Aqneursa Granule, For Suspension
FDA Label NDC 83853-101

<BRAND NAME> is indicated for the chronic treatment of Niemann-Pick Type C (NPC) in adults and children aged 4 years and older.

Start <BRAND NAME> if the patient has a diagnosis of NPC.

For patients aged 4 to 12 years, administer <BRAND NAME> orally (with or without food) after dissolving according to the dosage shown in Table 1. The recommended dosage of <BRAND NAME> is based on patient’s body weight in kg.

Table 1: Recommended <BRAND NAME> Dose in Patients Aged 4 to 12 Years

For patients aged 13 years and older, administer <BRAND NAME> orally (with or without food) 3 times daily (morning, afternoon and evening) after dissolving according to Table 2.

Table 2: Recommended <BRAND NAME> Dose in Patients Aged 13 Years and Older

Administration with Liquid

Pour the content of one sachet into 40 mL of water, orange juice or almond milk. Stir until fully dissolved. Do not use hot liquid. Drink all of the solution immediately after dissolving (within 30 minutes).

Administration via Feeding Tube

<BRAND NAME> may be administered via gastrostomy tube (French size 18 or larger). Empty the content of one sachet into 40 mL of water, orange juice or almond milk in a container. Mix until all the granules are dissolved in the liquid. After the granules have been dissolved, draw up the mixture into a catheter tip syringe. Apply steady pressure to dispense the contents of the syringe into the gastrostomy tube. Refill the dosing syringe with water and flush the tube with at least 20 mL of water. The mixture should be used immediately (within 30 minutes). Do not keep the mixture for later use.

If a dose of <BRAND NAME> is missed, the next dose should be taken as scheduled. Doses should not be doubled.

Granules for oral solution: 1 g <PROPOSED USAN> in single-dose sachet containing white to off-white, strawberry flavored granules.

None.

Anaphylactic and hypersensitivity reactions may occur after administration of <BRAND NAME>. Immediately discontinue <BRAND NAME> and provide necessary emergency treatment if such reactions occur. Re-administration to patients who have previously experienced severe or serious hypersensitivity reactions to <BRAND NAME> should only be done after careful consideration of the risks and benefits of continued treatment, and under direct supervision of qualified personnel with appropriate medical support measures readily available.

The following clinically significant adverse reactions are described elsewhere in the labeling:

Anaphylaxis and Hypersensitivity Reactions [see Warnings and Precautions ( 5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the <BRAND NAME> placebo-controlled, randomized, crossover trial, <BRAND NAME> was evaluated in 60 patients with Niemann-Pick Type C (NPC; age range 5 to 67 years, 45.0% female, 90.0% White, 3.3% Asian, 6.7% Other), with a median treatment duration of 12 weeks on both <BRAND NAME> and placebo. No patients discontinued due to adverse reactions.

Table 3 summarizes the frequency of adverse reactions that occurred in the double-blind treatment periods of the placebo-controlled trial in patients while treated with <BRAND NAME> and at an incidence greater than when the patients were treated with placebo.

<BRAND NAME> may be an inhibitor of multidrug-resistance-protein 1 (MDR1), breast cancer resistance protein (BCRP) or bile salt export pump (BSEP) [see Clinical Pharmacology ( 12.3)]. The relevance to humans is uncertain. A potential drug interaction of <PROPOSED USAN> with other drugs that are substrates of MDR1 (e.g. digoxin, dabigatran, loperamide, berberine, irinotecan, doxorubicin, vinblastine, paclitaxel, fexofenadine, seliciclib, quinidine, talinolol), BCRP (e.g. sulfasalazine, rosuvastatin) or BSEP cannot be excluded.

A potential drug interaction of <BRAND NAME> with N-acetyl-DL-leucine and N-acetyl-D-leucine has been identified in pharmacology studies indicating that N-acetyl-D-leucine competes with N-acetyl-L-leucine for uptake by the monocarboxylate transporters (MCTs).

Risk Summary

There are no available data of <BRAND NAME> use in pregnant women to inform a drug-associated risk of pregnancy-related outcomes. Animal reproduction studies have not been completed using <PROPOSED USAN>.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risks of birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Risk Summary

No information is available regarding the presence of <PROPOSED USAN> or its metabolites in human milk. This also applies to the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for <BRAND NAME> and any potential adverse effects on the breastfed infant from <BRAND NAME> or the underlying maternal condition.

Fertility and early embryonic development studies have not been completed. In chronic toxicity studies in rats and dogs, no effects on reproductive organs were observed.

Safety and effectiveness of <BRAND NAME> for NPC in pediatric patients under 4 years of age have not been established.

