July 6, 2015
AstraZeneca reported results of a phase III,
double-blind, multicenter, placebo-controlled
trial of lesinurad used in combination with
febuxostat for gout. The study evaluated
lesinurad (200mg or 400mg) in combination
with febuxostat 80mg in patients who had at
least one measurable tophus (deposits of uric
acid crystals in joints and skin). Patients were
administered febuxostat 80mg orally once
daily for three weeks before randomization to
the combination treatments. Results showed
lesinurad 200mg in combination with febuxostat
demonstrated greater (nominal p<0.05)
sUA lowering to the target for tophaceous
gout of <5mg/dL compared to febuxostat
alone at all months except at the time of the
primary endpoint, month 6 (56.6% v. 46.8%,
non-significant). In the important subgroup of
subjects with baseline sUA=5mg/dL, lesinurad
200mg in combination with febuxostat did
result in more subjects reaching target sUA
of <5mg/dL compared to febuxostat alone at
month six (44.1% v. 23.5% respectively; nominal
p=0.0243). Lesinurad 400mg in combination
with febuxostat met the primary endpoint,
with a significantly (p<0.0001) higher
proportion of patients reaching the target sUA
goal of <5mg/dL at month six compared to febuxostat
alone (76.1% v. 46.8%). The MAA and
NDA for lesinurad 200mg tablets in combination
with an XOI (febuxostat or allopurinol)
currently are under review by the CHMP/EMA
and the FDA.
August 18, 2014
AstraZeneca released results of three
phase III trials of lesinurad for the treatment
of symptomatic gout (CLEAR1, CLEAR2 and
CRYSTAL). CLEAR1 and CLEAR2 were 12-month
(U.S. and global, respectively) multicenter,
randomized, placebo-controlled studies (n=603
and n=610, respectively) comparing lesinurad
(200mg and 400mg once daily) when added to
the patient’s current dose of allopurinol (at least
300mg daily, and at least 200mg daily for those
with moderate renal impairment) compared
to placebo plus allopurinol. CRYSTAL was a
12-month, global, multicenter, randomized,
placebo-controlled study (n=324) comparing
lesinurad (200mg and 400mg once daily) in
combination with febuxostat (80mg) compared
to febuxostat (80mg) plus placebo in
gout patients with tophi and sUA levels above
target. In the CLEAR1 and CLEAR2 trials, patients
receiving both lesinurad 200mg and 400mg in
combination with allopurinol reached the target
sUA goal of <6.0mg/dL at month six compared
to allopurinol alone (p<0.0001). In the CRYSTAL
trial, patients receiving lesinurad 400mg in
combination with febuxostat reached the target
sUA goal of <5.0mg/dL at month six compared
to febuxostat alone (p<0.0001). Most commonly
reported adverse events in CLEAR1 and
CLEAR2 were upper respiratory tract infection,
nasopharyngitis and back pain. In CRYSTAL, the
most commonly reported adverse events were
nasopharyngitis, arthralgia and upper respiratory
July 9, 2012
Savient Pharmaceuticals released results from two replicate phase III trials of Krystexxa (pegloticase) for the treatment of refractory chronic gout (RCG). Subjects in these randomized, doubleblind, placebo-controlled studies received Krystexxa 8mg every two weeks or every four weeks, or placebo. Investigators measured patient-reported health-related quality of life (HRQOL) outcomes through four widely-utilized assessment tools: Medical Outcomes Study Short Form-36 physical component summary scores, the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient global assessment of disease activity and pain by visual analog scale. Results at week 25 demonstrated mean improvements from baseline were statistically significant and exceeded minimum clinically important differences in patients treated with Krystexxa 8mg every two weeks, the approved dose and schedule. The data demonstrated at least 50% of patients showed improvements in HRQOL parameters (except 45% for HAQ-DI). The most common adverse events were gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting. Savient Pharmaceuticals did not note its next steps for Krystexxa.
January 16, 2012
Biocryst reported results from a phase IIb extension trial evaluating BCX4208 for gout. The randomized, double-blind, dose-response, parallel-group design trial enrolled 279 subjects who had failed to reach the serum uric acid (sUA) objective of <6 mg/dL following treatment with allopurinol alone. Of the original 279 subjects enrolled, 160 entered the extension phase for a total of 24 weeks of treatment. The subjects received BCX4208 (5, 10, 20 or 40mg) or placebo, both administered once-daily in combination with allopurinol 300 mg. BCX4208 resulted in sustained sUA control over time. After 24 weeks of treatment, BCX4208 doses of 5 mg, 10 mg, 20 mg and 40 mg/day showed response rates of 40%, 50%, 46% and 55% respectively, compared to 25% for placebo. Subjects generated healthy immune responses to a vaccine challenge at 16 or 20 weeks of BCX4208 treatment. BCX4208 was generally safe and well-tolerated.
