ARC520 -Updates on the Phase2a study

[StephenCastlecrag]

Arrowhead Reports Fiscal 2014 Third Quarter Financial Results and Provides Update on ARC-520


- Conference Call Today at 4:30 p.m. EDT

PASADENA, Calif.--(BUSINESS WIRE)-- Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced financial results for its fiscal 2014 third quarter ended June 30, 2014 and provided an update on the Phase 2a study of ARC-520, its RNAi-based candidate for the treatment of chronic hepatitis B infection. The company is hosting a conference call at 4:30 p.m. EDT to discuss results. Conference call and webcast details can be found below.

ARC-520 Phase 2a Study Update

    Completed dosing of 1 mg/kg and 2 mg/kg dose cohorts
    Initial blinded data suggest that the magnitude of HBsAg knockdown is similar to non-human primate studies, including the chronically infected chimpanzee reported on previously
    Duration of knockdown appears to be substantially more sustained than in non-human primates, with patients in the 2 mg/kg group still demonstrating substantial knockdown after 8 weeks, which is the most recent time point available
    HBsAg levels appear to continue to decline in a number of patients at the 8 week time point in the 2 mg/kg group
    Based on initial review, dosing less frequent than once monthly will be explored in Phase 2b
    ARC-520 continues to be well tolerated, with no dropouts or serious adverse events reported
    The overall rate of AEs has been lower in the Phase 2a than in the Phase 1 normal volunteer study and safety labs continue to show no indication of end organ toxicity
    Enrolled and dosed additional subjects at 3 mg/kg in the still open normal volunteer study and the dose performed well, without detected differences from safety and tolerability results at the other doses. Overall AEs do not appear to be increasing in frequency or severity with dose
    Received IRB and DSMB approvals to proceed and began enrolling an additional dose cohort at 3 mg/kg in the Phase 2a patient study

Fiscal 2014 Third Quarter and Recent Company Highlights

    Nominated a second clinical candidate using our DPC delivery system, ARC-AAT, for the treatment of a rare liver disease associated with alpha-1 antitrypsin deficiency and hosted an analyst day to present preclinical data
    Signed an agreement with The Alpha-1 Project (TAP), the venture philanthropy subsidiary of the Alpha-1 Foundation. Under the terms of the agreement, TAP will partially fund the development of ARC-AAT. In addition, TAP will make its scientific advisors available to Arrowhead, assist with patient recruitment for clinical trials through the Alpha-1 Foundation Patient Research Registry, and engage in other collaborative efforts that support the development of ARC-AAT
    Initiated the final steps required to file an IND or equivalent application for ARC-AAT, including necessary toxicology studies
    Expanded intellectual property protection with U.S. Patent Application number 13/535,454 covering ARC-520's siRNA component, being recently allowed by the U.S. Patent and Trademark Office
    Presented data on advancements made to the DPC delivery system at multiple scientific meetings
    Arrowhead added to the broad-market Russell 3000 index and small-cap Russell 2000 index

Selected Fiscal 2014 Third Quarter Financial Results

Net loss attributable to Arrowhead for the quarter was $11.6 million, or $0.22 per share based on 51.9 million weighted average shares outstanding. This compares with a net loss attributable to Arrowhead of $6.1 million, or $0.23 per share based on 26.1 million weighted average shares outstanding, for the quarter ended June 30, 2013.

Total operating expenses for the quarter were $12.7 million, compared to $6.4 million for the quarter ended June 30, 2013. Research and development related expenses were $6.4 million and general and administrative expenses were $1.6 during the quarter.

Net cash used in operating activities for the first nine months of fiscal 2014 was $24.5 million, compared with $13.6 million in the prior year period.

The company's cash and investments of cash were $188.5 million at June 30, 2014, compared to $29.8 million at September 30, 2013. The increase in the cash balance reflects financings completed in October 2013 and February 2014, plus cash inflow from exercise of warrants and stock options of $12.4 million.

Common shares outstanding at June 30, 2014, were 52.9 million, and 58.5 million assuming conversion of preferred stock outstanding.

Conference Call and Webcast Details

To participate in the conference call, please dial 855-215-6159 (toll free from the US) or 315-625-6887 (for international callers) and enter Conference ID 82825377. Investors may also access a live audio webcast of this conference call on the Company's website at http://ir.arrowheadresearch.com/events.cfm.

A replay of the webcast will be available approximately two hours after the conclusion of the call and will remain available for 90 days. An audio replay will also be available approximately two hours after the conclusion of the call and will be available for 7 days. The audio replay can be accessed by dialing 855-859-2056 (toll free from the US), or 404-537-3406 (for international callers) and entering Conference ID 82825377.

