Progressive multiple sclerosis (PPMS + SPMS)
Primary progressive (PPMS) and non-active secondary progressive (SPMS) multiple sclerosis — the smoldering inflammation + chronic neurodegeneration phenotype that defines disability accrual in MS. Ocrelizumab (Ocrevus FDA 2017 PPMS via ORATORIO) and siponimod (Mayzent FDA 2019 active SPMS via EXPAND) anchor the DMT landscape; tolebrutinib's HERCULES 2024 positive Phase 3 readout in non-relapsing SPMS marks the field's first paradigm shift for the historically under-treated non-active SPMS population. Evobrutinib + fenebrutinib + remibrutinib BTK pipeline and frexalimab anti-CD40L Phase 2/3 follow. Symptomatic ladder: dalfampridine for walking, baclofen + tizanidine for spasticity, gabapentin for neuropathic pain, modafinil/armodafinil off-label for fatigue. AHSCT remains experimental and is limited mainly to highly active relapsing disease. AAN 2018 + ECTRIMS-EAN 2018 + AAN 2024 guidelines + NMSS anchor management. No peptide in the Juno library has a defensible discovery-card case here — Cerebrolysin and Semax are source-jurisdiction-registered for stroke / dementia / TBI (Russia + EU member states), not MS; Selank is anxiolytic and doesn't touch disease; NMN's NAD+ biology is mechanistically adjacent but not trial-supported in human progressive MS; LL-37 carries the autoimmune-contraindication thread from psoriasis and lupus literature and should not be approached in a CNS autoimmune disease without specialist input. Twenty-third deliberate non-elevation.
What changes during this transition
Progressive MS is defined by the absence of relapses in PPMS or the loss of relapse-driven activity in non-active SPMS — disability accrues from smoldering CNS inflammation in chronic-active (slowly-expanding) lesions plus axonal injury and chronic neurodegeneration in already-demyelinated areas. The drugs that work in relapsing-remitting MS (interferons, glatiramer, fingolimod, natalizumab, anti-CD20 broadly) work because they target peripheral immune trafficking into the CNS; progressive MS adds a CNS-compartmentalized inflammation problem that those agents only partially address. Ocrelizumab's PPMS approval (2017 via ORATORIO) and siponimod's active SPMS approval (2019 via EXPAND) were the first DMTs with progression-slowing endpoints in progressive disease, and the BTK inhibitor class — tolebrutinib's HERCULES 2024 positive Phase 3 readout in non-relapsing SPMS being the first positive Phase 3 in that population — is where the field is actively moving. Frexalimab anti-CD40L is in Phase 2/3. The Juno library's relationship with this axis is deliberate non-elevation. No peptide has controlled human progressive-MS data. Cerebrolysin and Semax are the source-jurisdiction-register cases — both have a real clinical anchor in their registered indications (Cerebrolysin for stroke / dementia / TBI in Russia + EU member states like Austria and Germany; Semax for stroke + cognitive disorders in Russia) — but registration in those indications does not propagate to progressive MS per Rule 6, and there are no controlled MS trials in any jurisdiction. Selank's anxiolytic case is real in source-jurisdiction context but doesn't address the disease. NMN's NAD+ biology has plausible mitochondrial adjacency to progressive MS axonal injury, but the human trial gap is total. LL-37 carries the autoimmune-contraindication thread strongly — the psoriasis (self-antigen) and lupus (interferon-driven autoimmunity) mechanistic literature establishes LL-37 as an autoimmune driver, and CNS autoimmune demyelinating disease is exactly the wrong context for an immunostimulatory antimicrobial peptide. Monitoring panel for progressive MS is standard: EDSS (Expanded Disability Status Scale), T25FW (timed 25-foot walk), 9-HPT (nine-hole peg test) for upper-limb function, SDMT (symbol digit modalities test) for processing speed, and annual MRI with and without contrast on a schedule that matches your DMT's safety panel. On ocrelizumab: IgG, IgM, lymphocyte subsets, hepatitis B screening at baseline. On siponimod: baseline cardiac evaluation, liver function, ophthalmology for macular edema, varicella titers, CYP2C9 genotyping. Vitamin D (target 30-50 ng/mL in most MS clinician practice), B12 with MMA + homocysteine if borderline, and TSH belong in the baseline panel regardless. Moscow / Mexico / Caribbean / Central American 'stem cell' clinics marketing mesenchymal infusions or intrathecal injections for progressive MS are not evidence-based and should be flagged honestly to users who encounter them; the AAN 2018 / ECTRIMS-EAN 2018 / AAN 2024 guidelines and NMSS patient resources are the credible reference points.
Important caveat
Progressive MS is neurology-managed disease — your MS neurologist anchors the DMT decision (ocrelizumab for PPMS via ORATORIO 2017; siponimod for active SPMS via EXPAND 2019; tolebrutinib post-HERCULES 2024 for non-relapsing SPMS pending regulatory; evobrutinib + fenebrutinib + remibrutinib + frexalimab pipeline), the symptomatic-management ladder (dalfampridine + baclofen + tizanidine + gabapentin + modafinil), and the standard progression panel (EDSS + T25FW + 9-HPT + SDMT + annual MRI). No peptide in the Juno library has controlled human progressive-MS data. Cerebrolysin (Russia + EU member states registered for stroke / dementia / TBI) and Semax (Russia registered for stroke + cognitive disorders) do NOT propagate to progressive MS per Rule 6. Selank's anxiolytic register is real in source-jurisdiction context but doesn't touch the disease — anxiety + mood symptoms in progressive MS need a real differential (depression, sleep apnea, hypothyroidism, B12 deficiency, pain-driven anxiety, steroid effects if on pulse therapy) before any peptide overlay. NMN's NAD+ biology is theoretically interesting but has zero controlled human MS trial data. LL-37 is contraindicated-framing — the psoriasis + lupus mechanistic literature establishes LL-37 as an autoimmune driver, and CNS autoimmune demyelinating disease is the wrong context. AHSCT remains experimental and is limited mainly to highly active relapsing disease, not progressive disease. Moscow / Mexico / Caribbean / Central American 'stem cell' clinics marketing mesenchymal infusions or intrathecal injections for progressive MS are not evidence-based — flag these honestly. The credible reference points are the AAN 2018 + ECTRIMS-EAN 2018 + AAN 2024 guidelines and NMSS patient resources. WADA athletes: BPC-157 (S0) and TB-500 (S2) prohibited at all times — neither has a progressive-MS use case anyway. Pregnancy: progressive MS pregnancies are typically managed by an MS neurologist + maternal-fetal medicine collaboration; ocrelizumab is held pre-conception per current guidance (B-cell repletion timing), siponimod is contraindicated in pregnancy, fingolimod is contraindicated, and DMT decisions during pregnancy require neurology-led, pregnancy-specific planning.
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