Primary progressive multiple sclerosis

Summary

Primary progressive multiple sclerosis (MONDO:0000451) is a disease with 1 cohort gene and 40 clinical trials. Top therapeutic interventions include ocrelizumab, fexofenadine, and idebenone.

At a glance

• Cohort genes: 1
• ClinVar variants: 2
• Clinical trials: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	primary progressive multiple sclerosis
Mondo ID	MONDO:0000451
EFO	EFO:0008520
DOID	DOID:0050784
ICD-11	1020720762
SNOMED CT	428700003
UMLS	C0751964
MedGen	155968
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › autoimmune disorder of central nervous system › multiple sclerosis › chronic progressive multiple sclerosis › primary progressive multiple sclerosis

Related subtypes (2): secondary progressive multiple sclerosis, progressive relapsing multiple sclerosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
206492	NM_002693.3(POLG):c.391T>C (p.Tyr131His)	POLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
405572	NM_002693.3(POLG):c.641C>T (p.Ala214Val)	POLG	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	1142.0×	9e-04	POLG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication proofreading	1	5617.3×	0.001	POLG
mitochondrial DNA replication	1	1532.0×	0.001	POLG
base-excision repair, gap-filling	1	1123.5×	0.001	POLG
DNA metabolic process	1	1053.2×	0.001	POLG
DNA-templated DNA replication	1	561.7×	0.002	POLG
base-excision repair	1	468.1×	0.002	POLG

