Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
Paroxysmal Nocturnal Hemoglobinuria (PNH), LFG316, LNP023
Brief summary
The purpose of this study was to determine whether LFG316 can induce a hematological response, as measured by reduction in hemolytic activity, in patients with paroxysmal nocturnal hemoglobinuria (PNH).
Detailed description
The study consisted of a 60-day screening period to assess eligibility and conduct vaccinations if required (for all patients not previously vaccinated at least 2 weeks prior to first dosing or if prior vaccination cannot be confirmed) and 4 treatment periods as follows. During the treatment period 1 (Days 1 to 29), all patients received infusions of LFG316 every 14 days. Following assessment of efficacy (hemolytic activity by serum LDH) at the end of treatment period 1, patients entered the optional 48-week treatment period 2 and continued LFG316 infusions every 14 days. At the end of treatment period 2, LFG316-responsive patients (assessed based on the investigator's judgment) were allowed to enter an additional extension period of up to 260 weeks (treatment period 3) in which they continued to receive LFG316 every 14 days. Period 4, which allowed patients to switch to LNP023, lasted approximately 21 weeks. During the first 4 weeks, patients continued to receive LFG316 in addition to oral administration of LNP023. After 4 weeks, patients discontinued LFG316 and continued with LNP023 monotherapy for approximately 16 weeks (+/- 28 days). Patients who participated in period 4 could join the long-term extension study CLNP023C12001B (NCT04747613) as soon as their eligibility was confirmed and study CLNP023C12001B was open to receive patients. There was no LNP023 treatment gap between the studies. As per strategic decision, further development of LFG316 was terminated in favor of LNP023, Novartis offered patients enrolled in study CLFG316X2201 a conversion from LFG316 to LNP023, aiming to provide uninterrupted treatment for these PNH patients. The CLFG316X2201 trial was not a terminated study.
Interventions
BIOLOGICALLFG316
LFG316 20 mg/kg was administered to all patients enrolled in the study: * Treatment Periods 1 to 3: LFG316 20 mg/kg as i.v. infusion every 2 weeks * Treatment Period 4: LFG316 20 mg/kg as i.v. infusion every 2 weeks for 4 weeks (total 2 infusions).
DRUGLNP023
Treatment Period 4: LNP023 200 mg b.i.d. for approximately 20 weeks. Four capsules (each 50 mg) were administered each time study medication was taken.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All patients were on active treatment. In treatment periods 1 to 3, patients received the following: • LFG316 20 mg/kg as i.v. infusion every 2 weeks Patients participating in treatment period 4 received the following: * LFG316 20 mg/kg as i.v. infusion every 2 weeks for 4 weeks (total 2 infusions) * LNP023 200 mg b.i.d. for approximately 20 weeks. Four capsules (each 50 mg) were administered each time study medication was taken. Down-titration was permitted only in case of LNP023 treatment discontinuation: * LNP023 30 mg taken in the evening (once daily) for 7 days (3 capsules of 10 mg each time study medication was taken). * Followed by LNP023 10 mg taken in the evening (once daily) for 7 days (1 capsule of 10 mg each time study medication was taken). * LFG316 was administered via i.v. infusion by the investigator or designated study staff over approximately 2 hours in Period 1 and between 40 minutes and 2 hours from Period 2 onwards.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent obtained before any assessment were performed. 2. Male and female patients \>= 18 years old with a diagnosis of PNH prior to screening. Based on local requirements (applicable in Czech Republic) only patients between the age of 18 to 65 (inclusive) with a diagnosis of PNH prior to screening were eligible for inclusion in this study. 3. A documented PNH clone size of \>= 10% by RBCs and/or granulocytes, measured by GPI deficiency on flow cytometry. 4. Serum LDH levels at least 1.5-fold above the ULN at screening. 5. Patients receiving treatment with corticosteroids and/or other immunosuppressive regimens could continue treatment throughout the study, if indicated for treatment of autoimmune disease (e.g., aplastic anemia). It was strongly recommended, at the investigator's discretion, that patients receive appropriate prophylactic antibiotics (e.g., ciprofloxacin, penicillin, erythromycin) while on treatment with any type of concomitant immunosuppressive agent other than LFG316 (including corticosteroids). 6. Negative pregnancy test for women of child-bearing potential at screening. 7. Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 at least 2 weeks prior to first dosing, and vaccination against meningitidis type B if available and acceptable by local regulations, at least 2 weeks prior to first dosing. 8. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Patients included in this study after protocol amendment 6 were also to fulfill the following: 9. To be carriers of the C5 gene minor variants as defined by nucleic acid changes that lead to amino acid exchanges in position p.Arg885. Additional inclusion criteria for period 4 10. Patients who participated in period 3 of the current study who wanted to join the long-term extension study with LNP023 (CLNP023C12001B). 11. Previous vaccination for the prevention of Streptococcus pneumoniae and Haemophilus influenzae at least 2 weeks prior to first dosing with LNP023 if locally available. If LNP023 treatment had to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment was required.
