FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies.

The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration's regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.

African American patients with gout: efficacy and safety of febuxostat vs allopurinol.

BACKGROUND: African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects. METHODS: This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study. RESULTS: Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m2; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (p < 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (p < 0.001) and allopurinol (p = 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (p < 0.05). Efficacy rates in all treatment groups regardless of renal function were comparable between African American and Caucasian subjects, as were AE rates. CONCLUSIONS: In African American subjects with significant comorbidities, febuxostat 80 mg is significantly more efficacious than either febuxostat 40 mg or allopurinol 200/300 mg. Febuxostat was well tolerated in this African American population.Please see related article: http://www.biomedcentral.com/1741-7015/10/15.

Stage-specific cancer incidence: an artificially mixed multinomial logit model.

Early detection of prostate cancer using the prostate-specific antigen test led to a sharp spike in the incidence of the disease accompanied by an equally sharp improvement in patient prognoses as evaluated at the point of advanced diagnosis. Observed outcomes represent age at diagnosis and stage, a categorical prognostic variable combining the actual stage and the grade of tumor. The picture is summarized by the stage-specific cancer incidence that represents a joint survival-multinomial response regressed on factors affecting the unobserved history of the disease before diagnosis (mixture). Fitting the complex joint mixed model to large population data is a challenge. We develop a stable and structured MLE approach to the problem allowing for the estimates to be obtained iteratively. Factorization of the likelihood achieved by our method allows us to work with only a fraction of the model dimension at a time. The approach is based on generalized self-consistency and the quasi-EM algorithm used to handle the mixed multinomial part of the response through Poisson likelihood. The model provides a causal link between the screening policy in the population and the stage-specific incidence.

Generalized Self-Consistency: Multinomial logit model and Poisson likelihood.

A generalized self-consistency approach to maximum likelihood estimation (MLE) and model building was developed in (Tsodikov, 2003) and applied to a survival analysis problem. We extend the framework to obtain second-order results such as information matrix and properties of the variance. Multinomial model motivates the paper and is used throughout as an example. Computational challenges with the multinomial likelihood motivated Baker (1994) to develop the Multinomial-Poisson (MP) transformation for a large variety of regression models with multinomial likelihood kernel. Multinomial regression is transformed into a Poisson regression at the cost of augmenting model parameters and restricting the problem to discrete covariates. Imposing normalization restrictions by means of Lagrange multipliers (Lang, 1996) justifies the approach. Using the self-consistency framework we develop an alternative solution to multinomial model fitting that does not require augmenting parameters while allowing for a Poisson likelihood and arbitrary covariate structures. Normalization restrictions are imposed by averaging over artificial "missing data" (fake mixture). Lack of probabilistic interpretation at the "complete-data" level makes the use of the generalized self-consistency machinery essential.

The degree of bone mineralization is maintained with single intravenous bisphosphonates in aged estrogen-deficient rats and is a strong predictor of bone strength.

The treatment of osteoporotic women with bisphosphonates significantly reduces the incidence of bone fractures to a degree greater than can be explained by an increase in bone mineral density. In this study, 18-month Fischer 344 rats were ovariectomized and treated with a single dose of risedronate (intravenous, iv, 500 microg), zoledronic acid (iv, 100 microg) or continuous raloxifene (2 mg/kg, po, 3x/week). High resolution microCT was used to measure lumbar vertebral bone microarchitecture, the degree of bone mineralization (DBM) and the distribution of mineral. Small angle X-ray scattering was used to investigate mineral crystallinity. We found prolonged estrogen deficiency, reduced trabecular bone volume, and increased micro architecture bone compression strength lowered the degree of mineralization. Treatment with resorptive agents (bisphosphonates>raloxifene) prevented the loss of mineralization, trabecular bone volume and bone compression strength. Crystal size was not changed with OVX or with anti-resorptive treatments. In conclusion, in the aged estrogen-deficient rat model, single intravenous doses of two bisphosphonates were effective in maintaining the compressive bone strength for 180 days by reducing bone turnover, and maintaining the DBM to a greater degree than with raloxifene.

Preservation of renal function during gout treatment with febuxostat: a quantitative study.

BACKGROUND: Hyperuricemia can accelerate renal decline associated with aging. Chronic kidney disease is frequently seen in patients with hyperuricemia and gout. OBJECTIVES: Assess the impact of urate-lowering therapy on renal function in subjects with gout who were treated with febuxostat for ≤ 48 months. METHODS: Subjects from 2 phase 3 clinical studies were enrolled in the phase 3, long-term, open-label Febuxostat/Allopurinol Comparative Extension Long-Term (EXCEL) study. In the EXCEL study, 1086 subjects initially were treated with febuxostat 80 or 120 mg daily, or allopurinol 300 mg daily. The subjects were permitted to switch between doses of febuxostat and/or allopurinol during the first 6 months of treatment to achieve and maintain a serum uric acid (SUA) level ≥ 3 to < 6 mg/dL. For the analysis presented in this article, data from 551 subjects who received only febuxostat throughout the duration of both the phase 3 and EXCEL studies (≤ 48 months) were used to determine the impact of SUA reduction on estimated glomerular filtration rates (eGFRs). RESULTS: At baseline of the 2 original phase 3 studies, subjects' mean SUA level was 9.8 mg/dL. Greater sustained decreases in subjects' SUA levels were associated with less renal function decline (P < 0.001) by statistical modeling. The study data predicted that for every 1 mg/dL of chronic reduction of SUA level in subjects with gout, there would be a preservation of 1.15 mL/min of eGFR. CONCLUSION: Sustained urate-lowering therapy with febuxostat appears to impede renal decline in patients with gout. The results discussed in this article support similar observations previously reported in 116 hyperuricemic subjects with gout who received febuxostat for ≤ 5 years.

Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones.

BACKGROUND AND OBJECTIVES: Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥ 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. RESULTS: Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. CONCLUSIONS: Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.

Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol.

OBJECTIVE: To compare the characteristics of female versus male gout patients and assess urate-lowering efficacy and safety of febuxostat or allopurinol treatment in women with gout. METHODS: This was a retrospective analysis of 4,101 hyperuricemic (serum urate [sUA] level ≥8.0 mg/dl) gout subjects enrolled in 3 phase III comparative trials and randomized to receive placebo, febuxostat (40 mg, 80 mg, 120 mg, or 240 mg daily), or allopurinol (100 mg, 200 mg, or 300 mg daily, based on renal function). Baseline demographics and characteristics were summarized and compared between female and male subjects. Urate-lowering efficacy, which was defined as the proportion of subjects with sUA levels <6.0 mg/dl at final visit, was assessed for all subjects and, among women, according to baseline renal function. RESULTS: Female gout subjects (n = 226) were older with significantly higher rates of obesity and metabolic and cardiovascular comorbidities than their male counterparts. The percentage of female subjects with sUA levels <6.0 mg/dl at final visit was 0% in the placebo group, 54.3%, 85.1%, 81.0%, and 100.0% in the febuxostat 40 mg, 80 mg, 120 mg, and 240 mg groups, respectively, and 45.9% in the allopurinol group. Similar patterns of urate-lowering efficacy rates were observed when stratified by renal function. Among all the female subjects, febuxostat 80 mg was significantly more efficacious than allopurinol (P < 0.001). Rates of adverse events (AEs) were low. The most frequently reported AEs were upper respiratory tract infections, musculoskeletal/connective tissue disorders, and diarrhea. CONCLUSION: These data suggest that febuxostat 80 mg may be more efficacious than commonly prescribed doses of allopurinol in female gout subjects with high rates of comorbidities.