Correspondence

Volume 356, Number 9230 19 August 2000

		Treatment of Gaucher's disease with OGT 918

Sir

Timothy Cox and colleagues (April 29, p 1481)¹ presented the long-awaited results of the trial of OGT 918 (N-butyledeoxynojirimicin) for type-1 Gaucher's disease. They are to be congratulated for timely reporting and for providing detailed data. However, the results raise important concerns about the safety of the drug and the interpretation of the data can be questioned. Despite an impressive body of preclinical data² and the finding that leucocyte G_M1 concentrations were reduced, these early results provide little convincing evidence that OGT 918 results in a reduction in the number of storage cells or the amount of storage material within cells. A significant reduction of organomegaly was found, but no significant change in haematological variables. There was a modest reduction of serum chitotriosidase, a marker not specific for Gaucher's disease, but the effect on serum or tissue glucocerebroside concentrations is not reported. There was a striking dissociation between mean reduction of hepatomegaly and splenomegaly at 12 months, lack of haematological response, and only a 16% reduction in chitotriosidase concentration. When comparable organ responses are achieved by reducing the amount of storage material using mannose-terminated glucocerebrosidase infusions, there is an impressive haematological response and reduction in serum chitotriosidase. This dichotomy comes into focus when the data are stratified according to spleen status, because of the impact of splenectomy on Gaucher's disease and its treatment. In the three patients who completed the study who had had a splenectomy there is 20% reduction of hepatomegaly, but no significant change of chitotriosidase at 12 months of treatment. Further, in the 18 patients with intact spleens in whom complete data are available, most hepatic and splenic responses occurred by 6 months and at this timepoint there was only a 5% reduction of chitotriosidase concentration. These discordant effects raise the worrying prospect that the shrinkage of organs is not due to reduction of the number of storage cells or the amount of storage material, but may reflect simply organ atrophy. Massive cell dropout involving the lymphoid system, has been reported in animal studies of OGT 918.³ With respect to lack of haematological response, it is of note that OGT 918 caused marrow toxicity in HIV trials.⁴ The indirect role of OGT 918 in Gaucher's disease proposed by the investigators as an explanation for lack of haematological response is somewhat tenuous because very significant regression of organomegaly had already occurred in this trial.

79% of patients developed diarrhoea and two withdrew from the study because of this side-effect; another two developed paraesthesiae. Paraesthesiae also occurred in the HIV trial. The protocol does not appear to monitor for any possible effects on cerebral function--brain glycosphinglipids could be altered, especially in the long-term because of their slow turnover.² One patient withdrew because of pre-existing pulmonary hypertension.

Was there progression of pulmonary hypertension during 4 months of treatment with OGT 918? Because of the number of patients who developed diarrhoea, it is important to know if there was weight loss and how this might have influenced organ volume measurement, as multiples of normal, of patients on OGT 918. There was only a single measurement for baseline parameters, and so assessment of response will be confounded by spontaneous amelioration of signs and symptoms.

Enzyme replacement therapy for type-1 Gaucher's disease is highly effective and it is extremely safe.⁵ In the 10-year history of the Comprehensive Gaucher's Disease Treatment programme, New York, USA, there have been no infusion-related infections and no patient has required a permanent catheter. The programme has strikingly improved the lives of patients and prevented premature deaths. Development of effective and safe oral therapy will immeasurably lessen the burden of the disease on the patients and their families. However, we are concerned that the press release from the pharmaceutical company announces the results of the trial as clear cut evidence of activity that further trials of combination/ maintenance therapy of OGT 918 or Cerezyme are underway (www.ogs.com accessed July 14, 2000). Such over-enthusiastic announcements have prematurely tantalised the hopes of patients and families affected by Gaucher's disease. I make a plea that Cox and colleagues apply their rigor to the long-term potential and side-effects of this drug, before combination trials are launched, because they will simply add to the confusion.

P K Mistry

Comprehensive Gaucher Disease Treatment Center, Mount Sinai School of Medicine, New York, NY 10029-6574,USA

1 Cox T, Lachmann R, Hollack C, Aerts J, et al. Novel oral treatment of Gaucher's disease with N-butyledeoxynojirimicin (OGT 918) to decrease substrate biosynthesis. Lancet 2000; 355: 1481-85.

2 Platt FM, Butters TD. New therapeutic prospects for the glycosingolipid lycosomal storage diseases. Biochem Pharmacol 1998; 56: 421-30 [PubMed].

3 Platt FM, Neises GR, Reinkensmeier G, et al. Prevention of lycosomal storage in Tay-Sachs mice treated with N-butyledeoxynojirimicin. Science 1997; 276: 428-31 [PubMed].

4 Fischl MA, et al. The safety and efficacy of combination N-butyl-deoxynojirimicin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm³. J Acquir Immune Defic Syndr Hum Retrovirol 1994; 7: 139-47 [PubMed].

5 Grabowski GA, Leslie N, Wenstrup R. Enzyme therapy for Gaucher disease: the first 5 years. Blood Rev 1998; 12: 115-33 [PubMed].

