Arrowhead’s ARC-520 Leads to Consistent Immune Reactivation in Chimpanzees with Chronic Hepatitis B Infection

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Arrowhead’s ARC-520 Leads...

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PASADENA, Calif.–(BUSINESS WIRE)–

Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical

company developing targeted RNAi therapeutics, presented data at HEP

DART 2015 showing that in chronically HBV-infected chimpanzees treated

with ARC-520 in combination with nucleoside analogs, 7 of 9 (78%)

exhibited signs of immune reactivation, which is likely a necessary step

for achieving a functional cure of chronic HBV. One chimpanzee also

exhibited an on-treatment therapeutic ALT flare and sustained virologic

improvements 31 weeks off all treatment. ARC-520 is currently being

studied in multiple Phase 2b global clinical trials.

“The hepatitis B virus causes infected cells to produce several proteins

that suppress the host immune system, and, therefore, enable chronic

viral infection by removing immune control. Our goal with ARC-520 is to

reduce expression of those proteins and thereby enable reconstitution of

the immune system. We now have shown that ARC-520 can do that, and not

just in 1 or 2 infected chimps, but in 7 of the 9 chimps we treated, and

this is a big deal,” said Christopher Anzalone, Ph.D., Arrowhead

president and CEO. “ARC-520 deeply reduces HBV proteins and we believe

the elevations in T-cell responsive serum cytokines observed in this

study represent a strong proof of principle that ARC-520 can begin the

process of immune reconstitution that many believe can lead to

functional cure. These data are particularly encouraging when combined

with our recent human data. Our Phase 2a clinical trial, which we

reported at AASLD last month, showed that ARC-520 can dramatically

reduce s-antigen, e-antigen, and core-related antigen in humans after a

single dose. During the ongoing Phase 2b clinical trials, we are

studying ARC-520 as monotherapy as well as in combination with other

agents with the goal of identifying a regimen that leads to consistent

functional cures.”

Christine Wooddell, Ph.D., director of liver targeting for Arrowhead,

presented poster number 152 titled, “Sustained reduction of HBV DNA,

RNA and proteins, and HBeAg seroconversion in a chronically HBV-infected

chimpanzee treated with nucleoside analog/ARC-520 combination therapy.”

In this presentation, Dr. Wooddell and co-authors show that 7 of 9

chimps, HBeAg positive and negative, exhibited indications of an immune

response during ARC-520 treatment, as evidenced by elevations in T-cell

responsive serum cytokines. Chimp Manetta exhibited deep decreases in

HBV DNA, RNA and viral proteins during ARC-520/NUC treatment. The

sustained induction of CXCL9 in Manetta was associated with a

therapeutic ALT flare (218 U/L) followed by HBeAg seroconversion.

Sustained virologic improvements were still observed 31 weeks after all

treatment was removed. At this final time point, serum HBV DNA was 5 log10

lower, HBsAg was 1.7 log10 lower, and liver HBV RNA was 99%

lower than pre-study.

HBV suppresses the immune system to allow chronic HBV infection.

Interferon gamma (IFN-γ) is a key antiviral cytokine critical to innate

and adaptive immune responses. IFN-γ produced by natural killer cells

and natural killer T cells induces the chemokines CXCL9 and CXCL10 to

mediate a T-cell response. An elevation of CXCL9 in the chimps studied

is a promising sign of immune system reactivation.

8 out of 9 chimps exhibited episodes of serum cytokine CXCL9 elevation.

For 7 chimps these occurred during ARC-520 treatment and in one chimp

(Tattoo) these coincided with seroclearance of HBeAg that began prior to

study.

To reduce viral replication prior to treatment with ARC-520, chimps were

treated for 8-24 weeks with entecavir or in one case (chimp Michele)

with entecavir and tenofovir. Following the NUC lead-in period, animals

were administered ARC-520 intravenously at 4-week intervals (q4w). Dose

levels were 2, 3, or 4 mg/kg ARC-520, along with maintenance doses of

entecavir or entecavir and tenofovir. All 9 chimpanzees responded to

ARC-520 with HBsAg reductions of 0.5 – 2.7 log10 at nadir,

the greater reductions being in HBeAg positive chimps. HBsAg levels in

all chimps continued to decrease with repeat dosing. Chimps were

monitored for up to 31 weeks off all treatment.

Copies of presentation materials can be accessed by visiting the Events

section of the company’s website at http://ir.arrowheadresearch.com/events.cfm.

About ARC-520

Arrowhead’s RNAi-based candidate ARC-520 is being investigated in the

treatment of chronic HBV infection. The small interfering RNAs (siRNAs)

in ARC-520 intervene at the mRNA level, upstream of the reverse

transcription process where current standard of care nucleotide and

nucleoside analogues act. Arrowhead is investigating ARC-520

specifically to determine if it can be used to achieve a functional

cure, which is an immune clearant state characterized by hepatitis B

s-antigen negative serum with or without seroconversion. Arrowhead is

conducting Phase 2b multiple dose and combination studies in chronic HBV

patients. Approximately 350-400 million people worldwide are chronically

infected with the hepatitis B virus, which can lead to cirrhosis of the

liver and is responsible for 80% of primary liver cancers globally.

About Arrowhead Research Corporation

Arrowhead Research Corporation is a biopharmaceutical company developing

targeted RNAi therapeutics. The company is leveraging its proprietary

Dynamic Polyconjugate™ delivery platform to develop targeted

drugs based on the RNA interference mechanism that efficiently silences

disease-causing genes. Arrowhead’s pipeline includes ARC-520 and ARC-521

for chronic hepatitis B virus, ARC-AAT for liver disease associated with

alpha-1 antitrypsin deficiency, ARC-F12 for hereditary angioedema and

thromboembolic diseases, and ARC-HIF2 for renal cell carcinoma.

For more information please visit http://www.arrowheadresearch.com,

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This news release contains forward-looking statements within the

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Litigation Reform Act of 1995. These statements are based upon our

current expectations and speak only as of the date hereof. Our actual

results may differ materially and adversely from those expressed in any

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future success of our scientific studies, our ability to successfully

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Source: Arrowhead Research Corporation

Arrowhead Research Corporation
Vince Anzalone, CFA
626-304-3400
ir@arrowres.com
or
Investor

Relations:
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Chad Rubin, 646-378-2947
ir@arrowres.com
or
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Source: Arrowhead Research Corporation

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