About ARC-520

Arrowhead's RNAi-based candidate ARC-520 is designed to treat chronic HBV infection by reducing the expression and release of new viral particles and key viral proteins. The goal is to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without sero-conversion. The siRNAs in ARC-520 intervene at the mRNA level, upstream of where nucleotide and nucleoside analogues act. In transient and transgenic mouse models of HBV infection, a single co-injection of Arrowhead's Dynamic Polyconjugate (DPC) delivery vehicle with cholesterol-conjugated siRNA targeting HBV sequences resulted in multi-log knockdown of HBV RNA, proteins and viral DNA with long duration of effect. The company is conducting a single dose Phase 2a study in chronic HBV patients, and expects to follow with a multi-dose, multi-national Phase 2b program. Approximately 350 million people worldwide are chronically infected with the hepatitis B virus. Chronic HBV infection can lead to cirrhosis of the liver and is responsible for 80% of primary liver cancers globally.

[Bob0620]

Link : http://rnaitherapeutics.blogspot.com/2014/08/dose-of-arc520-hbv-drug-candidate-to-be.html

[The_PS]

Great!!!

[SafiSifa]

I do wanna learn what Stef2011 thinks about that

[stef2011]

like for replicor i want to see good clinical trials with stable hbsag seroconversion if no seroconversion arc-520 is not useful

i think they will have to add on peginterferon and hbv vaccines since it looks like this drug has no seroconversion in monotherapy and then see if this can be kept

i have not checked their studies, did they measure cccdna with hbsag decline?because the point here, like for replicor, is cccdna decline with hbsag and if not how peginterferon can help clear cccdna when arc-520 has made very low hbsag

maybe the best thing this drug can do is lower hbsag to have a 100% peginterferon response and hbsag seroconversion

[stef2011]

http://clinicaltrials.gov/show/NCT02065336

i think this study will tell a lot i hope they will publish results before april 2015 or at least communicate pre-results

Estimated Enrollment: 16
Study Start Date: March 2014
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

[SafiSifa]

Hello Stef.

What is the difference between cccDNA and HBSAG? and What is the relation between them?

[luckyman316]

Stef, you're really big on the peginterferon combo and I can understand why. The numbers themselves prove it works. But I think this drug's goal is to actually get away from this kind of treatment and work QUICKER. I've known a few Hep C patients that did interfereon who have said the side effects were terrible to deal with. Some people may respond better to it than others, but most had bad sides and that is something I believe they want to do away with with this drug.

I do agree with you that without seroconversion, this is not useful. As you suggested, I guess it can known out hbsag and a vaccination can be provided. That could always be a course of action and a great suggestion. Wonder if they tried that yet?

I, of course, do have questions regarding this:

-They did a study with Entecavir. Will this work with Tenofovir?!

-If you are already undetectable, can you stop the anti-viral and just have this knock out the rest of hbsag?

-Once hbsag is knocked out, will you have to continue taking this drug or any other drug for maintenance to make sure it does not come back?

-What kind of side affects, if any, will this have?

-Is there anything that interfes with the drug (any vitamins, foods, drinks, etc.)?

So many questions left unanswered. I'm sure there are more. I'll be curious to see what happens in Phase IIb

[Seattledude]

Pre results were communicated yesterday and were very strong at lower doses, they are moving up to 3 and 4 mg/kg to achieve greater knockdown.

Full Data on 1 and 2 mg/kg and also 3 should be available at AASLD in Nov

One of the most encouraging results from yesterday is the continued decrease at 8 weeks of Hbsag with only one dose.

[stef2011]

we will see they showed too little data for now and poor quality trials (i mean too small and too little tests)
i also think combo with nucs alone is of little help, the real benefit will be from pegintf which will remove the infection by activating immune system.anyway we ll see from this study what it can do

hcv is not comparable to hbv as regards peginterferon treatment.they have a huge response to clear hcv by peg from 50 to 80% clearance according to genotypes but they also have a very potent immune activation by peg.
you ll never see such extreme sides on an hbv patient, most just experience fatigue or even no sides

[Seattledude]

"Poor quality trials" that is the nature if phase 2a, they are looking for the right dose at this point. 2b which starts in the next 6 months will be larger


IMO this has the potential as a single agent providing seroconversion

[StephenCastlecrag]

To understand how ARC520 will work, you must understand how REP9AC work, how TDF for few years then add-on PEGIFN is supposed to work. It is all about reducing all the suppression of the immune system caused by serum virions(HBVdna) , HBeAg, and HBsAg. The theory is that with the removal of these suppressions, our cd8 T cells immunity will recover and works to clear the infection. Not all experts believe this is sufficient for a majority of patients, something else to boost the immune system will also be needed. If you listen to the webcast by Arrowhead, all these will be explored in the phase2b trials to be conducted in the USA, Europe, and Asia, starting Q4 this year. At the same time, there will be separate studies to consider combinations with immune modulating agents.

