Alpha-1 Antitrypsin DeficiencyPhase 1/2PM647aNCT07887347
A Study of the Safety and Efficacy of Prime Editing (PM647a) in Participants With Alpha-1 Antitrypsin Deficiency
A Phase 1/2 study testing PM647a in people with Alpha-1 Antitrypsin Deficiency and Alpha-1 Antitrypsin Deficiency-associated Lung Disease, run by Prime Medicine, Inc..
Trial summary
The purpose of this study is to evaluate the safety, tolerability, biological activity, and initial efficacy of PM647a, an investigational Prime Editing therapy, in adults and adolescents with Alpha-1 Antitrypsin Deficiency (AATD). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Alpha-1 Antitrypsin Deficiency, Alpha-1 Antitrypsin Deficiency-associated Lung Disease, Alpha-1 Antitrypsin Deficiency (AATD)
- What is being tested?
- PM647a
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 54 participants
- Where
- No sites listed yet
- Study dates
- Oct 2026to Jan 2029
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participants at least 18 years of age at the time of consent and able to provide written consent
- Confirmed diagnosis of AATD as determined by medical history consistent with AATD, and diagnostic genetic testing performed by the designated central laboratory demonstrating homozygous presence of the SERPINA1 Pi*Z (E342K) allele
- Blood total AAT level < 11 μM or history of total AAT levels < 11 μM
- For individuals receiving augmentation therapy, willingness to stop augmentation therapy for at least 5 half-lives or 4 weeks, whichever is longer, prior to the planned infusion of PM647a through Week 16 post-PM647a infusion
- Group A only: Postbronchodilator FEV1 ≥ 30% of predicted (or ≥ 40% of predicted for participants on augmentation therapy) and at least ONE of the following:
- FEV1/FVC <70% at screening OR
Show all 15Show fewer
- Annualized decline in post-bronchodilator FEV1 of ≥100 mL, calculated from at least two spirometry assessments obtained at least 12 months apart
- Group A only: Radiologic or physiologic evidence of emphysema (obtained within 6 months of signing the ICF) defined as either:
- Chest CT imaging demonstrating a clinically significant burden of emphysematous change consistent with AATD-related disease (as judged by the Investigator or interpreting radiologist)
- DLCO ≤70% predicted (corrected for anemia, if present)
- Willingness to abstain from alcohol use and herbal medications from the start of the screening period through 28 days post-PM647a administration
- Willingness to avoid strenuous physical activity starting 1 week prior to PM647a infusion through 14 days after PM647a infusion
- Willingness to participate in a long-term extension study with the understanding that the total duration of participation is 15 years post-infusion
- Group B only: Liver histopathologic examination with a METAVIR fibrosis stage of F1, F2, or F3
- Group B only: FibroScan ≤12 kPa
Who cannot join
- Prior medically significant reaction to an LNP-based or PEG-containing product medication (e.g., severe hypersensitivity reaction, myocarditis)
- Use of any investigational product within 30 days (or 5 half-lives, whichever is longer) of signing ICF
- Prior receipt of genetic medicine for AATD
- History of lung or liver transplantation, or actively waitlisted,
- History of lung volume reduction surgery (LVRS) or endobronchial lung volume reduction (ELVR)
- Recent (within past 6 weeks) COPD exacerbation requiring antibiotic or steroid therapy, or requiring hospitalization
Show all 48Show fewer
- Resting SpO2 ≤88% on room air or requiring > 3 L/min supplemental oxygen to maintain SpO2 > 88%
- Body mass index (BMI) >35
- Current or recent regular smoking history (within the past 12 months) or not willing to abstain from smoking (including vaporizers/e-cigarettes, marijuana) for the duration of the study
- Liver disease with any of the following:
- Total bilirubin > 1.5 x ULN at screening, except for participants with documented Gilbert's Syndrome
- Decompensated cirrhosis or advanced liver disease
- Model for End-Stage Liver Disease (MELD) score > 13
- Group A only additional requirements:
- ALT or AST >1.5x upper limit of normal (ULN) at screening
- Total bilirubin levels >ULN at screening; if documented Gilbert's Syndrome, total bilirubin >2 × ULN
- FibroScan liver stiffness measurement ≥7.5 kilopascals (kPa)
- Known history of liver cirrhosis or complications of cirrhosis
- ≥F2 liver fibrosis if a patient has previously had a liver biopsy
- Acute hemolytic anemia
- Group A only: Significant burden of co-morbid liver disease or injury of any etiology (including AATD)
- Group B only: Significant burden of co-morbid liver disease or injury not attributable to AATD, including but not limited to alcohol-related liver disease, autoimmune hepatitis, AIH, PBC, PSC, hemochromatosis