Exclusion criteria
1. Known or suspected hereditary complement deficiency. 2. History of hematopoietic stem cell transplantation. 3. Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days or 5-times the half-life prior to screening. Note: clinical trials solely involving over-the-counter vitamins, off label use of drugs within published standard of care guidelines, supplements, or diet did not exclude an otherwise eligible patient. 4. Female patients who were pregnant, breastfeeding, or intended to conceive during the course of the study. 5. History of recurrent meningitis, history of meningococcal meningitis despite vaccination. 6. Presence or suspicion (based on judgment of the investigator) of severe active bacterial infection within 2 weeks prior to first dose of LFG316, or severe recurrent bacterial infections. 7. A positive HIV test result. 8. Under active therapy with other agents interfering with the complement system (e.g., eculizumab) Wash-out time was at least 5 half-lives, approximately 8 weeks for eculizumab. 9. Severe concurrent co-morbidities, e.g., patients with severe kidney disease (dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), unstable thrombotic event not amenable to active treatment as judged by the investigator. 10. Either one of the following laboratory abnormalities at screening: * Neutrophils \< 0.5 × 10\^9/L * Platelets \< 30 × 10\^9/L 11. Co-morbidities that were likely caused by underlying autoimmune diseases other than PNH, e.g., kidney disease in the context of lupus nephritis, ANCA-associated vasculitis. 12. Any medical condition deemed likely to interfere with the patient's participation in the study, or likely to cause serious adverse events during the study. 13. History of hypersensitivity to a drug of the same class (human IgG1 monoclonal antibody) or any other excipient of the formulation. 14. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during dosing and for 50 days after the last dose of LFG316. 15. Prohibited medication as specified in the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Overall (Up to Week 4), Period 1 Day 8, Period 1 Day 15, Period 1 Day 22, Period 1 Day 29 | The primary efficacy variable for assessing the effect of LFG316 over the first 4 weeks of treatment was response rate where a patient was considered a responder if the percentage reduction from baseline in serum lactate dehydrogenase (LDH) was at least 60% at any time up to and including week 4 for that patient. |
| Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period | Baseline, Period 1 Day 29 (end of Treatment Period 1), Period 2 Day 365 (end of Treatment Period 2), Period 3 Day 1429 (end of Treatment Period 3), Period 4 Day 141 (end of Treatment Period 4) | Lactate dehydrogenase (LDH) levels were measured in serum samples and the percentage change from baseline was calculated. For serum LDH, baseline was the average of all pre-dose measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve (AUC) From Time Zero to the Last Measurable Serum Concentration Sampling Time (0-tlast) for LFG316 | Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1. | Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. AUC (0-tlast) was summarized using descriptive statistics. |
| Maximum Observed Serum Concentration (Cmax) for LFG316 | Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1. | Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. Cmax was summarized using descriptive statistics. |
| Time to Reach Maximum Serum Concentration (Tmax) for LFG316 | Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1. | Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. Tmax was summarized using descriptive statistics. Actual sampling times were used for the calculation of PK parameters. |
| LFG316 Serum Concentration | Period 1 Day 1 (predose (trough), post-dose), Period 2 Day 337 (predose), Period 3 Day 1289 (predose) | The concentration of total LFG316 in serum was determined using Liquid chromatography/mass spectroscopy (LC/MS assay) and summarized using descriptive statistics. |
Countries
Czechia, Japan, Lithuania
Participant flow
Recruitment details
10 participants were enrolled at 7 sites in 3 countries.
Pre-assignment details
The study had a 60-day screening period to assess eligibility.
Participants by arm
| Arm | Count |
|---|---|
| LFG316 Then LNP023 Treatment periods 1 to 3: LFG316 20 mg/kg intravenous (i.v.) infusion every 2 weeks.
Treatment period 4: LFG316 20 mg/kg intravenous (i.v.) infusion every 2 weeks (Week 1 to 4) + LNP023 200 mg twice per day (b.i.d.) for approximately 20 weeks (Weeks 1 to 20) | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Period 1 to 3 (up to Week 312) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | LFG316 Then LNP023 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 43.0 Years STANDARD_DEVIATION 11.68 |
| Race/Ethnicity, Customized Asian | 7 Participants |
| Race/Ethnicity, Customized Caucasian | 3 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 10 / 10 | 6 / 9 |
| serious Total, serious adverse events | 3 / 10 | 0 / 9 |
Outcome results
Primary
Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period
Lactate dehydrogenase (LDH) levels were measured in serum samples and the percentage change from baseline was calculated. For serum LDH, baseline was the average of all pre-dose measurements.