December 12, 2011
Metabolex issued results from a clinical trial of arhalofenate in combination with febuxostat (Uloric) for hyperuricemia (gout). This open label trial enrolled 11 treatment nave subjects with serum uric acid (sUA) levels of at least 8 mg/dL. The subjects were treated with febuxostat (80 mg) for one week. Subsequently, they were administered 400 mg of arhalofenate for two weeks followed by up-titration of arhalofenate to 600 mg for an additional two weeks. The primary endpoint response rate, based on the percentage of subjects reaching sUA targets of 5 and 4 mg/dL. The addition of arhalofenate increased the response rates over those observed with febuxostat alone. Treatment with febuxostat alone resulted in response rates of 55 and 9%, respectively. After two weeks of treatment with 400 mg of arhalofenate, these response rates were increased to 100 and 36%, respectively. After treatment with 600 mg of arhalofenate, the response rates were 100 and 82%, respectively. Compared to treatment with febuxostat alone, the combination with arhalofenate increased the response rate to the 4 mg/dL target by 73% (p≡0.013).
October 10, 2011
BioCryst Pharmaceuticals issued results from a phase IIb trial evaluating BCX4208 for gout. This randomized, double-blind, dose-response, parallel-group design trial enrolled 279 subjects who had failed to reach the serum uric acid (sUA) objective of <6 mg/dL following treatment with allopurinol 300 mg alone. The subjects received BCX4208 (5, 10, 20 or 40mg) or placebo, both administered once-daily for 12 weeks in combination with allopurinol 300 mg. The primary endpoint, the proportion of subjects with sUA <6 mg/dL at day 85, was achieved. BCX4208 plus allopurinol was superior to placebo plus allopurinol (p≡0.009 overall). BCX4208 doses evaluated showed response rates ranging from 33% to 49%, compared to 18% for placebo. BCX4208 was generally safe and well-tolerated at all doses studied.
March 7, 2011
Regeneron Pharmaceuticals released results from a phase III trial of Arcalyst for the treatment of gout. This double-blind, placebo-controlled study, PRE-SURGE 2 (PREventative Study against URate-lowering drug-induced Gout Exacerbations-2), enrolled 248 subjects initiating allopurinol therapy. The subjects received Arcalyst 160mg initial loading dose, followed by weekly 80mg subcutaneous injections; Arcalyst 320mg initial loading dose, followed by weekly 160mg subcutaneous injections or weekly placebo injections. The primary endpoint was the number of gout flares per subject over 16 weeks of treatment. Both dose groups showed a 72% decrease in mean number of gout flares compared to the placebo group (p<0.0001). Secondary endpoints were also reached. Arcalyst reduced the proportion of subjects who experienced at least one gout flare during the study period by 63% for the 160mg arm (p<0.0001) and by 54% for the 80 mg arm (p≡0.0001) compared to placebo. Arcalyst also reduced the proportion of subjects who experianced two or more flares by 82% for the 160mg arm (p<0.0001) and by 74% for the 80mg arm (p≡0.0002) compared to placebo. Arcalyst was generally well tolerated.
September 27, 2010
Biocryst issued positive results from a phase II trial of BCX-4208 was initiated for gout. This randomized, double-blind, multi-center, placebo-controlled study (BCX4208-202) enrolled 87 subjects with serum uric acid (sUA) concentrations greater than or equal to 8 mg/dL. The subjects were randomized to receive BCX4208 at daily doses of 20 mg, 40 mg and 80 mg administered orally as monotherapy or in combination with allopurinol at daily doses of 100 mg, 200 mg and 300 mg administered orally. The primary endpoint was to estimate the dose response relationship of BCX4208 when administered as a monotherapy and in combination with allopurinol on sUA. A dose-response was demonstrated for both BCX4208 and allopurinol, and the combination of BCX4208 and allopurinol was shown to be superior to either drug alone. The mean reduction in sUA from baseline observed in all groups receiving combinations of BCX4208 and allopurinol ranged from 2.4 to 5.6 mg/dL. In five of these nine combination groups, 80% or more of the patients achieved a sUA concentration of less than 6 mg/dL. BCX4208 alone and in combination with allopurinol were generally safe and well-tolerated.
