- Greater than 50% improvement in proteinuria
(albumin to creatinine ratio) after 14 days of oral dosing with
ACH-4471 -
Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN)
today reported preliminary proof-of-concept results from group 1 of
its ongoing Phase 2, open-label, 14-day study of ACH-4471 for
patients with C3 glomerulopathy (C3G) or immune complex-mediated
membranoproliferative glomerulonephritis (IC-MPGN). The Principal
Investigator for this study is Dr. Tom Barbour, Royal Melbourne
Hospital, Melbourne, Australia, Department of Nephrology.
This trial, initiated in September 2017, has
currently completed treatment of the first group consisting of two
sentinel patients. Interim data from the two sentinel
patients in this ongoing trial demonstrated that ACH-4471 achieved
complement alternative pathway (AP) inhibition resulting in a
greater than 50% reduction in proteinuria, as measured by albumin
to creatinine ratio (ACR), over the 14-day treatment period, and
demonstrated a favorable tolerability profile.
“Preliminary data from this Phase 2 trial
suggest that ACH-4471 may reverse the AP hyperactivity in C3G based
upon the observed improvements in fragment: intact C3 and
proteinuria with 14 days of treatment with ACH-4471,” commented
Milind Deshpande, Ph.D., President and Chief Executive Officer of
Achillion. “We are excited by these early data and the potential of
ACH-4471 to be a novel and potentially disease-modifying treatment
for C3G and IC-MPGN.”
The on-going Phase 2 trial is assessing whether
ACH-4471 can reverse AP hyperactivity which is believed to be the
underlying driver of the pathogenesis and progression of C3G.
Patients with biopsy-established C3G or IC-MPGN with evidence of AP
hyperactivity are eligible for enrollment. Multiple complement
biomarkers indicative of AP activity, including the ratio of C3
fragments to intact C3 in plasma (fragment: intact C3), plasma Bb
levels, ex vivo Ba formation, and Ba levels in urine were measured.
Additional measures being evaluated include proteinuria, safety,
and pharmacokinetics. Preliminary data from this Phase 2 trial
suggest that ACH-4471 may have the potential to reverse AP
hyperactivity resulting in improvement in proteinuria.
Per protocol, group 1 evaluated the safety and
activity of 100 mg of ACH-4471 administered three times daily (TID)
for 14 days, followed by a seven-day taper period, and a subsequent
follow-up period. Achillion is currently screening patients for
group 2 and plans to enroll up to eight C3G or IC-MPGN patients to
evaluate additional doses of ACH-4471. Interim results from the two
patients enrolled in group 1 are summarized below.
In C3G, the underlying pathophysiology is
believed to be an overactive AP, mediated by increased C3
convertase activity. This increase in AP C3 convertase
activity leads to excessive consumption of intact C3, and
consequent elevations in the levels of C3 breakdown products, or C3
fragments. The subsequent deposition of these C3 fragments into the
kidney is thought to be responsible for kidney damage and loss of
function seen in this disease over time. As an inhibitor of factor
D, ACH-4471 may be able to normalize AP activity in these patients,
decreasing the excessive breakdown of intact C3. This change
may be assessed by evaluating the ratio of C3 fragments to intact
C3.
Both Patient A and Patient B are adult male
patients diagnosed with C3G based upon historical kidney biopsy.
Patient A had a baseline Bb, a byproduct of the interaction between
factor D and factor B, at the upper limit of normal and achieved a
30% reduction in Bb levels, consistent with reductions observed in
previously conducted Phase 1 healthy volunteer studies. Patient B
had a significantly elevated Bb level at baseline and experienced
near normalization with approximately a 50% reduction in Bb, during
the treatment period with ACH-4471.
