Thanks, J11! This thread reads now like a reference for all things homotaurine.
I think I am going to give it a try, even before it is approved by the FDA .
Celebration Thread! Homotaurine/Tramiprosate supplement
-
DoubleBond
- Contributor
- Posts: 24
- Joined: Wed Feb 06, 2019 4:21 pm
Re: Celebration Thread! Homotaurine/Tramiprosate supplement
DoubleBond, thank you for commenting.
My guess is that homotaurine will never be approved by the FDA.
They are now onto the second generation formulation of homotaurine.
Yes, I find that for something to truly register there needs to be a critical mass of information.
I was surprised that until this point the content concerning homotaurine/tramiprosate/ ALZ-801 on our forum
has been more at the level of whispers than clear statements with an ongoing and active discussion
on a thread. When the discussion is that muted, people who might even be quite active on forum
possibly could never receive a clear message about important products such as HT.
I looked back on some of my old posts and noticed that I referred to Alzhemed back in 2017.
I think I might have made others comments about it years ago, though they were largely
incidental. It is only when I saw some recent posts about it did I truly take notice of it
again and decided to see what was happening.
A very large development has happened in the last few days: the NIH appears
ready to pay for most of the phase 3 trial (see the company's news link below).
They are in for $50 million.
It clearly adds a substantial amount of confidence when the government
feels that you have a product too good to have go through a financing round.
This is probably even better than a financing round as experts have likely carefully
reviewed the science in a way that often can be compromised when trying to
launch an IPO for a startup biotech with a treatment for AD. So much
speculation becomes involved in biotech markets that clear thinking soon
becomes almost impossible.
AD is having such a large effect on our society, it is important that great products
such as tramiprosate (or derivatives) are brought to market as soon as possible.
https://alzheon.com/alzheon-news/
When you compare the side effects of homotaurine with the anti-bodies there is a clear
advantage for homotaurine. It will be difficult to have the amyloid anti-body patients to receive
quarterly MRI to check on ARIA.
My guess is that homotaurine will never be approved by the FDA.
They are now onto the second generation formulation of homotaurine.
Yes, I find that for something to truly register there needs to be a critical mass of information.
I was surprised that until this point the content concerning homotaurine/tramiprosate/ ALZ-801 on our forum
has been more at the level of whispers than clear statements with an ongoing and active discussion
on a thread. When the discussion is that muted, people who might even be quite active on forum
possibly could never receive a clear message about important products such as HT.
I looked back on some of my old posts and noticed that I referred to Alzhemed back in 2017.
I think I might have made others comments about it years ago, though they were largely
incidental. It is only when I saw some recent posts about it did I truly take notice of it
again and decided to see what was happening.
A very large development has happened in the last few days: the NIH appears
ready to pay for most of the phase 3 trial (see the company's news link below).
They are in for $50 million.
It clearly adds a substantial amount of confidence when the government
feels that you have a product too good to have go through a financing round.
This is probably even better than a financing round as experts have likely carefully
reviewed the science in a way that often can be compromised when trying to
launch an IPO for a startup biotech with a treatment for AD. So much
speculation becomes involved in biotech markets that clear thinking soon
becomes almost impossible.
AD is having such a large effect on our society, it is important that great products
such as tramiprosate (or derivatives) are brought to market as soon as possible.
https://alzheon.com/alzheon-news/
When you compare the side effects of homotaurine with the anti-bodies there is a clear
advantage for homotaurine. It will be difficult to have the amyloid anti-body patients to receive
quarterly MRI to check on ARIA.
Last edited by J11 on Sun Aug 30, 2020 12:37 pm, edited 1 time in total.
Re: Celebration Thread! Homotaurine/Tramiprosate supplement
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Re: Celebration Thread! Homotaurine/Tramiprosate supplement
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Re: Celebration Thread! Homotaurine/Tramiprosate supplement
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Re: Celebration Thread! Homotaurine/Tramiprosate supplement
High dose
This is a great one! The initial criticism about homotaurine was
that people who were asymptomatic would rush to buy the supplement
despite a lack of research evidence to support such self-dosing. This
figure suggests a way that such evidence could be provided.
Studies that considered hippocampal volume in the pre-symptomatic
could offer confirming evidence. It is difficult to imagine that
there could be any logical justification to argue that the hippocampus
on the right has the neurocognitive potential of the one on the left.
that people who were asymptomatic would rush to buy the supplement
despite a lack of research evidence to support such self-dosing. This
figure suggests a way that such evidence could be provided.