Clinical studies of <BRAND NAME> in NPC patients included insufficient numbers of patients aged 65 years and older to determine whether they respond differently to <BRAND NAME> than younger patients.

<PROPOSED USAN> is a modified amino acid. The chemical name is 2-acetamido-4-methylpentanoic acid. Its molecular formula is C8H15NO3, the molecular mass is 173.21 g/mol, and it has the following chemical structure:

Each sachet of <BRAND NAME> granules for oral solution contains 1 g <PROPOSED USAN>. The inactive ingredients are isomalt, hypromellose and strawberry flavor.

<PROPOSED USAN> targets underlying neurological dysfunction caused by mutations in the NPC1 or NPC2 genes. It enters enzyme-controlled pathways to correct metabolic dysfunction, improve mitochondrial function/adenosine triphosphate (ATP) production, and improve lysosomal function. This leads to a reduction in lipid and cholesterol storage and decreased lysosomal volume. The benefits of enhancing mitochondrial and lysosomal health include reducing neuroinflammation and improving cellular function.

No pharmacodynamic studies have been conducted with <BRAND NAME> in patients with NPC.

The full pharmacokinetic (PK) profile of <PROPOSED USAN> was assessed based on a PK analysis at the steady state of 17 NPC patients after 365 days (+/- 14 days) of dosing in the long-term extension phase of a Phase 2 study. Mean, dose-normalized (per gram of <PROPOSED USAN>) maximum concentration (Cmax) and area under the curve from time 0 to 24 hours (AUC0-24hrs) were 8.3 µg/mL and 33.2 h*μg/mL. No gender differences in PK parameters were observed.

Absorption

After oral administration, <PROPOSED USAN> is rapidly absorbed, with peak concentration times of between 0.5 to 2.5 hours.

Food Effect

Concomitant food administration had no effect on the oral bioavailability of IB1001.

Distribution

The mean (standard deviation [SD]) volume of distribution at steady state (Vss) was 253 (125) L.

<PROPOSED USAN> is taken up by ubiquitously expressed monocarboxylate transporters, thereby delivering <PROPOSED USAN> to all tissues including the central nervous system.

Elimination

The mean (SD) clearance is 139 (59) L/h. The estimated half-life is around 1 hour. No or only minor accumulation was observed after repeat administration.

Specific Populations

There were no clinically significant differences in the PK of <PROPOSED USAN> based on age (range 5 – 67 years), gender (female 45.5%, male 54.5%), race/ethnicity (White 91.1%, Asian 4.1%, Other or not specified 4.9%), or body weight (range 20.5 – 109.3 kg).

Racial or Ethnic Groups

The effect of other races/ethnicities on the PK of <PROPOSED USAN> has not been systematically evaluated.

Patients with Renal or Hepatic Impairment

The effect of renal or hepatic impairment on the PK of <PROPOSED USAN> has not been systematically evaluated.

Pregnant Women

The effect of pregnancy on the PK of <PROPOSED USAN> is unknown.

Drug Interaction Studies

In vitro studies showed that <PROPOSED USAN>, at therapeutic concentrations, does not significantly inhibit the enzyme activity of drug metabolizing cytochrome P450 (CYP450) isoforms. <PROPOSED USAN> does not have induction potential towards CYP450 enzymes.

In vitro, <PROPOSED USAN> inhibited the efflux transporters MDR1, BCRP and BSEP. The half-maximal inhibitory concentration (IC50) values were 227 (MDR1), 491 (BCRP) and 408 (BSEP) µg/mL equal to 1.31 (MDR1), 2.83 (BCRP) and 2.36 (BSEP) mM [see Drug Interactions (7)].

<PROPOSED USAN> also inhibited organic anion transporter (OAT) 1 and OAT3 at high IC50 values of 1030 (OAT1), 103 (OAT3) and 1700 organic cation transporter 2 (OCT2) μg/mL equal to 5.9 (OAT1), 0.59 (OAT3) and 9.7 (OCT2) mM in vitro. No in vitro inhibition of OATP1B1 and OATP1B3 was present at concentration of up to 900 µg/mL <PROPOSED USAN>.

In addition, <PROPOSED USAN> was a substrate of OAT1 and OAT3 in vitro, but not of OCT2, BCRP or MDR1 in vitro.

Carcinogenesis

No carcinogenicity studies have been conducted. Given the nature of the molecule and absence of findings indicative for carcinogenic potential in chronic toxicity studies, carcinogenetic potential of <PROPOSED USAN> is considered low.

Mutagenesis

<PROPOSED USAN> was not genotoxic in in vitro (bacterial reverse mutation, chromosomal aberration in human peripheral lymphocytes) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

Reproduction studies on impairment of fertility have not been conducted with <PROPOSED USAN>. In chronic toxicity studies, no effects on reproductive organs were observed.

