Lecanamab: Efficacy, Side Effects, and More

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Julie G
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

It was more like 1-4 punch with stroke + TPA + CAA + lecanemab.
Completely agree. Given the high prevalence of CAA for E4 carriers, are they giving baseline MRIs prior to lecanamb? If positive, is lecanamab contraindicated given the significant risk of bleeding? If this patient had a baseline MRI and CAA had previously been identified, why in the world would TPA have been given?

All of this is hitting close to home for me. My E4 mother just experienced a hemorrhagic stroke, CAA, the day after Thanksgiving. We're still in the ICU, but hope to be on our way to rehab soon. The likelihood of myself and my brothers having CAA is quite high. Once I'm out of the hospital, I plan to be evaluated.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Chicagogirl »

All of this is hitting close to home for me. My E4 mother just experienced a hemorrhagic stroke, CAA, the day after Thanksgiving. We're still in the ICU, but hope to be on our way to rehab soon.


So sorry Julie! Best wishes for a speedy and complete recovery for your mother.
;) 4/4 “Choose to be optimistic. It feels better.” Dalai Lama
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by J11 »

Julie G, best wishes!

Yes, the e44 patient given tPA for a MCA stroke was screened for CAA (that was the purpose of the baseline MRIs: when they found too many microhemorrhages at baseline this was used to indicate CAA and such patients were then excluded) and it came back negative. However, on autopsy moderate to severe CAA was found. There were probably quite a few others with significant CAA that made it through this screening, the problem seems to be that there is not a fool proof way of detecting it. Clarity rejected ~70% of those wanting to enroll, and yet there was still a lingering risk.

In my reading of CAA, it surprises me how much of it there is in AD. It is even more surprising how little apparent interest there has been in moving Lecanemab into the hemorrhagic prevention setting. One could well imagine that patients like your mother could benefit from beta amyloid mabs as a treatment approach to clear out the amyloid that can without treatment lead to this stroke behavior. The trap that we are now in for many patients with this in place CAA disease (without accompanying AD) is that it is not easy to know whether trying to treat it with mabs might cause more problems than just leaving it in place. However, for those not stuck in this bind, the risk benefit would seem to favor treatment with low dose mabs. I really wish that this will be considered over the short-medium term by the pharmaceutical companies and clinical trials conducted.

I am not sure whether the ~8% of placebo patients (even after heavy selection) who experienced isolated ARIA-H during their 18 months in Clarity is related to CAA, though if it were this would be quite disturbing. There could be a great deal of lingering risk in those that do not receive treatment that has not been talked about enough.

Julie G, I am interested in your perspective on this. Once Lecanemab is approved, hypothetically, would you see value in pre-titrating with low dose off-label Lecanemab, not for the anti-dementing effects, but entirely for the CAA reducing effects? I could also see the low dose approach used as a strategy to have the pipes clear for official on label treatment. The research has not been done on this to date, though it would seem reasonable that low dose pretitration would make the standard dosing protocol safer.
Last edited by J11 on Mon Dec 05, 2022 10:23 pm, edited 1 time in total.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Fri Dec 02, 2022 10:53 am... Given the high prevalence of CAA for E4 carriers, are they giving baseline MRIs prior to lecanamb? If positive, is lecanamab contraindicated given the significant risk of bleeding? If this patient had a baseline MRI and CAA had previously been identified, why in the world would TPA have been given?

All of this is hitting close to home for me. My E4 mother just experienced a hemorrhagic stroke, CAA, the day after Thanksgiving. We're still in the ICU, but hope to be on our way to rehab soon. The likelihood of myself and my brothers having CAA is quite high. Once I'm out of the hospital, I plan to be evaluated.
Julie, my deepest wish is for your mother to be out of the ICU soon and able to heal with her family's love.
My time spent with a loved one in the ICU was a rollercoaster of feeling that he was in the safest and yet scariest place, with the best people and yet with me not knowing how to help. Take care of yourselves during these difficult days.

