A Phase 2a Proof-of-Mechanism, Open-Label Study to Determine the Effect of ACH 0144471 on C3 Levels in Patients with Low C3 Levels Due to Either C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

See protocol P21-22:

1.3.1 Complement Factor D:
Factor D is one of nine serine proteases in the complement system. It is a
highly specific enzyme with only one known substrate, fB. Of all the
complement proteins, it has the lowest abundance in serum with a concentration
of approximately 2 µg/mL, and is the rate-limiting step of AP activation. It
is a low molecular weight protein (24 kDa) that is primarily produced by
adipocytes, but can also be produced and secreted by monocytes/macrophages and
astrocytes in humans. Due to its small size, it is freely filtered at the
glomerulus, and then taken up by the proximal tubule cell where it is
catabolized with an estimated fractional catabolic rate of 60% per hour. It is
this rapid catabolism that is responsible for maintaining low circulating fD
levels. As a result, renal dysfunction is associated with elevated fD levels,
which may lead to increased alternative pathway activity and inflammation. The
biochemical, physiological, and functional features of fD make it an attractive
target for pharmacological inhibition as this may prove useful in the treatment
of a wide spectrum of complement-mediated diseases, including C3G.


1.3.2 C3 Glomerulopathy:
C3 glomerulopathy (C3G) is an ultra-rare disease with an incidence rate of
approximately 2 per million people worldwide. It is widely accepted that C3G
is attributable to excessive alternative pathway (AP) activity. The clinical
course is characterized by variable amounts of proteinuria, hematuria,
hypertension, and decreased renal function, with approximately 30%-50% of
patients reaching end-stage renal disease (ESRD) within 10 years of diagnosis.
The diagnosis is based on predominant deposition of C3 in the glomerulus on
renal biopsy along with clinical evidence of hyper AP activity. C3G can be
further subdivided into two separate entities, dense deposit disease (DDD) and
C3 glomerulonephritis (C3GN), based on electron microscopic features of the
renal pathology. Although the two disorders have similar clinical features,
DDD tends to present earlier in life than C3GN. However, both diseases can
present in either childhood or adulthood.
Unfortunately, no specific therapy has proven effective for the treatment of
C3G. Therefore, care is largely non-specific and supportive. Given the lack
of available therapeutic options, immunosuppressive and plasma
infusion/exchange therapy are often attempted, as a subset of patients may
benefit. Treatment is otherwise focused on management of hypertension,
proteinuria and the manifestations of chronic kidney disease. Dialysis and
renal transplantation are options available for patients who reach ESRD;
however, disease recurrence is frequent after transplantation, occurring in
more than 50% of patients. Only about 50% of patients have a functioning graft
5 years after transplantation, which is significantly lower than renal graft
survival in other settings.
Studies in animal models have indicated that the pathophysiology of C3G
strongly relates to an excessive AP activity at the level of the C3
convertase. Specifically, mouse factor H-deficient animals have evidence of
uncontrolled alternative pathway activation, with low plasma levels of intact
C3, high levels of C3 breakdown product and evidence of C3G; yet, in mice
deficient in both factor H (fH) and fD (knock-out mice), serum C3 levels were
similar to wild-type and dense deposits were not present in the kidneys. These
studies confirmed that removal of fD prevented the renal pathogenesis of C3G in
the factor H-deficient mice.


1.3.3 Potential Advantages of ACH 0144471 in the Treatment of C3G:
Given that the pathophysiology of C3G derives from excessive C3 activation
through the AP, treatment of the disease with an AP complement inhibitor is
logical. Eculizumab, the only commercially available complement inhibitor, has
been tested in patients with C3G, even though its mechanism of action
(targeting the terminal complement pathway) would not be expected to affect C3
activation. Its use has been reported in more than 20 patients with C3G, of
whom the majority were reported as individual cases, and only six were reported
as part of an open-label proof-of-concept study. Of those presented as case
reports, the majority had a successful response. However, this may represent a
publication bias, as the results of the open-label trial were less impressive.
Specifically, two of the six patients in the open-label trial seemed to have a
good response, confirmed by worsening upon discontinuation of eculizumab. Of
the remaining four patients, three had an increase in serum creatinine while on
treatment. Based on the results of this open-label trial, the general
consensus is that only a subset of patients appears to benefit from eculizumab
therapy; however, identification of these patients prior to treatment remains a
challenge. It has been suggested that response to eculizumab may be more
likely in those patients with elevated soluble C5b-9 levels, indicative of
excessive terminal pathway activity, although this hypothesis remains to be
established.
A fD inhibitor like ACH 0144471, which inhibits directly at the level of the AP
C3 convertase formation, is expected to provide superior efficacy than
eculizumab or complement inhibitors that target the other complement pathways.
This hypothesis is supported by animal data in which the renal disease observed
with factor H deficiency, which is similar to human C3G, was completely
prevented in the setting of simultaneous fD or fB deficiency. In contrast C5
deficiency only ameliorated, but did not prevent, renal disease. Furthermore,
C6 deficiency had no effect on the renal disease in fH deficient mice. Taken
together, the data from the C5 and C6 deficient mice provide evidence that the
membrane attack complex itself plays little role in renal pathogenesis of C3G
in the setting of fH deficiency, but that C5a production may be a factor
contributing to disease.