In safety pharmacology studies, no effects were observed on central nervous system, cardiovascular or respiratory function.

The efficacy of <BRAND NAME> for treatment of NPC was established in a randomized, double-blind, placebo-controlled, crossover study (Study IB1001-301). This study (N=60) enrolled male or female patients aged 4 years or older with a genetically confirmed diagnosis of NPC.

The study was a crossover study. Patients were randomized 1:1 to receive either <BRAND NAME> or placebo for 12 weeks in Period I. In Period II, patients switched to the opposite study drug (either <BRAND NAME> or placebo) for 12 weeks. Patients aged ≥13 years received 4 g/day. The <BRAND NAME> dosage in children under 13 years was based on patient’s body weight [see Dosage and Administration ( 2)].

The major efficacy objective was the measurement of neurological signs, symptoms and functioning as measured by the modified Scale for the Assessment and Rating of Ataxia (mSARA). The mSARA, a 6-item clinical rating scale, comprises the original SARA functional assessments of ambulation, balance, and lower extremity function (Gait and Heel-shin slide domains), speech (Speech Disturbance domain), upper extremity function / fine motor skills (Finger Chase, Nose-Finger test and Fast Alternating Hand Movement domains). Scores range from 0 to 30, where 0 is the best neurological status and 30 the worst. An additional key efficacy outcome measure was the original SARA, which includes the same domains as the mSARA plus 2 balance domains (Stance and Sitting). Scores range from 0 to 40, where 0 is the best neurological status and 40 is the worst.

Treatment with <BRAND NAME> demonstrated a statistically significant difference in favor of <BRAND NAME> as compared to Placebo on mSARA and SARA (Table 4).

The 30 patients receiving placebo in Period I had no meaningful change in the mean mSARA/SARA score of -0.47/-0.60 compared to those on <BRAND NAME> who had a substantial change of -1.72/ -1.93. The remaining 30 patients who received <BRAND NAME> in Period I followed by placebo in Period II experienced significant worsening of symptoms on placebo, which effectively served as a washout from <BRAND NAME> (difference in mean mSARA / SARA score between Visit 4 and Visit 6 of +1.02 / +1.55), reflecting a deterioration in neurological signs and symptoms when treatment with <BRAND NAME> was stopped.

Additional secondary measures were included to assess the impact of <BRAND NAME> on neurological symptoms, functioning and quality of life. The modified Disability Rating Scale (mDRS) composite endpoint provided an additional assessment of ambulation, language and manipulation, and also evaluated swallowing, seizures, and ocular movements. Scores range from 0 to 24, where 0 is the best neurological status and 24 is the worst. The mDRS demonstrated an improvement versus placebo, estimated mean difference (95% confidence interval [CI]) -0.021 (‑0.040, -0.003), one-sided nominal p=0.013.

The Clinical Global Impression of Improvement (CGI-I) was assessed by the Investigators to provide an index of clinical importance. It is a stand-alone assessment of the Investigator’s view of the patient’s global functioning prior to and after initiating study treatment and takes into account all available information, including the patient’s medical history, symptoms, behavior and the impact of the symptoms on the patient’s ability to function/their quality of life. Scores range from 1 to 7, representing “very much improved” to “very much worse” relative to the initiation of treatment. The Investigator’s CGI-I demonstrated an improvement while on <BRAND NAME> versus placebo (in Period I), with mean (SD) scores of 3.3 (0.9) versus 3.9 (0.9), respectively; one-sided nominal p=0.008.

<BRAND NAME> is supplied as white to off-white granules for oral solution in a single-dose paper-backed aluminum/polyethylene sachet. Each sachet contains 1.7 g white to off-white granules, equivalent to 1 g <PROPOSED USAN>.

<NDC no.>: Carton containing 28 single-dose sachets

<NDC no.>: Multipack containing 112 single-dose sachets (4 cartons each containing 28 single-dose sachets)

Store at room temperature, 15°C to 25°C (59°F and 77°F); excursion permitted up to 30°C (86°F) [see USP Controlled Room Temperature].

Administration Instructions

Advise patients:

Administration with Liquid

- Pour the content of one sachet into 40 mL of water, orange juice or almond milk. Do not use hot liquid.

- Stir until fully dissolved.

- Drink all of the solution immediately after dissolving (within 30 minutes).

If a dose of <BRAND NAME> is missed, the next dose should be taken as scheduled. Doses should not be doubled.

Distributed by: IntraBio Inc., City, State

<BRAND NAME> is a registered trademark of IntraBio Inc.