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
784 drug discovery papers related to Progressive multifocal leukoencephalopathy, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
784 drug discovery papers related to Progressive multifocal leukoencephalopathy, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-06 | Structural characterization of human neutralizing antibodies against JC and BK polyomaviruses.
The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals. JCPyV frequently undergoes mutations in PML patients, and these variants are thought to establish "antibody recognition holes" that enable the virus to circumvent the antibody response of infected individuals. Many of these PML-associated mutations cluster in the glycan receptor-binding site of the virus. Using X-ray crystallography, we investigated the binding modes of JCPyV VP1-specific human monoclonal antibodies (mAbs) that were isolated from healthy donors and individuals who recovered from PML, and that can recognize a panel of PML-associated JCPyV variants. Our structural analyses show that three out of four of these mAbs bind epitopes that overlap with the glycan-receptor binding site at the surface of the virus particle. The observed interactions explain how PML-associated mutations strategically interfere with antibody recognition, resulting in immune evasion. In contrast, mAb 29B1 engages a region of the capsid that is distant from the glycan site and does not feature mutations associated with PML. The binding site is conserved in the closely related BK polyomavirus (BKPyV), and we show that mAb 29B1 binds both viruses with high affinity and blocks infection. Our findings form an excellent platform for the development of therapeutic Ab approaches and potential vaccination strategies that could protect at-risk patients from infections with both JCPyV and BKPyV. Moreover, small molecules that target the mAb 29B1 binding site could be potentially effective against both viruses.
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.
2026-07-06 | Structural characterization of human neutralizing antibodies against JC and BK polyomaviruses.
The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals. JCPyV frequently undergoes mutations in PML patients, and these variants are thought to establish "antibody recognition holes" that enable the virus to circumvent the antibody response of infected individuals. Many of these PML-associated mutations cluster in the glycan receptor-binding site of the virus. Using X-ray crystallography, we investigated the binding modes of JCPyV VP1-specific human monoclonal antibodies (mAbs) that were isolated from healthy donors and individuals who recovered from PML, and that can recognize a panel of PML-associated JCPyV variants. Our structural analyses show that three out of four of these mAbs bind epitopes that overlap with the glycan-receptor binding site at the surface of the virus particle. The observed interactions explain how PML-associated mutations strategically interfere with antibody recognition, resulting in immune evasion. In contrast, mAb 29B1 engages a region of the capsid that is distant from the glycan site and does not feature mutations associated with PML. The binding site is conserved in the closely related BK polyomavirus (BKPyV), and we show that mAb 29B1 binds both viruses with high affinity and blocks infection. Our findings form an excellent platform for the development of therapeutic Ab approaches and potential vaccination strategies that could protect at-risk patients from infections with both JCPyV and BKPyV. Moreover, small molecules that target the mAb 29B1 binding site could be potentially effective against both viruses.
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 articles and probability of success in trials forecasts:
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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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