ALNY v. ARWR...need a scientist

[holdencf]

I posted this on YMB but added the link to ALNY's slide show that "tabs223" posted.

"I have received several emails about the timing of ARWR's IND filing (or EU equivalent) versus when they will be "in the clinic." From what I understand they will file the 521 IND (or reg. equivalent) by end of June. That is not the target date for getting in the clinic. IMO, getting in the clinic will be some time late 3Q or into 4Q. Lots of factors affect that and we can't know with precision what the date will be.



Arguably a bigger question is...Is ALNY's one strand trigger sufficient to KD the manufacturing capability of HBsAg at the site it initially targeted AND iHBV?? Slide 9 of ALNY's HBV presentation leads me to believe that the trigger does not target both sites. (Someone posted that that slide from a November presentation had been removed from the slide DEC - I have not confirmed.) ARWR confronted this same issue and that is what gave rise to 521. So if 521 is in the clinic before ALN-HBV gets in the clinic, ARWR will have a drug for both eAg(+) and eAg(-) before ALNY has a drug in the clinic for either. What does that mean from a competitive perspective? ARWR will be a full three years ahead of ALNY in eAg(+) space assuming ALNY has optimal dose response with ALN-HBV. Can't even calculate how far ahead ARWR is in eAg(-) space. Why? Because we don't know the extent of ALNY's single trigger GalNAc stability/size problems. We certainly can't begin to consider how that balance might be affected if ALNY has to add a second strand to their current single strand molecule. If the size is too big with a single strand, can a second strand be added with any chance of cellular uptake?



It looks to me like ALNY is definitively and literally GalNAc'd with respect to its HBV program."

Slide 9 is ALNY pictoral representation as to where they hit the proteins versus ARWR.  If you look at the slide, it looks like ARWR dropped ARC-520 right on top of the protein pool, where as ALNY dropped ALN-HBV in the mud next to the pool.  That is my unscientific description as to what I see.  The word "Downstream" is a key word I do not understand.  That implies that somehow these antigens are flowing in a direction and that ALNY has cast a net to catch them as they flow "downstream."  Can anyone explain this?   And can anyone respond to my YMB speculation.  Does ALNY have to go back to the whiteboard and design a new delivery molecule that can accommodate a second trigger?  

www.alnylam.com/web/assets/ALN-HBV_AASLD_111515.pdf

[mudbug021]

Taken from the ALNY website



"We presented new pre-clinical data with ALN-HBV, an investigational RNAi therapeutic targeting the Hepatitis B Virus (HBV) genome for the treatment of HBV infection. The ALN-HBV siRNA targets a highly conserved site across genotypes A-J, mapping to the X open reading frame, which is downstream from the most prevalent integration hotspot targeted by siRNAs from other developers. ALN-HBV is thus expected to achieve potent knockdown of HBV surface antigen (HBsAg) expressed by both covalently closed circular DNA (cccDNA) and integrated HBV DNA. Pre-clinical study results in rodent HBV models showed that subcutaneous administration of ALN-HBV led to potent and durable knockdown of HBsAg. Single doses of ALN-HBV in mice resulted in an up to 3.6 log10 and a mean of 1.6 log10 reduction of HBsAg 15 days after a single dose. Further, multiple doses of ALN-HBV in rats showed highly durable knockdown, with effects lasting up to 4 months following three weekly doses of ALN-HBV at 3 mg/kg. In addition, ALN-HBV was generally well tolerated in all rodent models."

The way I have read this is ALNY is claiming they are on the "hotspot" while other developers are not (or downstream) What does not make sense to me is that they claim there is a "hotspot" to begin with.

The only thing I can suggest is you email ALNY and get clarification directly from them. To me it sounds like double talk. 

[Bio Boy Scout]

Mud,

ALNY's comments with regards to their HBV target are meant to confuse. If you read it carefully (and correctly), they are saying that they target a "highly conserved site" that is able to touch upon genotypes A-J. They are also saying that this conserved site also maps onto the X open reading frame (which it does). They are ALSO saying that THEY are downstream from the hotspot (if you look at the figure, they are actually upstream, but this doesn't make a difference either way). They actually point out that ARWR is directly at the "hotspot" in both figures. I believe that they are trying to imply that since they are downstream from the hotspot, that this allows them to hit genotypes A-J. Unfortunately, there is no chart showing genotype mapping. If you read the most up-to-date research with regards to which plasmids should be selected, look here: www.ncbi.nlm.nih.gov/pmc/articles/PMC2927532/ It tells you that B1789 is the most effective spot, and you guessed it, ARWR selected B1789 as their target.

In the end, my guess is that ALNY will have problems for 1 or 2 reasons: 1) they will not have as big or durable KD; and 2) they will have AE issues when they dose at higher levels. For these reasons, I believe their drug will take much longer to test and clear out of clinic than ARWR's.  Therefore, I believe ARWR has at least a 5 year lead, if not more.

[Bio Boy Scout]

Found one more really nice article of note regarding gene location, please pay particular attention to figure 4, as well as the write-up around figure 4. Note that ALNY is the 1550-1600 range (DR2) and ARWR is in the 1780-1850 range (DR1).

Article: genome.cshlp.org/content/22/4/593.full

Figure 4: genome.cshlp.org/content/22/4/593/F4.large.jpg

No doubt ALNY hit the DR2 range, but it's not even close to the ARWR's hotspot of DR1.

BTW, I believe the main author of both of the articles works for Gilead.

[mudbug021]

Bio,

Like holdencf I am no scientist. That said, I think youre more accurate pertaining to the hotspot explanation. My issue is I have a really skeptical opinion of ALNY's CEO. To me he comes across as a snake oil salesman. So I have a hard time trusting what I read when they publish anything. 

[Bio Boy Scout]

Mud,

I'm hoping that ALNY sees huge success, as that helps validate the science. Every upgrade for ALNY helps ARWR, and vice-versa, as that shows strength in the industry. You don't want to see weakness in the industry, as that will hurt everyone. My guess is that RNAi will be the really hot biotech field within 10 years, as that will not just treat symptoms, but provide actual cures with little to no side-effects. I easily see both ARWR and ALNY in the $100B market cap range in about 5-7 years (assuming they don't get bought out first).

[mudbug021]

Mar 11, 2016 16:06:23 GMT -5 Bio Boy Scout said:

Mud,

I'm hoping that ALNY sees huge success, as that helps validate the science. Every upgrade for ALNY helps ARWR, and vice-versa, as that shows strength in the industry. You don't want to see weakness in the industry, as that will hurt everyone. My guess is that RNAi will be the really hot biotech field within 10 years, as that will not just treat symptoms, but provide actual cures with little to no side-effects. I easily see both ARWR and ALNY in the $100B market cap range in about 5-7 years (assuming they don't get bought out first).

Bio

Whether you believe it or not, I have stated this same idea, almost verbatim on the YMB. As I have stated, I am not a scientist, ARWR is a small fish in a big ocean. Its all about patience. IMHO.