At baseline, Patient A had an elevated fragment:
intact C3 ratio that was approximately 178% of the upper limit of
normal (ULN) at baseline, which rapidly improved with normalization
during the dosing period. Similarly, Patient B had an elevated
fragment: intact C3 ratio that was approximately 187% of the ULN at
baseline with a rapid decrease after initiation of dosing with an
improvement to approximately 134% of the ULN by day 14. As an
additional assessment of AP activity and inhibition after dosing
with ACH-4471, an ex vivo assay was conducted in which Ba
production was measured as a means of quantitating the ability to
generate newly formed AP C3 convertase. Ba production serves as a
proxy for newly formed AP C3 convertase since factor B can only be
cleaved by factor D when it is already complexed with the
components required to form the active AP C3 convertase. In this
assay a 90%, or greater, reduction in the ability to form new AP
convertase was observed for both Patients A and B throughout the
dosing period.
In both Patients A and B, the primary clinical
manifestation was significant proteinuria (baseline ACR > 200
mg/mmol). In both cases, a greater than 50% reduction in
proteinuria, as measured by ACRs, was observed during the treatment
period.
|
|
|
|
|
Subject |
|
Albumin:Creatinine Ratio (ACR) |
C3 fragment/intact |
Ex vivo Ba production % |
|
Normal range |
0 - 2.5 mg/mmol |
0.0085 - 0.0949 (ratio) |
NHS 100% |
Patient A |
Baseline |
259.3 |
0.1692 |
132% |
|
On treatment |
114.5 (day 17) |
0.0606 (day 14) |
35% (day 15) |
|
% Reduction |
56% |
64% |
97% |
|
|
|
|
|
Patient B |
Baseline |
580.3 |
0.1775 |
142% |
|
On treatment |
263 (day 17) |
0.1273 (day 14) |
40% (day 14) |
|
% Reduction |
55% |
28% |
102% |
|
|
|
|
|
|
|
|
“C3G is a serious renal disease for which there
are no FDA-approved therapies,” commented Dr. Matthew Pickering,
Professor of Rheumatology, Imperial College of London, who focuses
on studying the role of complement and the mechanisms of kidney
injury in C3G. “I am pleased to see these early data in which the
biologic effects on complement proteins following administration
with ACH-4471 indicated that this may represent a novel and
promising approach for the treatment of C3G. Importantly, I am
particularly encouraged by the magnitude of change in proteinuria
this early in the treatment period. I look forward to results
from additional patients and the potential for longer-term
treatment durations with ACH-4471.” Dr. Pickering is a paid
scientific advisor for Achillion and Lead Investigator for an
Achillion-sponsored Natural History Study in C3G.
(Clinicaltrials.gov: NCT03124368 /EudraCT:
2016-003525-42)
C3G / IC-MPGN: Phase 2 12-month open-label trial
of ACH-4471
Achillion also plans to conduct a Phase 2
open-label, 12-month treatment trial for patients with
biopsy-confirmed C3G or IC-MPGN. All patients enrolled will receive
treatment with ACH-4471 with periodic assessment of clinical
endpoints including proteinuria and estimated glomerular filtration
rate (eGFR). Up to 20 patients are expected to be enrolled.
Enrollment is expected to be initiated in the first half of
2018.
C3G: Phase 2 6-month randomized,
placebo-controlled trial of ACH-4471
During the first half of 2018, Achillion plans
to initiate a randomized, placebo-controlled, double-blinded Phase
2 trial evaluating the efficacy and safety of ACH-4471 in patients
with C3G. The trial is designed to assess renal biopsy findings and
clinical endpoints such as proteinuria and eGFR. Up to 20 patients
are expected to be enrolled.
C3G / IC-MPGN: Global Natural History Study
Achillion is supporting a global natural history
study of C3G and IC-MPGN, to track the course of this disease over
time. The study is being led by Dr. Matthew Pickering and Dr. H.
Terry Cook, both of Imperial College of London, in collaboration
with C3G nephrologists worldwide. The aim of this study is to
collect data on disease progression. This study, which began
earlier this year, will run in parallel with other C3G clinical
trials, and the data from this study are expected to inform and
support product development and potential approval.
