A Phase 1 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate
the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a
Single Dose of DCR-PHXC in Patients with Primary Hyperoxaluria Type 3

Primary hyperoxaluria type 3 was first genetically characterized in 2010.
Approximately 50% to 65% of individuals with PH3 present with a stone prior to
the age of 5. Although the frequency and severity of stone activity appear to
abate in adolescence and adulthood, stone formation can occur throughout life.

Nephrocalcinosis has been reported only occasionally in individuals with PH3.
Over time, kidney function may become compromised from frequent stones and/or
nephrocalcinosis, resulting in chronic kidney disease (CKD). Kidney function
does appear to remain better preserved among individuals with PH3 compared with
those with PH1 or PH2.To date, only one individual with PH3 has been reported
to progress to end-stage renal disease (ESRD). In this 8-year-old patient,
stone removal procedures and urinary tract obstruction may have contributed to
the loss of kidney function.

At present, no therapies are approved by regulatory authorities for the
treatment of patients with PH3. A number of supportive therapies are used in an
attempt to mitigate some of the effects of the disease. Current medical
management before renal failure develops is underpinned by hyperhydration, with
fluid intake recommendations of at least 3 liters per day per square meter of
BSA, e.g., 5 L/day for a 70-kg adult. These regimens can be problematic in
infants and toddlers, necessitating placement of a gastrostomy tube to ensure
adequate nighttime fluid administration. Affected patients are at considerable
risk of serious complications during periods of increased fluid loss (fever,
diarrhea/vomiting, and urinary tract infections) or when oral hydration is
compromised (following surgical procedures). Oral potassium citrate
administration is used to inhibit crystallization and alkalinize the urine.

Primary objective:
To evaluate the safety and tolerability of a single dose of DCR-PHXC in
patients with PH3

Secondary objectives:
To characterize the plasma PK of a single dose of DCR-PHXC in patients with PH3
To assess the efficacy of a single dose of DCR PHXC in reducing oxalate burden
in patients with PH3

A placebo-controlled, double-blind, multicenter study

single dose of DCR-PHXC

At present, no therapies are approved for the treatment of PH. DCR-PHXC is
being evaluated in 5 ongoing studies in healthy volunteers (HV) and patients
with PH1 or PH2. No significant safety findings have emerged from these ongoing
studies. DCR-PHXC has been well tolerated by both healthy volunteers and
participants with PH1 and PH2

In studies with other drugs of the same class as the study drug, there have
been events such as a release of immune substances called a cytokine release, a
response of the body to injuries, resulting in inflammation, mild reddening,
soreness, itching, or swelling at the place where the study treatment was
injected (called injection site reactions), and elevated liver enzymes may be
indicative of abnormalities of the liver.

Other symptoms that patients may develop are fatigue, nausea, vomiting,
abdominal pain or tenderness around the liver, fever, or rash. Patients may
also have general muscle pain or weakness from the study drug.

Observations from older drugs of the same class as the study drug have been
changes in blood clotting, a reduction in blood platelets (called
thrombocytopenia), and mild or moderate abnormalities of the liver. The study
drug used in this research may have risks that are not well-known or
understood. Therefore, there may be other risks that are not yet known.

Side effects observed to date in a completed and ongoing phase I studies with
DCR-PHXC in healthy volunteers and PH patients.
In the completed phase I study the majority of side effects were mild and
disappeared without treatment. There were no severe side effects which were
attributed to taking the study drug.
The following side effects have been reported in participating subjects
receiving DCR-PHXC:
• an injection site reaction: mild reddening, sensitive/painful feeling,
itching or swelling at the place where the study drug was injected;
• gastrointestinal symptoms: nausea, vomiting, abdominal pain, or sensitivity
round the liver;
• urological symptoms: frequent urination;
• other symptoms such as: fatigue, fever, rash, back pain/kidney pain,
headache, lack of energy, menstrual pain, prickling feeling of the skin of the
lower abdomen, sniffling (nose), earache, nosebleed.