Celebration Thread! Biogen is going to the FDA with Aducan.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

SusanJ, thank you for replying. It is truly remarkable how this thread was able to document the emergence of the first generation of disease modifying AD treatments. It really feels like I caught a wave and it has brought us to the End of Alzheimer's. Mostly in science it is all about endless frustration and failure-- yet aducanumab was the right entre into unlocking the anti-amyloid monoclonals.

I feel so fortunate now that I do not have to live my life with the cloud of approaching dementia hanging over me.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

NF52, our family has been constantly on the move-- almost nomadic. The dementing illness has been present in all the environments that my family experienced. Governments have been able to point to people such as us as their raison d'etre, and then when it actually comes time to provide the labor intensive and expensive treatments they typically default. It is so easy to collect a lifetime of taxes from people, yet government then will usually have not put aside any money to finance all of the obligations that they have made. Surprisingly, the CMS did not appear to have had any funded Alzheimer account dedicated to their obligations. Perhaps what could be done now is people could be offered tax exempt personal Alzheimer savings plans that would allow people at risk to plan for their futures. It would be difficult to argue against allowing those at risk to use their own tax dollars to prepare for their future needs (especially when government so often neglects to have any funding for its obligations).

The great thing with the current genetic databases is that it can be possible to trace back in time many generations and to have some idea of the genetics of those on the AD line. From what I can see now, it does appear as though it is mostly e33 dominant AD that is the main genetic driver, though there are other genetic factors involved.

Yes, other aspects could be present. However, for it to have been so persistent and to have presented in the same way through the generations and across so many in the extended family, it almost has to have been some sort of a dominant mutation. Surprisingly, so many of the family are completely unaffected. The AD does not appear to have skipped generations. If one generation is all clear, then the illness does not ever seem to reemerge in that line.If it were more polygenic, then one might expect that it could reappear.

At this time I am actually really hoping that it is AD. The breakthroughs have been in AD; if it were something else, then the future treatment options might be much more limited.

I am very excited about the potential to go full genome sequencing on the DNA of one of the confirmed family members with our family's type of AD. Full genome sequencing should go mainstream in about 1-2 years as the price approaches $100. The entire dominant genome for AD should then rapidly unlock. Basically, all we would need is a million people to simply upload their genomes and say they do not have dominant AD. That would dramatically help us find the mutation of interest. I have a 5 million SNP full genome file that is nearly completely uninterpretable. If I could narrow the file down to even a few dozen variants then it would be possible to have a definitive answer. The online gene banks allow me to find extended relatives with a genotype at any position in my genome. This is extremely powerful and it would provide conclusive evidence for a disease causing mutation. I have already went through a first round with an exome scan with our family member and it found quite a few high scoring CADD results with AD potential. Full genome would complete the picture.

Yes, I have been unsure about the definitions used for cognitive functioning for AD. For us, our family member displayed marked cognitive deficits for many years. It is not obvious to me what is meant by clinical AD. If it is just being able to appear roughly normal to people who really do not know you that well, then yes you could progress into full early dementia and people might be largely unaware. It is only when you pay very close attention and ask the right sort of questions that such impairment becomes self-apparent.

I am not sure how this will work clinically when treatments such as Lecanemab are fully approved. They would not offer treatment to someone who is clearly cognitively impaired but does not meet the label? I really do not see how that would make sense for us. Perhaps our family member could score a 30 MMSE, though there was still obvious impairment present. Close friends and family saw this for years and years before a diagnosis. I do not see how withholding treatment in a mab approved universe would be realistic or clinically justifiable. The advantage for us is that even now we know that any persistent cognitive decline ahead of a diagnosis would more than likely be AD. Even better is that there are all of these blood tests available that will confirm all of this decades ahead. For most other people, AD really might not be something that they would immediately think of. At the first sign of cognitive decline going low dose Lecanemab would be our goto strategy.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

I want to go through the safety of Lecanemab for the upcoming ADCOM.

The starting point is to note the randomized portion of Clarity did not find a mortality effect of Lecanemab.
Those randomized to placebo in Clarity had a higher mortality rate than those treated with Lecanemab (though it was not higher in the statistical significance sense). Chasing after results in the open label extension can easily obscure this important finding.


The safety issues noted in the open label portion of Clarity then need to be understood in the context of an unblinded trial. We know that there will be fatalities in the open label portion because there were fatalities in the placebo arm of the blinded portion. The logical error then consists of automatically assuming that any fatality in the open label must be caused by Lecanemab.