I think the quickest answer to your final question is that the MRI would likely not have shown diagnostic proof of CAA. Per Karelena's post, the ER doctors may have believed from the MRI that they were treating an ischemic stroke initially, and only upon TpA did she have massive hemorrhagic bleed. Here's a 2018 listing of possible biomarkers of CAA, some of which require highly specialized tests such as diffusion tensor imaging (DTI), but one of which is a positive amyloid beta PET or CSF result. None of these are sufficient to diagnose CAA, I believe.
The ability to diagnose CAA during life with good specificity is a prerequisite for identifying other biomarkers of the disease’s presence, severity, and future behavior... Among the long (and likely still growing) list of CAA biomarkers made possible by the Boston criteria are (1) white matter T2 hyperintensities, with tendency for posterior predominance or a multiple subcortical spot pattern; (2) altered diffusion tensor imaging parameters such as global mean diffusion or diffusion tensor-derived global efficiency; (3) vascular reactivity to functional stimulation; (4) cortical thickness; (5) punctate diffusion weighted imaging hyperintensities suggestive of acute microinfarcts; (6) enlarged perivascular spaces in the centrum semiovale; (7) positron-emission tomography labeling with the amyloid ligands Pittsburgh compound B and florbetapir; and (8) reduced cerebrospinal fluid concentrations of β-amyloid. These multimodal biomarkers serve as both important windows into the pathogenesis of CAA and candidate outcome markers for clinical trials.
Diagnosis of Cerebral Amyloid Angiopathy Evolution of the Boston Criteria

The CLARITY and AHEAD studies require one MRI shortly before baseline randomization, in addition to ECGs, blood and urine tests, physical and soft-sign neurological exams and amyloid and tau PET scans. From what I have heard from researchers, anyone with either one macrohemorrhage (≥ 10mm) or 8 or more "microbleeds" (≤ 5mm) prior to baseline is excluded and anyone who meets that criteria during the study is withdrawn. Doctors at each site have final authority to exclude people when they feel that patient safety may be jeopardized.

An additional MRI is done during the titration period, at about 1 month and again at 6 months, and unscheduled MRIs are done if a trial participant has symptoms that are consistent with possible ARIA-E or ARIA-H (study personnel are of course blinded as to assignment). Blood tests, ECGs and physicals are done every 6 months, with additional consultation from the study site doctor if a participant has an illness. Infusions may be "paused" for a week or more on the decision of the study site doctor and heart rate and blood pressure readings are taken before and after infusions.

The safety issue for lecanemab is important. In the 11/29 CLARITY presentation on safety data, Dr. Marwan Sabbagh, a behavioral neurologist, noted that none of the patients who died after having a macro-hemorrhage had been diagnosed with ARIA-H or ARIA-E, nor had they been excluded due to use of anti-coagulant medications. About 5.7% of patients in both the placebo and lecanemab arms prior to open label extension (OLE) were on such drugs, in hopes of having participation consistent with common comorbidities and medications used in MCI and mild AD patients in communities. It will be important to learn why these other participants did not experience macro-hemorrhages while on the drug.
  • One of 897 participants on the placebo arms of the combined trials died of a macro-hemorrhage during the trials, a rate of 0.1% ; two of 1608 people receiving lecanemab died of macrohemorrhages, also a rate of 0.1%
  • The first patient who died while on lecanemab was 87, non-ApoE4, with anti-coagulant medication, prior heart attack, successive falls, and pneumonia before his macrohemorrhage, followed some months later by cardio-respiratory arrest. Given the association of advanced age with CAA even in non-poE 4 populations, and the prior history of heart disease, it seems likely that he should have been excluded from the CLARITY trial.
I heard at least one researcher note that the risk of death appears to be about 1 in 1000 people treated at this stage of disease. If that proves to be an accurate risk ratio for people with MCI/mild AD, it may be less with people in the AHEAD trial, and will be something each participant should have access to transparently to make an informed consent.