- History of significant liver disease other than AATD, including but not limited to alcohol-related liver disease ('alcoholic hepatitis'), autoimmune hepatitis, or hemochromatosis. On-going hepatitis A, B, C or E viral infection is excluded, regardless of viral load. However, individuals with confirmed resolved hepatitis A, B or C viral infection may be enrolled (i.e., hepatitis B surface antibody positive and viral load negative, while not on antiviral treatment; hepatitis C viral load negative on at least 2 occasions at least 6 months apart, while not on antiviral treatment)
- Evidence of Moderate or Severe Renal Impairment in the last 12 months since signing the ICF, defined as:
- eGFR < 30 mL/min/1.73m2 (CKD-EPI method)
- Presence of Nephrotic Syndrome
- Presence of Nephritic Syndrome
- Clinically significant coagulopathy or disorder of platelet function (as evidenced by any of the following or as judged by the Investigator)
- Requiring ongoing antiplatelet therapy (excepting low-dose acetylsalicylic acid [ASA]) that cannot safely be interrupted, or receipt of any such antiplatelet agent within the 14 days prior to PM647a administration
- Requiring ongoing anticoagulant therapy that cannot safely be interrupted, or receipt of any anticoagulant within the longer of 7 days or 5 half-lives prior to PM647a administration
- International Normalized Ratio (INR) > 1.3 on at least 2 evaluations performed ≥ 1 week apart. If the most recent test exceeds these values, then a repeat test should be performed ≥ 1 week later to confirm
- Absolute neutrophil count (ANC) <1500 cells/mm3 OR platelet count < 70 × 109 cells/L OR hemoglobin <10 g/dL for males or <9 g/dL for females
- Congestive Heart Failure (NYHA Class III-IV)
- Known or clinically suspected ischemic heart disease (unless adequately revascularized, free of angina or anginal equivalent, on maximal guideline-directed medical therapy for at least 12 months prior to screening)
- For male participants aged ≥ 40 years, a current calculated 10-Year ASCVD risk ≥ 20% (UNLESS ischemic evaluation performed within the 12 months before signing the informed consent or at the time of screening was in the Investigator's judgment sufficient to reasonably exclude the presence of clinically significant obstructive CAD / ischemic heart disease). If a lipid panel has been performed within the prior 12 months, the most recent lipid panel data may be used for ASCVD calculation
- Known or strongly suspected acute coronary syndrome (UA, NSTEMI, STEMI) or other clinically significant cardiovascular event (new reduction in LV systolic function, transient ischemic attack, cerebrovascular accident) within the 12 months prior to screening
- Known history of clinically significant arrhythmia (e.g., poorly controlled pAF, sustained ventricular tachyarrhythmia, etc.) with cardiac conduction disorder including but not limited to: congenital long QT syndrome, acquired prolonged QT ([QTcF] > 450 msec (males) or > 470 [females]), AV block (1st degree AVB is excepted)
- Active infectious disease including:
- Known or suspected active systemic infection
- Receipt of systemic antimicrobial therapy within 30 days of screening
- Positive for presence of human immunodeficiency virus (HIV)-1 or HIV-2 (evidence of infection, regardless of viral load)
- Prior or current malignancy (excluding Stage 1 or lower, fully treated/excised malignant and pre-malignant disease of the skin, cervix or colon. Additionally, any other malignant and pre-malignant disease that the Investigator, in consultation with the treating oncologist and Study Medical Monitor, deems to have been fully treated/excised for > 5 years)
- Any condition, laboratory abnormality, or reason that could adversely affect participant safety or study results, as determined by the Investigator, including, but not limited to:
- Significant neurological conditions within the prior 12 months which may impact participant safety or participation in the study, including ability to complete study requirements or procedures as outlined in the clinical study protocol in the opinion of the Investigator
- Any severe clinical condition of limited life expectancy
- Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participants
- Females of childbearing potential and non-sterile male participants who are or may become sexually active with female partners of childbearing potential are required to use highly effective contraception from Screening through at least 84 days after DP infusion
- History of Alcohol Use Disorder (AUD) or Drug Use Disorder (DUD) with < 3 years of continuous abstinence preceding the date of screening
About this study
Official title: A Phase 1/2 Multicenter Clinical Study to Evaluate Safety, Tolerability, Biological Activity, and Efficacy of an In Vivo LNP-Delivered Prime Editor Complex (PM647a) for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD)
The purpose of this study is to evaluate the safety, tolerability, biological activity, and initial efficacy of PM647a, an investigational Prime Editing therapy, in adults and adolescents with Alpha-1 Antitrypsin Deficiency (AATD).