These are the three patient fatalities from the open label portion of Clarity (from an FDA report noted earlier on thread). What can be learned from these patient experiences?


Patient 1: e33 male aged 87

"... in an 87-year-old male with a past medical history including atrial fibrillation, hyperlipidemia, coronary artery disease, lacunar stroke, and cerebral microhemorrhage, with current medications of donepezil, apixaban, and atorvastatin, as well as tamsulosin. The patient sustained a fall on Day 77 after 6 doses of study drug, followed by pneumonia, COVID, and an ulnar pseudoaneurysm treated with thrombin, and another fall from bed. A subsequent MRI on Day 116 showed a left occipital intracerebral hemorrhage (> 1 cm). Apixaban was stopped. This was followed by a myocardial infarction on Day 122 and TIA-like events on Day 126. The patient died on Day 144 due to the cardiopulmonary causes. ... , the cerebral hemorrhage was likely related to use of apixaban and possibly the fall
from the bed."


It is difficult to attribute this patient report to the use of Lecanemab. There was a substantial amount of co-morbid illness that was present and would seem more proximal to event evolution than the mab treatment. One potential lesson here though would seem to be that in such instances, mab treatment probably should be suspended until the patient is once again medically stable. mabs will benefit patients possibly a year or more into the future, it would be best to focus more on the short term struggles the patient might be experiencing than on the longer term cognitive benefits.



Patient 2: e44 65 female stroke treated with TPA

"The second event occurred in a 65-year-old woman with MCI, homozygous for ApoE ε4, who completed 301 Core on placebo and enrolled in 301 OLE. This case has been recently published.23 Four days after the third dose of lecanemab, the participant was noted to have garbled speech, and was taken to an emergency room. A CT of the head diagnosed a leftsided ischemic stroke due to an LM3 occlusion. Tissue plasminogen activator (tPA) was
administered. Within 8 minutes after tPA she experienced a headache, and within 40 minutes she became agitated. Repeat imaging showed bilateral intracerebral hemorrhage with subarachnoid hemorrhage. The tPA was stopped and cryoprecipitate and tranexamic acid were given for reversal of tPA. She was treated with Haldol for agitation and lorazepam and Keppra for seizures. Her blood pressure was greater than 200 mmHg, for which she was
started on nicardipine infusion. Her encephalopathy worsened and she was intubated. MRI performed 3 days after the CT scan showed extensive multicompartmental ICHs, innumerable hematomas, SAH and right intraventricular hemorrhage with 5 mm leftward midline shift and

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bilateral uncal herniation. At the patient’s directive, she was extubated and died eight days after the last dose of study drug. A subsequent autopsy was reported to show extensive, multi-focal intraparenchymal hemorrhage by gross pathology examination with microscopic examination demonstrating AD neuropathologic change and widespread necrotizing vasculitis involving blood vessels with cerebral amyloid angiopathy. ... a large vessel stroke, thrombolysis and cerebral amyloid angiopathy are all associated with an increased risk of intracerebral hemorrhage which confound the ability to draw any conclusions on causality."


This patient again does not appear to exhibit a proximal response to Lecanemab so much as a catastrophic response to tPA. For the purposes of the ADCOM, it would seem to be of importance to be already to address the concerns raised by this patient (e.g., by having a meeting item related to having a treatment network that could provide emergency stroke thrombolysis). Having these prearranged responses for these various patients would help to create a productive ADCOM.



Patient 3: 79 female e44 ? (I am not sure whether genotype had been previously reported)


"An additional notable report of death in the 301 OLE (Mfr. Control No. :EC-2022-123944(0), subject ), was submitted to FDA on December 20, 2022, and reported in the journal, Science, on December 21, 2022.4 This was a 79 year old female with early Alzheimer’s disease who completed 301 Core on placebo and was enrolled in the OLE in
. The patient was homozygous for ApoE ε4. The patient received 3 doses of lecanemab 10 mg/kg every two weeks in the OLE. The last dose of study drug was administered on . According to the CIOMS report, 1 week after the last
dose the subject experienced a sudden onset of difficulty speaking, staring into space, and left side weakness, reported as a “possible CVA (cerebrovascular accident)” and “possible seizure”. The subject was taken to an emergency department and was intubated and hospitalized. An MRI with and without contrast was reported as showing “no mass, no definite bleeding or edema or stroke”. A prior MRI from , was notable only for a
“a previously noted left parietal < 1 cm meningioma”. A seizure was suspected but no definite seizure activity was noted. It was reported that the subject had never been on anticoagulation during the study or in the hospital. The subject was extubated and 5 days after the original event, developed respiratory distress and passed away. According to the CIOMS report, the subject had risk factors for seizures, including underlying Alzheimer’s
disease, and for cerebrovascular disease, including advanced age, hyperlipidemia, aortic atherosclerosis, chronic kidney disease, and prediabetes. According to the CIOMS form, an autopsy was performed but results had not been reported to the investigator site. Descriptions of brain bleeding and swelling, treatment of the event with steroids, and multiorgan failure noted in the Science description, are not noted in the CIOMS form and have not been submitted to the Agency for review. The Agency has requested that the applicant provide additional information on the case, including MRI images and the autopsy report. The applicant has not been able to obtain additional information as of January 3, 2023. The confirmation of the events reported in the Science article and their relationship to study drug cannot be determined at this time; however, the available information does not
change the risk-benefit assessment for this review."


