A First in Human, Dose Escalation Study to Evaluate the Safety and Tolerability of BBP-671 in Healthy Volunteers and Patients With Propionic Acidemia or Methylmalonic Acidemia

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety, tolerability, PK and PD of BBP-671 in healthy volunteers and patients with Propionic Acidemia or Methylmalonic Acidemia.

Detailed Description
-----------------
This is the first-in-human study with BBP-671 and is designed to provide healthy subjects single- and multiple-dose and patient multidose safety, tolerability, PK, and PD data regarding BBP-671 for future clinical studies.

Official Title
-----------------
A First-in-human, Randomized, Placebo-controlled, Single and Multiple Ascending Dose Escalation to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BBP-671 in Healthy Subjects and In Patients With Propionic Acidemia or Methylmalonic Acidemia

Conditions
-----------------
Healthy Volunteers, Propionic Acidemia, Methylmalonic Acidemia, Organic Acidemia

Intervention / Treatment
-----------------
* Drug: BBP-671
* Drug: Placebo
* Drug: BBP-671


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (Healthy Volunteers): Subject is male or female 18 to 55 yrs old Subject has a BMI 18 to 32 kg/m^2 Female and male subjects must use effective method of birth control Female subjects must have negative pregnancy test prior to first dose of study drug Subject must not have any clinically significant history or presence of ECG findings Subject must be in good general health Inclusion Criteria (PA or MMA Patients): Patient is male or female 15 to 55 yrs old Patient has a BMI 18 to 32 kg/m^2 Female and male patients must use effective method of birth control Female patients must have negative pregnancy test prior to first dose of study drug Patient must have confirmed PA or MMA diagnosis Patient with MMA must have elevated plasma MMA levels Patient is willing to provide access to medical records for the last 6-12 months of care prior to study initiation Patient is on consistent disease management and treatment regimen is stable for at least 30 days prior to study initiation. Exclusion Criteria (Healthy Volunteers): Subject has used prescription drugs (contraceptive medications are allowed) within 4 weeks before first dose of study drug or over-the-counter medication within 7 days of the first dose of study drug Subject who is unable or unwilling to refrain from wearing contact lenses during participation in the study. Subject has a history of dry eye or eye surgery, including radial keratotomy and LASIK surgery. Subject who has taken the COVID-19 vaccine, the last vaccine dose must be at least 14 days prior to first dose of study drug. Subject has abnormal laboratory test results Subject has a baseline eGFR <90 mL/minute Subject has positive result for Hepatitis B, Hepatitis C, or HIV Female subject is non-pregnant and non-lactating Subject is a smoker or has used nicotine or nicotine-containing products Subject has a history of alcohol or drug abuse within 12 months prior to first dose of study drug and/or has a positive result prior to dosing or throughout the study Subject has donated blood or blood products >450mL within 30 days prior to study drug dosing Subject has a history of relevant drug or food allergies Subject has received study drug in another investigational study within 30 days of dosing Subject has undergone prior liver and/ or kidney transplant. Exclusion Criteria (PA or MMA Patients): Patient has used prescription drugs (contraceptive medications are allowed) within 4 weeks before first dose of study drug or over-the-counter medication within 7 days of the first dose of study drug that is not part of their PA or MMA disease management and treatment Patient who has taken the COVID-19 vaccine, the last vaccine dose (or booster) must be at least 14 days prior to first dose of study drug. Patient is unable or unwilling to refrain from wearing contact lenses during participation in the study. Patient has a history of dry eye or eye surgery, including radial keratotomy and LASIK surgery. Patient has clinically significant abnormal laboratory test results unrelated to PA or MMA Patient has a baseline eGFR <60 mL/minute Patient has positive result for Hepatitis B, Hepatitis C, or HIV Female patient is non-pregnant and non-lactating Patient has a history of alcohol or drug abuse within 12 months prior to first dose of study drug and/or has a positive result prior to dosing or throughout the study Patient has donated blood or blood products >450mL within 30 days prior to study drug dosing Patient has a history of relevant drug or food allergies Patient has received study drug in another investigational study within 30 days of dosing PA patient has undergone prior liver and/ or kidney transplant. Prior liver and/or kidney transplant is allowed for patients with MMA. Patient has had a recent infection requiring system antibiotics within 4 weeks of Baseline or any active infection that precludes the patient from participation Patient has Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association. Patient has been exposed to gene therapy for PA or MMA at any time prior to study entry. Patient is currently taking sensitive CYP3A4 substrates (e.g., tacrolimus or sirolimus)

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBP-671 for SAD<br>The SAD portion of the study will consist of up to 8 cohorts. Six (6) healthy male or female adult subjects will be randomized to receive BBP-671 per cohort (6:2 ratio, BBP-671:placebo). | Drug: BBP-671<br>* BBP-671, oral suspension<br>|
| Placebo Comparator: Placebo for SAD<br>The SAD portion of the study will consist of up to 8 cohorts. Two (2) healthy male or female adult subjects will be randomized to receive matching placebo per cohort (6:2 ratio, BBP-671:placebo). | Drug: Placebo<br>* Placebo matching BBP-671<br>|
| Experimental: BBP-671 for MAD<br>The MAD portion of the study will consist of up to 6 cohorts. Six (6) healthy male or female adult subjects will be randomized to receive BBP-671 per cohort (6:2 ratio, BBP-671:placebo). | Drug: BBP-671<br>* BBP-671, oral suspension<br>|
| Placebo Comparator: Placebo for MAD<br>The MAD portion of the study will consist of up to 6 cohorts. Two (2) healthy male or female adult subjects will be randomized to receive matching placebo per cohort (6:2 ratio, BBP-671:placebo). | Drug: Placebo<br>* Placebo matching BBP-671<br>|
| Experimental: BBP-671 for SAD Food Effect<br>Eight (8) healthy male or female adult subjects will be randomized to receive BBP-671. | Drug: BBP-671<br>* BBP-671, oral suspension<br>|
| Experimental: BBP-671 for PA and MMA Patients<br>Up to sixteen (16) patients with either PA or MMA will receive BBP-671. | Drug: BBP-671<br>* BBP-671, tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events following administration of BBP-671 |  | 49 days | 
| BBP-671 concentration dependent change in change from baseline in QTcF |  | 49 days | 
| Pharmacokinetic Assessments: Cmax | Time to maximum concentration (Cmax) | 49 days | 
| Pharmacokinetic Assessments: Tmax | Time to reach maximum observed plasma concentration (Tmax) | 49 days | 
| Pharmacokinetic Assessments: t1/2 | Plasma decay half-life (t1/2) | 49 days | 
| Pharmacokinetic Assessments: AUC0-tau | Area under the plasma concentration-time curve (AUC0-tau) | 49 days | 
| Pharmacokinetic Assessments: CL/F | Apparent clearance (CL/F) | 15 days | 
| Pharmacokinetic Assessments: Vz/F | Apparent volume of distribution (Vz/F) | 15 days | 
| Pharmacokinetic Assessments: CLr | Renal clearance (CLr) | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food Effect: Cmax | Time to maximum concentration | 10 days | 
| Food Effect: Tmax | Time to reach maximum observed plasma concentration | 10 days | 
| Food Effect: AUC | Area under the plasma concentration-time curve | 10 days | 
| Pharmacodynamic Assessment: Whole blood, plasma, and urine biomarker concentrations will be quantified and summarized using appropriate descriptive parameters | Measurement will be done using liquid chromatography-tandem mass spectrometry | 49 days |