Lentiviral Vector Gene Therapy - The Guard1 Trial of AVR-RD-02 for Subjects With Type 1 Gaucher Disease

The Guard1 Trial, an Open-Label, Multinational Phase 1/2 Study of the Safety and Efficacy of Ex Vivo, Lentiviral Vector-Mediated Gene Therapy AVR-RD-02 for Subjects With Type 1 Gaucher Disease

This was a multinational, open-label study to assess the safety and efficacy of AVR-RD-02 in approximately 8 to 16 subjects (male or female) who are ≥18 and ≤50 years of age and post pubertal at Screening with a confirmed diagnosis of Type 1 Gaucher disease (based on clinical phenotype, genotyping, and deficient GCase enzyme activity in whole blood).

Five study periods (Screening, Baseline, Pre-gene Therapy Infusion, Gene Therapy Infusion, and Post-gene Therapy Infusion Follow-up) comprised the study. During the Screening Period (approximately 60 days), written informed consent was obtained and the subject completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, subjects entered the Baseline Period (up to 7 days) during which time assessments were performed to establish Pre-gene Therapy Infusion baseline. Once baseline assessments were completed, the subject entered the Pre-gene Therapy Infusion Period (approximately 8 to 10 weeks) during which time mobilization, apheresis, AVR-RD-02 investigational product preparation and testing for release, busulfan conditioning regimen administration took place. Enzyme replacement therapy was discontinued at least 2 weeks before the scheduled Gene Therapy Infusion Day. Following completion of the Pre-gene Therapy Infusion Period, the subject entered the Gene Therapy Infusion Period (1 day) during which AVR-RD-02 infusion took place. After AVR-RD-02 Gene Therapy Infusion, the subject entered the Post-gene Therapy Infusion Follow-up Period (approximately 52 weeks) during which time periodic safety and efficacy assessments were performed to assess measures of safety, engraftment, and clinical response following AV-RD-02 infusion.

In August 2023, the study was terminated early by the Sponsor, which was not based on any safety or medical reasons and therefore, one subject did not complete the study (i.e., Week 52). Subsequently, in August 2023, the sponsor's long-term follow-up study (AVRO-RD-02-LTF01), was also terminated early for the same reason as the AVRO-RD-02-201 study, and therefore, no subjects completed the 15-year long-term follow-up study.

INCLUSION CRITERIA for all Enrolled (Switch-stable and Treatment-naïve) Subjects:

Note: No treatment-naïve subjects enrolled in this study.

1. Subject was ≥18 and ≤50 years old and post pubertal

2. Subject had a confirmed diagnosis of Type 1 Gaucher disease based on deficient GCase enzyme at Screening.

   a. For switch-stable subjects, documentation of GCase enzyme activity prior to having been started on ERT or if GCase levels prior to ERT were not available, deficient trough GCase enzyme activity in peripheral blood at Screening.

3. Female subjects of reproductive potential were counseled regarding the risks, benefits, limitations, and alternatives associated with female fertility preservation. Oocyte harvesting and cryopreservation were offered

4. Male subjects were willing to refrain from donating sperm at any time after receiving conditioning therapy. For subjects planning on (or for whom there is a possibility of) fathering children in the future, sperm cryopreservation before administration of the conditioning regimen was recommended.

5. All subjects who had not undergone successful surgical sterilization (ie, vasectomy, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) agreed to remain sexually abstinent or use two effective methods of contraception while sexually active from the day of conditioning administration until 52 weeks post-gene therapy infusion. Two methods of contraception were required even with documented medical assessment of surgical success of sterilization.

   1. For male subjects and for male spouses/partners of female subjects, condoms were an acceptable method of barrier contraception
   2. For female subjects and for female spouses/partners of male subjects, acceptable methods of barrier contraception included diaphragm, cervical cap, or contraceptive sponge.

6. Male and female subjects agreed to refrain from donating sperm and eggs, respectively, after undergoing conditioning.

7. Subject was willing to refrain from donating blood, organs, tissues, or cells for gene therapy infusion any time after AVR-RD-02 treatment.

8. Subject was willing and able to provide written informed consent for the study in accordance with applicable regulations and guidelines and to comply with all study visits and procedures, including the use of any data collection device(s) that may be used to directly record subject data.

9. Subject was willing to receive blood or blood products transfusion to manage adverse events (AEs).

   Additional Inclusion Criteria for Switch-stable Subjects (in addition to criteria 1-9 above):

10. Subject had undergone a stable dose (within 75% to125% of the prescribed dose) of ERT ≥ 15 U/kg and ≤ 60 U/kg every other week (or equivalent) for ≥ 24 consecutive months with no significant interruptions, in dosing over the last 6 months, in the opinion of the Investigator, prior to Screening

11. Subject had normal or near-normal hematologic values at Screening defined as one or more of the following:

    1. Hemoglobin concentration ≥10 g/dL
    2. Platelet count ≥80 x 10^9/L

12. Subject had stable Gaucher disease during the 6 months immediately preceding Screening defined by:

    1. Stable hemoglobin concentration (i.e., within a range of ±2 g/dL of the Screening value) based on documented historical clinical laboratory results and
    2. Stable platelet count (within ±20% of the Screening value) based on documented historical clinical laboratory results

13. Subject had not received SRT for Gaucher disease within 12 months of Screening

    Additional Inclusion Criteria for Treatment-naïve Subjects (in addition to inclusion criteria 1 through 9, above, treatment-naïve subjects must meet the following inclusion criteria for participation in this study):

14. Subject had neither received ERT nor SRT for Gaucher disease nor has received neither ERT nor SRT for Gaucher disease within 12 months of Screening.

