A Phase 1/2 Study of NTLA-3001 in Adults with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Intellia Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

completed 10 Jan 2025

Decision date (initial)

2024-11-18

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Intellia Therapeutics, Inc.

External identifiers

EU CT number

2023-508138-33-00

WHO UTN

U1111-1297-6845

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Efficacy, Safety, Others

To evaluate the safety and tolerability of NTLA-3001 following a single treatment in adult participants with AATD-associated lung disease

Secondary objectives 5

1. 1. Pharmacodynamics (PD). To evaluate the PD effect of NTLA-3001
2. 2. Pharmacokinetics (PK). To evaluate the PK of NTLA-3001.
3. 3. Immunogenicity. To evaluate the immune response to NTLA-3001
4. 4. Shedding (Phase 2 only). To evaluate AAV vector shedding following administration of NTLA-3001
5. 5. Exploratory. To evaluate the effect of NTLA-3001 on health-related quality of life (HRQoL)

Conditions and MedDRA coding

Pulmonary emphysema

Regulatory references

Scientific advice from competent authorities

Health Products Regulatory Authority

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Male or female participants, 18 to 75 years of age inclusive, at the time of signing informed consent.
2. 2. Diagnosis of AATD-associated lung disease meeting specific criteria.
3. 3. 3. Per Investigator assessment, the participant has either maximized or refused available standard of care. For participants on AAT augmentation therapy, the Investigator determines that it is clinically acceptable to hold augmentation therapy for at least 4 weeks prior to dosing and refrain from initiating augmentation therapy for at least 12 weeks postdosing. The Investigator will review the protocol with the participant, including temporary withholding of AAT augmentation therapy, and potential consequences.
4. 4. No prior diagnosis of protein-losing enteropathy or nephropathy or history of hypoalbuminemia.
5. 5. AAV TAb below the laboratory assay cut-off titer.
6. 6. Participants must meet specific laboratory criteria.
7. 7. aPTT, INR, fibrinogen and D-dimer within the reference range or clinically nonsignificant per Investigator assessment.
8. 8. Male participants must agree to the contraceptive requirements and sperm donation restrictions.
9. 9. Female participants must not be pregnant or breastfeeding and must agree to the contraceptive requirements and egg (ova, oocyte) restrictions.
10. 10. Participants must provide written informed consent before any protocol-specified assessment is performed.
11. 11. Participants must agree to the alcohol consumption restrictions.
12. 12. Participants must have a negative cotinine test and agree to the smoking and nicotine restrictions.

Exclusion criteria 17

1. 1. Impaired liver function.
2. 2. Any of the following within 12 months prior to Screening: (a) Myocardial infarction; (b) Transient ischemic attack; (c) Cerebrovascular accident; (d) Pulmonary embolism; (e) New York Health Association Class III or IV heart failure.
3. 3. History of hepatitis B or C infection or positive hepatitis B surface antigen (HbsAg) or hepatitis C virus antibody (HCV Ab) test. Laboratory results confirmed at Day -1.
4. 4. History of positive HIV status or positive HIV status at Screening. Laboratory results confirmed at Day -1.
5. 5. Known or suspected systemic parasitic, fungal, or viral infection, including COVID-19, or received antibiotics for bacterial infection; vaccines within 14 days prior to Screening; live vaccines within 30 days prior to Screening. Status confirmed at Day -1.
6. 6. Use of corticosteroids above 5 mg/day of prednisone (or equivalent) or other immunosuppressive medications within 4 weeks prior to Screening.
7. 7. Have had a serious COPD exacerbation (as determined by the Investigator) or used antibiotics for a COPD exacerbation or respiratory infection within 4 weeks prior to Screening.
8. 8. History of anaphylaxis or severe systemic reaction to AAT augmentation therapy, or immune response to AAT augmentation therapy as indicated by clinical history of an adverse immune response to infusion with decreased therapeutic effect in combination with documentation of serum anti-AAT antibodies.
9. 9. History of alcohol or drug abuse within 3 years prior to Screening.
10. 10. History of active malignancy within 5 years prior to Screening or during the Screening period, except curatively resected basal cell or squamous cell carcinoma of skin.
11. 11. Prior liver, heart, or other solid organ transplant; lung volume reduction surgery (LVRS); bone marrow transplant; or anticipated transplant or LVRS within 1 year of Screening. Note: Prior history of or planned corneal transplant is not exclusionary.
12. 12. Prior receipt of any gene therapy.
13. 13. Receiving an investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the drug prior to Screening. Note: Observational, non-interventional registry trials (studies with no procedural assessments) are acceptable.
14. 14. Uncontrolled hypertension (systolic BP > 160 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
15. 15. Participants who have known hypersensitivity to any LNP component (or its excipients) or formulation buffer used to suspend the viral vector, or contraindication to high-dose steroids.
16. 16. Unable or unwilling to take the required pretreatment medication regimen or postinfusion corticosteroid regimen.
17. 17. Participant is not considered suitable for study inclusion in the opinion of the Investigator for other reasons.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. Treatment-emergent adverse events (TEAE).

Secondary endpoints 8

1. 1. PD. Circulating alpha-1 antitrypsin (AAT) protein.
2. 2. PK. Plasma concentration-time profiles and PK parameters of the components of the study intervention.
3. 3. Immunogenicity. Total antibodies (TAb) and neutralizing antibodies (NAb) to AAV.
4. 4. Immunogenicity. Antibodies to AAT protein.
5. 5. Immunogenicity. Anti-drug antibodies to LNP.
6. 6. Immunogenicity. Anti-Cas9 protein antibodies.
7. 7. Shedding (Phase 2 only). AAV VGCN per cell in blood, urine, saliva, and semen samples.
8. 8. Exploratory. St George’s Respiratory Questionnaire & 36-item short form health survey questionnaire (SF-36).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Intellia Therapeutics Inc.

Sponsor organisation

Intellia Therapeutics Inc.

Address

40 Erie Street

City

Cambridge

Postcode

02139-4254

Country

United States

Scientific contact point

Organisation

Intellia Therapeutics Inc.

Contact name

Trial Manager at Intellia

Public contact point

Organisation

Intellia Therapeutics Inc.

Contact name

Trial Manager at Intellia

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 38 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications