An Open-Label Phase 2 Proof-of-Concept Study in Patients with C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) Treated with ACH-0144471.

See protocol P19-21:

1.2.1 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 *g/mL, and is the rate-limiting step of AP activation [2, 3].
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 [2, 3]. 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 [4,
5]. 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
and IC-MPGN.

11.2.2 C3 Glomerulopathy
C3 glomerulopathy (C3G) is an ultra-rare disease with an incidence rate of
approximately 2 per million people worldwide [6, 7]. It is widely accepted that
C3G is attributable to excessive alternative pathway(AP) activity [
8]. Although the disease is typically diagnosed during early adulthood in a
majority of patients, the manifestations of glomerular C3 deposition can be
detected in childhood and thus, it may be clinically meaningful to treat
patients as young as 12 years of age [7, 9, 10]. The clinical course of C3G is
characterized by variable amounts of proteinuria, hematuria, hypertension, and
decreased renal function, with approximately 30% to 50% of patients reaching
end-stage renal disease (ESRD) within 10 years of diagnosis [7, 11, 12, 13].
The diagnosis is based on predominant deposition of C3 in the glomerulus on
renal biopsy along with clinical evidence of AP hyperactivity. 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 [8]. 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 [13].
Unfortunately, no specific therapy has proven effective for the treatment of
C3G. Care is therefore 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 [13, 14].
Treatment is otherwise focused on management of hypertension, proteinuria and
the manifestations of chronic kidney disease.
The overall prognosis of C3G is poor, with approximately 30% to 50% of patients
progressing to ESRD within 10 years of diagnosis. 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 [13, 14, 15].
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 renal pathology consistent with 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
[16, 17]. These studies confirmed that removal of fD prevented the renal
pathogenesis of C3G in the factor H-deficient mice.
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. Based on the published results of an open-label trial in 20
patients, 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 [8, 13, 14, 18]. 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 [18].
A fD inhibitor like ACH-0144471, which inhibits directly at the level of the AP
C3 convertase formation, provides a more targeted rationale for efficacy than
existing complement inhibitors that target the terminal complement pathway.
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 [16, 17]. 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 [
13, 19].
1.2.3 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 primary IC-MPGN. Patients with primary 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 IC-MPGN pathology is at least in part attributable
to overactivity of the classical pathway, evidence of C3 and/or C3 fragment
staining on renal biopsy suggests alternative pathway-related pathophysiology
[20]. IC-MPGN patients should therefore benefit from fD inhibition.

See protocol P5:

The primary objective of this study is to evaluate the efficacy of 12 months of
oral ACH-0144471 in participants with C3G or ICMPGN
based on histologic scoring and proteinuria

The secondary objectives of this study are:
* To evaluate the clinical effect of 12 months of oral ACH-0144471 in
participants with C3G
or IC-MPGN based on significant improvement in slope of estimated glomerular
filtration
rate (eGFR) relative to baseline over time
* To evaluate for improvement in eGFR following treatment with ACH-0144471
* Where available evaluate the change in measured (m) eGFR relative to baseline
at the end of
12 months of treatment with ACH-0144471
* To evaluate the safety and tolerability of ACH-0144471 in participants with
C3G or ICMPGN
by assessing serious adverse events (SAEs)

See protocol P23-24:

