A Study of the Safety and Efficacy of Prime Editing (PM647a) in Participants With Alpha-1 Antitrypsin Deficiency

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.

• PM647a (Drug): 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)

Primary outcomes

• Safety and tolerability of PM647a. Quantified by frequency and severity of treatment emergent adverse events (TEAEs) [Immediately post-infusion up to Week 48]

Secondary outcomes

• Frequency and severity of Dose Limiting Toxicities (DLTs) [Infusion up to and including 28 days]
• Percentage of participants with ≥ 11 µM total serum alpha-1 antitrypsin (AAT) levels [Week 12 post-infusion]: For participants treated with a dose of PM647a at or above the OBD, central laboratory quantitative immunoturbidimetry
• Percentage of participants with ≥ 11 µM total serum AAT levels [Week 4, Week 6, Week 12, Week 24 and Week 48 post-infusion]: Central laboratory quantitative immunoturbidimetry
• Percentage of participants with total serum AAT levels ≥ the lower limit of normal [Week 4, Week 6, Week 12, Week 24 and Week 48 post-infusion]: Central laboratory quantitative immunoturbidimetry
• Change in total serum AAT levels, including changes in levels of pathogenic AAT (Z-AAT) and normal (M-AAT) [Baseline to Week 4, Week 6, Week 12, Week 24, and Week 48 post-infusion]: Total AAT measured by immunoturbidimetry; M-AAT and Z-AAT isoforms by liquid chromatography/mass spectrometry (LC/MS)
• Time from PM647a infusion to total serum AAT levels ≥ 11 µM, ≥ 20 µM, or within the normal range [Measured over the course of the study (through Week 48)]
• Change in Forced Expiratory Volume (FEV1) [From baseline to Week 6 and to Week 48 post-infusion]: Pulmonary function testing (PFT), using standardized pre- and post-bronchodilator spirometry
• Change in Forced Vital Capacity (FVC) [From baseline to Week 6 and to Week 48 post-infusion]: Spirometry measuring the volume of air forcibly exhaled following maximal inspiration
• Change in FEV1/FVC [From baseline to Week 6 and to Week 48 post-infusion]
• Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) [From baseline to Week 6 and to Week 48 post-infusion]
• Change in annualized Chronic Obstructive Pulmonary Disease (COPD) exacerbations [Infusion through the Week 48 Visit compared to the 2-years prior to signing ICF]: Measured by GOLD healthcare utilization criteria (severity and frequency), higher frequencies and severity indicate greater COPD exacerbation burden
• Change in SGRQ-C [From baseline to Weeks 12, 24, 36, and 48 post-infusion]: 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
• Change in CAT [From baseline to Weeks 12, 24, 36, and 48 post-infusion]: 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.
• Evaluation of health-related quality of life (HRQoL) [From baseline to Week 24 and Week 48]: 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
• Change in Liver Stiffness using transient or shear wave elastography [From baseline to Week 24 and Week 48]: Group B Only, measured using transient or shear wave elastography
• Change in pathogenic AAT (Z-AAT) in the liver [From baseline to Week 12 post-infusion and, for participants undergoing optional Week 48 liver biopsy, from baseline to Week 48 post-infusion]: Group B Only, measured by liver biopsy specimen
• Change in pathogenic AAT globule burden score [From baseline to Week 12 post-infusion and, for participants undergoing optional Week 48 liver biopsy, from baseline to Week 48 post-infusion]: Group B Only, measured by liver biopsy specimen. Score ranges from 0 to 5 with a higher score indicating greater globule burden.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 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

  a) 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:

  1. FEV1/FVC <70% at screening OR
  2. 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:

  1. Chest CT imaging demonstrating a clinically significant burden of emphysematous change consistent with AATD-related disease (as judged by the Investigator or interpreting radiologist)
  2. 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

Exclusion Criteria:

* 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
* 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:

  1. Total bilirubin > 1.5 x ULN at screening, except for participants with documented Gilbert's Syndrome
  2. Decompensated cirrhosis or advanced liver disease
  3. Model for End-Stage Liver Disease (MELD) score > 13
  4. Group A only additional requirements:

     1. ALT or AST >1.5x upper limit of normal (ULN) at screening
     2. Total bilirubin levels >ULN at screening; if documented Gilbert's Syndrome, total bilirubin >2 × ULN
     3. FibroScan liver stiffness measurement ≥7.5 kilopascals (kPa)
     4. Known history of liver cirrhosis or complications of cirrhosis
     5. ≥F2 liver fibrosis if a patient has previously had a liver biopsy
     6. 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:

  1. eGFR < 30 mL/min/1.73m2 (CKD-EPI method)
  2. Presence of Nephrotic Syndrome
  3. 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)

  1. 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
  2. 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
  3. 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:

  1. Known or suspected active systemic infection
  2. Receipt of systemic antimicrobial therapy within 30 days of screening
  3. 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:

  1. 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
  2. Any severe clinical condition of limited life expectancy
* Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participants

  a) 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