June 28, 2010
Novartis reported positive preliminary results from a phase II trial of canakinumab for the prophylaxis of acute flares in chronic gout patients initiating allopurinol therapy. This 24-Week, dose-ranging, multi-center, double-blind, randomized, active-controlled study enrolled 423 subjects who were treated with varying doses of canakinumab or colchicine, the current standard of care. The primary endpoint was a reduction in the mean number of gout flares occurring during the 16 weeks after randomization. Canakinumab significantly reduced the rate of flares by 48% to 75% compared to colchicine (p≡0.05) and reduced the risk of developing at least one flare by 61% to 80% versus colchicine (p≡0.05). Canakinumab was generally well tolerated with similar incidence of adverse events across all treatment groups.
June 14, 2010
Regeneron reported positive results from a phase III trial of rilonacept for the treatment of allopurinol-induced gout flares. This North American, randomized, double-blind, placebo controlled study, dubbed PRE-SURGE 1 (PREventative Study Against URate-Lowering Drug-Induced Gout Exacerbations 1), enrolled 241 subjects who were evaluated over the first 16 weeks following initiation of allopurinol therapy. The subjects received rilonacept 160 mg as an initial subcutaneous loading dose, followed by weekly 80 mg subcutaneous injections; rilonacept 320 mg as an initial subcutaneous loading dose, followed by weekly 160 mg subcutaneous injections or subcutaneous weekly placebo injections. The primary objectives were reached. Subjects who received rilonacept 160 mg weekly had an 80% decrease in mean number of gout flares compared to the placebo group over the 16 week treatment period (0.21 flares vs. 1.06 flares, p<0.0001). Subjects who received rilonacept 80 mg weekly had a 73% decrease compared to the placebo group (0.29 flares vs. 1.06 flares, p<0.0001). All secondary endpoints were also reached, including a reduction in the two or more gout flares during the study period.
May 10, 2010
BioCryst issued positive interim results from a phase IIa trial of BCX4208 for the treatment of gout (hyperuricemia). This randomized, double-blind, placebo-controlled study is being conducted in two parts. This data is from part one. A total of 60 subjects with serum uric acid concentrations greater than or equal to 8 mg/dL were randomized to placebo or to one of three different doses of BCX4208 (40 mg, 80 mg or 120 mg) administered once-daily for 21 days. The primary endpoint was change in serum uric acid concentration after 21 days of treatment compared to baseline concentration prior to treatment. All three doses of BCX4208 demonstrated a statistically significant reduction in serum uric acid levels compared to placebo at day 22. The median reductions in serum uric acid levels were 2.7, 3.3 and 3.4 mg/dL for the three treatment arms, respectively, versus -0.4mg/dL for placebo. BCX4208 also demonstrated a statistically significant difference in the proportion of subjects with uric acid levels less than 6 mg/dL, compared to placebo. Among subjects with a baseline uric acid concentration below 10 mg/dL, up to 63% showed uric acid levels below 6 mg/dL on day 22. BCX4208 was generally safe and well-tolerated. The second part of the study is now underway and is evaluating the safety and efficacy of up to three higher doses of BCX4208.
EnzymeRx reported positive results from a phase I trial of pegsitacase for the treatment of refractory gout and for the management of hyperuricemia associated with tumor lysis syndrome. The open label trial enrolled 20 subjects with a mean baseline uric acid of approximately 8 mg/dL. The subjects received escalating single doses of pegsitacase (0.05 mg/kg, 0.10 mg/kg, 0.20 mg/kg, 0.30 mg/kg or 0.40 mg/kg), administered by intravenous infusion over one hour, without any premedication. Pegsitacase demonstrated rapid, potent and long-lasting suppression of uric acid in these subjects even at the lowest dose tested. Within three hours of administration, uric acid levels had dropped by an average of more than 5 mg/dL. All subjects achieved uric acid levels of 1 mg/dL or lower within a day of pegsitacase administration and maintained them at that level for at least a week. In addition, 12 of the 16 subjects receiving the highest four doses of pegsitacase still had uric acid levels of 1 mg/dL or lower by day 12, and eight maintained these very low uric acid levels through day 24. Pegsitacase was well tolerated, with no infusion reactions, and a potent uric acid-lowering effect.
April 12, 2010
Ardea BioSciences issued positive results from phase IIb trial of RDEA594 for the treatment of hyperuricemia and gout. This 28-day, randomized, double-blind, placebo-controlled, dose-escalation study enrolled 123 gout patients with hyperuricemia (serum urate levels greater than or equal to 8 mg/dL). The subjects received RDEA594 200 mg once-daily (qd) 400 mg qd, 600 mg qd or matching placebo. The primary endpoint was a significant increase in the proportion of subjects who achieved a response, defined as a reduction of serum urate to <6 mg/dL after 4 weeks of treatment, compared to placebo. The primary endpoint was achieved. Reductions in serum urate and response rates increased in a dose-related manner and were statistically significant at both the 400 mg qd and 600 mg qd dose levels. At the highest dose, there was a 38% median reduction in serum urate levels after 4 weeks compared to a 1% increase on placebo (p<0.0001); a response rate of 45%, compared to 0% for placebo (p<0.0001). The response rate at the highest dose in patients with baseline serum urate levels of <10 mg/dL (9.2 mg/dL on average) was 58% (p≡0.0012). Treatment was well tolerated.
