RARE DISEASE
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Synonyms: PML, Progressive multifocal leukoencephalitis
Synonyms: PML, Progressive multifocal leukoencephalitis
Synonyms: PML, Progressive multifocal leukoencephalitis
Drug discovery
6
drugs
With orphan designations
Overview
Progressive multifocal leukoencephalopathy (PML) is a rare, lethal demyelinating CNS infection caused by JC virus reactivation in immunocompromised individuals. It manifests with progressive neurological deficits (e.g., motor impairment, cognitive decline, vision/speech changes) and is diagnosed via MRI white matter lesions and CSF JC virus PCR [1][5][11]. Prognosis remains poor despite immune restoration therapies [1][7].
Therapies
Immune reconstitution: ART for HIV-PML [10], immunosuppressant withdrawal +/- plasma exchange (e.g., natalizumab-associated PML) [3][6].
Experimental agents: PD-1 inhibitors (pembrolizumab), JCV-specific T-cell therapy, and IL-7 immunotherapy under investigation [13][18].
Supportive care: Corticosteroids for immune reconstitution inflammatory syndrome (IRIS) [6][8].
Categories: rare infectious diseases, rare neurological diseases
Research Papers
787 drug discovery papers about Progressive multifocal leukoencephalopathy, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
787 drug discovery papers about Progressive multifocal leukoencephalopathy, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Guideline of the German Society of Neurology (DGN): "diagnosis and therapy of HIV-1-associated neurological disorders".
Epidemiology and treatment of HIV changed substantially within the last three decades. However, HIV-associated neurological disorders such as mild forms of HIV-associated neurocognitive disorder (HAND) as well as HIV-associated distal symmetrical sensory polyneuropathy are amongst the most frequent complications in patients with longstanding HIV infection. Opportunistic infections occur less frequently compared to former years, but especially in patients with late presentation of HIV progressive multifocal leukoencephalopathy (PML) (0.7 per 1,000 patient-years), toxoplasma encephalitis (0.4 per 1,000 patient-years) and cryptococcal meningitis (0.2 per 1,000 patient-years) remain the most common opportunistic infections. The guidelines for diagnosis and treatment of HIV-associated neurological disorders of the German Society of Neurology were revised addressing recent changes in treatment opportunities of HAND, HIV associated complications of the peripheral nervous system and muscles and opportunistic infections of the central nervous system (CNS).
2026-08-07 | Adoptive T-cell therapies in neuroinfectious and neuroinflammatory diseases.
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
2026-07-06 | Treatment of Progressive Multifocal Leukoencephalopathy with Third-Party Allogeneic BK Virus T Cells.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC polyomavirus (JCV) that affects immunosuppressed individuals and has no approved therapy. Here we evaluate the safety and efficacy of third-party, off-the-shelf, partially HLA-matched BK virus-specific T cells (BK-VST) in patients with PML. We conducted a single-center phase 2 study where 37 patients received most closely HLA-matched BK-VST at 2.0 x 105 T cells/kg, with additional infusions permitted for subjects who did not achieve a complete response. Twenty-three patients had an underlying diagnosis of hematologic malignancy. Each patient received a median of 2 doses (range, 1-12; IQR 2). Overall response (OR) was defined as virologic clearance with neurologic stabilization or improvement. During 12 months of follow-up, 21 patients (56.8%) achieved an OR, including 16 (43.2%) with a complete response. Responses were rapid (median 23 days) and durable, with no loss of response observed despite limited HLA matching. The 1-year overall survival was 61.1% (95% CI, 41.9-77.4). Patients achieving an OR after the first infusion had markedly improved 1-year survival compared with non-responders (93.3% vs 0%; p<0.001). Higher donor IL-2 and IFN-γ-producing T-cell frequencies and greater HLA matching correlated with clinical benefit. These data demonstrate that third-party BK-VST infusions are safe and potentially effective, supporting a scalable immunotherapeutic approach for this otherwise fatal disease. (ClinicalTrials.gov NCT02479698).
2026-07-03 | Efficacy and safety of extended-interval dosing of natalizumab in multiple sclerosis: a systematic review and meta-analysis with subgroup evaluation.
