Belimumab: a BLyS-specific inhibitor for systemic lupus erythematosus.

OBJECTIVE: To review the efficacy, safety, dosing, drug interactions, as well as economic and therapeutic considerations of belimumab, an investigational B-lymphocyte stimulator (BLyS) inhibitor. DATA SOURCES: A systematic, English-language MEDLINE search (1966-August 2010) was conducted using the search terms belimumab, Benlysta, B-lymphocyte stimulators, BLyS-specific inhibitors, and systemic lupus erythematosus (SLE). Press releases and bibliographies were reviewed for additional information and citations. STUDY SELECTION AND DATA EXTRACTION: Belimumab was first identified and studied as a human protein target in 1999. Therefore, all published clinical trials and abstracts evaluating the safety and efficacy of belimumab for treatment of SLE as well as review articles from 1999 to present were evaluated for inclusion. Additional data were extracted from the manufacturer's Web site and Food and Drug Administration (FDA) documents. DATA SYNTHESIS: Current therapies for SLE target nonspecific sites for inflammatory reduction and immune system suppression. Belimumab is a target-specific, human IgG1λ monoclonal B-lymphocyte stimulator inhibitor currently in late stage investigation for the treatment of SLE. Unpublished Phase 3 trials have reported statistically significant results for primary endpoints when belimumab 10 mg/kg plus standard of care was compared to placebo plus standard of care in seropositive patients with SLE. Overall, belimumab has been relatively well tolerated with discontinuation rates and adverse events similar to those of placebo. If belimumab is approved by the FDA, its US market launch would be expected in 2011. CONCLUSIONS: Belimumab has shown significant benefits for patients with SLE in the few Phase 3 trials that have been published. However, questions remain regarding optimal patient population, duration of treatment, place in therapy, and long-term adverse effects.

Plerixafor: a peripheral blood stem cell mobilizer.

Autologous hematopoietic stem cell (HSC) transplantation is a treatment strategy for restoring normal hematopoietic function in patients with select hematologic malignancies. The number of CD34(+) cells available for transplantation has been reported to be the strongest predictor of transplantation success, as measured by rapid and durable hematopoietic recovery. Currently, granulocyte colony-stimulating factor (G-CSF) alone or G-CSF plus chemotherapy are the most commonly used methods for stem cell mobilization. Unfortunately, 5-30% of patients do not respond to these agents. Plerixafor is a new HSC mobilizing drug that antagonizes the binding of chemokine stromal-cell-derived factor-1alpha (SDF-1alpha) to CXC chemokine receptor 4 (CXCR4). It is indicated in combination with G-CSF to mobilize HSC to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Results of clinical trials have shown that plerixafor plus G-CSF allow for the collection of a high yield of HSC with fewer apheresis sessions in patients with NHL and MM. Plerixafor has also shown promising results in small studies enrolling patients with Hodgkin's lymphoma. Moreover, for patients who fail G-CSF mobilization alone, plerixafor with G-CSF may be useful as a salvage mobilization strategy. Overall, plerixafor has been generally well tolerated with adverse effects classified as mild to moderate. The most common adverse effects reported in randomized clinical trials were injection site reactions and diarrhea, with approximately 33% of patients experiencing these effects. To our knowledge, clinical trials comparing G-CSF plus plerixafor with G-CSF plus chemotherapy and cost-effectiveness analyses have not been published; therefore, questions remain regarding the optimal role of plerixafor in the clinical practice setting.

Aromatase inhibitors for ovulation and pregnancy in polycystic ovary syndrome.

OBJECTIVE: To evaluate evidence for use of aromatase inhibitors for ovulation induction and pregnancy in patients with polycystic ovary syndrome (PCOS). DATA SOURCES: A MEDLINE search (1966-May 2009) was conducted using the search terms anastrozole, aromatase inhibitors, exemestane, letrozole, ovulation, and polycystic ovary syndrome to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Prospective clinical trials published in English and conducted in humans were identified. Trials using intrauterine insemination methods for pregnancy were excluded. The resulting articles were separated into 2 groups: aromatase inhibitor use in clomiphene-resistant patients and use in treatment-naïve patients. Eleven trials were reviewed. DATA SYNTHESIS: Accepted pharmacologic treatments for women with PCOS and infertility include clomiphene citrate, gonadotropins, and gonadotropin-releasing hormone (GnRH) analogs. Each medication has variable efficacy rates and adverse effects. Therefore, other treatments are needed for a subset of women with PCOS and infertility. Evidence suggests that nonsteroidal aromatase inhibitors, specifically letrozole and anastrozole, may have ovulation-inducing effects by inhibiting androgen-to-estrogen conversion. Select trials with aromatase inhibitors have demonstrated efficacy for increased endometrium thickness, ovulation rates, and pregnancy rates when used in clomiphene citrate-resistant or treatment-naïve patients. CONCLUSIONS: Further trials comparing aromatase inhibitors with clomiphene citrate are necessary before aromatase inhibitors can be recommended routinely for ovulation induction in women with PCOS and infertility. However, aromatase inhibitors may be considered in a subset of this population, specifically women who are clomiphene citrate resistant or those who, after discussion of risks and benefits, are not candidates for clomiphene citrate, gonadotropins, or GnRH analogs.

