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.

Postby J11 » Tue Oct 12, 2021 9:06 pm

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

Postby J11 » Tue Oct 12, 2021 9:12 pm

It is very helpful to post all the intermediate steps on the thread so that whenever I want to find something it is right there on the thread. I realize that this makes reading the thread somewhat excessively wordy, though I know from personal experience how frustrating it can be trying to find a supporting document when it is just left on the hard drive--- somewhere, in the thousands of gigabytes.

The above figure is the reported result for the Gantenerumab phase 3; each of the arms had substantial numbers of patients. The reported result was 0.10 for 105 mg and 0.18 for the 225 mg at week 104.

In the post on Sun Mar 14, 2021 6:12 pm page 43 of the thread. I reported extracting the ganta phase 3 dots from this article and found 0.04 and 0.155 CDR-sb benefit, though this was probably from an earlier time frame.

"OK, "High" dose ganta at week 76 extracted from the above figure gave a 0.155 CDR-sb benefit with 0.11 SUVR.
"Low" dose ganta at week 76 gave a 0.04 CDR-sb reduction (versus placebo) with 0.03 SUVR."

Hmm, that is actually quite funny. I went back to my old page with the calculations for the ganta phase 3 results and I actually
made an error: 177 - 158 is not 21: it's 19. The ganta high dose that I plotted using data extraction shouldn't be at -0.155 it should be at -0.14. This result is now exactly on the regression line. I suppose I could recalculate this regression.

Yet, it appears that I might have been off on the low dose. Somehow I calculated -0.04 for the low dose, however, it appears that at week 78 the low dose might have been 0.01 worse than placebo, but at week 88 low dose was 0.10 better than placebo.

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

Postby J11 » Tue Oct 12, 2021 10:08 pm

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

Postby J11 » Tue Oct 12, 2021 10:14 pm

This is the update with the new positions for Ganten. The G3Hi dose has moved to (-0.13, 0.14). It had been at -0.11, though the placebo actually move away by 0.02. so, relative to placebo the high dose was actually at -0.13. Also as noted above, the G3 low dose actually was slightly worse than placebo at week 76. The one problem here is that ganten appears to use a different titration scheme. This would tend to diminish the reported treatment effect compared to the standard 76/78 week readouts. This is most notable for the low dose as in the next reported value at week 88 the CDR-sb benefit has expanded to 0.10 which is a fair way better than expected from the regression.

Err, to interpolate the 76 week value for high dose SUVR we can look at the week 60 value of -0.13 or we could consider the -0.11 value for week 100. The placebo and the high dose converge from week 60 to week 100.

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

Postby J11 » Wed Oct 13, 2021 7:17 pm

Gantenerumab appears to be quite similar to the other aducan class amyloid mab such as aducanumab, lecanemab and donanemab.
My best guess is that it will remove ~0.30 SUVR of amyloid and will report a ~0.40 CDR-sb benefit versus placebo if the demographics (e.g., APOE epsilon 4 % etc.) are similar to what was reported in the other recent amyloid trials.

There is, though, some probably small chance that this will not go to plan. There were no placebo controlled phase 2 trials and it is not clear what time point that they are using for the primary readout of the upcoming phase 3s. The other readouts (e.g., aducan 301/302, and the phase 2 leca trials) reported at 18 months so there is now a well established pattern when cognition is tested then. {It is somewhat surprising that some of these trials have not tried to extend out the trials somewhat (or at least try some exploratory dosing) as there might yet be additional treatment benefit that could be accessed.} The problem is that different time points can produce different answers. For example, in the previous ganten phase 3, there was a benefit at week 76 but not at week ~104. I would interpret any miss as being a false fail. Without a phase 2 result it becomes somewhat tricky to call the right time to measure as the finish line.
The company likely has good internal research that justifies their choice, yet one still would have some doubt how it will work out. Considering the different titration schedules, the 76 week readout that will happen for one of the Graduate phase 3s in January might not correspond to the traditional 18 month trials that we are used to.

I went to the roche.com website, though it was nearly impossible to find any information about gantenerumab. The Roche pipeline has pages and pages of drug candidates. Gantenerumab was one of dozens of others. In fact, I was unable to find anything specific about ganten from the page; I just gave up. It was like going to a shopping mall and feeling so overwhelmed that you decide to it would be better to shop online. Largely the same experience when I went to the Lilly site for information on donanemab. Fortunately, Biogen has a near constant stream of updates about aducanumab and lecanemab. I will focus this thread mostly on Biogen's products, though donanemab and gantenerumab are highly similar beta-amyloid mabs.

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

Postby J11 » Wed Oct 13, 2021 7:24 pm

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

Postby J11 » Wed Oct 13, 2021 7:51 pm

The thread is approaching it's 2 year anniversary!
Great!

There has been a lot of developments during the last two years.
I think a Celebration of this Celebration thread is in order!