Studies that considered hippocampal volume in the pre-symptomatic
could offer confirming evidence. It is difficult to imagine that
there could be any logical justification to argue that the hippocampus
on the right has the neurocognitive potential of the one on the left.
You do not have the required permissions to view the files attached to this post.
Last edited by J11 on Sun Aug 30, 2020 12:43 pm, edited 2 times in total.
Re: Celebration Thread! Homotaurine/Tramiprosate supplement
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Re: Celebration Thread! Homotaurine/Tramiprosate supplement
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Re: Celebration Thread! Homotaurine/Tramiprosate supplement
I wanted to add in some figures to have some references points in the discussion.
This is pretty much all the figures that I could find online.
This is pretty much all the figures that I could find online.
Re: Celebration Thread! Homotaurine/Tramiprosate supplement
This is the extension study for tramiprosate out to week 130.
It would help a great deal with some figures for these data points, though from what I can understand,
HT maintained its benefit over `2.5 years. This is very impressive.
We have see with other symptomatic type drugs that after about 6 months the benefits can almost
disappear, this does not appear to be true with the new generation of AD medications.
With aducan the benefit in their extensions lasted for years and years.
Same appears to be true with HT.
"For CDR-SB, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 0.7 (p= 0.22), 0.9 (p=0.12), and 1.0 (p=0.09) for the 150mg-150mg group; the 100mg-150mg group showed no difference from the placebo-150mg group."
"In the Mild AD subgroup of APOE4/4 homozygotes (MMSE 22-26), the positive effects at the 150mg-150mg group were larger for both ADAS-cog and CDR-SB."
Notice that in the first quote above they appear to have combined all 44s in the 150-150 group into one CDR-SB score. Yet, we know from the phase 3 that the benefit only became quite obvious when you considered only out the mild subgoup of 44 on high dose.
This is what the second quote reiterates, though does not show how this separation into mild and moderate AD 44s in the high group fared in the extension. Would be good to see the published paper for this.
So the first quote is only giving part of the potential benefit. Even still what is impressive is that from week 78 --> 104 --> 130 CDR-SB changed by 0.7, 0.9 and 1.0 against baseline in the 44s high dose. For 2.5 years that is not a large change in CDR-SB as one would expect.
https://alzheon.com/clinical-effects-tr ... ion-study/
Sustained Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Alzheimer’s Disease Over 130 Weeks: Results of Phase 3 Extension Study
Abstract
Background: ALZ-801 is in development as an oral AD treatment with disease modification potential. ALZ-801 is a pro-drug of tramiprosate that provides improved pharmacokinetics and GI tolerability. Tramiprosate, the active agent in ALZ-801, inhibits the aggregation of beta amyloid (Aβ) monomers into toxic, soluble Aβ oligomers through a recently reported enveloping molecular mechanism of action (Kocis et al. 2017). In transgenic CRND8 mice tramiprosate reduced amyloid plaque and soluble Aβ42 in brain (Gervais et al. 2007). In a 12-week study in AD patients, tramiprosate showed a dose-dependent decrease in soluble Aβ42 in CSF, with up to 70% reduction at 150mg BID (Aisen et al. 2006). On this basis, tramiprosate was evaluated in two global Phase 3 studies, one in North America (NA study), and the other in Western Europe (EU study). The NA study did not show efficacy in the overall Mild to Moderate AD study population, and therefore the EU study was terminated. Recent re-analyses of the NA dataset based on APOE4 genotype showed positive effects of tramiprosate in APOE4/4 homozygotes at 150mg BID (Abushakra et al. 2016), with larger effects in the Mild subgroup of patients (Abushakra et al. 2017). The NA study had a safety extension of up to an additional 52 weeks of treatment (Study 017). We evaluated efficacy and safety of tramiprosate in APOE4/4 homozygotes in the Extension Study.
Methods: The NA Study was a randomized, double-blind, placebo-controlled parallel-arm multi-center study of 78-weeks duration, and enrolled 1,053 AD patients (MMSE range 16-26) to either placebo, 100mg BID, or 150mg BID. The NA placebo-controlled study included 148 APOE4/4 subjects. ADAS-cog11 and CDR-SB were the co-primary efficacy outcomes. Subjects who completed this study were offered enrollment into the blinded extension study for up to 52 weeks of treatment, where all subjects received 150mg BID after a titration period. All subjects and sites remained blinded to treatment assignment in the placebo-controlled phase. Efficacy was analyzed in APOE4 subgroups as described previously for the placebo-controlled study (Abushakra et al. 2016). Changes in ADAS-cog and CDR-SB from original baseline up to 130 weeks were analyzed using a mixed effects model with repeated measures (MMRM).
