ITI-007 (7) represents a new approach to the treatment of schizophrenia, targeting an improvement in social function in addition to antipsychotic efficacy and an associated highly favorable safety and tolerability profile. ITI-007 is a small molecule therapeutic agent interacting with serotonergic, dopaminergic and glutamatergic neurotransmitter targets in a complex, unique and regionally selective manner [23, 24]. ITI-007 is designed specifically to combine potent serotonin 5-HT2A receptor antagonism with modulation of phosphoprotein pathways downstream of dopamine receptors and with serotonin reuptake inhibition. ITI-007 has dual properties, acting as a post-synaptic antagonist and as a pre-synaptic partial agonist at dopamine D2 receptors in vivo with mesolimbic/mesocortical selectivity [23]. Though the effect of ITI-007 at pre-synaptic D2 receptors resembles that of aripiprazole [106, 107], the post-synaptic D2 interactions are different. Whereas aripiprazole is a partial agonist at pre-synaptic and post-synaptic receptors, ITI-007 is an antagonist at post-synaptic receptors. The structural features of the compound responsible for this unique interaction at D2 receptors for ITI-007 have not been defined. ITI-007 also indirectly modulates glutamatergic activity by increasing the phosphorylation of the NR2B (or GluN2B) subunit of N-methyl-D-aspartate (NMDA) channels in extrastriatal dopamine-rich brain regions (e.g. nucleus accumbens). The precise molecular pathway underlying this effect of ITI-007 has not been elucidated, though phosphorylation of NR2B at the tyrosine-1472 (Y1472) residue is known to be regulated through a pathway downstream of dopamine D1 receptor activation impacting Fyn kinase [123]. The spectrum of biochemical actions is referred to as dopamine receptor protein phosphorylation modulation (DPPM). The combination of ITI-007’s high potency blockade of 5-HT2A receptors, efficient dopamine modulation, serotonin reuptake inhibition, and indirect enhancement of glutamatergic neurotransmission has been shown to yield antipsychotic efficacy without motor side effects or cardiometabolic safety issues. ITI-007 demonstrated a reduction of positive symptoms in patients with schizophrenia comparable to risperidone, but with significantly lower blood levels of biomarkers indicative of potential metabolic dysfunction (i.e., insulin, glucose, cholesterol and triglycerides) and prolactin [124]. ITI-007 was also associated with lower rates of motor side effects, such as akathisia, and cardiovascular side effects, such as tachycardia, than risperidone. Moreover, ITI-007 showed a greater efficacy in the improvement of negative symptoms and prosocial behavior than risperidone.
What’s up @twinklestars. Any word in iti-007 as far as a release date goes?
Hey @MeghillaGorilla1 welcome back.
Nothing new on iti-007, probably won’t be much til the bipolar trials conclude, around Aug 2018. I keep my eye out (and my google alerts on) for anything in the interim though.
Thanks. It would be a dream come true for a lot of us if something like that came out
Is this a kind of a better version of abilify?
If it’s approved, it will be an entirely new class of AP.
But, it failed one of its stage 3 trials, but that appears to be because the placebo response shot up (the overall response to the drug was similar in the stage 2 and 3 trials. ) So it may be approved but that is not yet clear. The FDA has said they will consider it, but Intracellular will probably not submit an NDA until they have more data.
May 17: company has provided an update on discussions with the FDA - while there are no issues with the human clinical development programme, the FDA has raised concerns over effects seen in some pre-clinical animal toxicology studies. The company and its expert advisers do not believe that these are relevant to human safety due to significant species differences in the metabolism of the drug and are preparing a response to the FDA request for more information: if this is deemed sufficient, they expect to submit a New Drug Application by mid-2018 [6].
No development for UK or the European market. â– â– â– â– â– â– â– â– !
Mid-2018 is also when the bipolar trials will end (estimated in Aug 2018) so they will have more data to support efficacy and safety.
Whatever concerns the FDA has about safety weren’t enough to stop the trials, so that’s a good sign.
Indeed. I’m actually really excited about this drugs but I guess development status “unknown” means it’ll never get to Europe or if it does it’ll take another (half) decade.