Achillion has solicited and received scientific
advice from the FDA, the European Medicines Agency and the
Medicines and Healthcare Products Regulatory Agency with respect to
the design of the Phase 2 trials for C3G and paroxysmal nocturnal
hemoglobinuria (PNH) and the safety monitoring plan, as well as,
the plans for clinical pharmacology and nonclinical studies needed
to support potential future registration for ACH-4471. In
addition, investigational new drug applications are open in the
United States for both PNH and C3G.
About the Achillion Complement Factor D
Platform
Achillion has leveraged its internal discovery
capabilities and a novel complement-related platform to develop
small molecule drug candidates that are oral inhibitors of
complement factor D. Factor D is an essential serine protease
involved in the complement pathway, a part of the innate immune
system. Achillion's complement platform is focused on seeking to
advance small molecule compounds that inhibit factor D and can
potentially be used in the treatment of immune-related diseases in
which complement alternative pathway plays a critical role.
Potential indications being evaluated for these compounds include
paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G),
immune complex-mediated membranoproliferative glomerulonephritis
(IC-MPGN), and geographic atrophy (GA).
About Achillion
Pharmaceuticals
Achillion Pharmaceuticals, Inc. (NASDAQ:ACHN) is
a science-driven, patient-focused company seeking to leverage its
strengths across the continuum from discovery to commercialization
in its goal of providing better treatments for people with serious
diseases. The company employs a highly-disciplined discovery and
development approach that has allowed it to pursue best-in-class
oral antiviral therapy for chronic hepatitis C (HCV) and build a
platform of potent and specific complement inhibitors. Achillion is
rapidly advancing its efforts to become a fully-integrated
pharmaceutical company with a goal of bringing life-saving
medicines to patients with rare diseases. More information is
available at http://www.achillion.com.
Cautionary Note Regarding
Forward-Looking Statements
This press release includes forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995 that are subject to risks, uncertainties and
other important factors that could cause actual results to differ
materially from those indicated by such forward-looking statements.
Achillion may use words such as “expect,” “anticipate,” “project,”
“target,” “intend,” “plan,” “aim,” “believe,” “seek,” “ estimate,”
“can,” “could” “focus,” “will,” “look forward,” “goal,” and “may”
and similar expressions to identify such forward-looking
statements. These forward-looking statements also include
statements about: Achillion’s expected plans, timing, data readouts
and results from ongoing and planned clinical trials and natural
history studies of ACH-4471; the potential therapeutic effects and
benefits of ACH-4471 as a treatment for C3G, IC-MPGN and other
indications; and statements concerning Achillion’s strategic goals,
milestone plans, and prospects. Among the important factors that
could cause actual results to differ materially from those
indicated by such forward-looking statements are risks relating to,
among other things Achillion’s ability to: advance the preclinical
and clinical development of ACH-4471 under the timelines it
projects in current and future preclinical studies and clinical
trials; obtain and maintain patent protection for its drug
candidates and the freedom to operate under third party
intellectual property; demonstrate in any current and future
clinical trials the requisite safety, efficacy and combinability of
its drug candidates; replicate in later cohorts or later trials any
favorable results from earlier cohorts and earlier trials; obtain
and maintain necessary regulatory approvals; establish commercial
manufacturing arrangements; identify, enter into and maintain
collaboration agreements with third-parties; compete successfully
in the markets in which it seeks to develop and commercialize its
product candidates and future products; manage expenses; manage
litigation; raise the substantial additional capital needed to
achieve its business objectives; and successfully execute on its
business strategies. These and other risks are described in the
reports filed by Achillion with the U.S. Securities and Exchange
Commission, including its Annual Report on Form 10-K for the year
ended December 31, 2016, its Quarterly Report on Form 10-Q for the
fiscal quarter ended September 30, 2017, and its other SEC
filings.
In addition, any forward-looking statement in
this press release represents Achillion's views only as of the date
of this press release and should not be relied upon as representing
its views as of any subsequent date. Achillion disclaims any duty
to update any forward-looking statement, except as required by
applicable law.
Investors & Media:
Glenn Schulman, PharmD, MPH
Executive Director, Investor Relations
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com
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