Time frame: Baseline, Period 1 Day 29 (end of Treatment Period 1), Period 2 Day 365 (end of Treatment Period 2), Period 3 Day 1429 (end of Treatment Period 3), Period 4 Day 141 (end of Treatment Period 4)
Population: Pharmacodynamic (PD) analysis set - Only participants with a value at both Baseline and post-baseline visit included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LFG316 Then LNP023 | Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period | Period 1 Day 29 | -78.35 % change from baseline in serum LDH | Standard Deviation 11.19 |
| LFG316 Then LNP023 | Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period | Period 2 Day 365 | -78.56 % change from baseline in serum LDH | Standard Deviation 11.55 |
| LFG316 Then LNP023 | Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period | Period 3 Day 1429 | -81.65 % change from baseline in serum LDH | Standard Deviation 8.138 |
| LFG316 Then LNP023 | Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period | Period 4 Day 141 | -78.69 % change from baseline in serum LDH | Standard Deviation 9.288 |
Comparison: Period 1 Day 29 serum LDH levelsp-value: <0.00195% CI: [0.15, 0.23]Mixed Models Analysis
Comparison: Period 2 Day 365 serum LDH levelsp-value: <0.00195% CI: [0.15, 0.23]Mixed Models Analysis
Comparison: Period 3 Day 1429 serum LDH levelsp-value: <0.00195% CI: [0.14, 0.2]Mixed Models Analysis
Comparison: Period 4 Day 141 serum LDH levelsp-value: <0.00195% CI: [0.15, 0.24]Mixed Models Analysis
Primary
Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate
The primary efficacy variable for assessing the effect of LFG316 over the first 4 weeks of treatment was response rate where a patient was considered a responder if the percentage reduction from baseline in serum lactate dehydrogenase (LDH) was at least 60% at any time up to and including week 4 for that patient.
Time frame: Overall (Up to Week 4), Period 1 Day 8, Period 1 Day 15, Period 1 Day 22, Period 1 Day 29
Population: The Pharmacodynamic (PD) analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Overall (Up to Week 4) | Responder | 10 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Overall (Up to Week 4) | Non Responder | 0 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 8 | Responder | 6 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 8 | Non Responder | 4 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 15 | Responder | 9 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 15 | Non Responder | 1 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 22 | Responder | 9 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 22 | Non Responder | 1 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 29 | Responder | 9 Participants |
| LFG316 Then LNP023 | Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate | Period 1 Day 29 | Non Responder | 1 Participants |
Comparison: Up to Week 495% CI: [81.9, 100]
Secondary
Area Under the Concentration-time Curve (AUC) From Time Zero to the Last Measurable Serum Concentration Sampling Time (0-tlast) for LFG316
Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. AUC (0-tlast) was summarized using descriptive statistics.
Time frame: Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.
Population: Pharmacokinetic (PK) analysis set included all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LFG316 Then LNP023 | Area Under the Concentration-time Curve (AUC) From Time Zero to the Last Measurable Serum Concentration Sampling Time (0-tlast) for LFG316 | 73700 hour*microgram/milliliter (h*µg/mL) | Standard Deviation 12600 |
Secondary
LFG316 Serum Concentration
The concentration of total LFG316 in serum was determined using Liquid chromatography/mass spectroscopy (LC/MS assay) and summarized using descriptive statistics.
Time frame: Period 1 Day 1 (predose (trough), post-dose), Period 2 Day 337 (predose), Period 3 Day 1289 (predose)
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LFG316 Then LNP023 | LFG316 Serum Concentration | Period 1 Day 1 (predose (trough)) | 182 nanograms per milliliter (μg/mL) | Standard Deviation 31.4 |
| LFG316 Then LNP023 | LFG316 Serum Concentration | Period 1 Day 1 (postdose) | 538 nanograms per milliliter (μg/mL) | Standard Deviation 80 |
| LFG316 Then LNP023 | LFG316 Serum Concentration | Period 2 Day 337 (predose) | 248 nanograms per milliliter (μg/mL) | Standard Deviation 55.9 |
| LFG316 Then LNP023 | LFG316 Serum Concentration | Period 3 Day 1289 (predose) | 313 nanograms per milliliter (μg/mL) | Standard Deviation 89.2 |
Secondary
Maximum Observed Serum Concentration (Cmax) for LFG316
Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. Cmax was summarized using descriptive statistics.
Time frame: Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.
Population: Pharmacokinetic (PK) analysis set included all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LFG316 Then LNP023 | Maximum Observed Serum Concentration (Cmax) for LFG316 | 407 nanograms per milliliter (μg/mL) | Standard Deviation 69.2 |
Secondary
Time to Reach Maximum Serum Concentration (Tmax) for LFG316
Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. Tmax was summarized using descriptive statistics. Actual sampling times were used for the calculation of PK parameters.
Time frame: Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LFG316 Then LNP023 | Time to Reach Maximum Serum Concentration (Tmax) for LFG316 | 2.56 hour (h) |