If they get it approved in the US, they’ll probably then pursue approval in Europe. It’s a big market, they won’t ignore it. And if the FDA accepts the data, it’s likely EU authorities will too. I think you’re probably right about the 5 ish year time frame though.
Great news!!!
Yeah, but it’s really frustrating!! Like Latuda, Cariprazine and the phase III drug for depression (ALKS-5641). I the near future ALKS-5641 is about to get an NDA in the US. Here in Europe it’s still in phase II. I guess it’s all about money, guess they can charge more for a med in the US than Europe.
Maybe you know, here 28 pills of 37mg Latuda costs 80euros (that’s 90-100 USD). How much is there?
The original linked article was a very long one, but interesting as it talked about the degree of occupancy for the D2 receptors in typical and atypical APs. Apparently, a level of 65% or greater is required for antipsychotic effect, except in Clozaril. Bad side effects start with occupancy of 50%. It is unknown why Clozaril is an exception, but certainly indicates there’s more to it than just D2. Particularly because some people who don’t respond to the D2 APs do respond to Clozaril. I don’t think ITI 007 has been tried or suggested in treatment resistant sz yet but perhaps it will be helpful.
Quote from the original article:
"Positron emission tomography (PET) imaging studies have demonstrated that clinical antipsychotic response is usually associated with at least 65% occupancy of striatal D2 dopamine receptors, while 50-73% occupancy can be associated with hyperprolactinemia and over 80% occupancy is associated with extrapyramidal side effects [173-180]. Therefore, it is difficult to achieve antipsychotic efficacy without concomitant motoric disturbances and hyperprolactinemia with both typical and atypical antipsychotic drugs. This relationship between D2 receptor occupancy, clinical response and side effects, even in first episode patients, is well-established
“Haloperidol, for example, often gives high (>80%) striatal D2 receptor occupancy at therapeutic doses and results in motor disturbances such as parkinsonism and akathisia [174]. Similarly, risperidone, across its effective dose range of 4 to 12 mg/day, is associated with 72 – 81% striatal D2 receptor occupancy [152, 175, 181-183]. With aripiprazole, D2 and D3 receptor occupancy levels are high, with average levels ranging between ~71% at a low, sub-therapeutic dose of 2 mg/day to ~96% at 40 mg/day [155, 184]. Although aripiprazole is associated with relatively less liability for parkinsonism, other motoric side effects such as akathisia occur at relatively high rates. Clozapine is an exception with relatively low striatal D2 receptor occupancy (<60%) at antipsychotic doses and a low liability for parkinsonism, akathisia, and hyperprolactinemia [152, 174, 183, 185, 186]. At a low single dose of 10 mg in healthy volunteers, ITI-007 demonstrated low (~12%) striatal D2 receptor occupancy and high (>80%) cortical 5-HT2A receptor occupancy [156]. ITI-007 demonstrated an average of 29% (peak of 39%) D2 occupancy at the highest evaluated dose in healthy volunteers. At a 40 mg dose, ITI-007 also demonstrated occupancy of serotonin transporters in healthy volunteers in a range similar to that of its D2 receptor occupancy, consistent with its in vitro pharmacological profile and antidepressant-like effects. In a double-blind, placebo-controlled efficacy trial, a dose of 60 mg ITI-007 was evaluated in patients with acute schizophrenia and demonstrated antipsychotic efficacy with a placebo-like motor side effect profile and no hyperprolactinemia [124]. Subsequently, 60 mg ITI-007 demonstrated approximately 40% striatal D2 receptor occupancy at plasma steady state after two weeks of administration in patients with schizophrenia who had been washed off their previous antipsychotic medications for at least two weeks prior to a within-subject baseline PET scan [125]. These data suggest that ITI-007 achieves antipsychotic efficacy at low levels of striatal D2 receptor occupancy yielding a lower risk for extrapyramidal side effects and hyperprolactinemia.”
I mainly want to try ITI-007 so I can go around introducing myself as, “Bond, James Bond.”
Yoink!
