Targeting tau protein, the third phase of the new drug for Alzheimer's disease is now dawning
November 29, 2017 Source: WuXi PharmaTech
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Recently, TauRx Therapeutics announced the final result of the second clinical phase 3 trial of tau protein aggregation inhibitor called LMTX in the treatment of Alzheimer's disease (AD) in the Journal of Alzheimer's Disease. Published in the magazine. The results obtained from this phase III trial, called TRx-237-005, are similar to the results of the first phase III trial called TRx-237-015. The results of both clinical trials support that LMTX as a monotherapy may be effective in patients with mild or moderate AD at a therapeutic dose of 4 mg twice daily.
AD is a neurodegenerative disease that is the most common type of Alzheimer's disease. Due to the death of nerve cells in the brain, the cognitive function of AD patients will gradually decline. Currently FDA-approved drugs are mainly cholinesterase inhibitors, which, although they can be used to relieve symptoms, do not delay the death of nerve cells. Many of the research-based therapies that attempt to alter the progression of AD disease have suffered setbacks in later clinical trials, so AD patients are in desperate need of innovative therapies that can change the course of the disease.
LMTX developed by TauRx is a tau protein aggregation inhibitor. In addition to amyloid deposition, the neurofibrillary tangle formed by tau aggregation is also one of the classic features in brain tissue of AD patients. The success of a therapy targeting tau protein aggregation is even more interesting after numerous therapies for amyloid targeting. The results obtained by LMTX in the first clinical trial can be said to be unexpected. In a clinical trial called TRx-237-015, the researchers added LMTX (dosage 75 mg or 150 mg twice daily) to standard therapy for AD to see if it enhances the patient's Efficacy. LMTX is a methylene blue-based drug that metabolizes urine in the body, which can lead patients to know that they are taking medication and may have a placebo effect. In order to prevent patients from knowing that they were taking the treatment, the researchers asked the patient to take a dose of 4 mg twice daily LMTX in the control group. Their idea is that at very low doses, LMTX does not produce a therapeutic effect, while also allowing the urine to discolor.
The trial found that the addition of LMTX to standard therapy for the treatment of AD had no significant effect on the decline in cognitive ability. However, some patients in the trial only received treatment with LMTX and did not receive standard therapy at the same time. The cognitive ability of these patients treated with LMTX monotherapy was significantly improved compared to patients receiving combination therapy with LMTX and standard therapy. Moreover, the "control" patients who received a dose of 4 mg twice daily for LMTX monotherapy had significantly improved cognitive performance compared with patients treated with combination therapy.
To test the efficacy of LMTX in the TRx-237-015 clinical trial, nearly 800 patients with mild or moderate AD were divided into 4 groups in the TRx-237-005 clinical phase 3 trial. They received LMTX monotherapy (100 mg or 4 mg each time, twice daily) or combination therapy with LMTX and AD standard treatments. The ADAS-cog and ADCD-ADL scales were then used to compare the cognitive abilities of patients receiving LMTX monotherapy with those receiving combination therapy. At the same time, the researchers used MRI scans to detect the rate of atrophy in the brain.
The results of the trial showed that LMTX monotherapy significantly increased cognitive performance (p < 0.025) at two different doses compared with patients receiving combination therapy. And the dose of 4 mg per dose, twice daily LMTX therapy, increased the level of cognitive ability to a dose of 100 mg per dose, twice daily for LMTX therapy. These results are very similar to the results of the first clinical phase 3 trial. The MRI scan found that patients who received LMTX monotherapy had the same rate of brain atrophy at the start as those who received combination therapy, but after 9 months of treatment, the rate of brain atrophy was significantly reduced in patients receiving monotherapy.
Since LMTX as a monotherapy has the same efficacy as a high dose at low doses and has fewer side effects, TauRx will conduct a clinical trial containing placebo to test LMTX as a monotherapy at 4 mg each time, twice daily. The efficacy of sub-dose in the treatment of patients with mild to moderate AD.
â–² Dr. Claude Wischik (Source: University of Aberdeen)
“Although the patient group receiving monotherapy was a minority in the first and second clinical trials, the second independent trial yielded the same results indicating that our findings were not accidental,†University of Aberdeen. Professor Claude Wischik, Ph.D., CEO of TauRx, said: "We are also beginning to understand the pharmacological basis for the negative effects of AD standard therapy on the efficacy of LMTX, which we have been able to repeat in animal tau protein aggregation model tests."
â–² Dr. Gordon Wilcock (Source: Alzheimer's Society)
Dr. Gordon Wilcock, a senior author of the study and honorary professor of geriatrics at the Department of Clinical Neuroscience at the University of Oxford, said: "These data suggest that we should continue clinical trials to detect low doses of LMTX at different times. The efficacy of the case in patients with AD."
Reference materials:
[1] Second Phase 3 Study Results for LMTX® published in the Journal of Alzheimer's Disease
[2] Potential of Low Dose Leuco-Methylthioninium Bis (Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial
[3] Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial
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