Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy.

Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio >300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN.

Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis.

Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.

Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy.

INTRODUCTION: Inflammatory cell recruitment, which is potentially mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor type 2 (CCR2) system and by C-C chemokine receptor type 5 (CCR5) activity, may play a role in the development and progression of diabetic nephropathy. PF-04634817 is a dual chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy. METHODS: We evaluated the efficacy of PF-04634817 compared with matching placebo for reduction of albuminuria after 12 weeks of treatment in subjects with type 2 diabetes who received standard of care (SOC; angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy), in a randomized, double-blind, placebo-controlled, parallel-group phase 2 study. RESULTS: A total of 226 subjects who received SOC with baseline estimated glomerular filtration rates between 20 and 75 ml/min per 1.73 m2 and a baseline urinary albumin-to-creatinine ratio (UACR) of ≥300 mg/g were randomly assigned 3:1 to receive PF-04634817 (150 or 200 mg orally, once daily) or placebo. The primary analysis was Bayesian, with an informative prior for placebo response (equivalent to including an additional 80 subjects in the placebo arm). We observed a placebo-adjusted reduction in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75-1.09) at week 12 in the PF-04634817 arm. PF-04634817 appeared to be safe and well-tolerated. CONCLUSION: Despite the good safety profile shown by PF-04634817, clinical development for this indication was discontinued in light of the modest efficacy observed.

Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis.

BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) reduces fracture risk in postmenopausal women with osteoporosis. We assessed the safety and incidence of new vertebral fractures after withdrawal of teriparatide. METHODS: This study is a follow-up to the Fracture Prevention Trial (FPT), a randomized, placebo-controlled study of postmenopausal women with osteoporosis treated with teriparatide (20 or 40 microg) once daily for a mean of 18 months. More than 90% of the women remaining at the end of the FPT continued into the follow-up study (n = 1262). Patients and investigators were unblinded to original treatment group assignment. Women were treated according to standard clinical practice, including elective use of osteoporosis drugs. New vertebral fractures were determined by semiquantitative scoring of lateral thoracic lumbar spine radiographs 18 months after the end of the FPT. RESULTS: During the follow-up study, the reduction in fracture risk associated with previous treatment with teriparatide, 20 and 40 microg, was 41% (P = .004) and 45% (P = .001), respectively, vs placebo. The absolute reduction from the FPT baseline to the 18-month follow-up visit was 13% for both doses. Osteoporosis drugs were used by 47% of women during follow-up, with greater use in the former placebo group (P = .04); nevertheless, persistent fracture protection of previous teriparatide therapy was evident. Post hoc analysis also suggests that teriparatide treatment substantially reduced the increased risk of subsequent fracture in women who sustained a fracture during the FPT (P = .05). CONCLUSION: Vertebral fracture risk reduction by teriparatide administration persists for at least 18 months after discontinuation of therapy.

Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis.

Both raloxifene (RLX) and alendronate (ALN) can treat and prevent new vertebral fractures, increase bone mineral density (BMD), and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis. This phase 3, randomized, double-blind 1-yr study assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis (femoral neck BMD T-score, less than -2). Women (aged < or = 75 yr; > or = 2 yr since their last menstrual period) received placebo, RLX 60 mg/d, ALN 10 mg/d, or RLX 60 mg/d and ALN 10 mg/d combined. At baseline, 6 and 12 months, BMD was measured by dual x-ray absorptiometry. The bone turnover markers serum osteocalcin, bone-specific alkaline phosphatase, and urinary N- and C-telopeptide corrected for creatinine were measured. The effects of RLX and ALN were considered to be independent and additive if the interaction effect was not statistically significant (P > 0.10) in a two-way ANOVA model. All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups, and between the RLX and RLX+ALN groups (P < 0.05). On average, lumbar spine BMD increased by 2.1, 4.3, and 5.3% from baseline with RLX, ALN, and RLX+ALN, respectively. The increase in femoral neck BMD in the RLX+ALN group (3.7%) was greater than the 2.7 and 1.7% increases in the ALN (P = 0.02) and RLX (P < 0.001) groups, respectively. The changes from baseline to 12 months in bone markers ranged from 7.1 to -16.0% with placebo, -23.8 to -46.5% with RLX, -42.3 to -74.2% with ALN, and -54.1 to -81.0% in the RLX+ALN group. RLX and ALN increased lumbar spine and femoral neck BMD, and decreased osteocalcin and C-telopeptide corrected for creatinine in an additive and independent manner, because the interaction effects were not significant. Although the ALN group had changes in BMD and bone markers that were approximately twice the magnitude as in the RLX group, it is not known how well these changes correlate to the clinical outcome of fracture. RLX+ALN reduced bone turnover more than either drug alone, resulting in greater BMD increment, but whether this difference reflects better fracture risk reduction was not assessed in this study.

A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis.

Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.

Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture: a double-blind, randomized, controlled phase-II/III trial.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation. METHODS: Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone. RESULTS: Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups. CONCLUSIONS: In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. 24306696