September 8, 2008
Regeneron released positive results from a phase II trial of Arcalyst for the treatment of gout. This double-blind, placebo-controlled study enrolled 83 subjects. Following the induction of gout flares by the initiation of allopurinol, a uric acid-lowering drug therapy, the subjects received placebo or an initial 320 mg dose of Arcalyst, followed by weekly doses of 160 mg. The primary endpoint, the mean number of flares per subject over the first 12 weeks of urate-lowering therapy, was achieved. The mean number of flares per subject was 0.79 with placebo and 0.15 with Arcalyst (p=0.0011), an 81% reduction. During the first 12 weeks of therapy, 14.6% of subjects receiving Arcalyst experienced a gout flare compared to 45.2% of subjects treated with placebo (p=0.0037). In addition, 47.4% of subjects treated with placebo had more than one flare while none of the subjects treated with Arcalyst reported more than one flare. Based on the results, Regeneron plans to commence phase III trials early in 2009 for the prevention of gout flares.
May 19, 2008
Roche issued positive results from an ongoing phase III trial of Actemra for the treatment of rheumatoid arthritis. This three-arm, randomized, double-blind, placebo- controlled study, dubbed LITHE (TociLIzumab Safety and THE Prevention of Structural Joint Damage), enrolled 1,196 subjects across several international sites. The subjects received Actemra (4 mg/kg or 8 mg/kg) or placebo administered via intravenous infusion every four weeks combined with methotrexate weekly. Response to treatment was analyzed by measuring structural damage in the joints through X-rays. Disease activity, measured by the ACR (American College of Rheumatology) score and improvement in physical function, measured through the Health Assessment Questionnaire (HAQ) were also assessed. The one-year data showed that a greater proportion of subjects treated with Actemra plus methotrexate versus placebo plus methotrexate over 52 weeks achieved a significant reduction in the progression of structural joint damage. Actemra also reduced disease signs and symptoms at one year. Treatment was well tolerated. Full results from this study are expected in 2009. A BLA is for Actemra is currently under review by the FDA.
Savient released positive interim results from an ongoing open label extension trial of Puricase for the treatment of gout. This study enrolled 82 subjects with treatment-failure gout who had completed previous phase III trials with Puricase. Of these 82 subjects, half received Puricase 8 mg every two weeks and half received Puricase every four weeks. Continued normalization of plasma uric acid (PUA) was seen in 100% and 70% of subjects who had normalized PUA during the original phase III trials in the two- and four-week dosing groups, respectively. Approximately 25% of subjects who did not have PUA responses during the original trials attained PUA normalization in the study with nine months or more of continuous Puricase treatment either every two or four weeks. Of the non-responders for the resolution of gout tophi in the previous studies, 31% showed a complete response in this study with additional subjects showing a partial response for tophus resolution. No incidence of gout flares was reported in the two-week arm after five months. Infusion reactions were reported by 21% of subjects, which was comparable to that reported during the original trials. Savient plans to submit a BLA to the FDA in September of 2008.
January 7, 2008
Savient reported positive results from two phase III trials, GOUT 1 and GOUT 2, of Puricase for the treatment of gout. 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. The primary endpoint was normalization of plasma uric acid during months three and six of the clinical trials. In the Intent-to-Treat analysis the mean responder rate for the every two week dose group pooled across both studies was 42% (p is less than 0.001) and the mean responder rate for the every four week dose group was 35% (p is less than 0.001). In the Per Protocol analysis the responder rate for the every two weeks dose group was 61% (p is less than 0.001), and every four weeks was 50% (p is less than 0.001). The placebo responder rate for placebo was zero in both the ITT and Per Protocol analyses. A key secondary endpoint was reduction of 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. The every four week dose group did not attain statistical significance. Treatment was generally well tolerated. Based on these results, Savient planned to file a BLA with the FDA in 2008.