"Isolated ARIA-H", defined as one or more microbleeds with or without symptom but without ARIA-E, was seen in 7.8% of placebo participants and 8.9% of lecanemab participants, suggesting that microbleeds in isolation in this population occur with only a slightly higher rate on lecanemab and may be most influence by age and vascular disease. The incidence of ARIA-H in addition to ARIA-E was 8.4% on the treatment arm vs 1.2 % in the placebo group, suggesting that ARIA-E (edema) may induce stress on the small blood vessels. Study protocol was to withdraw people once they had ≥ 8 macrobleeds or one macro-hemorrhage ≥ 10mm. Neither of the patients who died had that history.

My maternal grandmother died of a massive stroke at age 45, and my mother had multiple microbleeds with uncontrolled high blood pressure in her 70's, leading to mixed dementia in her 80's. I strongly support the need for better and earlier diagnosis of CAA as an independent risk for major brain bleeds for those of us with ApoE 4/4 . Yet, I still believe this drug may be of significant help to those who wish to slow the rate of progression, since the widening curve between placebo and treated patients suggests that the benefit will exceed 27% beyond 18 months, and results presented suggested the biggest change was in perceived burden and perceived functional skills by caregivers of those on the treatment arm--while they were unaware of their loved one' study arm.

I hope that we will learn more from this and other studies. From what I have seen and heard, the most important information may have been presented by Dr. Reisa Sperling, one of the principal co-investigators on the AHEAD studies. She stated in an opening address that we need to recognize that anti-amyloid treatments may be necessary for those who appear highly likely to progress on the path to MCI and AD--AND that researchers need to design combination therapies and multi-modal trials that address vascular, metabolic, inflammatory, toxic, social and age-related contributors to Alzheimer's related dementia.

Sending hope for better news soon for your mother.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by J11 »

NF52, what is the thinking about the fatality in the Clarity OLE with the MCA stroke and then treated with tPA? From the peanut gallery perspective, tPA in that context seems like an incredibly bad idea. Using a strong clot dissolver after Lecaneamb had interacted with the amyloid vasculature would reasonably be expected to have catastrophic consequences. Indeed apparently within minutes of the tPA injection the patient went into medical crisis ... and then the adverse response was attributed to Lecanemab? As suggested previously on thread going to thrombectomy would seem a highly attractive alternative. Is there any discussion that would make this part of the FDA labeling? It is possible that there could be certain types of ischemic strokes where thombectomy might not be possible; it would then be very unclear how to treat such a stroke after treatment with Lecanemab.

NF52 is the implication of the last quote that you have bolded is that patients should be treated off label as I have suggested in the pre-MCI stage in order to condition the existing CAA pathology for Lecanemab treatment (i.e., low dose pretitration)? Essentially, treat the underlying CAA pathology?

Specifically, Does on the path to MCI and AD in the quote "we need to recognize that anti-amyloid treatments may be necessary for those who appear highly likely to progress on the path to MCI and AD" mean before MCI ?
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

Thanks all for your good wishes. We're taking it one day at a time. Late Friday night she was discharged to a rehab facility (love the timing!) but has only been approved for a short stay despite significant disabilities because of her insurance plan. We're scrambling to put a plan in place to ensure her safety and continued rehabilitation.

This has been such a great discussion and gets to the heart of my concern with lecamamb and really all of the "mabs." I appreciate that they're doing a baseline MRI for this study, but suspect that it may not be an MRI with a microhemorrhage sequence (MP-RAGE), which can reliably find current and prior bleeds. Any hemorrhagic finding combined with carriage of ApoE4 should be highly suspicious for CAA and reason for exclusion from this trial. I'd love to hear from anyone who's participating (esp. Dr. Karalena) to see if this specific type of MRI was done at baseline.