Author's reply

Sir

P K Mistry raised important points but we must first correct a misapprehension: our study indeed showed a significant haematological response with an increase in platelets at one year (p=0·014). We also found decreased biosynthesis of the glycolipid substrate G_M1, ganglioside. Moreover, plasma glucosylceramide concentrations, which represent the storage material of Gaucher's disease, were also decreased. This material, ultimately responsible for the disease, can thus be reduced in patients with glycosphingolipidosis by decreasing the supply of its cognate substrate. Plasma chitotriosidase is a useful marker of Gaucher's disease activity and is in widespread clinical use for monitoring. It has been well-established that raised activity in Gaucher's disease is associated with the presence of pathological macrophages. The comment on the specificity of chitotriosidase is irrelevant to our study since the enzyme activity was greatly increased in all patients in whom it could be measured.

One cannot presume to interpret all the changes observed in our study mechanistically in the context of the results obtained with enzyme replacement therapy: the two modes of action, though potentially complementary, are quite distinct. Our study showed a significant reduction in chitotriosidase activity. Neither plasma chitotriosidase activity nor haematological variables change consistently with the reduction in organ volume when enzyme replacement therapy is introduced. Furthermore, we do not believe it is sound to use a statistical test using a subset of only three patients in our complete cohort, as suggested by P K Mistry.

When P K Mistry refers to a lack of haematological response he fails to point out that not all patients were cytopenic at baseline. Of the nine anaemic patients at the start of the trial, the mean increase in haemoglobin over 12 months was greater than 0·5 g/dL. For platelets there was a small but consistent increase over the study period with an overall trend to significant improvement. We have no evidence for marrow toxicity and in quoting the reports from trials in patients with HIV we should point out that these trials used doses of OGT 918 that were up to ten times greater than those used in Gaucher's disease.

P K Mistry's main concern about the trial is that the significant decreases in organ volume measurements that occur with OGT 918 were not associated with a therapeutic effect on Gaucher's disease. He suggests that a shrinkage phenomenon caused by lymphoid atrophy or simple weight loss may be responsible. We do not accept the suggestion that there is a striking dissociation between the changes in spleen and the changes in liver volumes--reduced volume was significantly correlated for these variables at 6 months and 12 months, respectively. In comparing the trial data with animal studies Mistry omitted to state that the latter studies involved much higher doses of OGT 918 with 10-fold greater plasma concentrations--lymphoid depletion noted in these studies was not observed in the liver. Long-term safety studies of OGT 918 in the rat showed a small increase in liver weight; in a 1-year primate toxicology study there were no significant histological changes in the liver and spleen. The number of circulating lymphocytes has been assessed routinely in all patients participating in the trial and remain clinically unchanged. Weight loss was not a major concern and the mean bodyweight reduction during the study was 6·4%, making no adjustment for a large weight reduction in one individual who was overweight at baseline and adhered to a strict diet during the trial. No significant correlation was observed between change in liver or spleen organ volume and bodyweight change. Lymphoid tissue is, of course, a minor component of the liver and the significant reduction in liver volume related to OGT 918 cannot be explained by a direct effect on this tissue. This fact, together with the observation that changes in liver size are probably the best quantitative index of clinical response,¹ only serves to emphasise the importance of the liver volume changes that we observed.

Diarrhoea usually occurred when therapy started and we included patients with mild intermittent diarrhoea. For most participants diarrhoea did not present insuperable difficulties. None of the patients developed pulmonary hypertension during the trial and none of the three patients with pre-existing pulmonary hypertension deteriorated. Parasthesiae were noted in earlier clinical trials when OGT 918 was given at higher doses to HIV patients. Although this was not statistically significant and there were no effects on cerebral function, we remain vigilant.

We acknowledge that enzyme replacement therapy is a safe and effective treatment for Gaucher's disease but an oral therapy would indeed lessen the burden of the disease. We are encouraged that our study with oral OGT 918 met the predefined efficacy endpoint in Gaucher's disease. Infants and children with the disease have required permanent intravenous cannulae for administration of the enzyme and the astronomical costs of enzyme replacement therapy preclude its use in many parts of the world.

I thank my co-workers for their input to this reply.

Timothy Cox

Addenbrooke's Hospital, Cambridge CB2 2QQ, UK

1 Beutler E, Demina A, Laubscher K, et al. The clinical course of treated and untreated Gaucher disease: a study of 45 patients. Blood Cells Mole Dis 1995; 21: 86-108 [PubMed].

Sir--As a public company Oxford GlycoSciences is obliged to disseminate material information on investigational drugs. The press release of April 28, 2000, coincided with the public dissemination of the clinical data in The Lancet and was factually correct, complete, and balanced. Comments on the drug are taken directly from the paper, which completed the peer-review process, adverse effects are highlighted and so was the fact that this was the first trial. The statement in the press release "clear-cut evidence of activity of OGT 918" is true.

A further randomised, combination/ maintenance study is ongoing. This study was carefully designed and received approval by the required ethical and regulatory authorities. Such clinical studies are the correct way to fully assess the efficacy and safety of OGT 918, and will provide physicians treating patients with Gaucher's disease with the answers and choices they deserve. As Mistry himself states: "development of effective and safe oral therapy will immeasurably lessen the burden of the disease on the patients and their families."

Michael Kranda

CEO, Oxford GycoSciences plc, Abingdon Science Park, Oxford, OX14 3YS, UK