My understanding.

[Seattledude]

That was my understanding as well, but the fact that Hbsag is still declining in the 2mg/kg group 8 weeks after a single dose may change that. If 3mg/kg can provide greater initial knockdown at longer duration (coupled with a repeat dose if needed) it may stimulate the immune system enough to clear without Peg.

The fact that no sides developed in the 3mg/kg is very encouraging and going to 4 is interesting as well. They will find the sweet spot

[StephenCastlecrag]

Yes, for some patients, the drop in serum HBsAg is sufficient to kick start their immune system, and ARC520 alone will be enough. But I don't think it will be the case for most patients. Anyhow, we must first repeat the success of REP9AC. After all, is the drop in serum HBsAg the cause or just effect of other factors at work in clearing the infection?

[stef2011]

i think same as stephen, since cccdna can remain for decades even after hbsag clearance and hbsab in acute infection i think pegintf is always needed and cccdna test needed too because like for replicor we are artificially bringing hbsag down but what about cccdna

i cannot tell this for sure because i dont know if arc520 lowers cccdna or not, anyway a great achievement for hbv cure in combo with peg and nucs.too bad replicor had no investors too

[stef2011]

while on sequential nucs and peg add on hbsag goes down because cccdna is gong down, so in this case we dont need to check cccdna too much

[DMach921]

But if Arc is dropping HBSag wouldn't it be safe to say cccdna would be dropping as well??? Your last 2 posts contradict each other.

[stef2011]

cccdna is the main producer of hbsag the immune system targets cccdna to lower hbsag (among all other attacks)

replicor drug has no direct effect on cccdna or hbsag, it just blocks the release of hbsag from cells

The siRNAs in ARC-520 target the mRNAs that produce HBsAg proteins, the viral polymerase, the core protein that forms the capsid, and the HBeAg.from this statment it looks like action is not on cccdna but on its final product hbsag and other antigens

[makeadifferencenow]

Steff mate  when  I spoke with Arrow Head  before they said the same more or less as what your saying the aim is not mono therapy it will have to be combined with something  but only time will tell. But it could deliver a rapid knockdown in surface I don't think they are anticipating clearing CCCDNA  (wouldn't it be nice if it did). Looks like they are moving in the right direction! Just my input on it!

[DMach921]

So it looks like a cocktail of Arc - Tenefovir and peg add on might be the knockout combination

[StephenCastlecrag]

"while on sequential nucs and peg add on hbsag goes down because cccdna is gong down, so in this case we dont need to check cccdna too much "

I agree with your statement. It is either the pool of CCDNA is decreased by degradation of the cccDNA or killing of cells infected with cccDNA, or cccDNA is rendered inactive, eg. by epigenetic control. But what is responsible for all these? Interferon or our re-activated immune system? Why Interferon alpha seems to be more effective when serum HBsAg is low?

The proponents of ARC520/REP9AC would like to think it is due to our immune system, now recovered from suppression due to excess serum HBsAg. Interferon alpha, as opposed to Interferon gamma, is not known to degrade cccDNA, but I think it can inhibit (I maybe wrong) cccDNA to some degrees. It can certainly modulate the immune system.

So, this bring me back to my question: Is the decrease in serum HBsAg a cause or effect?

Comments from studyforhope would be most appreciated.

[stef2011]

i have not checked all studies but i think most of the purge of cccdna is thanks to cytokines like intf gamma which is increased under pegintf while the killing of infected cells is mostly from cd8 cells but the killing strategy alone is not that efficent.i myself had alt at 1500 for about 6 months at about 18-19years old and this wont cleared the infection despite hbvdna was undetectable in th end.at that time no hbsag quant or hbvdna quant was available but hbvdna qualitative was about 100copies/ml

i also saw some studies trying on those clearing hbsag and they did not find strong immune activity vs chronic phase so they are still wondering what pushes hbsag clearance in chronic patients...maybe maily the cytokines

[luckyman316]

I like this thread, lots of good information. I'm concerned though. If the USA is not measuring Hbsag in quantitive, then how will they know if the drug is actually working here?! I'm curious to see what types of tests they run for this before they say "you're cured!"

[melcul]

maybe in trials they do test hbsAG quant .

[luckyman316]

According to the trial I am on, they are indeed measuring Hbsag in quantitive, but they are not making the numbers comercially available to the patients. I'm at a loss as to why... probably something with the FDA approval here.