Phase III Results

Aldurazyme is an enzyme replacement therapy for the treatment of MPS I disease. Phase III results with aldurazyme warranted filingfor marketing approval in 2002. MPS I is a genetic disease caused by the deficiency cf... 

Phases I and II have eovered planning and undertaking a P2 audit, resulting in the preparation of a material balance for each unit operation. Phase III represents the interpretation of the material balance, to identify process areas or components of concern. 

OPG has been shown to reduce bone turnover in postmenopausal women. More recently, Denusomab, an anti-RANKL mAb, has been tested for its ability to increase BMD and to reduce bone turnover. Results were promising and clinical phase III studies with fracture endpoints are presently under way. 

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

Compound 34 (BCZ-1812, RWJ-270201, peramivir) showed selective inhibition of influenza virus sialidases over bacterial and mammalian sialidases (Babu et al. 2000 Bantia et al. 2001 Sidwell and Smee 2002). Successful inhibition of influenza virus infectivity in vitro (Smee et al. 2001) and upon oral administration in vivo [mice (Bantia et al. 2001) and ferrets, reviewed in Sidwell and Smee 2002] led to human clinical trials of orally administered peramivir (Barroso et al. 2005). While orally administrated peramivir successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was showing neither major side effects nor toxicity (Sidwell and Smee 2002), preliminary results of the Phase III trials (June 2002) demonstrated no statistically significant difference in the primary efficacy endpoint, possibly due to low bioavailability (Barroso et al. 2005). 

Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, Lee JH, Fox TL, Alomar A (2004) Imiquimod 5% cream for the treatment of actinic keratosis results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 51 547-555... 

Thiboutot D, Thieroff-Ekerdt R, Graupe K (2003) Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea results from 2 vehicle-controlled, randomized, phase III studies. J Am Acad Dermatol 48 836-845... 

Pharmacologic neuroprotection, which might be expected to prevent tissue necrosis or apoptosis until tissue reperfusion can be achieved with rt-PA, is a theoretically attractive adjunct to rt-PA treatment. Despite positive studies in animals, all evaluations of neuroprotective agents in humans have failed. Most recently, the promising initial results for intravenous NXY-059, a ffee-radical-trapping agent, were not replicated in a confirmatory phase III trial (unpublished data). 

Direct Fibrinolytics Alfimeprase is a recombinant tmncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising, but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for I AT in acute stroke (CARNEROS-1) is planned to begin soon. 

Obviously, the greater the number of subjects studied, the larger the cost. Nevertheless, having too few subjects may lead to inconclusive results, requiring that the study be repeated. Another important consideration is the availability of qualified participants. If the inclusion and exclusion criteria are very restrictive, the cost of recruiting subjects may exceed that of the actual testing. In pharmaceutical development trials, it is not unusual to see recruitment budgets of US 500- 1000 per randomized subject. Thus, for a Phase III development study with several hundred participants, often more than US 500 000 in cost is allotted to efforts to identify qualified subjects who are interested in participation. 

The four main phases involved in a field soil dissipation study are (I) planning and design phase, (II) field-conduct phase, (III) sample processing/analysis phase, and (IV) data handling/reporting phase. Each phase is vitally linked to the next and each is critical to study success. Results from an otherwise perfectly executed study may be made useless by uneven test substance application or improper sampling, sample handling, and/or analytical techniques. Each of these phases is discussed below. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

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