anti-MAG neuropathy auto-immune
Conditions
Interventions
Subjects in the first phase, SAD, who comply with all the inclusion criteria
and do not meet any of the exclusion criteria will be assigned to a single dose
escalation study.
SAD phase: Single IV i
Sponsors
Polyneuron Pharmaceuticals AG
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: - Written informed consent. - Age between 18 and 80 years, male and female. - Patient with a confirmed diagnosis of monoclonal IgM associated with monoclonal gammopathy of undetermined significance (MGUS) with anti-MAG activity (titer of > 10*000 Bühlmann Titer units [BTU]) and demyelinating neuropathy defined by electrophysiological criteria according to European Federation of Neurological Societies/Peripheral Nervous System paraproteinemic demyelinating neuropathy (EFNS/PNS PDN) guideline, 2010. - Clear clinical signs of disability: with at least ONLS * 2 in lower extremities. - Inflammatory Neuropathy Cause and Treatment sensory sum score (ISS) * 2. - Patients must have adequate hepatic function as evidenced by total bilirubin
Exclusion criteria
Exclusion criteria: - Patients with total serum IgM levels >30 g. - Hematological malignancy (e.g. known multiple myeloma or confirmed Waldenström's macroglobulinemia based on bone marrow analysis). - Patients with any history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. - Previous immunosuppressive treatment with intravenous immunoglobulin (IVIG) or apheresis/plasmapheresis in the preceeding 3 months, and/or cyclophosphamide and biologicals (e.g. rituximab): in the preceeding 6 months prior to enrolment. - Other neurological, neuromuscular, rheumatologic or orthopedic conditions with significant impact on the capability of walking preventing evaluation of neurological scores. - Anti-MAG neuropathy patients with persistent clinically significant laboratory abnormalities not related to the anti-MAG neuropathy, such as significant renal dysfunction, hepatic dysfunction, cardiac disease or other significant neurological disorder. - Anti-MAG neuropathy patients with a modified Rankin Scale (mRS) score > 4. - Participation in another interventional clinical trial. - Any other significant finding that would increase, according to the Investigator, the risk of having an adverse outcome from participating in the study. - Any other medical condition, including mental illness or substance abuse deemed by the investigator(s) to likely interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results. - Patients who have undergone major surgery * 2 weeks prior to starting study drug or who have not recovered from the side-effects of surgery. - A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening: PR > 200 msec.; QRS complex > 120 msec.; QTcF > 450 msec (males); QTcF > 460 msec (females); History of familial long QT syndrome or known family history of Torsades de Pointes; Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study. - Sexually active males must use a condom during intercourse after the start of the IMP administration and for at least one week after stopping study medication and should not father a child in this period after completion of the study medication (SAD and MAD phases). A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. In addition, male participants should not donate sperm for the time period specified above. - Use of other investigational drugs at the time of enrolment, or within 5 half-lives of enrolment, or within 30 days, whichever is longer; or longer if required by local regulations. - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after discontinuation of the investigational drug.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety endpoints: - Frequency, duration, severity and outcome of AEs, treatment emergent AEs (TEAEs), and Serious AEs (SAEs) from time of informed consent signature to the EOS visit including follow-up as required. - Any concomitant medications and relevant non-drug therapies. - Signs and symptoms of infusion-related reactions on infusion days continuously during the infusion of the study drug until 1 hour after the end of infusion, and at 8 and 24 hours (Day 2) after the start of administration. - Physical examination from screening, baseline, on infusion day (before dosing with the IMP), and 8 during SAD and EOS visit and during MAD during each visit until the EOS visit. - Vital signs with the 12-lead ECG at screening, on infusion days predose, during the infusion of the IMP at 60 min (120 min for optional 3200 mg dose) and then at 2 hours and 8 hours after start of infusion during SAD and EOS visit. During the MAD, vital signs with the 12-lead ECG at each day of visit until the EOS. - 1-lead ECG on infusion days continuously during the infusion of the IMP until 2 hours after start of infusion for both the SAD and MAD. - Safety hematology, clinical chemistry and urinalysis at screening, baseline, on Day 8, and EOS during the SAD and on Day 8, 28, 42, 98 and EOS during the MAD. - Blood sampling for anti-drug-antibodies (ADA) (immunogenicity) at screening and predosing, then Day 28 (EOS) in the SAD and Days 42 and EOS in the MAD. Pharmacokinetic endpoints: PPSGG*s PK will be determined in serum in the SAD phase on infusion Day 1 (30 min, 60 min, 2h, 6h, and 8h after start of administration), and on Day 2, 4, 8, 14 and 28 of the SAD phase. The sampling for the potential 3200 mg dose would be at 30 min, 60 min, 2h, 3h, 6h, 8h and 10h after start of infusion. In the MAD phase on each of Days 1, 3, 5, and 42 at predose, at 30 min, 60 min, at 2h, 6h, and 8h after start of infusion. An additional PK sample will be taken on Day 150 (EOS). The | — |
Secondary
| Measure | Time frame |
|---|---|
| Endpoints for the MAD phase only - Neurofilament light chain (NfL) to measure the degree of axonal damage. - B-cell activating factor (BAFF). - Indirect immunofluorescence on sciatic nerves. - Motor Unit Number Index (MUNIX) in selected sites. | — |
Countries
Netherlands
Outcome results
None listed