1.3.4 Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN):
Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) is a renal
disease which shares many clinical, pathologic, genetic and laboratory features
with C3G, and therefore can be considered a sister disease of C3G. In the
majority of patients with IC-MPGN, an underlying disease or disorder (most
commonly infections, autoimmune diseases or monoclonal gammopathies) are
identified to which the renal disease is secondary. Of note, the most common
infections associated with IC-MPGN are hepatitis B and C. Up to 40% of
patients with IC-MPGN have no identifiable underlying etiology, and are
considered to have idiopathic IC-MPGN. Patients with idiopathic IC-MPGN can
have low C3 and normal C4 levels, similar to those observed in C3G, as well as
many of the same genetic or acquired factors that are associated with abnormal
alternative pathway activity. Although there are current hypotheses suggesting
that the majority of IC-MPGN is attributable to overactivity of the classical
pathway, those patients with a low C3 and a normal C4 are likely to have
significant overactivity of the alternative pathway. Therefore, IC-MPGN
patients with a low C3 and a normal C4 may benefit from alternative pathway
inhibition.

The Primary objective is to determine whether the administration of ACH 0144471
can increase C3 levels in patients with low C3 levels due to either C3G or
IC-MPGN.

The secondary objectives are:
* To evaluate the safety and tolerability of ACH 0144471 in patients with C3G
or IC-MPGN
* To evaluate the pharmacokinetic (PK) profile of ACH 0144471 in patients with
C3G or IC-MPGN
* To evaluate the effect of ACH 0144471 on biomarkers of alternative pathway
activity (AP) in patients with C3G or IC-MPGN
* To explore the relationship between study drug exposure and changes in C3
levels and other biomarkers of alternative pathway activity


The exploratory objectives are:
* To explore patients* experience of their disease (C3G or IC-MGPN), its
impact, and its management on everyday lives, from first symptoms to definitive
diagnosis and beyond
* To explore patients* expectations of ACH 0144471 in the treatment of their
disease.

This open-label study will enroll up to 10 patients (between the ages of 16 and
65 years) with biopsy-confirmed C3G or idiopathic IC-MPGN and a low C3 level.
The trial will evaluate the ability of ACH 0144471 to increase C3 levels via
inhibition of factor D (fD) by enrolling patients in two groups. Group 1 will
serve as a sentinel group consisting of two patients who will receive ACH
0144471 at a dose of 100 mg three times daily (TID) for 14 days followed by a
taper over 7 days. Group 2 will be initiated upon confirmation that dosing was
well-tolerated in Group 1 (based on Group 1 safety data through at least Day
28), and may include up to 8 patients. As discussed in Section 3.2.2, the dose
for Group 2 will be selected based on the available safety, PK, and PD data
from Group 1, but will not exceed 200 mg TID. The 100 mg TID dose level for
Group 1 was selected based on safety, PK, and pharmacodynamics (PD) data from
the Phase 1 single-ascending dose (SAD) and multiple-ascending dose (MAD)
studies (ACH471-001 and ACH471-002), which demonstrated that similar dosing
regimens in healthy volunteers were well-tolerated and able to inhibit the
alternative pathway of complement. In addition, the relative bioavailability
study (ACH471 006) supports transition from the liquid filled capsule (LFC)
dosage form used in the SAD and MAD studies to the tablet dosage form to be
used in this study. All patients will receive active drug.
Patients will receive study drug for 14 days (Treatment Period), followed by a
taper over the next 7 days (Taper Period) to minimize the potential adverse
effects of a rapid surge in complement activity following drug withdrawal.
Patients will have daily clinic visits for the first 3 days of the taper, and
then will continue to be followed for 28 days after the last dose of study drug
(Follow-Up Period). Long-term follow up visits to allow collection of
longitudinal observational data are included, but are not required. During the
long-term follow up period, patients will be asked to return for an outpatient
clinic visit approximately every 45 days for a maximum of 1 year.
If a patient has a C3 level that, at 2 consecutive evaluations, is greater than
125% the upper limit of normal (ULN), or is greater than 3× their baseline and
greater than or equal to the lower limit of normal (LLN), then the taper period
will be initiated before completion of the 14 days of dosing, as
proof-of-mechanism will already be established for that patient. Furthermore,
early tapering and possible prevention of supraphysiologic C3 levels may
mitigate the theoretical risk for acute precipitation of C3 into the glomerulus
upon drug discontinuation.
Safety, PK, and PD data will be obtained at multiple time points during the
Treatment, Taper and Follow-Up periods. The primary endpoint for the study
will be changes in C3 levels. Additional endpoints include the incidence of
adverse events (AEs), serious adverse events (SAEs), and discontinuations due
to AEs. Clinical measures of renal disease will be monitored (e.g.,
creatinine, proteinuria, and blood pressure), but are not expected to improve
in this short-duration non-therapeutic trial. Additional secondary and
exploratory endpoints will include functional assays of complement activity and
measurement of selected complement components in blood and urine, as described
in Section 6.15. Finally, a PK/PD analysis will be conducted to explore the
relationship between study drug exposure and changes in C3 levels and/or other
secondary endpoints.
Concomitant medications will be considered on a case-by-case basis, and
decisions made jointly between the PI and Sponsor, based on knowledge of ACH
0144471 and risks for drug-drug interactions, as well as potential to interfere
with interpretation of the study.
Based on data from Groups 1 and 2, additional patients may be added to study
additional dose levels or regimens (not to exceed 200 mg TID for two weeks,
followed by a 7-day taper) or additional C3G or IC-MPGN patients.