This is an open-label study in which all participants will receive active
treatment with ACH-0144471 for approximately 24 months. The study will enroll
approximately 20 participants with biopsy-confirmed C3G or IC-MPGN, 12 years of
age or older, who have not undergone renal transplant. Participants who
completed ACH471-201 are eligible to participate, as long as they do not meet
any exclusion criteria.
Participants who did not participate in ACH471-201 must meet all inclusion and
exclusion criteria to be eligible. In particular, they must have a
biopsy-confirmed diagnosis of C3G or IC-MPGN. The initial diagnosis should have
been made at least 3 months prior to dosing, unless otherwise approved by the
sponsor. Participants must also have clinical evidence of ongoing disease
(defined as proteinuria of *500 mg/day of protein in a 24-hour urine) that is
attributable to C3G or IC-MPGN in the opinion of the Principal Investigator
(PI). Participants who completed ACH471-201 may enroll in this study following
a washout period of at least 30 days between the last dose of ACH-0144471 in
study ACH471-201 and the renal biopsy (if collected during screening; Section
6.3) or the 24-hour urine collection during screening. These participants will
not be required to re-establish their diagnosis of C3G or IC-MPGN, but must
meet the other eligibility requirements described in Section 4.
For all participants, eligibility will be confirmed based on the results from
the screening eligibility assessments. Once eligibility is confirmed,
arrangements can be made for a renal biopsy (if necessary to confirm the
diagnosis of C3G or IC-MPGN as described in Section 6.3.1, or to establish a
baseline for participants who choose to participate in the renal biopsy
sub-study as described in Section 6.3.2) and/or vaccinations. Biopsies will not
be obtained from participants less than 18 years of age (unless a biopsy is
determined to be clinically indicated by the treating provider), or from
participants for whom a biopsy is contraindicated. The initial screening visit
must occur no more than 75 days before the first dose date.
All participants should be vaccinated against Haemophilus influenzae (H.
influenzae), Streptococcus pneumoniae (S. pneumoniae), and Neisseria
meningitidis (N. meningitidis) as recommended by the Advisory Committee on
Immunization Practices (ACIP) guidelines at least 2 weeks before the start of
dosing with ACH*0144471, as described in Section 6.4, to minimize the risk of
serious infection with an encapsulated organism, unless otherwise recommended
by local vaccination guidelines, or precluded by licenses or availability. The
PI may institute additional prophylactic measures, including the use of
prophylactic antibiotics, if deemed appropriate by local clinical practice
and/or guidelines for treatment with a complement inhibitor.
The starting dosage will be 100 mg of ACH-0144471 TID, for a total daily dose
of 300 mg. After 2 weeks of treatment, dosing will be escalated to 200 mg TID
(or 150 mg TID for participants less than 60 kg). For each participant, the
medical monitor will consult with the investigator before making the decision
to dose escalate. Upon treatment discontinuation, regardless of the timing or
reasons for discontinuation, a 6-day taper period is required unless the PI
determines this taper period poses a risk to the participant. The taper period
is in place to prevent the theoretical risk of marked increase or rebound in
complement activity, as described in Section 5.1.1.
A sub-study is being conducted to evaluate the effects of ACH*0144471 on renal
pathology (see Section 6.3.2); participation in this study is not required. For
participants in the renal biopsy sub-study, biopsies will be obtained prior to
dosing and after approximately 28 and 104 weeks of dosing. Only one biopsy will
be obtained prior to dosing; If for any reason, any additional renal biopsies
are performed (e.g., for a clinical indication), then every effort will be made
to make these biopsy samples and results available to the central pathology
laboratory for evaluation.
Patient-reported outcome (PRO) questionnaires will be administered to
participants at various time points as specified in the Schedule of Assessments
(Appendix 1), to assess participants* health-related quality of life (HRQOL),
fatigue, and kidney-related fears and worries (e.g. kidney failure, dialysis,
kidney transplant), and to determine health states value, over the course of
treatment with ACH-0144471.

See protocol P36-37:

ACH-0144471 tablets will be administered at a starting dosage of 100 mg TID.
Study drug administration will then continue for the remainder of the 24-month
Treatment Period. When dosing is to be discontinued, the dose will be tapered
over approximately six days (Taper Period) to minimize the potential adverse
effects of a rapid surge in complement activity following drug withdrawal.

For the starting dose, participants will take one 100-mg ACH-0144471 tablet
three times daily (TID): a dose in the morning, a second dose 8 hours later,
and a third dose 8 hours after the second dose. Doses should be taken at
approximately the same time each day and as close as possible to 8 hours apart.
All doses should be taken approximately 15 to 30 minutes after completion of a
meal. Water intake is not restricted. If a dose is missed, it should be taken
within 4 hours of the originally scheduled time. After 4 hours, the missed dose
should be skipped. In either case, the next dose should be taken according to
the original dosing schedule.