J11, great question about the even greater need for mabs with CAA. From everything I've learned, amyloid is the body's response to an insult (insulin resistance, hypoxia, toxins, etc.) It's essentially nature's band-aid for the brain. The best course of action for us all is to identify and address all underlying insults so the body no longer has a need to produce amyloid. That may be wishful thinking, especially for homozygotes, so promotion of clearance is also important. Maybe after root causes have been healed, micro-dosing with a mab could be helpful for this vulnerable population. Dr. Bredesen has even spoken about pulsing curcumin up to 5g for short periods to do the same. Ensuring quality restorative sleep is another way we can all promote amyloid clearance.
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Re: Lecanamab: Efficacy, Side Effects, and More

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Julie G wrote: Sun Dec 04, 2022 12:21 pm...I appreciate that they're doing a baseline MRI for this study, but suspect that it may not be an MRI with a microhemorrhage sequence (MP-RAGE), which can reliably find current and prior bleeds. Any hemorrhagic finding combined with carriage of ApoE4 should be highly suspicious for CAA and reason for exclusion from this trial....
Hi Julie,

I both wish and anticipate that you and your family will be successful in advocating for a planned and safe discharge for your mother. When I worked with kids with TBI many years ago, the initial rehab authorization was often painfully limited, but statements of need by physiatrists, PTs, OTs (especially regarding safety at home) and families often resulted in extensions, or extended supports through outpatient programs. Hope that happens for you.

The CLARITY exclusions criteria indicates the capability of diagnosing microhemorrhages, and the MRIs are specifically timed frequently during titration to identify ARIA-H. Here's a partial list from CLARITY:
  • History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening
  • Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than Alzheimer's disease
  • Other significant pathological findings on brain MRI at screening, including but not limited to: more than 4 microhemorrhages (defined as 10 millimeter [mm] or less at the greatest diameter); a single macrohemorrhage >10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and <1 centimeter [cm] at their greatest diameter need not be exclusionary)
  • Participants with a bleeding disorder that is not under adequate control (including a platelet count <50,000 or international normalized ratio [INR] >1.5 for participants who are not on anticoagulant treatment, example, warfarin). Participants who are on anticoagulant therapy should have their anticoagulant status optimized and be on a stable dose for 4 weeks before Screening. Participants who are on anticoagulant therapy are not permitted to participate in cerebrospinal fluid (CSF) assessments
  • Any other medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments
ClinicalTrials.gov: CLARITY AD
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Re: Lecanamab: Efficacy, Side Effects, and More

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J11 wrote: Sat Dec 03, 2022 1:08 pm...Using a strong clot dissolver after Lecaneamb had interacted with the amyloid vasculature would reasonably be expected to have catastrophic consequences....Is there any discussion that would make this part of the FDA labeling? ...

NF52 is the implication of the last quote that you have bolded is that patients should be treated off label as I have suggested in the pre-MCI stage in order to condition the existing CAA pathology for Lecanemab treatment (i.e., low dose pretitration)? Essentially, treat the underlying CAA pathology?

Specifically, Does on the path to MCI and AD in the quote "we need to recognize that anti-amyloid treatments may be necessary for those who appear highly likely to progress on the path to MCI and AD" mean before MCI ?
Lots of great questions, all of which are above my pay and expertise grade.

But I'll try to accurately share what was presented, with the caveat that I am not affiliated with or authorized to speak for Clarity study sites or the companies!

The death of the 65 year old woman with ApoE 4/4 on the Open Label Extension Study (OLE) almost certainly was not "reasonably expected".
  • No deaths from macrohemorrhage occurred on lecanemab among 898 people in the CORE study, while one occurred from macrohemorrhage among the 897 people in the placebo arm.
  • Almost 6% of those on lecanemab had been treated with blood thinners in the first CORE phase of the trial without any deaths. Five people on lecanemab in the CORE study had a macrohemorrhage ≥10 mm; not to minimize that, but none of those resulted in death. It's unclear from the presentation whether those were symptomatic or only diagnosed from MRI.
From the presentation, this woman was not on a blood thinner previously, and passed the OLE study's exclusionary criteria, which are listed in my post above. She would have had an MRI weeks before starting infusion , and presumably a month or two before her stroke, that showed:
  • No evidence of ≥ 4 microhemorrhages , a single macrohemorrhage, white matter disease, severe small vessel disease, or uncontrolled heart disease.
That may add to the case for lecanemab being a key factor in her death. It also leaves open the question if what Dr. Sabbagh described as an "occlusive" stroke was a clot that would not have shown up on an MRI, and was treated by a clot-busting treatment which triggered her symptom-less, but clearly severe CAA, with or without lecanemab. She had only been in the OLE for a month, I believe, which would have been two half-dose treatments, two weeks apart.