AATD is caused by a mutation (change) in a gene called SERPINA1 that prevents the cells in your liver from producing a functional protein (alpha-1 anti-trypsin; AAT) that helps protect your lung tissue. PM647a is designed to precisely correct the prevalent disease-causing mutation (SERPINA1 Pi*Z (E342K)) with the goal of restoring functional AAT. This is the first study of PM647a in humans. Participants will receive a single intravenous (IV) infusion of PM647a and will be monitored closely to evaluate safety, how the body responds to treatment, changes in AAT protein levels, and whether treatment may improve signs and symptoms of AATD.
Read the detailed description
This is a Phase 1/2 open label study evaluating PM647a in adults and adolescents with Alpha-1 Antitrypsin Deficiency (AATD) who are homozygous for the SERPINA1 p.E342K pathogenic variant, also known as the PiZ allele (PiZZ genotype). Enrollment and treatment will begin with Group A, which includes participants with lung manifestations only. Group B will open subsequently and will include participants with both lung and liver manifestations or liver manifestations only. Additionally, a set of 3 to 6 participants with AATD penetrant lung disease (with or without liver disease), will be enrolled to further understand the effects of PM647a on local pharmacodynamic effects through BAL (BAL cohort).
The study will evaluate the safety of PM647a, determine an appropriate dose for future studies, and assess whether treatment restores normal synthesis and secretion of functional AAT and improves clinical measures of AATD. Participants will receive a single IV infusion of PM647a and will undergo regular safety evaluations, laboratory testing, imaging, and clinical assessments for approximately 48 weeks after treatment. Participants will then be asked to enroll in a separate long-term follow-up study to continue monitoring safety and treatment effects for an additional 14 years.
- Conditions
- Alpha-1 Antitrypsin Deficiency, Alpha-1 Antitrypsin Deficiency-associated Lung Disease, Alpha-1 Antitrypsin Deficiency (AATD), AATD
- Being tested
- PM647a
- Keywords
- gene therapy, gene editing, Prime Editing, PM647a, SERPINA1, AATD, Pi*ZZ, Pi*Z
- Medical subject headings
- alpha 1-Antitrypsin Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PM647aDrug
PM647a is being evaluated in participants with Alpha-1 Antitrypsin Deficiency (AATD) caused by a homozygous Pi*Z allele (Pi*ZZ genotype), with an observed lung phenotype (Group A), or an observed liver and lung or liver alone phenotype (Group B)
| Study group | Role | What they receive |
|---|---|---|
| PM647a | Experimental | PM647a is a sterile suspension of lipid nanoparticle (LNP)-formulated Prime Editors (PEs) intended for single dose intravenous (IV) infusion for the treatment of Alpha-1 Antitrypsin Deficiency (AATD) Receives: Drug: PM647a |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and tolerability of PM647a. Quantified by frequency and severity of treatment emergent adverse events (TEAEs)
Measured: Immediately post-infusion up to Week 48
Secondary outcomes (17)
Frequency and severity of Dose Limiting Toxicities (DLTs)
Measured: Infusion up to and including 28 days
Percentage of participants with ≥ 11 µM total serum alpha-1 antitrypsin (AAT) levels
For participants treated with a dose of PM647a at or above the OBD, central laboratory quantitative immunoturbidimetry
Measured: Week 12 post-infusion
Percentage of participants with ≥ 11 µM total serum AAT levels
Central laboratory quantitative immunoturbidimetry
Measured: Week 4, Week 6, Week 12, Week 24 and Week 48 post-infusion
Percentage of participants with total serum AAT levels ≥ the lower limit of normal