I am not clear about this patient. Perhaps the ADCOM will have further details. It seems very unusual that there were no obvious signs on MRI for a problem. If Lecanemab were the cause of a problem, then one might expect that there would be some visible indication on MRI. With this patient there did not seem to be any such indication.


Admittedly, it should be noted that there were other patients who experienced macro-hemorrhages that were more frequent with Lecanemab treatment.


From our family perspective, Lecanemab as a potential treatment for our future AD needs would be a very low risk option. At most we are now in the early amyloid accumulation stage, so low doses of mabs would be a safe treatment. largely devoid of ARIA risk. We also do not have co-morbidities that would amplify treatment risk. The point of interest is that there are many tens of millions of others that would also be in a similar pre-treatment watchful waiting phase. This overwhelmingly large pre-treatment group will experience mabs as a very safe treatment for AD.


It is somewhat less clear-cut for those currently in the clinical phase of AD. There is some level of risk as noted above, though these risks could be weighed by patients and physicians. Of additional note is that there continues to be rapid evolution in even the residual risk that remains. For those patients who felt comfortable slowing treatment at the margin for the next year, there could be even better treatment options available to them. I know for us thinking through the risk calculations would be very difficult to cope with; fortunately, we are in the situation where none of this will apply. We can wait out the next year or two and AD treatment risk will likely disappear.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Thu May 18, 2023 8:07 pm I want to go through the safety of Lecanemab for the upcoming ADCOM.
.
J11

Loved your analysis. Thanks for presenting this.

You should post this in the

Lecanamab: Efficacy, Side Effects and More thread also.

viewtopic.php?t=8303

I think that those who are following the AHEAD trial would then see it.
;) 4/4 “Choose to be optimistic. It feels better.” Dalai Lama
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Chicagogirl, thank you for your comment!

I have been somewhat lazy recently as I am just letting it drift over the finish line and waiting to declare the celebration. This is not how it ever worked out at school. You would always be cramming at the last minute and then begin praying under high unction to pass the final. Yet, all the thread homework has been done and now I can merely skim over previous findings and get ready for the ADCOM! It is great to be well prepared (and much less stressful).

Sorry, I have been somewhat obstinate about not posting to the AHEAD thread. It is only that I see this thread as somewhere that I can have my work area and drone on somewhat excessively about details. I am actually glad I have done so, because after relentlessly posting the mab regressions, they have really clicked into place for me. The recent parabolization of the mabs and the very tight fit is still something that I view as approaching magic. I know that in theory this is how it should work, though I am not sure if I am confident enough in the theory for it to work in a crunch.

The pieces have locked in super tight and it is still quite surprising. I am glad that the psychometric instruments have done the job so well. At the group level, CDR-sb, iADRS, ADAS-cog, ADCS-ADL, and ADCOMS have been very good ones.


Aside from all the technocratic aspects of upcoming Lecanemab approval, being well prepared also allows me to reflect on thread about how profoundly important this approval will be in the broader history of my family's dementia experience and in the broader history of the dementing peoples. It really has been so devastating. The first record that I could find of the family was a court record in which a family member was sentenced to transport to a penal colony for their crime. This was how early 19th Century society managed the children of my family-- as convicted petty criminals. My genetics suggest that we have been chased all across Europe over many centuries-- it is not difficult to imagine that there has been ongoing genocide against my family and others in the dementia community. When we needed medical services that we paid into over a lifetime, such services were likely never forthcoming. It has been so easy to defraud us as we have constantly been coping with new demented relatives. Dementia was a full time job on top of our other life commitments; I suppose our future will become filled with the friendships and community that dementia displaced for us.

