Swedish Company Announces Results of Phase II study of Dopamine Stabilizing Compound

HD Lighthouse Contributing Editor's Comment: We haven't covered dopaminergic stabilizers on the Lighthouse before and we usually wait to see peer reviewed journal articles before responding to press releases. However, it is exciting to learn that Phase III clinical trials are being planned and it seems like a good time to learn about dopaminergic stablizers and start following this line of research.

ACR16 is an antagonist to the Dopamine 2 (D2) receptor while acting overall as a stabilizer of the dopamine system. Dopamine stabilizers are of interest to the HD community for two reasons. First, because these drugs may treat chorea with fewer side effects than the dopamine depleting agents currently in use.

Second, this could be a treatment for the disease. The company thinks that it might be because it improves akinesia (slow, reduced movement) which is associated with disease progression and because they got some cognitive improvement. There is some research to suggest that normal levels of dopamine have toxic affects in HD patients and that antagonizing the D2 receptor might slow progression. (more on dopamine) ACR16 is an antagonist of that receptor so that's encouraging.

Third, the drug has been given orphan drug status by the FDA. I hope that the Phase III trials will include more measures of disease progression and that Carlsson research will consult in advance with the FDA even if trials will not be held in this country to maximize the changes of fast track approval if Phase III trials show continued safe and efficacy for treating symptoms or the disease or both.

In addition to the press release about the Phase II study with HD below, I've included information about dopamine stabilizers from the Carlsson Research website, and abstracts from two other studies involving ACR16, both with rodent models of psychosis.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 29 May 2006

Carlsson Research announces that the results from the ACR16C007 Phase II study indicate that ACR16 improves the symptoms associated with Huntington disease. The study was performed in six University clinics in Sweden and Norway.

The study ACR16C007 is a double blind, placebo-controlled study, investigating the effects of ACR16 and placebo in patients with Huntington disease. Altogether 58 patients were randomized to receive either ACR16 or placebo for four weeks. In the study, effects on commonly encountered symptoms such as disturbances in motor function, psychiatric symptoms as well as cognitive functions were assessed.

ACR16 was well tolerated; analysis showed there was no appreciable difference between the treatment groups, placebo or ACR16, in the quality, frequency, or severity or of side effects. ACR16 treatment improved motor function, particularly chorea (involuntary movements), gait and dysarthria. Subsequent analysis also demonstrated that ACR16 reduced akinesia, a symptom characterized by underlying slowness and poverty of movements. There was also a strong trend towards reduction of symptoms of anxiety and depression in ACR16 treated patients and a marked improvement in performing the Trail Making test, a test for cognitive function.

Dr Joakim Tedroff, Chief Medical Officer at Carlsson Research stated “the results from this study are very encouraging and validates our drug discovery technology, ISP, in humans. We are particularly encouraged by the finding of reduced akinesia, a symptom strongly associated with functional decline in Huntington disease patients. This study supports our development approach for ACR16 in the disorder”.

Given the broad action of ACR16 in preclinical models, Carlsson Research believes ACR16 can be used as a symptomatic treatment for a number of symptoms associated with Huntington disease including motor and mental symptoms. Phase III studies will now be undertaken to bring the compound to the market.

From their site: Dopaminergic stabilisers

Dopaminergic stabilisers are compounds that can either enhance or counteract central dopaminergic effects, depending on the initial level of dopaminergic activity. Typically, a dopaminergic stabiliser displays a DA D2-like neurochemical profile in conjunction with absence of, or at most limited, effects on normal exploratory behaviour. In states of hyperactivity, the level of activity is reduced to a normal level. The most advanced compound in this project is the CD ACR16, which is effective in experimental animal models of schizophrenia, yet leaving the behaviour of intact animals unaffected. Unlike current antipsychotic compounds, ACR16 restores not only behavioural quantity, but also quality, in rodent psychosis models in a unique fashion. On the whole, the pre-clinical profile of ACR16 suggests that the compound can be used to treat the full range of symptoms associated with schizophrenia, including positive and negative symptoms and symptoms not reached by current therapies such as impairment of cognitive and social functions. ACR16 has a low likelihood of inducing extrapyramidal side effects, or side effects related to the reward system. The DA stabilisation properties of ACR16 also makes it a candidate for treatment of neuropsychiatric disorders, such as ADHD, Huntington’s disease (HD), late stage Parkinson’s disease (PD), and dementia. ACR16 has been clinically explored in a phase Ia/Ib programme showing a good safety/PK profile and clear indications of efficacy in HD, PD and schizophrenia. Beneficial effects were noted on psychotic symptoms, and on cognitive, emotional, and motor functions as well as on sleep in these patient populations. No anti-psychotic like side-effects such as EPS or sedation were observed.

Their 2004 publication:

M. Nilsson, A. Carlsson, K. Markinhuhta, C. Sonesson, F. Pettersson, M. Gullme and L. Carlsson. "The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition." Progress in Neuro-Psychopharmacology and Biological Psychiatry Vol. 28, Issue 4, July 2004, Pages 677-685

The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.

Other research publications:

S Natesan, KA Svensson, GE Reckless, JN Nobrega, KB Barlow, AM Johansson, and S Kapur. "The dopamine stabilizers (-)-OSU6162 and ACR16 show high in vivo D2 receptor occupancy, antipsychotic- like efficacy and low potential for motor side effects in the rat." The Journal of Pharmacology and Experimental Therapeutics. 2006 Apr 28; [Epub ahead of print]

"Dopamine stabilizers" is a new class of compounds which have the ability to reverse both hypo as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (-)-OSU6162 & ACR16, although lacking high in vitro binding affinity for dopamine D2 receptor ((-)-OSU6162:Ki 447nM, ACR16:Ki >1microM) show functional actions suggestive of their interaction. Hence we evaluated in vivo D2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical and endocrine models relevant to the dopamine system and antipsychotic effect. Both (-)-OSU6162 and ACR16 showed robust dose dependent striatal D2 occupancy with ED50 values of 5.27 and 18.99 mg/kg, s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37-87% (3-60 mg/kg) for (-)-OSU6162 and 35-74% (10-60 mg/kg) for ACR16, we observed both inhibitory (amphetamine induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but failed to activate habituated animals. In the conditioned avoidance response (CAR) assay, ACR16 was clearly more efficacious than (-)-OSU6162. Also both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens as compared to the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects with low motor side-effect liability, in a dose range that corresponds to high D2 in vivo occupancy.

Source: press release, personal communication, journal articles

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