New drug for Huntington's disease! Austedo (deuterated butbenazine) 3 years of long-term treatment data: effective, safe and well tolerated!

October 25, 2022 /BioValleyBIOON/ --Teva Pharma has announced the results of
its ARC-HD clinical trial.
This is an approximately 3-year open-label, single-arm, 2-cohort, multicenter extension study that is evaluating the safety and tolerability of Austedo (Chinese trade name: Antetan, generic name: deutetrabenazine, deuterium butenazine tablets) in the long-term treatment of Huntington's disease (HD)
-related chorea.
The study was conducted
by Teva in collaboration with the Huntington Research Group (HSG).

The results of the ARC-HD study showed that the safety and tolerability of Austedo treatment was comparable
to that of the First-HD randomized, double-blind, placebo-controlled 12-week study.
In the ARC-HD study, patient medication adherence was greater than 90%
over an open-label expansion period of approximately 3 years.
According to the Huntington's Disease Unified Rating Scale (UHDRS) Total Exercise Score (TMC), Austedo treatment improved and maintained chorea control
in both the Rollover and Switch cohorts throughout the study period.

Chorea is one of the most prominent physical manifestations of Huntington's disease (HD), occurring in about 90% of HD patients
.
Chorea can have a significant functional impact on
the lives of HD patients and their caregivers.
The data released this time provides important insights
into the long-term use of Austedo for the treatment of HD chorea.

The analysis included a total of 119 patients: 82 patients completed a randomized, double-blind, placebo-controlled First-HD trial (Rollover cohort), and 37 patients switched from a stable tetrabenazine dose to Austedo overnight and subsequently dose-adjusted (Switch cohort).

At the end of the study, the average daily dose of Austedo was 45.
7 mg
.
The findings have been published online in CNS Drugs
.
(See: The Safety of Deutetrabenazine for Chorea in Huntington Disease: An Open-Label Extension Study)

ARC-HD clinical trial results (Image source: CNS Drugs)

- 3-year safety results: exposure-adjusted incidence rates (EAIRs) were used to compare the frequency of
adverse events (AEs) in long-term open-label extended studies with short-term First-HD studies.
The AE-related EAIR is comparable
to the EAIR in the pivotal First-HD trial.
Common AEs in the Rollover and Switch queues (≥4% of each cohort) include: falls, depression, anxiety, insomnia, lethargy, akathisia
.
There are no new security issues
.

- 3-year TMC and Total Exercise Score (TMS) Results: Studies have shown that mean TMC scores decrease from baseline to week 8 and maintain chorea control
over approximately 3 years 。 Key outcomes were as follows: (1) In patients in the Rollover cohort after the end of the pivotal First-HD study, mean dance scores were reduced by 4.
5 points (standard deviation [SD]: 3.
1; 95% CI: -5.
2, -3.
7) and mean TMS was reduced by 7.
1 points (SD: 7.
3; 95% CI: -8.
8, -5.
5) from baseline to week 8; (2) In Switch cohort patients who switched from tetrabenazine overnight, the mean dance score was reduced by 2.
1 points (SD: 3.
3; 95% CI: -3.
1, -1.
0) and the mean TMS was reduced by 2.
4 points (SD: 8.
7; 95% CI: -5.
4, 0.
5).

(3) From week 8 to week 145 (or end of treatment, whichever is earlier), the reduction in TMC in all patients in both cohorts was maintained (-0.
5 [SD: 5.
2; 95% CI: -1.
9, 1.
0]).

Austedo: The world's first deuterated drug

Huntington's disease (HD) is a rare and fatal neurodegenerative disease with an overall prevalence of 0.
40 per 100,000 people in Asia and an average age of onset of 40 years
.
Chorea, which is one of the most pronounced physical manifestations of chorea (involuntary, random and sudden movements of wriggling and/or turning) occurs in about 90% of patients
.
Chorea interferes with daily functioning, causes social isolation, increases the risk of injury, and leads to a reduced
quality of life in HD patients.

