PASADENA, Calif.--(BUSINESS WIRE)--
Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical
company developing targeted RNAi therapeutics, today issued the
following open letter to shareholders from President and CEO,
Christopher Anzalone, Ph.D.:
Dear Arrowhead Shareholders,
Market reaction to our AASLD abstract took us by surprise because we
have always believed that our public communications surrounding the
ARC-520 Phase 2a study have been consistent and, more importantly,
properly reflected the data we were seeing in the initial two cohorts.
We still believe that, but the market clearly expected something
different and/or misunderstood the data. Therefore, I wanted to clarify
recent events for our shareholders.
Let us begin with our goal. We have said for some time that our goal was
to identify a dose of ARC-520 capable of achieving HBsAg reduction of
around 1 log (corresponding with 90% knockdown) after a single
administration. This was a somewhat arbitrary goal since it is unknown
what level of HBsAg reduction is necessary to de-repress the immune
system and potentially enable a functional cure. Indeed, the entire
concept of enabling a functional cure by suppressing HBsAg release
remains an untested theory, but that is one of the challenges of being a
pioneer in the field. We chose 1 log as a goal because, according to the
scientific literature, the small number of patients who achieve
functional cure from Interferon therapy demonstrate ½ log reduction in
HBsAg (approximately 70% knockdown) after 12 weeks and 1 log (90%
knockdown) after 24 weeks. We expected that if ARC-520 is active it
should lead to more rapid reduction, particularly on repeat dosing, so a
full log might not be needed after a single administration. Even so, we
believed that a 1 log goal is intellectually honest and we wanted to
share our thinking publicly rather than establish an artificially low
goal just so we could beat it.
With this goal in hand and on the back of a Phase 1 study that suggested
ARC-520 was well tolerated, we embarked on our ongoing Phase 2a
dose-finding study. Given our animal data across multiple species we
believed that we could achieve our goal, but we did not know what dose
level would be needed in humans. As is always appropriate with a new
technology, we started on the low end of what we expected to be the
active dose range, 1 - 2 mg/kg. We characterized these doses as, in our
view, potentially active but always added that we were prepared to go
higher. On our
August 12th quarterly conference call, we
disclosed that the first 2 dose levels tested in patients with chronic
HBV would not meet our goal. This was not alarming to us because the
safety data from the Phase 1 study in healthy volunteers suggested that
we could continue to dose-escalate with little risk of toxicity.
Therefore, we began a new cohort at a higher dose: 3 mg/kg. At the time
of our August update, the study was still blinded and ongoing but we
wanted to provide some information about what we were seeing.
Recognizing that we were still blinded to which patients had received
ARC-520 and which received placebo, we described the apparent HBsAg
knockdown at 1mg/kg as "modest" and 2mg/kg as "moderate." The study is
now unblinded with respect to the first two cohorts and, as was reported
in the recent AASLD abstract, we now know that the mean peak knockdown
was 39% at 1 mg/kg and 51% at 2 mg/kg. Those numbers still feel "modest"
and "moderate" to us, as we initially reported. Since the August
conference call, we have remained consistent with that terminology.
We also said on the August conference call that we believed the
knockdown we were seeing in humans was similar in magnitude to that
which we have seen in previous studies with non-human primates at
similar doses. More specifically, the chimpanzee with chronic HBV that
we treated received two doses of ARC-520: 2 mg/kg on day 1 and then 3
mg/kg on day 15. Prior to receiving the second dose, HBsAg was reduced
about 50% from baseline. To repeat, we reported mean peak HBsAg
knockdown of 51% in patients receiving 2 mg/kg in the Phase 2a while the
chimpanzee knockdown at that dose was approximately 50%. The chimpanzee
ultimately experienced 80-85% reduction in HBsAg, but only after
receiving the 3 mg/kg dose. That was not the only study with non-human
primates that can be referenced. In a paper we published in the
scientific journal
Molecular Therapy in
May 2013, we showed that
doses around 2 mg/kg (using siRNAs targeting a different liver-expressed
gene) inhibit Factor 7 activity between 30-60%. As with the chimpanzee
study, this certainly feels similar in magnitude to the 51% HBsAg
knockdown we saw in patients receiving 2 mg/kg ARC-520.
So where are we? We have only completed the first two dose levels in an
ongoing dose finding study and have not yet identified a dose in humans
that will meet our knockdown goal… but we are not yet finished. We now
have unblinded Phase 1 safety data in healthy volunteers through 4 mg/kg
and we continue to see a favorable safety profile: no dose-limiting
toxicities or adverse events rated serious or severe. We have just
finished dosing all 8 patients in the 3 mg/kg cohort and as data come
in, we will decide whether to escalate to 4 mg/kg. We do not expect
timing of the program to be impacted. We plan to submit regulatory
filings by the end of the year in support of the multi-dose Phase 2b
study whether or not we escalate to 4mg/kg in the Phase 2a study.
We continue to be excited about ARC-520 and the potential to enable a
functional cure for patients with chronic HBV infection. There is still
much we do not know about ARC-520 and how effective a therapy it may be
one day, but there are some important things that we do know. It appears
to be well tolerated at all doses tested in our prior Phase 1 study: 1
mg/kg - 4 mg/kg. The drug appears to do what it is designed to do. We
have seen clear knockdown in the first 2 doses tested in patients and
the favorable safety profile enables us to increase the dose to see if
we can induce deeper knockdown. Interestingly, we have seen unexpectedly
durable knockdown in patients, even though the low doses provided
relatively shallow depth of HBsAg reductions. At the final time points
studied, nearly 3 months after a single injection, we continue to see
knockdown. We believe that this is important and quite unique. We expect
that it will provide significant advantages, particularly as we increase
dose and initiate planned multi-dose studies.
We remain committed to long term value creation for our shareholders,
and this includes timely and honest communication. We have always
provided as much information as possible and have tried to be
transparent about our thinking and planning, and we will continue to do
so.
Sincerely,
Christopher Anzalone, Ph.D.
President and CEO
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. Arrowhead has
completed enrollment in a Phase 1 single ascending dose study in normal
volunteers. The company is conducting a single dose Phase 2a study in
chronic HBV patients, and expects to follow with multi-dose,
multi-national Phase 2b studies. 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.
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 for chronic
hepatitis B virus, ARC-AAT for liver disease associated with Alpha-1
antitrypsin deficiency, and partner-based programs in obesity and
oncology.
For more information please visit
http://www.arrowheadresearch.com,
or follow us on Twitter
@ArrowRes.
To be added to the Company's email list and receive news directly,
please visit
http://ir.arrowheadresearch.com/alerts.cfm.
Source: Arrowhead Research Corporation
Arrowhead Research Corporation
Vince Anzalone, CFA
626-304-3400
ir@arrowres.com
or
Investor
Relations:
The Trout Group
Lauren Glaser
646-378-2972
ir@arrowres.com
or
Media:
Russo
Partners
Martina Schwarzkopf, Ph.D.
212-845-4292
martina.schwarzkopf@russopartnersllc.com
Source:
Arrowhead Research Corporation
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