Natalizumab is effective for relapsing-remitting multiple sclerosis (RRMS) but increases the risk of progressive multifocal leukoencephalopathy (PML). Extended-interval dosing (EID) may lessen this risk by reducing drug exposure, though its efficacy and safety compared with standard-interval dosing (SID) remain unclear. This review and meta-analysis evaluates both regimens across clinical and MRI outcomes. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, Cochrane Library, and ScienceDirect from inception to July 2025. Eligible studies compared extended- (5-12 weeks) and standard-interval (4 weeks) natalizumab dosing in MS. Meta-analyses used random- or fixed-effects models with results as RR or MD based on heterogeneity (I²). Twenty-five studies were included. Analysis showed no significant differences between EID and SID in disability progression (MD -0.09, 95% CI: -0.46 to 0.29), or the risk of new T2 lesions (RR 1.24, 95% CI: 0.96 to 1.61). For PML incidence (RR 1.03, 95% CI: 0.29-3.60), the analysis was severely underpowered due to rare events; the wide confidence interval precludes any firm conclusion about comparative safety. However, EID was associated with a significantly higher risk of gadolinium-enhancing lesions (RR 1.35, 95% CI: 1.03-1.77). EID was associated with a borderline reduction in the risk of clinical relapse (RR 0.91, 95% CI: 0.83 to 1.00), but this finding is likely influenced by selection bias and should be considered hypothesis-generating rather than confirmatory. Subgroup analysis suggested a possible difference between intervals (P = 0.0323 for T2 lesions), but this finding is based on very sparse data, with only one subgroup (Q5-8 W) containing multiple studies and all other subgroups relying on single studies. Therefore, no definitive conclusion about optimal interval length can be drawn; the result is hypothesis-generating only. Extended-interval dosing of natalizumab shows efficacy and safety comparable to standard dosing. Although relapse reduction was noted, this may reflect selection bias. Shorter EID intervals (5-8 weeks) appear to maintain better radiologic control, supporting EID up to 6-8 weeks as a viable option pending long-term and biomarker-guided validation.
2026-06-25 | Progressive Multifocal Leukoencephalopathy or Lymphoma? A Massive Unilateral Hemispheric Mimicker in a Patient Undergoing Lymphoma Treatment.
An 81-year-old woman with follicular lymphoma treated with obinutuzumab and bendamustine developed cognitive impairment and dysarthria. Three months before death, neurological exams showed dysarthria, right hemiparesis, and gait disturbance. Blood tests showed lymphocytopenia (lymphocyte 10.4%). Cerebrospinal fluid (CSF) findings were unremarkable, including with respect to cytology. Brain MRI demonstrated a mass-like hyperintense lesion in the left parietal lobe and band-like abnormalities in the left fronto-temporal white matter that lacked contrast enhancement. Symptoms progressed to hemiplegia and mutism; severe dysphagia eventually necessitated intravenous fluid management. Follow-up MRI one month before death revealed a lesion encompassing nearly the entire left hemisphere, with hyperperfusion observed during arterial spin labeling (ASL). JC virus was detected in CSF (221 copy/mL), confirming that the patient had progressive multifocal leukoencephalopathy (PML). Subsequently, she exhibited poor arousal, followed by death. Here, lymphoma recurrence or PML was suspected due to a post-chemotherapy unilateral expanding brain lesion. These conditions are usually differentiated by contrast-enhancement patterns, but PML can also enhance during immune reconstitution. Moreover, lesions rarely cause a mass effect and more often exhibit hyperperfusion, which may aid in diagnosis. While unilateral PML has been reported, especially in the early stage, such an extensive lesion involving nearly an entire single hemisphere, as seen in our case, is rare.
2026-08-14 | Guideline of the German Society of Neurology (DGN): "diagnosis and therapy of HIV-1-associated neurological disorders".
Epidemiology and treatment of HIV changed substantially within the last three decades. However, HIV-associated neurological disorders such as mild forms of HIV-associated neurocognitive disorder (HAND) as well as HIV-associated distal symmetrical sensory polyneuropathy are amongst the most frequent complications in patients with longstanding HIV infection. Opportunistic infections occur less frequently compared to former years, but especially in patients with late presentation of HIV progressive multifocal leukoencephalopathy (PML) (0.7 per 1,000 patient-years), toxoplasma encephalitis (0.4 per 1,000 patient-years) and cryptococcal meningitis (0.2 per 1,000 patient-years) remain the most common opportunistic infections. The guidelines for diagnosis and treatment of HIV-associated neurological disorders of the German Society of Neurology were revised addressing recent changes in treatment opportunities of HAND, HIV associated complications of the peripheral nervous system and muscles and opportunistic infections of the central nervous system (CNS).
2026-08-07 | Adoptive T-cell therapies in neuroinfectious and neuroinflammatory diseases.
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
2026-07-06 | Treatment of Progressive Multifocal Leukoencephalopathy with Third-Party Allogeneic BK Virus T Cells.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC polyomavirus (JCV) that affects immunosuppressed individuals and has no approved therapy. Here we evaluate the safety and efficacy of third-party, off-the-shelf, partially HLA-matched BK virus-specific T cells (BK-VST) in patients with PML. We conducted a single-center phase 2 study where 37 patients received most closely HLA-matched BK-VST at 2.0 x 105 T cells/kg, with additional infusions permitted for subjects who did not achieve a complete response. Twenty-three patients had an underlying diagnosis of hematologic malignancy. Each patient received a median of 2 doses (range, 1-12; IQR 2). Overall response (OR) was defined as virologic clearance with neurologic stabilization or improvement. During 12 months of follow-up, 21 patients (56.8%) achieved an OR, including 16 (43.2%) with a complete response. Responses were rapid (median 23 days) and durable, with no loss of response observed despite limited HLA matching. The 1-year overall survival was 61.1% (95% CI, 41.9-77.4). Patients achieving an OR after the first infusion had markedly improved 1-year survival compared with non-responders (93.3% vs 0%; p<0.001). Higher donor IL-2 and IFN-γ-producing T-cell frequencies and greater HLA matching correlated with clinical benefit. These data demonstrate that third-party BK-VST infusions are safe and potentially effective, supporting a scalable immunotherapeutic approach for this otherwise fatal disease. (ClinicalTrials.gov NCT02479698).