Group 1:
Treatment Period: 100 mg TID for 14 days (Days 1 * 14)
Taper Period:
100 mg twice daily (BID) for 3 days (Days 15, 16, and 17)
50 mg BID for 2 days (Days 18 and 19)
50 mg once daily (QD) for 2 days (Days 20 and 21)


Group 2:
The dose and taper schedule will be determined based on data from Group 1, with
a maximum possible dose of 200 mg TID followed by a 7 day taper.

See protocol Page 22:

1.3.3 Potential Advantages of ACH 0144471 in the Treatment of C3G:
Given that the pathophysiology of C3G derives from excessive C3 activation
through the AP, treatment of the disease with an AP complement inhibitor is
logical. Eculizumab, the only commercially available complement inhibitor, has
been tested in patients with C3G, even though its mechanism of action
(targeting the terminal complement pathway) would not be expected to affect C3
activation. Its use has been reported in more than 20 patients with C3G, of
whom the majority were reported as individual cases, and only six were reported
as part of an open-label proof-of-concept study. Of those presented as case
reports, the majority had a successful response. However, this may represent a
publication bias, as the results of the open-label trial were less impressive.
Specifically, two of the six patients in the open-label trial seemed to have a
good response, confirmed by worsening upon discontinuation of eculizumab. Of
the remaining four patients, three had an increase in serum creatinine while on
treatment. Based on the results of this open-label trial, the general
consensus is that only a subset of patients appears to benefit from eculizumab
therapy; however, identification of these patients prior to treatment remains a
challenge. It has been suggested that response to eculizumab may be more
likely in those patients with elevated soluble C5b-9 levels, indicative of
excessive terminal pathway activity, although this hypothesis remains to be
established.
A fD inhibitor like ACH 0144471, which inhibits directly at the level of the AP
C3 convertase formation, is expected to provide superior efficacy than
eculizumab or complement inhibitors that target the other complement pathways.
This hypothesis is supported by animal data in which the renal disease observed
with factor H deficiency, which is similar to human C3G, was completely
prevented in the setting of simultaneous fD or fB deficiency. In contrast C5
deficiency only ameliorated, but did not prevent, renal disease. Furthermore,
C6 deficiency had no effect on the renal disease in fH deficient mice. Taken
together, the data from the C5 and C6 deficient mice provide evidence that the
membrane attack complex itself plays little role in renal pathogenesis of C3G
in the setting of fH deficiency, but that C5a production may be a factor
contributing to disease.

See protocol Page 28-29:

3.2.4 Safety Considerations:
3.2.4.1 Risk of Infection:
One of the primary functions of the complement system is to fight infections as
part of the innate immune system. As suggested by individual case reports with
complement system deficiencies including complement factor D, inhibition of the
complement system may result in a lifetime increased risk of infection, notably
with Neisseria meningitidis (N. meningitidis), and other encapsulated organisms.
Because of this potential risk, special safety precautions will be taken for
patients participating in ACH471-201. Patients will be required to be
previously vaccinated, or to receive vaccinations for N. meningitidis
(serogroups A, C, Y and W135), Streptococcus pneumoniae (S. pneumoniae), and
Haemophilus influenzae (H. influenzae) prior to receiving ACH 0144471.
Throughout the study, including at clinic visits, patients will be monitored
for the development of fever. A specific Fever Management Plan has been
developed for this study.
Patients will also be counseled about behaviors to avoid during the study, and
to recognize early and react appropriately to signs and symptoms of infection.
3.2.4.2 Hepatic Injury:
Hepatobiliary cholestasis has been observed in the dog toxicology studies at
exposures higher than those intended for clinical use. In humans, elevations
in ALT levels have been observed in some healthy volunteers with doses of 500
mg twice daily and 800 mg twice daily for 14 days. However, treatment-emergent
ALT elevations have not been observed in healthy volunteer subjects receiving
doses up to 200 mg twice daily for 14 days, or in PNH patients receiving up to
150 mg TID for 56 days. In this study, the selected doses are expected to
result in similar or lower exposures to those following 200 mg twice daily.
Nonetheless, liver function tests, including ALT, AST, alkaline phosphatase,
GGT, and total, direct, and indirect bilirubin, will be closely monitored.