Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders.

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies.

New drugs and new molecular entities in dermatology.

OBJECTIVE: To identify and analyze the possible reasons that so few drugs with new molecular entities (NMEs) are first developed for "dermatologic diseases," especially diseases treated primarily by dermatologists. DESIGN: Systematic review and analysis. IMS Health (the pharmaceutical industry worldwide product database) was searched using the terms first launch, topical, and skin/dermatological for the preceding decade. These terms were used for inclusion but not exclusion so that intravenous and oral agents were also identified if they were for skin or dermatologic use. The US Food and Drug Administration (FDA) New Molecular Entities Drug and New Biologic Approvals Web site for the 10 years from 1999 to 2009 was examined for approval of dermatologic agents. To determine the frequency of drug development for dermatologic drugs compared with other fields, the total number of NMEs by therapeutic category for the 5-year period 2005 to 2009 was assessed. RESULTS: Worldwide, the total number of NMEs for diseases treated primarily by dermatologists for almost a decade was 13. Using the FDA Web site, 5 NMEs for diseases treated primarily by dermatologists were approved in 10 years. CONCLUSIONS: The major factors precluding NME development for dermatologic diseases seem to be (1) the economic potential of dermatologic drugs, (2) the benefit-to-risk relationship, (3) the limited number of surrogate end points and "soft" semiquantitative end points, and (4) the limited or inadequate basic knowledge of the pathophysiologic characteristics of skin diseases.

Salvage treatment of histoplasmosis with posaconazole.

Six patients received salvage treatment with posaconazole oral suspension (800 mg/day in divided doses) for severe forms of histoplasmosis. One patient had pulmonary disease and 5 had disseminated disease. Previous antifungal therapy consisted of amphotericin B, itraconazole, fluconazole, or voriconazole. Posaconazole treatment duration for individual patients ranged from 6 weeks to 34 weeks. All patients had successful clinical outcomes with significant clinical improvements noted during the first month of therapy. Although the number of patients evaluated in this case series is small, the findings are encouraging and provide preliminary evidence that posaconazole may be a useful salvage treatment option for histoplasmosis involving a variety of infected tissues and organs.

Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial.

BACKGROUND: Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. RESULTS: Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. CONCLUSIONS: Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions.

BACKGROUND: Conventional amphotericin B-based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a > or = 70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species. METHODS: In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy. RESULTS: Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia. CONCLUSION: These results suggest that posaconazole is useful for the treatment of invasive fusariosis.

Refractory coccidioidomycosis treated with posaconazole.

BACKGROUND: Disseminated coccidioidomycosis (which is caused by the endemic fungi of the genus Coccidioides) can be a life-threatening systemic fungal infection. Although conventional antifungal therapies have activity against Coccidioides, the disease can be refractory to standard therapies. Drug-associated toxicities also may limit the clinical utility of the standard antifungal drugs. In addition, relapses in patients with disseminated coccidioidomycosis are common, making long-term management of this disease challenging. METHODS: We report the outcomes of 6 patients with coccidioidomycosis who were treated with posaconazole salvage therapy after treatment with conventional antifungal therapies failed to produce sustained clinical improvement. Patients were administered posaconazole oral suspension 800 mg/day in divided doses as part of an open-label clinical trial. A modified version of the Mycoses Study Group Coccidioides scoring system was used to evaluate the burden of disease. Posaconazole therapy resulted in rapid clinical improvements in the signs and symptoms of coccidioidomycosis. RESULTS: At the end of therapy, 5 of 6 patients had successful outcomes. Posaconazole was well tolerated despite long-term administration (1-2 years), and 2 patients continued to receive posaconazole maintenance therapy at the time of writing. CONCLUSIONS: The successful outcomes observed in this case series suggest that posaconazole is an effective therapy for coccidioidomycosis.