Results: 735 subjects completed the 78-week NA study and enrolled in the Extension Study. 104 subjects were APOE4/4 homozygotes: 43, 33 and 28 from the original placebo, low and high-dose groups respectively; and 27, 25, 18 completed a total of 130 weeks on study drug. The baseline demographics of the 3 dose arms were similar at the start of the Extension Study. Mean baseline MMSE were: 21.6, 21.3, and 21.0 for placebo, low and high dose arms respectively. The 150mg-150mg group showed significantly larger ADAS-cog benefits at both 104 and 130 weeks compared to the placebo-150mg group. On ADAS-cog, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 2.4 (p= 0.12), 3.3 (p=0.04), and 3.9 (p=0.03); the effects were smaller for the 100mg-150mg group. For CDR-SB, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 0.7 (p= 0.22), 0.9 (p=0.12), and 1.0 (p=0.09) for the 150mg-150mg group; the 100mg-150mg group showed no difference from the placebo-150mg group. For the 150mg-150mg group, ADAS-cog effect showed a trend to increase with time. In the Mild AD subgroup of APOE4/4 homozygotes (MMSE 22-26), the positive effects at the 150mg-150mg group were larger for both ADAS-cog and CDR-SB. Across all 735 patients, which included 471 who received active drug for up to 130 weeks, the most common TEAE were falls, nausea, urinary tract infection, diarrhea, and decreased weight. The safety profile in the 115 APOE4/4 homozygotes was similar.
Conclusions: Reanalysis of two prior tramiprosate studies showed promising efficacy in the APOE4/4 homozygous patients with Mild and Moderate AD over 78 weeks. We further analyzed the efficacy analysis of the APOE4/4 homozygotes subgroup over an additional 52 weeks in the Extension Study. In APOE4/4 patients, tramiprosate 150mg BID exhibited sustained cognitive and functional benefits over 2.5 years, compared to the “delayed start” group who initially received placebo. The differences between the two treatment groups increased with time in the Extension Study. These results suggest potential disease modifying effects of tramiprosate, consistent with its molecular mechanism inhibiting formation of amyloid oligomers. The safety profile remained favorable with no new toxicities observed at exposures up to 2.5 years. This profile of sustained efficacy and favorable long-term safety supports further development of ALZ-801, an optimized prodrug of tramiprosate, in an upcoming confirmatory study in APOE4/4 homozygous AD patients.
It would help a great deal with some figures for these data points, though from what I can understand,
HT maintained its benefit over `2.5 years. This is very impressive.
We have see with other symptomatic type drugs that after about 6 months the benefits can almost
disappear, this does not appear to be true with the new generation of AD medications.
With aducan the benefit in their extensions lasted for years and years.
Same appears to be true with HT.
"For CDR-SB, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 0.7 (p= 0.22), 0.9 (p=0.12), and 1.0 (p=0.09) for the 150mg-150mg group; the 100mg-150mg group showed no difference from the placebo-150mg group."
"In the Mild AD subgroup of APOE4/4 homozygotes (MMSE 22-26), the positive effects at the 150mg-150mg group were larger for both ADAS-cog and CDR-SB."
Notice that in the first quote above they appear to have combined all 44s in the 150-150 group into one CDR-SB score. Yet, we know from the phase 3 that the benefit only became quite obvious when you considered only out the mild subgoup of 44 on high dose.
This is what the second quote reiterates, though does not show how this separation into mild and moderate AD 44s in the high group fared in the extension. Would be good to see the published paper for this.
