VOLUME 21, ISSUE 4, P342-354, APRIL 01, 2022
Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme
Prof Simon Mead, FRCP Azadeh Khalili-Shirazi, PhD Caroline Potter, PhD Tzehow Mok, MRCP Akin Nihat, MRCP Harpreet Hyare, FRCR et al.
Summary
Background
Human prion diseases, including Creutzfeldt–Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence.
Methods
We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80–120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls.
Findings
We treated six patients (two men; four women) with CJD for 7–260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22–70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66–182 nM).
Interpretation
Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure.
Funding
The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.
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Discussion
We report our experience of the first-in-human treatment of six patients with CJD with PRN100. We show that PRN100 was safe and able to access the brain (CSF data in four patients and autopsy data in one patient) in target concentrations after intravenous dosing. Limited brain autopsy evidence from two patients showed that PRN100 treatment did not induce neurotoxicity and suggests that PRN100 might help to clear disease-related PrP from the brain. At this stage, the number of treated patients is too small to determine whether PRN100 altered the course of the disease. Based on these safety data and demonstration of brain accessibility to PRN100 following intravenous administration, a larger study, ideally at the earliest possible intervention, is now warranted.
All prion diseases are relentlessly progressive, invariably fatal conditions. However, our understanding of their requirement for PrPC for pathogenesis and unequivocal preclinical validation10, 12, 13 of the effect of targeting PrPC provide a strong expectation that passive immunotherapy with anti-PrPC monoclonal antibodies should be an effective therapeutic strategy, assuming adequate concentrations reach brain tissue without dose-limiting toxicity and that treatment is initiated before major neuronal loss and irreversible secondary neurodegenerative processes are underway. Such a treatment strategy is expected to be particularly promising as secondary prophylaxis in asymptomatic individuals known to be infected with prions or harbouring a pathogenic PRNP mutation. By targeting the obligate substrate for prion propagation and neurotoxicity, rather than prions themselves, the treatment should also be effective against all prion strains and avoid the development of drug resistance by strain adaptation and selection.34
On this firm scientific foundation, we have treated six patients with CJD with PRN100 under a Specials Licence, proceeding with great caution and independent oversight. The nature of the recruitment process for this first-in-human treatment programme meant that most patients were rapidly progressing and at the mid-stages of the disease at onset of therapy. In addition, our cautious intravenous dose-escalation protocol meant that it took a mean of 47 days to reach the target CSF concentration of 50 nM and clinically significant further neurological decline occurred during this period (for context, in the NPMC study [544 individuals with sporadic CJD], median survival from enrolment was 25 days (Q1–Q3 10–97).27 Our interpretations are necessarily limited by the small number of patients who could be treated with our single available batch of drug product, their rapid clinical progression and well established neurodegeneration at the outset of treatment, and the fact that we evaluated an NHS treatment and did not do a clinical trial with prespecified outcomes, analyses, and research biomarkers. This approach meant that clear evidence of efficacy could be concluded only if one or more patients ceased to decline neurologically or showed sustained improvement on treatment, an outcome we have not seen in our natural history study.25
Encouragingly, intravenous administration did reach our target CSF drug concentration of 50 nM in four patients and direct intracerebroventricular infusion was unnecessary. Indeed, CSF analysis indicated that PRN100 itself might have resulted in increased permeability of the blood–brain barrier, compared with baseline and controls, perhaps via interaction with PrPC on the surface of endothelial cells,35 facilitating its own entry. Most importantly, we saw no clinical evidence of toxicity and there was no evidence of cytotoxicity related to therapy in the two patients in whom autopsy examination was done. Intravenous infusion of PRN100 was well tolerated and there were no acute or chronic adverse events for up to 8 months of treatment.
Although disease progression was not halted or reversed in any patient, MRC Prion Disease Rating Scale scores did appear to stabilise in three patients for periods when CSF drug concentrations reached the target concentration, but the small number of patients precluded meaningful statistical analysis. However, neuropathological examination of patient 2 provided strong evidence of target engagement and drug effect, with striking attenuation of abnormal PrP immunoreactivity in the parietal cortex and occipital cortex, markedly altered distribution of disease-related PrP in subventricular areas, and PrP cerebral amyloid angiopathy, which was not seen in untreated patients. We note that amyloid β cerebral amyloid angiopathy has been observed as a consequence of amyloid β monoclonal antibody therapy, but we did not detect amyloid-related imaging abnormalities in any patient. The second patient on whom autopsy was done only received a single dose of 80 mg/kg but also showed altered PrP labelling in periventricular regions. Compared with untreated historical controls, concentrations of tissue-bound drug estimated in post-mortem brain tissue were similar to those in CSF, well in excess of concentrations shown to cure cells of prion infection.