Sipuleucel-T: a vaccine for metastatic, asymptomatic, androgen-independent prostate cancer.

OBJECTIVE: To review the design, efficacy, safety, dosing, therapeutic, and pharmacoeconomic considerations of sipuleucel-T, an investigational, autologous, dendritic, cell-based prostate cancer vaccine. DATA SOURCES: English-language literature searches of MEDLINE (1966-September 2007) and the Cochrane Database (2007, Issue 3) were performed using the terms sipuleucel-T, APC8015, and prostate cancer vaccine. Other data sources were identified from bibliographies of selected articles and from press releases. STUDY SELECTION AND DATA EXTRACTION: All published articles or abstracts on human studies of sipuleucel-T for androgen-independent prostate cancer (AIPC) were reviewed for inclusion. Manufacturer Web sites, Food and Drug Administration (FDA) documents, and the clinical trials registry were used to obtain information regarding ongoing clinical trials. DATA SYNTHESIS: AIPC is an incurable disease with a median survival rate of 18-20 months. Docetaxel-based chemotherapy is currently the only FDA-approved treatment for AIPC with a survival benefit (2.4 mo). Sipuleucel-T is a novel active cellular immunotherapy under investigation for the treatment of metastatic, asymptomatic AIPC. In clinical trials, the primary endpoint of time to disease progression was not met; however, an underpowered analysis of data suggests that sipuleucel-T prolongs survival by a median of 4.5 months compared with placebo. Sipuleucel-T has been relatively well tolerated, although a possible increased risk of cerebrovascular events may exist. In May 2007, the FDA did not approve the biologics license application for sipuleucel-T since the primary endpoint of the Phase 3 trials was not met. However, its approval will be reconsidered by the FDA once interim survival results from an ongoing Phase 3 trial, IMPACT, are determined. These data are anticipated to be released in the fourth quarter of 2008. CONCLUSIONS: Metastatic AIPC is an incurable disease that currently has limited treatment options. Approval of sipuleucel-T hinges on results from the IMPACT trial. If improved survival is shown, sipuleucel-T may become the first approved active cellular immunotherapy for treating metastatic, asymptomatic AIPC.

Human papillomavirus vaccines.

OBJECTIVE: To review the pharmacology, efficacy, safety, tolerability, and pharmacoeconomics of Cervarix and Gardasil, 2 human papillomavirus (HPV) vaccines. DATA SOURCES: English-language articles were obtained by MEDLINE search (1966-February 2006) using the key words human papillomavirus vaccine, Cervarix, and Gardasil. Bibliographies of selected articles were used to identify additional sources. STUDY SELECTION AND DATA EXTRACTION: All available published articles or abstracts reporting the results of human studies of HPV vaccines were reviewed for inclusion in this article. Additional information about ongoing clinical trials was obtained from manufacturers' Web sites. DATA SYNTHESIS: Cervarix and Gardasil are recombinant vaccines against HPV. Cervarix targets HPV-16 and -18, which are responsible for 70% of cervical cancers. Gardasil also targets HPV-16 and -18, plus the HPV-6 and -11 types responsible for more than 80% of genital warts. Both vaccines have been effective in preventing persistent infection with targeted HPV types and in preventing cervical intraepithelial lesions, while Gardasil has also been effective in preventing vulvar and vaginal neoplasia and genital warts. Both vaccines have been well tolerated, with the most common adverse effects occurring at the injection site. Phase III trials are ongoing to further evaluate vaccine efficacy. CONCLUSIONS: Cervarix and Gardasil are effective for prevention of HPV infection and cervical lesions. Issues remaining to be addressed include duration of protection, efficacy for prevention of cervical cancer, optimal age for vaccination, feasibility of application to the developing world, the ideal combination of HPV subtypes, and the most efficient combination of vaccination and cervical cancer screening.

Mycophenolate mofetil treatment of myasthenia gravis.

OBJECTIVE: To review published literature evaluating the effectiveness of mycophenolate mofetil for the treatment of myasthenia gravis (MG). DATA SOURCES: Searches of MEDLINE (1966-August 2005) and Cochrane Database (1993-August 2005) were conducted. Studies conducted in humans and published in English were retrieved. Additional data were identified through subsequent bibliographic reviews. DATA SYNTHESIS: Interruption of T- and B-lymphocyte proliferation in various autoimmune diseases has been investigated. Mycophenolate is known to inhibit lymphocyte proliferation and has shown improved clinical responses in several autoimmune diseases including lupus erythematosus, rheumatoid arthritis, and systemic vasculitis. Data suggesting similar benefits in MG treatment have been reported in case reports, retrospective analyses, an open-label trial, and a randomized, double-blind trial. CONCLUSIONS: Limited evidence from retrospective analyses and clinical trials suggests that mycophenolate is a possible treatment option for patients with MG. Improvement in clinical symptoms and a steroid-sparing effect have been reported when mycophenolate is used in this patient population. Larger, randomized, controlled, and comparative trials are needed to establish optimal dose, time to effect, specific therapeutic role, and long-term safety for mycophenolate when used for treating MG.