The earliest photo that I have of a family member was in a wheel chair with obvious dementing illness. It has been very helpful that I have had all of these years to process my emotional response to this. For me, I am not sure how I could have coped with a simple and quick approval. Perhaps I am somewhat slow on such adaptation, though this really needed to be a journey of years for me.

I have been having a building sense of triumph over the last few years ... when aducanumab was approved ... then when lecanemab was presented at CTAD ... then with the accelerated approval ... and now the approach of full approval. There has been a near constant sense of joy. Amyloid dementia is becoming a treatable illness! This is the most cohesive time I can remember in my life. We have been building year after year for the winner's podium!

In response to this increasing inevitability, I have surrounded myself with deep soulful music that speaks of the overcoming of deep personal challenges. It's the most unambiguously honest personal experience I have had in my life. Centuries of my family have dreamed of the approaching days and I am so fortunate to be the one that is here to declare victory for all of them. I suppose that I should be prepared for the possible denouement, though I'll cross that bridge when I get to it.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Percentiles 1.png
tau terciles.GIF
Percentile 2.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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[Edit: From the Lilly press release "Nearly half (47%) of the participants on donanemab (compared to 29% on placebo) had no clinical progression at 1 year (defined as no decline in CDR-SB)" So the orange and pink dots in the figure above are not entirely comparable to the Lecanemab result as the phase 2 data points in the figure presumably are from the 18 month time point.]


I want to move forward from the brief skim through on safety to think about efficacy. The one big problem when everything is moving upfield so quickly is that we can be left behind from the leading edge of the conversation. My impression is that even the current results of Lecanemab are to some extent stale dated by the Donanemab results.

In Trailblazer-2 they included dual amyloid and tau selection. This moved the topline result on CDR-sb from 27% slowing on Clarity to 36% for Trailblazer-2. My feeling is that Lecanemab would approach this 36% result of Donanemab or at least would be on the same parabolic regression. Lecanemab did not dual select with tau so there would be some topline dilution on patients who were too early and some dilution for those who were too late. It is somewhat of a surprise to me that a Leca trial with dual selection has not already been starting to replicate the dona result. The steady progression in results that we have seen from 22% --> 27% --> 36% --> 50% (possibly) has created a sense of near inevitability of the arrival of the era of mab treatment for AD.

I included a figure above for the percentile result for the phase 2 Lecanemab trial and then added in the Trailblazer-2 in orange as a qualitative estimate of the Donanemab percentile. The only point that we have to go on was the 47% of patients unchanged that I have indicated with the big orange dot. The pink dot was the ~30% on placebo who were unchanged. I was somewhat surprised how well the Leca and Dona percentiles seemed to line up. The phase 2 did not have a great deal of patients to work with in the top dose which I have shown in blue. Clarity will have a great number of patients so we should have a very good feel for its percentile plot. I have thought this to be a particularly important visualization from the patient perspective because 27% slowing does not really provide the same insight. The percentile plot above shows that in fact a great many of the patients receive substantial benefit.

The Trailblazer press release made especial note of the 47% of treated patients who did not decline. It is not easy to dismiss that result as not being clinically meaningful. It is. I will be very interested to see what the actual shape of the orange plot is for Dona especially from 70% to 100%. Once again those patients who might enter into the lift off stage of dementia progression could choose to stop treatment as they might be too late to be helped with a mab. The question that I have is how successful was dual selection in avoiding the lift off type patients in Traiblazer? While perhaps these lift off type patients could be a boost on the top line, I am sure that patients would be even more interested in seeing the orange percentile curve being relatively flat across the entire range of percentages. This would mean that essentially all patients were largely stable. Of course, this could also mean that the placebo were also flatter.

We are starting to get a possible glimpse of the dementia patient waiting rooms of the future where a great percentage could do quite well on treatment and those that do not do well could select against additional treatment. This certainly has a very positive feeling to it.
Last edited by J11 on Fri May 26, 2023 10:43 pm, edited 3 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The middle figure above is another reminder that the topline of Trailblazer-2 left quite a bit left unsaid. The shoe that i am waiting to drop is the closer description of the intermediate subgroup. As noted before it does not seem as though they actually fully reported the pre-determined responder subgroup. This subgroup actually had a 50% slowing in the phase 2. It would be clearly encouraging if they could report a similar result in the phase 3. Additional results for Dona suggested that the APOE e4-s did not respond to treatment. This was what we seemed to see with other trials and yet Clarity reported a strong e4- result. I am not sure whether I could unambiguously accept a miss for the APOE 4- in Trailblazer given these previous findings. Yet, once again the problem is that the Dona phase 3 results likely will not be available before the Leca ADCOM, so it will not be included in the conversation.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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It is getting close to the ADCOM so I should get posting!