So the first quote is only giving part of the potential benefit. Even still what is impressive is that from week 78 --> 104 --> 130 CDR-SB changed by 0.7, 0.9 and 1.0 against baseline in the 44s high dose. For 2.5 years that is not a large change in CDR-SB as one would expect.
https://alzheon.com/clinical-effects-tr ... ion-study/
Sustained Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Alzheimer’s Disease Over 130 Weeks: Results of Phase 3 Extension Study
Abstract
Background: ALZ-801 is in development as an oral AD treatment with disease modification potential. ALZ-801 is a pro-drug of tramiprosate that provides improved pharmacokinetics and GI tolerability. Tramiprosate, the active agent in ALZ-801, inhibits the aggregation of beta amyloid (Aβ) monomers into toxic, soluble Aβ oligomers through a recently reported enveloping molecular mechanism of action (Kocis et al. 2017). In transgenic CRND8 mice tramiprosate reduced amyloid plaque and soluble Aβ42 in brain (Gervais et al. 2007). In a 12-week study in AD patients, tramiprosate showed a dose-dependent decrease in soluble Aβ42 in CSF, with up to 70% reduction at 150mg BID (Aisen et al. 2006). On this basis, tramiprosate was evaluated in two global Phase 3 studies, one in North America (NA study), and the other in Western Europe (EU study). The NA study did not show efficacy in the overall Mild to Moderate AD study population, and therefore the EU study was terminated. Recent re-analyses of the NA dataset based on APOE4 genotype showed positive effects of tramiprosate in APOE4/4 homozygotes at 150mg BID (Abushakra et al. 2016), with larger effects in the Mild subgroup of patients (Abushakra et al. 2017). The NA study had a safety extension of up to an additional 52 weeks of treatment (Study 017). We evaluated efficacy and safety of tramiprosate in APOE4/4 homozygotes in the Extension Study.
Methods: The NA Study was a randomized, double-blind, placebo-controlled parallel-arm multi-center study of 78-weeks duration, and enrolled 1,053 AD patients (MMSE range 16-26) to either placebo, 100mg BID, or 150mg BID. The NA placebo-controlled study included 148 APOE4/4 subjects. ADAS-cog11 and CDR-SB were the co-primary efficacy outcomes. Subjects who completed this study were offered enrollment into the blinded extension study for up to 52 weeks of treatment, where all subjects received 150mg BID after a titration period. All subjects and sites remained blinded to treatment assignment in the placebo-controlled phase. Efficacy was analyzed in APOE4 subgroups as described previously for the placebo-controlled study (Abushakra et al. 2016). Changes in ADAS-cog and CDR-SB from original baseline up to 130 weeks were analyzed using a mixed effects model with repeated measures (MMRM).
Results: 735 subjects completed the 78-week NA study and enrolled in the Extension Study. 104 subjects were APOE4/4 homozygotes: 43, 33 and 28 from the original placebo, low and high-dose groups respectively; and 27, 25, 18 completed a total of 130 weeks on study drug. The baseline demographics of the 3 dose arms were similar at the start of the Extension Study. Mean baseline MMSE were: 21.6, 21.3, and 21.0 for placebo, low and high dose arms respectively. The 150mg-150mg group showed significantly larger ADAS-cog benefits at both 104 and 130 weeks compared to the placebo-150mg group. On ADAS-cog, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 2.4 (p= 0.12), 3.3 (p=0.04), and 3.9 (p=0.03); the effects were smaller for the 100mg-150mg group. For CDR-SB, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 0.7 (p= 0.22), 0.9 (p=0.12), and 1.0 (p=0.09) for the 150mg-150mg group; the 100mg-150mg group showed no difference from the placebo-150mg group. For the 150mg-150mg group, ADAS-cog effect showed a trend to increase with time. In the Mild AD subgroup of APOE4/4 homozygotes (MMSE 22-26), the positive effects at the 150mg-150mg group were larger for both ADAS-cog and CDR-SB. Across all 735 patients, which included 471 who received active drug for up to 130 weeks, the most common TEAE were falls, nausea, urinary tract infection, diarrhea, and decreased weight. The safety profile in the 115 APOE4/4 homozygotes was similar.
Conclusions: Reanalysis of two prior tramiprosate studies showed promising efficacy in the APOE4/4 homozygous patients with Mild and Moderate AD over 78 weeks. We further analyzed the efficacy analysis of the APOE4/4 homozygotes subgroup over an additional 52 weeks in the Extension Study. In APOE4/4 patients, tramiprosate 150mg BID exhibited sustained cognitive and functional benefits over 2.5 years, compared to the “delayed start” group who initially received placebo. The differences between the two treatment groups increased with time in the Extension Study. These results suggest potential disease modifying effects of tramiprosate, consistent with its molecular mechanism inhibiting formation of amyloid oligomers. The safety profile remained favorable with no new toxicities observed at exposures up to 2.5 years. This profile of sustained efficacy and favorable long-term safety supports further development of ALZ-801, an optimized prodrug of tramiprosate, in an upcoming confirmatory study in APOE4/4 homozygous AD patients.
