The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy.

PURPOSE: Hematopoietic stem-cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. METHODS: In this single-arm open-label pivotal trial (NCT02222545), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed. RESULTS: The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern. CONCLUSION: In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab.

In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway's effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

BACKGROUND: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. METHODS: In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. FINDINGS: 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). INTERPRETATION: Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. FUNDING: Allon Therapeutics.

An atypical presentation of breast cancer metastasis.

A 78-year-old woman heard a crack in her left mandible while eating a biscuit and reported to her dentist, who urgently referred her to the oral and maxillofacial surgery department. On examination she had a lesion in the body of her left mandible, which had eroded through the lower border and caused a pathological fracture. Her past medical history included a left mastectomy and level II axillary lymph node dissection for a 27 mm grade III invasive ductal carcinoma of the left breast 9 months prior to her mandibular fracture. A transoral incisional biopsy was performed which confirmed the mandibular lesion to be an osteolytic metastasis from the breast. The metastasis was subsequently surgically removed and the remaining mandible repaired with a reconstruction plate followed by postoperative radiotherapy. The patient regained full function of her mandible and is now eating normally. She is being closely followed-up in the oncology outpatient department.

Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial.

PURPOSE: We evaluated the efficacy and safety of tadalafil 20 mg, taken on demand, in men with erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy (BNSRRP). MATERIALS AND METHODS: This randomized, double-blind, placebo controlled multicenter study consisted of a 4-week treatment-free run-in period (baseline) followed by 12 weeks of treatment. A total of 303 men (mean age 60 years) with preoperative normal erectile function who had undergone a BNSRRP 12 to 48 months before study were randomized (2:1) to tadalafil (201) or placebo (102). The 3 co-primary end points were changes from baseline in the International Index of Erectile Function erectile function domain score, and the percentage of positive responses to Sexual Encounter Profile questions 2 (successful penetration) and 3 (successful intercourse). The Global Assessment Question and the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire were secondary end points. We defined a priori a subgroup of 201 patients reporting evidence of postoperative tumescence, defined as 50% or greater "yes" responses to Sexual Encounter Profile question 1 (ability to achieve at least some erection) during baseline intercourse attempts and stratified randomization based on this criterion. RESULTS: Patients receiving tadalafil reported greater improvement on all primary and secondary end points (p <0.001) compared to placebo. For all randomized patients and for the subgroup with evidence of postoperative tumescence, the mean International Index of Erectile Function erectile function domain score increased for patients receiving tadalafil (mean +/- SEM 5.3 +/- 0.5 and 5.9 +/- 0.7, respectively, p <0.001 vs placebo for both). For all randomized patients who received tadalafil, the mean percentage of successful penetration attempts was 54% and the mean percentage of successful intercourse attempts was 41%. For the subgroup with evidence of postoperative tumescence these values were 69% and 52%, respectively. Of all patients randomized to tadalafil 62% and of the subgroup patients randomized to tadalafil 71% reported improved erections. Patients receiving tadalafil reported greater treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction than those receiving placebo. Headache (21%), dyspepsia (13%) and myalgia (7%) were the most commonly reported adverse events. CONCLUSIONS: Tadalafil 20 mg, taken on-demand, was an efficacious and well tolerated treatment for erectile dysfunction following BNSRRP.

Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses.

PURPOSE: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg up to a maximum of once daily [DOSAGE ERROR CORRECTED] in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of "yes" responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question. RESULTS: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Patients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in International Index of Erectile Function erectile function domain score from baseline (p <0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p <0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p <0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events. CONCLUSIONS: Tadalafil was effective and well tolerated in this patient population.