15. Subject had a hemoglobin level ≤2 g/dL below the lower limit of normal (LLN) for age and sex at Screening and at least one of the following at Screening:

    1. Platelet count <120 x 10^9/L
    2. Enlarged liver by palpation, confirmed on abdominal MRI
    3. Moderate splenomegaly by palpation, confirmed on abdominal MRI

16. For any subject who was treatment-naïve, ERT peri-procedurally (from the Screening Period throughout 2 weeks prior to Gene Therapy Infusion) was considered in consultation with the PI and Sponsor Medical Monitor.

EXCLUSION CRITERIA:

1. Subject had Type 2 or 3 Gaucher disease, had severe neurological signs and symptoms, defined as complete ocular paralysis, overt myoclonus or history of seizures, characteristic of neuronopathic Gaucher disease, or had a tremor, peripheral neuropathy or symptoms of Parkinson's disease.

Subject had any one of the following:

1. Hemoglobin value <9.0 g/dL, or

2. Platelet count <70 x 10˄9/L, or

3. Spleen volume >10 x normal, or

4. Pulmonary hypertension 3. Subject had experienced a prior anaphylactic or anaphylactoid reaction (of any severity) to ERT.

   4. Treatment-naïve subject had history of clinically significant (CS) anti-GCase antibodies.

   5. Subject had a contraindication to ERT, in the opinion of the Investigator. 6. Subject had a contraindication to HSC transplantation (HSCT), in the opinion of the Investigator.

   7. Subject presented with iron, folic acid, and/or vitamin B12 deficiency sustained anemia during Screening.

   8. Subject had idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), thrombocytopenia, anemia, hepatomegaly, splenomegaly, and/or osteoporosis, unrelated to Gaucher disease, in the opinion of the Investigator.

   9. Subject had a clinical co-morbidity such as neurologic, cardiovascular, pulmonary, hepatic, gastrointestinal, renal, hematologic, endocrine, metabolic, genetic, immunologic, neoplastic, or psychiatric disease, other medical condition(s), or intercurrent illnesses that may have confounded the study results or, in the opinion of the Investigator, may have precluded participation in the study.

   10. Subject was a pregnant and/or lactating female. 11. Subject was unable to understand the nature, scope, and possible consequences of the study.

   12. Subject had diabetes mellitus (Type 1 or Type 2). 13. Subject had active, progressive bone necrosis. 14. Subject had an active chronic infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study.

   15. Subject had an active uncontrolled acute bacterial, viral, fungal, parasitic, or prion-associated infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study.

   16. Subject had a history of (or current) tuberculosis. 17. Subject tested positive for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV, Type 1 or 2), human T-cell lymphotropic virus (HTLV)-1, HTLV-2, and/or syphilis on Venereal Disease Research Laboratory (VDRL) test, chemiluminescent microplate immunoassay (CMIA), or enzyme immunosorbent assay (EIA) at Screening.

   18. Subject had a prior history of (or current) cancer or precancerous lesion or has a known genetic predisposition to cancer. The one exception was a prior history of resected squamous cell carcinoma.

   19. Subject had any other medical condition that predisposes him/her to (or conveys increased risk of) malignancy, in the opinion of the Investigator - including history of (or current) monoclonal gammopathy of undetermined significance (MGUS).

   20. Subject had a history of alcohol or illicit drug abuse, according to the Investigator's judgment.

   21. Subject had undergone, or was scheduled to undergo, bone marrow transplant, HSC transplant, and/or solid organ transplant. NOTE: Subjects who were otherwise eligible for the study but were scheduled for bone marrow or HSC transplant to treat Type 1 Gaucher disease may have been enrolled in the study (instead of receiving an allogeneic transplant) and undergo gene therapy infusion with AVR-RD-02.

   22. Subject had white blood cell count (WBC) < 3.0 x 10˄9/L and/or uncorrected bleeding disorder from enrollment (i.e., signing of informed consent at Screening) through the Gene Therapy Infusion Period of the study (i.e., the day of AVR-RD-02 gene therapy infusion).

   23. Subject had clinically significant immunosuppressive disease or condition, in the opinion of the Investigator, at Screening.

   24. Subject was on (or requires treatment with) cytotoxic or immunosuppressive agents from 60 days prior to signing informed consent at Screening (i.e., study enrollment) through the Week 52 study visit; the one exception was treatment with cytotoxic or immunosuppressive agents required per protocol for stem cell transplant.

   25. Subject was on (or requires treatment with) red blood cell (RBC) growth factor (e.g., erythropoietin) from 6 months prior to enrollment (i.e., signing of informed consent at Screening) through the Week 52 study visit.

   26. Subject had any condition that made it impossible to perform MRI studies. 27. Subject had medical condition(s) and/or was receiving medication(s) that would contraindicate ability to undergo mobilization (including contraindication to granulocyte colony-stimulating factor (G-CSF) and/or plerixafor), apheresis, or conditioning.

   28. Busulfan was contraindicated for the subject. 29. Subject had previously received treatment with AVR-RD-02 or any other gene therapy.

   30. Subject was participating in (or plans to participate in) any other investigational drug trial or plans to be exposed to any other investigational agent, device and/or procedure, from 30 days prior to enrollment (i.e., signing of informed consent at Screening) through study completion.