A Phase 2, Multicenter, Multinational, Open-Label, Dose-Escalation Study to Evaluate the Safety and Efficacy of ORGN001 (formerly ALXN1101) in Pediatric Patients with Molybdenum Cofactor Deficiency (MoCD) Type A Currently Treated with Recombinant Escherichia coli-derived Cyclic Pyranopterin Monophosphate (rcPMP)

Molybdenum cofactor deficiency (MoCD) is a rare, life-threatening, autosomal
recessive, inborn error of metabolism characterized by disruption of the
metabolic pathway for production of molybdenum cofactor (MoCo), which is
essential for the function of the following 3 critical enzymes: sulfite oxidase
(SO), xanthine dehydrogenase, and aldehyde oxidase. While all 3 enzymes are
dependent on MoCo, the loss of SO activity is exclusively responsible for the
severe and rapidly progressive neurologic damage seen in MoCD.
Little documentation is available regarding the prevalence of MoCD since the
first recognition of the condition in 1978. MoCD is estimated to affect less
than 200 patients worldwide. While there is incomplete information on the
natural history of MoCD, affected individuals usually present as neonates with
severe symptoms such as intractable seizures, burst-suppression
electroencephalogram (EEG), metabolic acidosis, exaggerated startle reactions,
axial hypotonia, limb hypertonia, and feeding difficulties. Neuronal damage is
severe and is rapidly progressive as a result of accumulation of toxic levels
of sulfite in the brain. Death commonly occurs in the neonatal period, and
patients who survive that period develop a severe static encephalopathy and
developmental delay due to central nervous system (CNS) injury including
subcortical cystic cavitation, hydrocephalus, diffuse cortical atrophy, and
basal ganglia injury. At present, there is no cure.
Although there are 3 types of MoCD, two-thirds of MoCD patients have Type A,
which is due to a mutation in the MOCS1 gene localized on 6p21.3. In MoCD Type
A, the first of the four synthetic steps in the formation of MoCo is
interrupted, and guanosine triphosphate (GTP) cannot be converted into cyclic
pyranopterin monophosphate (cPMP). Diagnosis of MoCD Type A is based on
clinical presentation, biochemical phenotype (such as elevated urinary sulfite
and/or S sulfocysteine [SSC], and low or absent uric acid in the urine or
plasma), and diagnosis is then confirmed by genetic testing.
ORGN001 (formerly ALXN1101) provides a therapeutic approach for the treatment
of MoCD Type A by restoring the MoCo biosynthesis. Results of preclinical
pharmacology studies with ORGN001 (formerly ALXN1101) suggest that the
metabolic derangement in MoCD Type A could be corrected by administration of
synthetic cPMP, resulting in restoration of enzymatic activity and thus,
correction of the metabolic pathways that would otherwise lead to the
accumulation of toxic metabolites causing CNS injury. These results are
supported by data obtained in pediatric patients with MoCD Type A treated with
a recombinant Escherichia coli-derived cPMP product (rcPMP) from Colbourne
Pharmaceuticals GmbH (Colbourne), which has been administered on a
named-patient basis following request from their individual physicians.
Published individual case reports suggest that intravenous (IV) administration
of rcPMP restores MoCo -dependent enzyme activities as evidenced by the
reduction in levels of biomarkers of the disease (e.g., SSC in urine) and
improvement in neurologic outcome. This study is designed to evaluate the
safety and efficacy of escalating doses of ORGN001 (formerly ALXN1101) in
pediatric patients with MoCD Type A currently treated with rcPMP.

Primary:
• To evaluate the safety of ORGN001 (formerly ALXN1101) over the first 6 months
of treatment

Secondary:
• To characterize the pharmacokinetics (PK) of increasing doses of ORGN001
(formerly ALXN1101)
• To evaluate the effect of ORGN001 (formerly ALXN1101) on urine and blood SSC
levels
• To evaluate the effect of ORGN001 (formerly ALXN1101) on neurologic, motor,
and cognitive functions
• To evaluate the effect of ORGN001 (formerly ALXN1101) on CNS structure
• To evaluate the long-term safety of ORGN001 (formerly ALXN1101)

Exploratory:
• To describe the effect of ORGN001 (formerly ALXN1101) on MoCD-associated
urine and blood biomarker levels including, but not limited to, uric acid and
xanthine

This Phase 2, multicenter, multinational, open-label, dose-escalation study is
designed to evaluate the safety and efficacy of ORGN001 (formerly ALXN1101)
administered to infants and children with MoCD Type A currently treated with
rcPMP. Eligible patients will be identified through named-patient use with
rcPMP. This study will include a screening period (Days -21 to Day -1), a
6-month Initial Treatment Period which includes escalating doses of ORGN001
after the first 2 months of treatment with ORGN001 (Day 1 [first dose of study
drug] to Day 180), and an Extension Period (after Day 180).

ORGN001 (formerly ALXN1101) is a synthetic form of cPMP. Patients will begin IV
infusions of ORGN001 (formerly ALXN1101) at the same dose as their current dose
of rcPMP. After the first 2 months of treatment with ORGN001 (formerly
ALXN1101) , if the patient*s clinical, PK, and safety assessments permit
(including absence of signs and symptoms of drug-related toxicity), dosing with
ORGN001 (formerly ALXN1101) will increase every month by no more than 240 µg/
kg/day increments until either 1) Day 180, 2) the patient reaches a dose that
is not tolerated, or 3) the patient*s exposure approaches or exceeds that of
the NOAEL in toxicology species, whichever comes first. Unscheduled dose
adjustments of ORGN001 (formerly ALXN1101) are possible based on recommendation
by the SRC. The SRC chair will also convine the DMC if a dose escalation is
being considered, or will notify the DMC if the dose is decreased. After dose
escalation is complete, the patient can be returned to the prior dose based on
the patient*s clinical status at the discretion of the treating physician after
consultation with the SRC. All doses will be administered by IV infusion over
approximately 10 to 15 minutes and infusion times would increase proportionally
with increasing dose.
ORGN001 (formerly ALXN1101)is supplied as a sterile, non-pyrogenic, white to
slightly yellow lyophilized powder in a 10 mL vial to be reconstituted using
sterile Water for Injection prior to administration.

Risk/benefit assessment:

MoCD Type A is a rare, life-threatening, autosomal recessive, inborn error of
metabolism. Within a few hours to days after birth, newborn infants with MoCD
Type A present a severe clinical picture with profound and progressive neuronal
damage. Death may occur in the neonatal period. Currently, no approved therapy
is available in the EU for the treatment of patients with MoCD Type A.
Treatment strategies for individuals with this disorder are only symptomatic
and aim to provide relief of clinical manifestations of the disease and
palliative care of the patient.
Because of the life-threatening and debilitating nature of the disease and lack
of treatment, there is a significant need to provide safe and effective
treatment for pediatric patients with MoCD Type A, which targets the underlying
cause of the disease, the inability to synthesize MoCo from its precursor, GTP.
Treatments, such as ORGN001 (formerly ALXN1101) , that aim to restore MoCo
biosynthesis represent one of the most promising therapeutic interventions.
Considering the identical molecular structures of ORGN001 (formerly ALXN1101)
and rcPMP, the clinical results reported with rcPMP in the literature, together
with the nonclinical results with ORGN001 (formerly ALXN1101), it is
anticipated that ORGN001 (formerly ALXN1101) will benefit patients with MoCD
Type A by correcting the metabolic derangement, reconstituting the synthesis of
MoCo, and thus restoring SO enzymatic activity and reducing the levels of the
toxic metabolites, sulfite and SSC.