We are therefore encouraged by these findings, which, taken together, suggest that intravenous administration of PRN100 treatment is safe and can attain, and sustain in the long term, brain tissue concentrations in the range expected to be therapeutically active without detectable toxicity. It will be important to now evaluate PRN100 in a regulated phase 2 study in which we would seek to enrol patients at the earliest clinical stages and perform much more rapid dose escalation to achieve target CSF drug concentrations within 48–72 h. Modelling studies based on the NPMC dataset with genetic stratification by PRNP codon 129 genotype estimate that a suitably powered trial can be conducted with 50 patients.27 The availability of this large natural history dataset of a rare disease allows innovative trial designs to assess efficacy with minimal or no randomisation to placebo, which is understandably challenging for this patient population to accept.4
Subject to satisfactory safety data, further studies to evaluate PRN100 for secondary prophylaxis to prevent the clinical onset of disease could be undertaken in carriers of PRNP mutations and those exposed to prions via medical or surgical procedures or laboratory incidents, which includes a large number of individuals treated with human cadaveric growth hormone potentially contaminated by prions (around 1800 people in the UK; around 5000 people in the USA). Possible blood biomarkers of proximity to clinical onset in people at risk could be important components of preventive studies.26 Dietary exposure to prions resulted in the historical epidemic of kuru, transmitted by ingestion of human tissues at mortuary feasts in Papua New Guinea, and variant CJD from exposure to bovine spongiform encephalopathy prions in the UK and some other countries. Although variant CJD is now very rare, screening of anonymised archived tissue has suggested that around one in 2000 people in the UK population could be silently infected following exposure to bovine spongiform encephalopathy in the 1980s and 1990s.36 Variant CJD prion infection has also been iatrogenically transmitted by blood transfusion or blood products and several thousand UK individuals have been notified that they are at risk of developing prion disease as a result of such exposure.
In addition to meeting the unmet clinical need to treat and prevent prion disease, it is anticipated that much will be learned in the course of these future clinical studies about the capacity for cognitive and neurological recovery upon halting a neurodegenerative process in humans. Such knowledge could be extremely valuable in the development and evaluation of therapies for the more common dementias. Furthermore, a growing body of data supports a role for PrPC in Alzheimer's disease in its binding of synaptotoxic amyloid β assemblies.37 The interaction between PrPC and synaptotoxic amyloid β assemblies can be efficiently blocked by PRN100, suggesting a possible future role for anti-PrP antibodies in treating Alzheimer's disease38 and, possibly, other common neurodegenerative diseases.39
Contributors
JC led the development of PRN100 with SM, AK-S, CP, NM, NE, PH, and MW. Patient assessment and treatment and review of investigations was done by JC, SM, PR, TM, AN, and HH. PRN100 assays and other laboratory investigations were designed, conducted, or designed and conducted by AK-S, SC, CS, TC, and LD. Neuropathology was done by ZJ, JL, and SB. VL and BW provided clinical advice and coordinated and liaised with the Oversight Committee. The underlying data have been verified by JC, SM, HH, AK-S, and SB. The manuscript was drafted by JC and SM, with contributions from all authors. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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World-first CJD treatment shows promising early results
A world-first treatment for Creutzfeldt-Jakob disease (CJD), developed by scientists at the Medical Research Council (MRC) Prion Unit at UCL, has shown “very encouraging” early results following its use in six patients at University College London Hospitals (UCLH) NHS Foundation.
CJD is a rare but devastating disease that causes brain damage and for which there is currently no licensed treatment. It is always fatal and most patients sadly die within a few months of diagnosis.
Researchers at the MRC Prion Unit at UCL have developed a monoclonal antibody, called PRN100, which was given to six UCLH patients with CJD between October 2018 and July 2019.
The results, published in the Lancet Neurology, show the treatment is safe and able to access the brain. In three patients, disease progression appeared to stabilise when dosing levels were in target range.
Given the small number of patients treated, researchers say the findings should be regarded as preliminary and further studies are needed to draw more comprehensive conclusions.
None of the six patients experienced side effects while receiving the treatment but all sadly died as a result of their condition.
Professor John Collinge, Director of the MRC Prion Unit at UCL and UCLH consultant neurologist, who led the development of the PRN100 treatment, said: “Drugs used to treat other diseases have been tried experimentally in treating CJD in the past but none has had an impact on disease progression or mortality.
