Robin H. Lachmann’s research while affiliated with University College London Hospitals NHS Foundation Trust and other places

Background Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. Results: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment. Conclusions Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .

Phenylalanine (PHE), an essential aromatic amino acid, is mainly metabolised in the liver by the PHE hydroxylase (PAH) system. The first step in the irreversible catabolism of PHE is hydroxylation to tyrosine (TYR) by PAH. This enzyme requires the active pterin, tetrahydrobiopterin (BH4), which is formed in three steps from guanosine triphosphate (GTP), and DNAJC12 which functions as a co-chaperone with HSP70 for correct folding and stability of the aromatic amino acid hydroxylases. During the hydroxylation reaction BH4 is converted to the inactive pterin-4a-carbinolamine. Two enzymes regenerate BH4 via q-dihydrobiopterin (qBH2). BH4 is also an obligate co-factor for TYR hydroxylase and tryptophan hydroxylases 1 & 2, (necessary to produce dopamine, catecholamines, melanin and serotonin), and for alkylglycerol monooxygenase (AGMO) and 3 isoforms of nitric oxide synthase. The physiological role of AGMO, which is involved in ether lipid metabolism, is not yet fully characterised. Defects in either PAH, the production or recycling of BH4 or DNAJC12 may result in hyperphenylalaninaemia (HPA), as well as in deficiency of TYR, L-dopa, dopamine, melanin, catecholamines and 5-hydroxytryptophan (5HT). When hydroxylation to TYR is impeded, PHE may be transaminated to phenylpyruvic acid (a ketone excreted in increased amounts in the urine, whence the term phenylketonuria or PKU), and further reduced and decarboxylated.

The liver is a major site of lipoprotein synthesis and metabolism. Liver manifestations of chronic visceral ASMD include hepatomegaly, fibrosis, elevated liver enzymes and a pro-atherogenic lipid profile. Measurements of sphingomyelin (SM) levels in liver biopsies and lyso-SM in plasma were used as pharmacodynamic biomarkers. Five adult patients with chronic visceral ASMD were enrolled in a 26-week phase 1b trial of enzyme replacement therapy (ERT) with olipudase alfa (NCT01722526) followed by an ongoing long-term extension study (NCT02004704). We compare the changes in hepatic SM levels, plasma lyso-SM, and lipoprotein profiles after 42 months of treatment. Progressive clearance of histologic SM storage was observed throughout the trial, along with similar reductions in plasma lyso-SM. Improvements in liver enzymes were observed at 6 months and remained stable at 42 months. Progressive reductions from baseline in pro-atherogenic lipid profiles (total cholesterol, LDL-C, VLDL-C, triglycerides) were observed at month 6 and 42. Conversely, there were progressive increases in anti-atherogenic markers, HDL-C and apolipoprotein A-I, with HDL-C increases up to 200% over baseline levels after 42 months of treatment. These data demonstrate that hepatic clearance of SM during olipudase alfa treatment over 42 months is associated with overall improvements in the lipid profiles of ASMD patients. The clinical relevance of these findings needs to be determined in the future, but we speculate that these improvements may reduce the risk for liver cirrhosis and cardiovascular disease. Trial registration: Clintrials.gov trial registration # NCT01722526

The first enzyme replacement therapy (ERT) for a lysosomal storage disorder (LSD) was approved in 1991 and we now have more than 25 years of experience of treating patients with type 1 Gaucher disease. Because of the remarkable success of this therapy, enormous effort and resource has gone into developing other ERTs, for Gaucher (where three different enzyme preparations have now been approved) and for other LSDs. We now have more than ten years of clinical experience in using ERT to treat Gaucher, Fabry, Pompe and MPS I, II and VI. This article aims to assess the real‐life experience of a selection of these innovative and expensive treatments to see if they have met the high expectations which were set for them when they launched. This article is protected by copyright. All rights reserved.

Newborn screening for phenylketonuria and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of phenylketonuria, including mental retardation and epilepsy. However, concerns remain that long‐term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine‐restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early‐treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, IQ appears normal but specific deficits in neuropsychological and social functioning were reported in early‐treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardised neuropsychological tests. Future research should employ standardised neurological, neuropsychological and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated phenylketonuria‐specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life. This article is protected by copyright. All rights reserved.

Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures. Electronic supplementary material The online version of this article (10.1007/s10545-017-0123-6) contains supplementary material, which is available to authorized users.