September 24, 2007
Regeneron announced positive results from a phase I trial of rilonacept (IL-1 Trap) for the treatment of gout. This single-blind, placebo run-in-controlled study enrolled 10 subjects with chronic, active gout for whom standard therapies were ineffective. Disease activity changes during a blinded placebo run-in period were compared to changes during subsequent blinded treatment with rilonacept. During blinded active treatment, mean pain scores were significantly reduced (-41%, p=0.025, during the first two weeks of active treatment, and -56%, p less than 0.004, after six weeks of active treatment) compared to blinded two-week placebo run-in period (-13%). After six weeks 70% of the subjects in the rilonacept cohort achieved at least a 50% improvement in their pain scores while none of the subjects in the placebo group reached this same achievement. Based on the results, Regeneron recently initiated phase II trials of rilonacept.
November 21, 2005
Biogen Idec issued positive results of a phase II trial of Amevive (alefacept) for the treatment of psoriatic arthritis (PA). Amevive is currently approved to treat psoriasis. Trial results indicated that 54% of subjects receiving the drug achieved ACR20 response, vs. 23% of subjects receiving placebo (p<0.001). 17% achieved ACR50 and 7% achieved ACR70 with Amevive, vs. 10% and 2% respectively for placebo. Improvements in tender-joint (31% vs. 18%) and swollen-joint count (46% vs. 34%) were also noted. This randomized, double-blind, placebo- controlled study enrolled 185 PA patients, who received standard therapy with methotrexate plus Amevive (n=123) or placebo (n=62).
Jazz Pharmaceuticals announced positive results of a phase II trial of Xyrem (sodium oxybate) for the treatment of fibromyalgia. Xyrem is currently approved for the treatment of narcolepsy. Results from the study indicated that both the low and high dose regimens of the drug produced significant reductions in composite primary outcome variable (including Pain Visual Analog Scale, Fibromyalgia Impact Questionnaire, and Patient Global Impression of Change) compared to placebo: 34.5% in the low dose group (p=0.005) and 27.3% (p=0.048) achieved significant improvement in this measure, vs. 12.5% for placebo. Treatment was generally well tolerated. This randomized, double-blind, placebo-controlled study enrolled 188 patients, who received one of two daily doses of Xyrem (4.5g or 6g) or placebo for 8 weeks, taken in two divided doses (first at bedtime, second 2.5 to 4 hours later).
Savient issued positive results of a phase II trial of Puricase (PEG-uricase) for the treatment of refractory gout. This randomized, open label, multicenter, parallel group study enrolled 41 patients, who received one of 4 regimens of the drug (4 mg every 2 weeks, n=7; 8 mg every 2 weeks, n=8; 8 mg every 4 weeks, n=13; 12 mg every 4 weeks, n=13). The drug was shown to reduce plasma urate levels at all trial doses (from 7.56 mg/dL to 4.20; from 9.09 to 1.42; from 9.08 to 2.57; and from 8.47 to 2.60, respectively). The doses also maintained urate levels below 6 mg/dL for 73%, 92% 86% and 84% of the time. There were 5 serious adverse events reported, including gout flare (n=3), hypersensitivity reaction (n=1), and anemia (n=1).
May 16, 2005
Savient Pharmaceuticals announced preliminary results of a phase II trial of Puricase, for the treatment of symptomatic gout. The drug demonstrated efficacy in the studys primary endpoint, producing a significant reduction from baseline in serum uric acid levels for all doses, both at 24 hours after the first dose (p<0.0002) and at the conclusion of the 12 week treatment cycle (p<0.0003). Degree of reduction was generally dose dependent, though the highest volume dose did not yield significant superiority over mid- volume regimens. Overall adverse events were generally manageable, and were reduced in incidence This randomized, open label, parallel design study enrolled 41 patients with severe gout, who received one of four doses of the drug (4 mg or 8 mg once every 2 weeks, or 8 mg or 12 mg once every 4 weeks) over 12 weeks. The company announced plans to move forward with phase III testing, based on these results.
October 25, 2004
Savient Pharmaceuticals has issued positive results from a pair of phase I studies of Puricase (PEGylated uricase), for the treatment of severe gout. Results from both trials demonstrated a significant, dose-related reduction in plasma uric acid levels compared to baseline; this reduction was sufficient to return uric acid levels to a normal range. The drug was found to be safe in both studies, but significant incidence of injection site reaction and drug intolerance was observed when the drug was delivered via subcutaneous (SC) injection in the first trial; switching to an intravenous (IV) formulation in the second trial eliminated these reactions. These single-dose, dose-escalating studies investigated two formulations of Puricase in subjects with allopurinol-refractory-or-intolerant severe gout, and enrolled a total of 37 subjects (13 SC, 24 IV). Data from these studies were used to support Savient’s ongoing phase II trials of the drug, which the company hopes to complete before the end of 2004.