Austedo is the first deuterated drug
approved worldwide.
In the US, Austedo was approved in April 2017 for the treatment of chorea, which is associated with Huntington's disease, and in August 2017 for the treatment of tardive dyskinesia (TD)
in adults.
In China, Austedo was approved in May 2020 for the treatment of adult Huntington's disease (HD)-related chorea and tardive dyskinesia (TD).

In addition, Austedo was officially included in the National Basic Medical Insurance, Work-Related Injury Insurance and Maternity Insurance Drug Catalogue (2020) in December 2020, which will greatly improve the treatment burden of patients and improve the accessibility of innovative therapies
.

China is the second country in the
world to ratify Austedo after the United States.
The active pharmaceutical ingredient of Austedo is deutetrabenazine, a small molecule oral inhibitor that targets vesicle monoamine transporter 2 (VMAT2), which regulates levels
of chemicals such as dopamine, serotonin, epinephrine, norepinephrine and other chemicals in the brain.
Deutetrabenazine is a deuterated drug for the marketed Huntington's disease treatment drug
tetrabenazine.
After deuteration, the pharmacokinetic profile is improved and the half-life is significantly extended, allowing the use of lower therapeutic doses
.

The deuterated technology used by Austedo imparts a good pharmacokinetic curve to the active ingredient, which allows to reduce the frequency of administration, while showing effectiveness and acceptable safety and tolerability
in the treatment of patients with Huntington's (HD) disease and adult tardive dyskinesia (TD).

Teva: a pioneer in the field of deuteration

Deuteration technology

Deuterium (D) is abundant in nature and can form stable molecular bonds
with other elements.
In an adult, the average D content is about 2 g
.
Although D and hydrogen (H) are basically identical in atomic size and shape, D also differs fundamentally from H in that D contains an extra neutron
.
As a result, the chemical bond formed by D with carbon (C) is more stable
than the chemical bond formed by H and C.
In general, D-C bonds are 6-9 times more stable than H-C bonds, which has very important implications in drug development because drug metabolism often involves the breakage
of H-C chemical bonds.

Traditional drug discovery methods take a long time and have a high
failure rate.
Deuterium chemistry methods, usually based on drugs already on the market, are more efficient and less
expensive to develop.
The use of deuteration (deuterium substitution) can enhance certain properties of drugs: since D and C form more stable chemical bonds, Dylation can change the metabolism of drugs in some cases, including improving metabolic stability, reducing the formation of toxic metabolites, increasing the formation of desired active metabolites, or a combination
of these effects.
Deuterated compounds have longer half-lives in vivo and increased systemic exposure compared to their non-deuterated analogues, properties that may confer therapeutic benefits such as improved safety, efficacy, tolerability, and convenience
.

Typically, deuterated compounds are expected to retain biochemical potency and selectivity
similar to their hydrogenated analogues.
The effect of deuterium substitution on metabolic properties is highly dependent on the specific molecular position of
D-substituted H.
However, the metabolic effects of deuterium substitution, if any, are unpredictable, even in
compounds with similar chemical structures.

At present, a number of pharmaceutical companies are developing deuterated drugs for drugs
currently on the market.
For example, Concert has developed a new product, CTP-543, using deuterium chemistry to develop the JAK1/JAK2 inhibitor ruxolitinib, which has achieved strong efficacy
in the treatment of alopecia areata.
Ruxolitinib has been approved in the United States for sale under the brand name Jakafi for the treatment of a variety of blood disorders
.
Deuterium chemical modifications of ruxolitinib can alter its human pharmacokinetics, thereby enhancing its use
as a treatment for alopecia areata.
(Bio Valley Bioon.
com)

Teva Announces Results from 3-Year Study Assessing the Safety and Tolerability of AUSTEDO (deutetrabenazine) Tablets for the Treatment of Chorea Associated with Huntington's Disease