History
Asfotase alfa was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in September 2008.Asfotase alfa is manufactured by Alexion Pharmaceuticals and it was granted breakthrough therapy designation by the U.S. FDA in 2015 as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. It was approved in October 2015, in the U.S. and in August 2015, in the EU.The safety and efficacy of asfotase alfa were established in 99 participants with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that participants with perinatal- and infantile-onset HPP treated with asfotase alfa had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated participants were alive at one year of age compared to 42 percent of control participants selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated participants compared to less than 50 percent for the natural history control participants.Participants with juvenile-onset HPP treated with asfotase alfa showed improvements in growth and bone health compared to control participants selected from a natural history database. All treated participants had improvement in low weight or short stature or maintained normal height and weight.
The involvement of the orbitofrontal cortex and dorsolateral prefrontal cortex in OCD is shared with bipolar disorder, and may explain the high degree of comorbidity. Decreased volumes of the dorsolateral prefrontal cortex related to executive function has also been observed in OCD.People with OCD evince increased grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, with decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri. These findings contrast with those in people with other anxiety disorders, who evince decreased (rather than increased) grey matter volumes in bilateral lenticular/caudate nuclei, as well as decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri. Increased white matter volume and decreased fractional anisotropy in anterior midline tracts has been observed in OCD, possibly indicating increased fiber crossings. Cognitive models
Generally, two categories of models for OCD have been postulated. The first category involves deficits in executive dysfunction and is based on the observed structural and functional abnormalities in the dlPFC, striatum and thalamus. The second category involves dysfunctional modulatory control and primarily relies on observed functional and structural differences in the ACC, mPFC, and OFC.One proposed model suggests that dysfunction in the OFC leads to improper valuation of behaviors and decreased behavioral control, while the observed alterations in amygdala activations leads to exaggerated fears and representations of negative stimuli.Due to the heterogeneity of OCD symptoms, studies differentiating various symptoms have been performed.