Central laboratory quantitative immunoturbidimetry
Measured: Week 4, Week 6, Week 12, Week 24 and Week 48 post-infusion
Change in total serum AAT levels, including changes in levels of pathogenic AAT (Z-AAT) and normal (M-AAT)
Total AAT measured by immunoturbidimetry; M-AAT and Z-AAT isoforms by liquid chromatography/mass spectrometry (LC/MS)
Measured: Baseline to Week 4, Week 6, Week 12, Week 24, and Week 48 post-infusion
Time from PM647a infusion to total serum AAT levels ≥ 11 µM, ≥ 20 µM, or within the normal range
Measured: Measured over the course of the study (through Week 48)
Change in Forced Expiratory Volume (FEV1)
Pulmonary function testing (PFT), using standardized pre- and post-bronchodilator spirometry
Measured: From baseline to Week 6 and to Week 48 post-infusion
Change in Forced Vital Capacity (FVC)
Spirometry measuring the volume of air forcibly exhaled following maximal inspiration
Measured: From baseline to Week 6 and to Week 48 post-infusion
Change in FEV1/FVC
Measured: From baseline to Week 6 and to Week 48 post-infusion
Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)
Measured: From baseline to Week 6 and to Week 48 post-infusion
Change in annualized Chronic Obstructive Pulmonary Disease (COPD) exacerbations
Measured by GOLD healthcare utilization criteria (severity and frequency), higher frequencies and severity indicate greater COPD exacerbation burden
Measured: Infusion through the Week 48 Visit compared to the 2-years prior to signing ICF
Change in SGRQ-C
For participants who take the St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C), scores range from 0 to 100, higher scores indicate greater respiratory health impairment and poorer respiratory-related quality of life
Measured: From baseline to Weeks 12, 24, 36, and 48 post-infusion
Change in CAT
Assessed by COPD Assessment Test (CAT), scores range from 0 to 40, higher scores indicate greater COPD symptom burden and a more substantial impact of COPD on daily life.
Measured: From baseline to Weeks 12, 24, 36, and 48 post-infusion
Evaluation of health-related quality of life (HRQoL)
Using the age-appropriate EuroQol 5 Dimension 5-Level instrument (EQ-5D-5L) or alternative EQ-5D version (e.g., EQ-5D-3L) as indicated by country-specific availability, scores range from 0 to 100 with higher scores indicating better health
Measured: From baseline to Week 24 and Week 48
Change in Liver Stiffness using transient or shear wave elastography
Group B Only, measured using transient or shear wave elastography
Measured: From baseline to Week 24 and Week 48
Change in pathogenic AAT (Z-AAT) in the liver
Group B Only, measured by liver biopsy specimen
Measured: From baseline to Week 12 post-infusion and, for participants undergoing optional Week 48 liver biopsy, from baseline to Week 48 post-infusion
Change in pathogenic AAT globule burden score
Group B Only, measured by liver biopsy specimen. Score ranges from 0 to 5 with a higher score indicating greater globule burden.
Measured: From baseline to Week 12 post-infusion and, for participants undergoing optional Week 48 liver biopsy, from baseline to Week 48 post-infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2026
- Study startOct 2026 (estimated)
- Primary completionDec 2028 (estimated)
- Study completionJan 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alpha-1 Antitrypsin DeficiencyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 54 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Prime Medicine, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07887347
- Sponsor's protocol ID
- Prime-0301
- Acronym
- PM647a
- Status last verified
- Oct 2026
- First submitted
- 8 Oct 2026
- Last updated
- 21 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No