“This is the first time in the world a drug specifically designed to treat CJD has been used in humans and the results are very encouraging.
“While the number of patients we treated was too small to determine whether the drug altered the course of the disease, this is nevertheless an important step forward in targeting prion infections.
“It has been a huge challenge to reach this milestone and we still have a long way to go but we have learned a great deal and these results now justify developing a formal clinical trial in a larger number of patients.”
Looking further into the future, Professor Collinge added: “We hope the drug may also have the potential to prevent the onset of symptoms in people at risk of prion disease due to genetic mutations or accidental prion exposure and may contribute to the development of therapies for more common dementias, such as Alzheimer’s disease.”
In a comment piece published alongside the results in the Lancet Neurology, Professor Inga Zerr, from the Department of Neurology at Georg-August University of Gottingen, Germany, also called for further studies in this area.
“These outcomes are very encouraging and long awaited but, in light of the limitations, such as the small number of patients included and the use of historical controls, these results must be considered preliminary,” she said.
UCLH provided the PRN100 drug to patients under a “Specials” exemption, rather than a regulated clinical trial. A “Specials” exemption permits a healthcare professional to treat an individual patient with an unlicensed drug when their special clinical needs cannot be met by a licensed product on the market.
Three of the six patients were able to consent to receiving the PRN100 antibody themselves. The other three did not have the capacity to consent, so with the support of their families, UCLH sought the opinion of a judge in the Court of Protection in order to proceed.
UCLH created an oversight group, independent of the MRC Prion Unit at UCL and treating clinicians, to consider the numerous and complex clinical, safety, legal and ethical issues arising from the potential use of this unlicensed treatment. The group comprised world-leading experts from a range of disciplines and met regularly with lawyers and patient advocates from the Cure CJD Campaign.
Professor Bryan Williams, director of the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre (BRC), said: “UCLH is a bold healthcare institution which, along with its academic partner UCL, is always seeking to push the frontiers of medicine and science to deliver innovative treatments to patients.
“Creutzfeldt-Jakob disease (CJD) is a rare and cruel disease which rapidly destroys the brain and for which there is currently no cure or licensed treatment. It was extremely important to us to find a way through the many challenges arising from the potential use of this novel treatment in order to offer it to a small group of patients.
“We are encouraged by these results which demonstrate the treatment is safe and there is some signal of benefit. The hope is that this could pave the way for new treatments for other neurodegenerative diseases.”
Patient story
Carole Kiralyfi was one of the six patients to receive the PRN100 antibody.
Her husband, Laszlo, said a fall during a game of tennis in January 2019 was one of the first signs that something was not right with Carole, who was 70 years old at the time. Her vision then began to deteriorate and she had difficulties managing everyday tasks.
When Carole was diagnosed with sporadic CJD in March 2019, Laszlo said the whole family was “absolutely devastated”.
“It was such a shock, everything happened so quickly. Carole had always been so healthy and active – I had always thought she would outlive me.”
With Laszlo’s support, Carole decided to receive the PRN100 drug after being thoroughly assessed by neurologists at UCLH’s National Prion Clinic.
“Carole came to terms with her diagnosis a lot better than we (her family) did – she was not afraid. The drug was our only option so we decided to go ahead.”
Carole sadly died of her condition in April 2019 before the target level of PRN100 was achieved but Laszlo takes comfort in the fact that she may have contributed to the development of a potential treatment of the future.
“Obviously, I wish there could have been a treatment for Carole but if we are one step closer to achieving that now, it means her death was not in vain.
“The team that looked after her was so caring and compassionate – they have dedicated their lives to finding a cure for this terrible disease so I want this for them too.
“CJD may be rare but it is devastating and that is why it is so important there is more research in this area.”
Paying tribute to his wife of 28 years, Laszlo, who is now 74, added: “She was an extraordinary person with a big heart; a wonderful wife and fantastic mother. She was very popular and had many friends – when she walked into a room it lit up and when she left the light remained. She will remain forever in our hearts.”
Links
Image
- 'Medical drip with patient in the hospital', credit: Kwangmoozaa on iStock
Media contact
Henry Killworth
Tel: +44 (0) 7881 833274
E: h.killworth [at] ucl.ac.uk
https://www.ucl.ac.uk/news/2022/mar/world-first-cjd-treatment-shows-promising-early-results
MANY THANKS to the Lancet Journal for open access and especially to all the Scientist working to find a cure for CJD TSE PrP...terry
