Savient Pharmaceuticals, Inc. said its gout drug Puricase (pegloticase) showed statistically significant positive results in late stage phase II trials conducted under support of a Special Protocol Assessment (SPA) with the US Food and Drug Administration (FDA).
The primary endpoint under the assessment was normalization of plasma uric acid during months three and six of the clinical trials while secondary endpoint was the gout tophi achieved by the two week dose groups and four groups. Analysis of other secondary efficacy endpoints also showed favourable numerical trends in one or both pegloticase dose groups. There were no expedited reports of serious adverse events during the phase III trials. The company plans to file a Biologics Licenses Applications (BLA) with the FDA in 2008 based on the positive results from its phase III trials, following a pre-BLA meeting with the reviewing Division.
Puricase 8 mg administered by a two-hour intravenous infusion every two weeks or every four weeks met the primary efficacy endpoint in the Intent to Treat (ITT) and Per Protocol analyses in each of two replicate, six-month phase III clinical trials, (the studies are termed, Gout Outcomes and Urate Therapy, GOUT 1 and GOUT 2).
The treatment-failure gout population is characterised by very severe gout symptoms such as frequent crippling gout flares and gout tophi representing progressive disease, as well as a very high degree of co-morbidity such as hypertension, cardiovascular disease, diabetes, kidney disease, obesity, osteoarthritis and, medical histories of multiple drug hypersensitivities and diverse environmental allergies. The combination of advanced disease progression, important co-morbidities requiring polypharmacy, and multiple allergic histories makes this population exceptionally difficult to treat in clinical practice today.
"Our initial impression of the pegloticase phase III top line data is very favourable," said Zeb Horowitz, MD., Sr. vice president and chief medical officer. "We believe that the Savient GOUT studies are very important in two regards. We believe that the phase III data show that pegloticase has the potential to be the first effective therapeutic option to control uric acid in treatment-failure gout patients. Second, we believe that our assessment of tophi in GOUT 1 and GOUT 2 by digital photography and image analysis uniquely demonstrates the attainment of a statistically significant and medically relevant clinical outcome, in this most difficult to treat gout patient population."
The phase III results confirm that the pre-specified primary efficacy endpoint for both pegloticase treatment arms was met in each placebo-controlled study in the ITT analysis. In the ITT analysis of the primary endpoint all discontinued patients were imputed as non-responders, making this a very conservative assessment of therapeutic response. The mean responder rate for the every two week dose group pooled across both studies was 42 per cent (p is less than 0.001) and the mean responder rate for the every four week dose group was 35 per cent (p is less than 0.001). In the Per Protocol analysis the responder rates were higher: every two week was 61 per cent per cent (p is less than 0.001), and every four week was 50 per cent (p is less than 0.001). The placebo responder rate was zero in both trials for both the ITT and Per Protocol analyses.
The most clinically important of the secondary efficacy outcomes assessed in these studies was the effect of pegloticase on gout tophi. The every two week dose arm attained statistical significance in the pre-specified pooled analysis (p equal to 0.005) for the elimination of gout tophi (complete elimination of at least one tophus and no new tophi), whereas the every four week dose group did not attain statistical significance.
Although many secondary efficacy endpoints were explored in this phase III programme, the company has not yet finished analysing this aspect of the data base, and thus cannot include these in the top line results. It appears that in some statistical analyses significance was observed and in others, favourable numerical trends were noted.
As anticipated, patients in both dose arms showed an increase in gout flares as compared to placebo only in the early study period. However, in the last three months of the study period both pegloticase dose arms showed reduced gout flare frequency compared to the first three months, but not attaining statistical significance relative to placebo. The numerical trend toward reduction of gout flare frequency below the placebo rate is considered favourable. Despite the pre-study history of frequent severe gout flares and the evidence that pegloticase treatment, as any other uric acid lowering treatment, initially induces gout flares in susceptible patients, unlike other uric acid lowering therapies the increase in gout flares induced by pegloticase appears to persist only during the early portion of the treatment period.