One thing I found notable recently was the emergence of suvorexant. Suvorexant is an FDA approved insomnia drug that targets orexin. Of interest is that it appears to lower amyloid levels. It has already completed a phase 3 in AD patients but this trial was in the context of insomnia. Apparently it was not realized that suvorexant might be a disease modifying treatment for AD until later.

Currently there is a phase 2 trial in AD with suvorexant with a primary measure of PET amyloid (SToP-AD) .
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=2

We have now entered into an era in which the clinical path to accelerated approval in AD might be fairly non-strenuous. After over a thousand posts to this this thread, the relationship between change in amyloid and change in cognitive ability is all too clear to us. We even have a formula around here somewhere that mathematically specifies what the expected result should be for a given level of amyloid clearance. Pharma companies with their extensive chemical libraries of already approved treatments can search for those that might lower amyloid. Accelerated approval beckons for a compound that can lower amyloid. With PET amyloid scans establishing that a drug can lower amyloid is easily determined (unlike the uncertainties that can arise with cognitive tests). This would seem to offer a high reward-low risk proposition for pharma. Of importance with suvorexant, there were no reported instances of ARIA in the AD phase 3; it is an oral medication and it has been on the market for years without notable side effects.

It is remarkable how much improvement we have seen in the clinical trial picture for AD treatment during the time of this thread. It feels like there has been nearly continuous improvement in safety, efficacy, comfort, convenience, and patient expense. I will be very interested in knowing what the feel of the AD regulatory environment will be like over the next year as other regulators consider Lecanemab and Donanemab for approval.

Clearly Alz-801 could enter into the regulatory decision making process. Alz-801 has not shown the ARIA risk with e44 and e34s that has been reported with mabs. Having an alternative treatment especially for the e44s would make the mab regulatory process much easier. With full approval of Lecanemab, clinicians would be in the difficult position of having a mab, but no second line treatment if a mab was thought not appropriate for a e44 patient.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Wed May 24, 2023 9:38 pm... Additional results for Dona suggested that the APOE e4-s did not respond to treatment. This was what we seemed to see with other trials and yet Clarity reported a strong e4- result. I am not sure whether I could unambiguously accept a miss for the APOE 4- in Trailblazer given these previous findings.
Hi J11,
You may have seen these articles on a different analysis of the benefit to ApoE 4/4s, by a team at Eli Lilly using both internal data and apparently available public data on other companies' trials.

Here's the synopsis: Antiamyloid Therapies Tend to Perform Better in APOE e4 Carriers

And here's the original article published May 19, with emphasis added.
APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials
Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non-carriers. Carrier and non-carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS-Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases...
DISCUSSION:
We hypothesize that APOE ε4 carriers have same or better response than non-carriers to amyloid-targeting therapies and similar or less disease progression with placebo in amyloid-positive trials.

HIGHLIGHTS

* Amyloid-targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers.
* Clinical decline is the same/slightly faster in amyloid-positive APOE ε4 non-carriers.
* Prevalence of non-carriers in trial populations could impact outcomes.
You understand statistics far better than I do, but the conclusions seem to bear out a comment I heard at the Lecanemab CTAD presentation, which I'll paraphrase as: "We think the reason ApoE4's didn't appear to benefit from treatment is that the placebo group of ApoE 4's just didn't progress very much (i.e. decline in scores), so there just wasn't a big difference compared to ApoE 3/3 in placebo and treatment groups.

It may be that two things can both be true:
  • That as a group ApoE 4 carriers have a long "plateau period" before a sharp decline in late mild AD--something I've heard and seen on other charts
and
  • ApoE 4 carriers DO benefit from removing amyloid in their brains because they continue to stay on that plateau, or even improve slightly.
So comparing treated populations by sub-groups and placebo populations by sub-groups may be an important analysis. Also, if ApoE 4/4s on placebo stayed stable, it MAY be possible to treat them with anti-amyloid drugs as long as those with heart conditions and severe CAA are screened out. The current AHEAD trial in cognitively healthy people with intermediate or elevated levels of amyloid may be the group most likely to benefit, since they are less likely to have severe CAA and risk of severe ARIA-H.
4/4 and still an optimist!
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