2026-07-03 | Efficacy and safety of extended-interval dosing of natalizumab in multiple sclerosis: a systematic review and meta-analysis with subgroup evaluation.
Natalizumab is effective for relapsing-remitting multiple sclerosis (RRMS) but increases the risk of progressive multifocal leukoencephalopathy (PML). Extended-interval dosing (EID) may lessen this risk by reducing drug exposure, though its efficacy and safety compared with standard-interval dosing (SID) remain unclear. This review and meta-analysis evaluates both regimens across clinical and MRI outcomes. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, Cochrane Library, and ScienceDirect from inception to July 2025. Eligible studies compared extended- (5-12 weeks) and standard-interval (4 weeks) natalizumab dosing in MS. Meta-analyses used random- or fixed-effects models with results as RR or MD based on heterogeneity (I²). Twenty-five studies were included. Analysis showed no significant differences between EID and SID in disability progression (MD -0.09, 95% CI: -0.46 to 0.29), or the risk of new T2 lesions (RR 1.24, 95% CI: 0.96 to 1.61). For PML incidence (RR 1.03, 95% CI: 0.29-3.60), the analysis was severely underpowered due to rare events; the wide confidence interval precludes any firm conclusion about comparative safety. However, EID was associated with a significantly higher risk of gadolinium-enhancing lesions (RR 1.35, 95% CI: 1.03-1.77). EID was associated with a borderline reduction in the risk of clinical relapse (RR 0.91, 95% CI: 0.83 to 1.00), but this finding is likely influenced by selection bias and should be considered hypothesis-generating rather than confirmatory. Subgroup analysis suggested a possible difference between intervals (P = 0.0323 for T2 lesions), but this finding is based on very sparse data, with only one subgroup (Q5-8 W) containing multiple studies and all other subgroups relying on single studies. Therefore, no definitive conclusion about optimal interval length can be drawn; the result is hypothesis-generating only. Extended-interval dosing of natalizumab shows efficacy and safety comparable to standard dosing. Although relapse reduction was noted, this may reflect selection bias. Shorter EID intervals (5-8 weeks) appear to maintain better radiologic control, supporting EID up to 6-8 weeks as a viable option pending long-term and biomarker-guided validation.
2026-06-25 | Progressive Multifocal Leukoencephalopathy or Lymphoma? A Massive Unilateral Hemispheric Mimicker in a Patient Undergoing Lymphoma Treatment.
An 81-year-old woman with follicular lymphoma treated with obinutuzumab and bendamustine developed cognitive impairment and dysarthria. Three months before death, neurological exams showed dysarthria, right hemiparesis, and gait disturbance. Blood tests showed lymphocytopenia (lymphocyte 10.4%). Cerebrospinal fluid (CSF) findings were unremarkable, including with respect to cytology. Brain MRI demonstrated a mass-like hyperintense lesion in the left parietal lobe and band-like abnormalities in the left fronto-temporal white matter that lacked contrast enhancement. Symptoms progressed to hemiplegia and mutism; severe dysphagia eventually necessitated intravenous fluid management. Follow-up MRI one month before death revealed a lesion encompassing nearly the entire left hemisphere, with hyperperfusion observed during arterial spin labeling (ASL). JC virus was detected in CSF (221 copy/mL), confirming that the patient had progressive multifocal leukoencephalopathy (PML). Subsequently, she exhibited poor arousal, followed by death. Here, lymphoma recurrence or PML was suspected due to a post-chemotherapy unilateral expanding brain lesion. These conditions are usually differentiated by contrast-enhancement patterns, but PML can also enhance during immune reconstitution. Moreover, lesions rarely cause a mass effect and more often exhibit hyperperfusion, which may aid in diagnosis. While unilateral PML has been reported, especially in the early stage, such an extensive lesion involving nearly an entire single hemisphere, as seen in our case, is rare.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for Progressive multifocal leukoencephalopathy.
6 orphan drug designations for Progressive multifocal leukoencephalopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Human IgG1 monoclonal antibody against JC polyomavirus, major capsid protein VP1 | antibodies | EMA | 2026-06-19 | — | Pomona Ricerca S.r.l. |
Allogeneic JC polyomavirus-specific T-cell therapy | cell therapies | FDA | 2022-10-19 | — | Cellevolve Bio Inc. |
Recombinant human interleukin-7 fused to a hybrid crystallizable fragment region of a human antibody (rhIL-7-hyFc). | proteins | FDA | 2020-06-11 | — | NeoImmuneTech, Inc. |
imatinib mesylate | small molecules | FDA | 2014-05-06 | — | Inhibikase Therapeutics, Inc. |
glycosylated recombinant human interleukin-7 | proteins | FDA | 2012-09-27 | — | Cytheris, Inc. |
Recombinant human interleukin-7 | proteins | EMA | 2012-07-04 | — | Inserm-ANRS (Agence Nationale de Recherches sur le Sida et les Hépatites Virales) |
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