Throughout the study period patient safety was assessed by frequent review of adverse events and laboratory findings, and real-time assessment of serious adverse events (SAEs). No signal for adverse safety findings has appeared in preliminary analysis of the unblinded data set, except for the occurrence of infusion-related adverse events.
Three deaths occurred in the treatment phase of the pooled ITT population, including death in one patient who voluntarily withdrew consent for renal dialysis. (A fourth patient, not included in the ITT population, died after completing the study when she elected to withdraw from antibiotic treatment of MRSA sepsis.) None of the patient deaths appear to be causally related to pegloticase treatment, as judged by the clinical investigators and Savient medical monitors.
In the pooled ITT population, infusion reactions occurred at some time during the studies in 56 pegloticase treated patients (33 per cent): 22 were in the every two week dose group and 34 were in the every four week dose group. Two placebo patients (5 per cent) experienced an infusion reaction. Typically, an infusion reaction involved back or chest pain, muscle cramps, sweating, and flushing. Infusion reactions were most often mild or moderate in severity and usually controlled by slowing the infusion rate and/or giving diphenhydramine. However, infusion reactions could be severe, especially in terms of chest or back pain. Nineteen patients (11 per cent of pegloticase treated patients) experienced an infusion reaction termed serious or severe: 6 in the every two week group and 13 in the every four week group. Sixteen patients (9 per cent) reported infusion reaction as the reason for withdrawal from the studies, 8 patients in each of the every two week and every four week dose groups.
The occurrence of infusion reactions as a proportion of total infusions administered in the pooled ITT population is another way to view this adverse event representing lack of tolerability. The number of infusion reactions as a proportion of all infusions administered was 5 per cent (43/851) for the every two week dose group, 8 per cent (70/846) for the every four week dose group, and 0.8 per cent (4/502) for the placebo group.
Infusion reactions that involved symptoms of transient lingual swelling, peri-oral edema, wheezing, or hypotension occurred in two patients in each treatment group, or 2.4 per cent of patients who were exposed to pegloticase. Only one of the four patients was administered epinephrine and two were administered corticosteroids. All patients recovered fully, some very rapidly and others within approximately 60 minutes. None of the four were re-challenged and all withdrew. Although we continue to have uncertainty as to whether some or all of these patients actually experienced an anaphylactic reaction to the drug, these symptoms have been interpreted to represent anaphylaxis in other drug programs and may be interpreted so in the GOUT trials as well.
In one circumstance, a multiply allergic patient developed urticaria five days after pegloticase dose administration. Although suggestive of delayed type hypersensitivity, the multiply allergic condition of this patient and other factors makes assigning causality to any level of certainty difficult.
Puricase (pegloticase) is a pegylated recombinant mammalian urate oxidase, in development to control hyperuricemia and its clinical consequences in patients for whom conventional therapy is contraindicated or has been ineffective. The two phase III pivotal trials assessed the safety and efficacy of a six-month course of pegloticase therapy in patients with treatment-failure gout. Savient has licensed worldwide rights to the technology related to Puricase (pegloticase) from Duke University and Mountain View Pharmaceuticals, Inc. Puricase is a registered trademark of Mountain View Pharmaceuticals, Inc.
Approximately three to five-million Americans suffer from gout, many of whom experience only limited success in the long term management of their painful symptoms. Within this group, we estimate that allopurinol, the mainstay of therapy for control of uric acid, is contraindicated or has failed to achieve therapeutic success at appropriate dosages in approximately 25,000 to 100,000 patients, meaning that today tens of thousands of gout patients have no effective treatment option. It is for these treatment-failure patients that pegloticase potentially offers a unique benefit and for which the product has been granted Orphan drug designation.
Savient Pharmaceuticals is a biopharmaceutical company engaged in developing and distributing pharmaceutical products that target unmet medical needs in both niche and broader markets.