Therapeutics

Drugs indicated for this disease

1 approved, 8 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ocrelizumab	Approved (phase 4)
Desloratadine	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Dimethyl Fumarate	Phase 3 (in late-stage trials)
Diphenhydramine	Phase 3 (in late-stage trials)
Fingolimod	Phase 3 (in late-stage trials)
Methylprednisolone	Phase 3 (in late-stage trials)
Natalizumab	Phase 3 (in late-stage trials)
Tolebrutinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Corticotropin, Estriol, Laquinimod, Lipoic Acid, Alpha, Norethindrone, Rituximab.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 40.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	12
PHASE2	7
PHASE1	7
PHASE1/PHASE2	6
PHASE3	5
PHASE4	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07483450	PHASE4	RECRUITING	A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Ocrelizumab in Participants With Relapsing Multiple Sclerosis and Primary Progressive Multiple Sclerosis
NCT02208050	PHASE4	COMPLETED	A Study of the Effectiveness of Fampridine in Improving Upper Limb Function in MS
NCT04688788	PHASE3	ACTIVE_NOT_RECRUITING	Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple Sclerosis
NCT00731692	PHASE3	TERMINATED	This Was an Open-label, Single-arm Extension Study (CFTY720D2306E1) to a Double-blind, Randomized Multicenter, Placebo-controlled, Parallel-group Core Study (CFTY720D2306) in PPMS.
NCT03691077	PHASE3	UNKNOWN	Effect of Ocrelizumab on Brain Innate Immune Microglial Cells Activation in MS Using PET-MRI With 18F-DPA714
NCT04458051	PHASE3	COMPLETED	Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS)
NCT05232825	PHASE3	COMPLETED	A Phase III, Non-Inferiority, Randomized, Open-Label, Parallel Group, Multicenter Study To Investigate The Pharmacokinetics, Pharmacodynamics, Safety And Radiological And Clinical Effects Of Subcutaneous Ocrelizumab Versus Intravenous Ocrelizumab In Patients With Multiple Sclerosis
NCT05893225	PHASE2	ACTIVE_NOT_RECRUITING	Metformin Add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination And Neurodegeneration
NCT07477639	PHASE1/PHASE2	RECRUITING	Treatment of Participants With Primary or Secondary Progressive Multiple Sclerosis
NCT00950248	PHASE1/PHASE2	COMPLETED	Clinical Trial of Idebenone in Primary Progressive Multiple Sclerosis (IPPoMS)
NCT01077466	PHASE2	COMPLETED	Natalizumab Treatment of Progressive Multiple Sclerosis
NCT01191996	PHASE1/PHASE2	COMPLETED	Safety Study of an Immunomodulating Microparticle to Treat Progressive Multiple Sclerosis
NCT01466114	PHASE2	UNKNOWN	Estriol Treatment in Multiple Sclerosis (MS): Effect on Cognition
NCT01854359	PHASE1/PHASE2	COMPLETED	Idebenone for Primary Progressive Multiple Sclerosis
NCT01950234	PHASE2	TERMINATED	ACTH in Progressive Forms of MS
NCT02273635	PHASE1/PHASE2	UNKNOWN	Efficacy, Safety and Tolerability of Andrographolides Versus Placebo in Patients With Progressive Forms of MS
NCT02284568	PHASE2	COMPLETED	A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo
NCT02959658	PHASE2	COMPLETED	Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis
NCT03283826	PHASE1/PHASE2	TERMINATED	Phase 1/2 Study to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis
NCT03362294	PHASE2	TERMINATED	Safety and Efficacy of Monthly Long-acting IM Injection of 25mg or 40 mg GA Depot in Subjects With PPMS
NCT03783416	PHASE1	RECRUITING	SIZOMUS Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis
NCT06900192	PHASE1	NOT_YET_RECRUITING	A Study of Allogeneic Hematopoietic Cell Transplantation for Primary Progressive Multiple Sclerosis
NCT02253264	PHASE1	COMPLETED	A Phase 1 Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients
NCT03493841	PHASE1	COMPLETED	Comparing Tolerability and Absorption of Racemic and R-lipoic Acid in Progressive Multiple Sclerosis
NCT04943289	PHASE1	COMPLETED	Intrathecal Administration of DUOC-01 in Adults With Primary Progressive Multiple Sclerosis
NCT05029609	PHASE1	WITHDRAWN	Phase 1b Multiple Ascending Dose Study of Foralumab in Primary and Secondary Progressive MS
NCT06677710	PHASE1	SUSPENDED	IDP-023 g-NK Cells Plus Ocrelizumab in Patients With Progressive Multiple Sclerosis
NCT05349474	EARLY_PHASE1	COMPLETED	Metformin Treatment in Progressive Multiple Sclerosis
NCT05177523	Not specified	RECRUITING	Imaging the Interplay Between Axonal Damage and Repair in Multiple Sclerosis
NCT07280871	Not specified	NOT_YET_RECRUITING	Clinnova-MS: A Prospective Cohort Study of Patients With Multiple Sclerosis: A Trans-regional Digital Health Effort Unlocking the Potential of Artificial Intelligence and Data Science in Health Care
NCT07426991	Not specified	RECRUITING	Cognitive Performance, Sleep Disturbances and Fatigue in Multiple Sclerosis
NCT01776060	Not specified	COMPLETED	Serial Collection of Primary Progressive Multiple Sclerosis Participants in the MURDOCK Study
NCT02016222	Not specified	COMPLETED	Tear Analysis in the Diagnosis of Multiple Sclerosis
NCT02549703	Not specified	COMPLETED	Mitochondrial Dysfunction and Disease Progression
NCT03094364	Not specified	COMPLETED	Video Game-based Therapy for Arm Weakness In Progressive Multiple Sclerosis
NCT03562975	Not specified	COMPLETED	Upper Extremity Function in Multiple Sclerosis Patients With Advanced Disability Treated With Ocrevus
NCT04977622	Not specified	UNKNOWN	Gray Matter Demyelination in Primary Progressive MS at 7T
NCT05229861	Not specified	UNKNOWN	The Influence of HIIT Versus MCT on Cardiorespiratory Fitness in PPMS
NCT05974839	Not specified	COMPLETED	Effect of Ocrelizumab on Cortical Lesion Accumulation in Patients With PPMS (ORATORIO-Cortical)
NCT05974852	Not specified	COMPLETED	Effect of Ocrelizumab on Choroid Plexus Changes in Patients With PPMS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OCRELIZUMAB	4	7
FEXOFENADINE	4	3
IDEBENONE	4	2
ACETAMINOPHEN	4	1
CORTICOTROPIN	4	1
DALFAMPRIDINE	4	1
DIMETHYL FUMARATE	4	1
ESTRIOL	4	1
FINGOLIMOD HYDROCHLORIDE	4	1
NATALIZUMAB	4	1
NORETHINDRONE	4	1
LAQUINIMOD	3	1
LIPOIC ACID, ALPHA	3	1
TOLEBRUTINIB	3	1
EVRULEUCEL	2	1
CHEMBL4082273	0	1
CHEMBL4579631	0	1