I have deep sympathy for the family of the 65-year old woman, since my 67 year-old, ApoE4+ father died of cardiac arrest only a few hours after the RNs at his cardiac rehab program pronounced his heart rate "perfect", seven months after "successful" quadruple bypass surgery. That taught me at the age of 34 to be recognize our limits in preventing all adverse events and predicting the future.

Here's some of the Safety Assessment chart data from the Clarity presentation by Dr. Sabbagh, emphasis added by me:
  • There is a low rate of macrohemorrhage with lecanemab therapy (0.6-0.7%), which is higher than placebo (0.2%)
  • Rate of macrohemorrhage for subjects on both anticoagulants and lecanemab was 2.4-3.6%. Background rate of macrohemorrhage in AD patients on anticoagulation is not known but is expected to be higher than in non-AD patients due to CAA; therefore, comparative risk is difficult to assess.
  • No clear relationship of macrohemorrhage to ApoE4 status, baseline MRI, or timing of treatment
  • Subjects allowed to continue on anticoagulation in OLE with informed consent language regarding increased risk of cerebral hemorrhage with concomitant anticoagulant use
As a lay person, it seems reasonable to assume that the FDA would want some warning language about use of anti-coagulants with lecanemab, or treatment of strokes in the context of prior or current lecanemab use.
  • I did hear multiple presenters outside of the CLARITY presentation state that the evidence from lecanemab, donanemab and especially the completed, but unsuccessful gantenerumab trial is that amyloid removal must get down to 20-25 centiloids in order to show a clinically meaningful cognitive benefit, which appears likely to increase over time beyond 18 months. The logical extension of this, also stated by multiple presenters such as Reisa Sperling and Roger Nitsch, is that "secondary prevention" in people with intermediate amyloid (20-40 centiloids) and elevated amyloid (>20 centiloids) is predicted to avoid tau deposition, which has been seen as early as 3 centiloids of amyloid beta, and reduce or delay progression to MCI. That does NOT mean that doctors would be encouraged to provide off-label use of the drug, especially since lecanemab, donanemab are currently in well-designed Phase 3 trials with cognitively unimpaired people with amyloid.
As a side note, on the list of current accelerated drugs is one being studied "for patients treated with rivaroxaban [Eliquis] and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding That drug may not currently be in wide use, since the study is due to complete in 2023, but might be an option for the situation you described, in which a patient with no history of ARIA or known diagnosis of CAA develops life-threatening macro-hemorrhage. https://www.fda.gov/drugs/accelerated-a ... -approvals
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by Julie G »

The CLARITY exclusions criteria indicates the capability of diagnosing microhemorrhages, and the MRIs are specifically timed frequently during titration to identify ARIA-H. Here's a partial list from CLARITY:
Yes, thank you, NF52. I'm aware of the criteria but still have questions about HOW they are obtaining that information and look forward to hearing from those those who are partaking in the trial.
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Re: Lecanamab: Efficacy, Side Effects, and More

Post by karelena »

Julie, I hope your mother is recovering well. I know she is fortunate to have you as her advocate.

I have been reading the posts on this thread, and the ones about brain volume loss with lecanemab. I am not entirely convinced that the volume loss is not due to loss of amyloid. I don't think they can accurately estimate the volume of amyloid based on the PET scan. The units they use are "standard uptake value ratios," not weight or volume.

But I will certainly ask about it this week when I have my next appointment for the study. They are going to give me my amyloid PET scan results, and also do some blood tests for "biomarkers" and I will find out exactly what those are, and ask about the MRI sequences they are using to detect ARIAs.

It would be interesting to follow the brain volume measurements over time, do they stabilize after treatment is completed or continue to decrease?

When is treatment completed? When the amyloid is reduced by a certain percentage? It seems like in the CLARITY trial that they continued to receive treatment in the open label extension. What was the end point for that trial?
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