Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). FDA label
Also known as RAVICTI, Glycerol phenylbuterate, GT4P, Glycerol phenylbutyrate, GPB
HPN-100 · 8 trials · 4 indications
Rate of adverse events during the Switch-Over portion of the Protocol
Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. Arm A day 14 and Arm B day 28 data were combined as a NaPBA treatment Arm. Arm B day 14 and Arm A day 28 data were combined as a HPN-100 treatment Arm.
To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders (UCDs)
Part A: The rate of AEs and tolerability of 6 mL and 9 mL doses of HPN-100 were considered the primary safety endpoints for Part A. Safety assessments included adverse events, laboratory tests (including ammonia, hematology, coagulation, liver function and serum chemistry parameters), vital signs, physical and neurological examinations, and electrocardiograms.
An HE event was defined as occurrences of either a West Haven (WH) Grade ≥2 or a WH Grade 1 and asterixis grade increase of 1 (if baseline WH = 0). The WH criteria are widely used for rating the severity of HE and are summarized below: Grade 1: trivial lack of awareness, euphoria or anxiety, shortened attention span, impaired performance of addition Grade 2: lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate behavior, impaired performance of subtraction Grade 3: somnolence to semi-stupor but responsive to verbal stimuli, confusion, gross disorientation Grade 4: coma (unresponsive to verbal or noxious stimuli) Asterixis was assessed after arm and forearm extension along with wrist dorsiflexion for 30 seconds and assigned a grade according to the following criteria: Grade 1: rare flaps Grade 2: occasional irregular flaps Grade 3: frequent flaps Grade 4: continuous flaps
Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose.
| Arm | Type | Description |
|---|---|---|
| HPN-100 | EXPERIMENTAL | Switch over from sodium phenylbutyrate to open label HPN-100 oral liquid over 10 days then open label, long term treatment for 12 months |
| Buphenyl (NaPBA) /HPN 100 Placebo | EXPERIMENTAL | Subjects in Arm A were randomly assigned to receive NaPBA + HPN 100 placebo for 2 weeks and then crossed over to receive HPN 100 + NaPBA Placebo for 2 weeks. |
| HPN-100/NaPBA Placebo | EXPERIMENTAL | Subjects in Arm B were randomly assigned to receive HPN-100 + NaPBA placebo for 2 weeks and then crossed over to receive NaPBA + HPN 100 placebo for 2 weeks. |
| HPN-100 and NaPBA | EXPERIMENTAL | 1 week of NaPBA treatment followed by 1 week of HPN-100 treatment. |
| Placebo | PLACEBO_COMPARATOR | - |
| BUPHENYL® to HPN-100 vs. HPN-100 | ACTIVE_COMPARATOR | Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment. |
| Arm 1 | PLACEBO_COMPARATOR | Cohort A: 9 mL HPN-100 or placebo Cohort B: 12 mL HPN-100 placebo |
| Arm 2 | PLACEBO_COMPARATOR | This study requires 4 periods. In each of the periods you will receive one of the dose groups listed below. At the completion of the study you will have participated in all 4 dose groups. The order in which you participate in each dose group will be randomly assigned. Dose Group A: 9 mL placebo via oral syringe 3 times daily for 3 days Dose Group B: single oral dose of 400 mg moxifloxacin on study Day 3 Dose Group C: 6 mL HPN-100 and 3 mL placebo via oral syringe 3 times daily for 3 days Dose Group D: 9 mL HPN-100 via oral syringe 3 times daily for 3 days |
| Name | Type | Description |
|---|---|---|
| HPN-100 | DRUG | HPN-100 is a pro-drug of PAA that combines with glutamine to provide an alternative vehicle for waste nitrogen elimination. It is a liquid with minimal taste and odor. Approximately three teaspoons of HPN-100 (\~17.4 mL) delivers an equivalent amount as PBA that 40 tablets of NaPBA. |
| Buphenyl (NaPBA) | DRUG | Buphenyl (NaPBA) will be the comparator drug to HPN-100 in this study. |
| NaPBA | DRUG | NaPBA tablets for oral administration and NaPBA powder for oral, nasogastric, or gastrostomy tube administration contain the active ingredient sodium phenylbutyrate. NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys. |
| Placebo | DRUG | Part B: same as experimental arm |
| BUPHENYL® | DRUG | BUPHENYL® (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS. |
| HPN-100 or Placebo | DRUG | single oral dose of 12 mL HPN-100 given via syringes 3 times daily for 3 days |
| Moxifloxacin | DRUG | single oral 400-mg dose on study Day 3 |
Inclusion Criteria: * Male and female subjects 29 days to \< 6 years old. If the subject is born prematurely, calculation of the lower age limit begins at the corrected gestational age of 40 weeks. * Signed informed consent by the subject's legally acceptable representative * Suspected or confirmed...
HPN-100 is an investigational small molecule developed by Amgen Inc. (ticker AMGN). It has been studied in cirrhosis, drug toxicity, hepatic encephalopathy, and urea cycle disorders. The program is in Phase 2 development, and all five of its registered clinical trials have been completed.
HPN-100 has been studied for urea cycle disorders, cirrhosis, episodic hepatic encephalopathy, and drug toxicity. Trials have enrolled adults with urea cycle disorders and cirrhosis with episodic hepatic encephalopathy, plus pediatric subjects with urea cycle disorders. It remains investigational and is not described as approved for any indication.
HPN-100 is developed by Amgen Inc., which trades under the ticker AMGN. Amgen is the sponsor associated with the clinical development program for this small molecule across its urea cycle disorder, cirrhosis, hepatic encephalopathy, and drug toxicity studies.
HPN-100 is in Phase 2 development. Its registered program includes Phase 1, Phase 2, and Phase 3 trials, all of which are completed, and no trials are currently active. It is an investigational agent rather than a marketed product.
Five completed trials have studied HPN-100. These include NCT00999167 in cirrhosis and episodic hepatic encephalopathy, NCT00992459 and NCT01347073 in urea cycle disorders, and NCT01135680, an electrocardiogram effects study in healthy volunteers. The trials were randomized, double blind, and placebo controlled, with 189 participants in the largest study.