mouse models of CF lung disease.

IONIS-ENAC-2.5 mRNA reductions of 40 percent or more resulted in significant improvement in mouse models of CF lung disease.

ARO-ENAC mRNA reductions of 66 percent or more resulted in significant improvement in Rat model of cf lung disease.

So if we look at this, 55.6 percent decrease mRNA expression IONIS-ENAC human data, can we assume ARO-ENAC could do 26% better? Not exactly but you get the idea. ARO-ENAC is safe so far. We will be better in potency duration, and safety IMO.

Here is some more data Comparing LP(a)Akcea Therapeutics.AKCEA-APO(a) vs Amgen AMG890

AKCEA-APO(a) 35% drop... dose every 4 weeks or 80% drop... dose weekly 20 mg

People randomized to one of five dosing regimens of APO(a)-LRx had large drops in Lp(a) by the sixth month, the reduction ranging from 35% from baseline (at a dose of 20 mg every 4 weeks) to 80% (at 20 mg every week) compared with a 6% drop in the saline placebo arm (P=0.003 and P<0.001, respectively).

Amgen AMG890 90% drop... single dose every 6 months

AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of > 90% and effects persisting for more than 6 months at doses of 9 mg or higher.

Like CA said we win on potency and dosing.

@Only Arwr

I was confused by your statement about IONIS and ENAC. Page 16 of their presentation form last week states ENAC is a target for 2021. It was also mentioned in the cc. Where did you see they are cancelling it.

Thanks

https://static.seekingalpha.com/uploads/sa_presentations/345/66345/original.pdf

I posted this earlier, but the post disappeared.

I was reviewing SLN's Feb 2021 corp presentation slide 14 :

Title of slide: Early-stage GalNAc-conjugated RNAi Programs Have a MuchGreater Likelihood of Approval vs. Industry Average

Likelihood of Approval from Current Phase: GalNAc RNAi vs. Others:

PI - RNAi 51% vs Others 9%
PII - RNAi 56% vs Others 17%
PIII - RNAi 67% vs Others 53%

as stated by ALNY and others on this board, this seems to be in-line with others.

IMO, ARWR is significantly undervalued given each drug in PI or beyond is more than 50% likely to be approved.

I know that Coldlander and many others already commented on the changes to the ARO-ENaC trial, but I believe it bears repeating. Changing the single dose phase measurements from 15 days down to 5 is a good sign that they could be seeing the drug working much faster than they thought; AND changing the multiple dose measurements to 30 days instead of 21 days suggests that they're seeing more durable knock-down than they initially thought. Lastly, increasing the number of participants by 38 patients from 54 to 92 is yet another great sign. No doubt good news all the way around. I feel like a kid in a candy store!

Well, sold 20 June $100 calls today @ $8--generating proceeds of $16K--Still retaining a very large ARWR share position.--Actually would like, or certainly be quite OK with 2K shares being called away at $100 sometime between now and June 18th. Hopefully a win-win scenario with the call buyer doing well with his or her purchase---This week have raised my long standing $84-$134 year end 2021 price target range to----$100-$134--Historically, have been more conservative than many here--Hopefully the upper end of the range (or higher as some well informed individuals have prognosticated) attained by year end. Thanks, and best wishes to all for a great upcoming weekend.

If you haven't noticed, some (if not nearly all) of the news that's now trending, and also beginning to dominate in the markets is "new variants". Just Google it and new variants of the coronavirus have become a huge concern. Nobody was talking about new variants a month or two ago, in fact, that wasn't even a concern back in all of 2020 ...... EXCEPT for Arrowhead. Yes, that's right, Chris was talking about being able to develop drugs that would help stop the coronavirus on multiple fronts, but that it would also apply to other versions or variants of the coronavirus. Pure genius! Hats of to Chris and the Arrowhead team for being way ahead of the game on that call. It would be nice to get a more in-depth update from them on this, as at this point, there really is not much sense in hiding your coronavirus strategy from your competitors.

Just FYI, HBV Patent Application update filed today.
United States Patent Application 20210052624
Kind Code A1
WOODDELL; Christine I. ; et al. February 25, 2021
RNAI THERAPY FOR HEPATITIS B VIRUS INFECTION
Abstract
Described are compositions and methods for inhibition of Hepatitis B virus gene expression. RNA interference (RNAi) triggers and RNAi trigger conjugates for inhibiting the expression of Hepatitis B virus gene are described. Pharmaceutical compositions comprising one or more HBV RNAi triggers optionally with one or more additional therapeutics are also described. Delivery of the described HBV RNAi triggers to infected liver in vivo provides for inhibition of HBV gene expression and treatment.

Below is a follow up on ARO-ENAC clinical trial increase in patients as reported by Colander....as Lefty alluded to...look for the next trial to be a pivotal one...below is Chris Anzalone excerpt from q4 2020 transcript related to question asked on which pipeline drugs could first get to the finish line....

"A wildcard here could be ARO-ENaC. I don't -- again, I don't want to get out over my SKIs because we haven't seen any data yet. But should those data be exciting, should the data in this Phase I/II study suggest that we have something here, it could be that WE COULD MOVE DIRECTLY INTO A PHASE II/III STUDY.. The earliest that could be would be the end of next year because we don't have tox coverage until then, but that's a possibility."

Sounds like the COPD trial start will possibly be in the next few months as it was delayed due to the switch over to an inhaler vs nebulizer. CA is hoping the "time to market" will not be affected because this development work is taking place now instead of later.
"We don't think this slows the program's time to market. And in the end, it may actually shave some time off overall development if the inhaler formulation work enables a more direct path. The ultimate goal is to take forward a therapeutic with optimal efficacy, safety and convenience in a form that is useful to physicians and their patients. We will provide an update over the next quarter, pending completion of a few ongoing studies."