Dose Adjustment
After 2 weeks of treatment, dosing will be escalated to 200 mg TID (or 150 mg
TID for participants less than 60 kg) unless the participant has not tolerated
treatment. While the intent is to maintain a steady dose for the duration of
the study, dose adjustments are permitted for participant safety or in order to
create the best opportunity for each participant to have a therapeutic benefit.
Dosing may be adjusted by the MM (or designee) in consultation with the PI,
within the parameters provided below and based on review of available safety,
PK, and PD results.
Dose increases should be such that the new total daily dose is no more than 2×
the prior total daily dose.

See protocol P19:
Benefit:
ACH-0144471, a small molecule, orally administered, factor D (fD) inhibitor, is
in development by Achillion Pharmaceuticals, Inc. (*Achillion*, or the sponsor)
for the treatment of complement-related diseases, such as paroxysmal nocturnal
hemoglobinuria (PNH) and C3 glomerulopathy (C3G). Factor D is a serine protease
that catalyzes the cleavage of factor B, a rate-limiting step in the
alternative pathway (AP) of complement. By inhibiting fD, ACH-0144471 potently
and specifically inhibits AP activity.
Because C3G is a disease of AP hyperactivity, ACH-0144471 represents an ideal
therapeutic approach to C3G, as it has the potential to reverse the underlying
pathophysiology of the disease. Primary immune-complex membranoproliferative
glomerulonephritis (IC-MPGN), which shares many clinical, pathologic, genetic,
and laboratory features with C3G and in which complement also likely plays a
key role, may also be an attractive therapeutic target.

See protocol P28-29:
Risks:
Risk of Infection:
Since one of the primary functions of the complement system is to fight
infections, pharmacologic inhibition of the complement system could
theoretically result in an increased rate or severity of infections. However,
high doses of C1 esterase inhibitor in transplant patients with rejection did
not show a signal for infection [36]. Thus, it remains unclear as to whether fD
inhibition would increase risk for infection.
In vitro work was done to understand potential infection risk, especially
meningococcal infection risk that is associated with AP inhibition. As
summarized in Sections 4.1.2 and 6.5.1 of the Investigator's Brochure [1],
ACH-0144471 showed minimal inhibition of protective bactericidal and
opsonophagocytic activities in studies that included several strains of the
clinically important pathogen N. meningitidis and blood samples from immunized
individuals, suggesting that vaccination should provide protection from
meningococcal infections in participants receiving ACH-0144471.
Nonetheless, this study takes steps to minimize the risk of serious infection.
Participants should be vaccinated according to applicable national and/or local
guidelines or local clinical practice for N. meningitidis, H. influenza, and S.
pneumonia (see Section 6.4), and antibiotic prophylaxis is permitted if deemed
appropriate by local clinical practice and/or guidelines, as described in
Section 6.5. Achillion will also create and distribute a wallet card for
outpatient studies with warning signs and symptoms of serious infection, and
appropriate steps of action for all participants. Finally, a fever management
plan has been incorporated into the study protocol (see Appendix 2).

Hepatic Injury:
Hepatobiliary cholestasis has been observed in dog toxicology studies at
exposures higher than those intended for clinical use, and higher than those
planned for this study. Based on clinical observations, the cholestasis is
reversible and can be monitored with hepatic safety biomarkers.
Elevations of transaminases have occurred clinically with ACH-0144471. Grade 3
or Grade 4 liver enzyme elevations occurred in 2 active phase 1 study
participants receiving higher doses of ACH-0144471 (500 mg twice daily [BID]
and 800 mg BID), although these elevations occurred after dosing was completed
(3 days and 7 days after last dose). One PNH participant had elevated
transaminases associated with breakthrough hemolysis and discontinued
ACH-0144471. All abnormal transaminase findings were transient, were not
associated with evidence of hepatic decompensation, and resolved within a short
time period. Transaminases will be monitored in this study.
Stopping criteria have been included ensuring prompt discontinuation of any
participant with evidence of unexplained liver injury. Finally, participants
with evidence of active hepatic or hepatobiliary disease will be excluded.