How have we progressed with Alzheimer's clinical medicine in the last 2 years?
Aducanumab has been approved by the FDA.
Clearly this is a major milestone on the road to effective treatment of Alzheimer's.

Yet, what is perhaps of even greater importance is the realization that anti-amyloid medicine truly can be an effective treatment approach. Even the FDA Aducanumab approval hedged somewhat on this question. Nevertheless after all of the hundreds of thread posts, I no longer believe it can be credibly asserted that anti-amyloids are ineffective. There are simply too many regressions across multiple amyloid mabs including Aducanumab, Lecanemab, Donanemab and Gantenerumab - supporting the strength of association between clearing amyloid and cognition. The stronger psychometric measures such as ADAS-cog/ADCS-ADL (versus CDR-sb) demonstrate even clearer benefit as do well-defined subgroups notably APOE epsilon 4s etc.. The argument against the efficacy of anti-amyloids has deteriorated to not much more than "No, It ain't." I have tried to search out legitimate counter-arguments without success. After over a century of basic research, Alzheimer's has a disease modifying therapy.

The confusion that has arisen over the last few months is how this effective treatment has largely not translated into a clinical success. I am guessing here, though I believe that it is unprecedented for an FDA approved medicine with large clinical need to be stalled in distributing it to patients. Why is that?

For patients Aducanumab is on paper a reasonably attractive treatment option. It has shown clear effectiveness and the safety appears relatively encouraging. The above figure suggests that perhaps 1% would have a serious side effect. At first glance, this anti-amyloid would seem to have all the characteristics of a breakthrough product, though there are price challenges involved. What is holding it back?

I think the main feature involved is that the medical system balked. From the medical perspective Aducanumab is not that safe; it does not represent a good bet for patients to make. When we look more closely at the figure above what I had overlooked was that these 29 serious side effects occurred in the high dose arms of 301/302 trials. 29 serious events out of ~600 patients? Yet, the dosing of the patients on high dose changed mid-way through the trial, and the APOE epsilon 4s were at especially high risk. The risk of serious side effects was considerably larger than I had realized. Those prescribing Aducanumab would have been constantly aware of the long line of patients that were arriving at the ICU (many of these patients especially the MCI patients would have minimal cognitive impairment making this all of the more difficult) because of anti-amyloid treatment, while those patients who were spared serious side effects would not be that much clearly improved. The tradeoff for those on the front line would not seem to be worth it.

It isn't that Aducanumab is not effective; it is more that it is not safe enough.
By discussing this more honestly and directly perhaps solutions could be advanced.

In this respect I continue to wonder about how the dosing titration might be modified to be safer. It is still surprising how "dangerous" early low doses of Aducanumab were in high dose 301/302. The second dose 3 mg/kg dose had 11 of the serious side effect events. All of the 10 mg/kg doses had only 5 of the serious events (3 of which were within the first 2 high doses). The last 8 high doses had 0 serious events. Once patients have been titrated, high doses of Aducanumab can be unexpectedly free of side effects. Addressing this issue and greatly reducing side effects would seem an obvious step forward, though for whatever reason this has not been pursued.

Thinking of anti-amyloid treatment more as a lifestyle medical intervention would probably be of great benefit. There are many millions of APOE epsilon 4s who are just on the edge of aging into cognitive impairment. They would greatly appreciate a treatment that reduced their amyloid levels, though only if the treatment offered minimal risk of side effects. The first 1 mg/kg dose apparently induced 0 serious side effects,while the second 1 mg/kg dose caused 2 serious side effects (it is possible though that these side effects require some time to become clinically apparent). This suggests that a dose lower than 1 mg/kg might cause essentially 0 side effects. Mice studies found that dosages ~~500 times less than therapeutic still reduced amyloid though without ARIA. Patients who are possibly years away from clinical onset, would probably be relatively happy with a no side effect slow uptitration which could also be very reasonably affordable, even if paid out of pocket. Establishing the clinical parameters for this implementation represents a near term large scale payoff. It would be of benefit to millions and a relief for tens of millions of others.

The clinical trials for low scale dosing would not need to be prolonged; establishing clinical benefit would not be the main yardstick of success-- removing amyloid with no risk of ARIA would be. With a low enough dose there might not be much of a titration phase that would be required. Without such uptitration ongoing treatment would not pose the same risks involved in the trials where dosage kept increasing ever higher. Patients on low dose would also not be in any particular hurry so they might take drug holidays every once and a while.

The micro-dosing approach would put safety front and center. There would be no need to infuse maximal doses over the shortest possible time frame. This is the only reason that safety issues have emerged in the anti-amyloid trials. Current trials are treating right at the maximal dose; in order to treat people right near the onset of clinical cognitive decline this has been thought necessary. With the micro-dosing strategy, there would be no incentive to treat aggressively, if anything the strategy would be biased to cautious dosing. The aim would be to strive for zero side effects for clinical measures of decline that might be up to decades in the future. It would be a money maker for the pharma companies who have worked so hard to bring these anti-amyloids through the clinic only to find yet more hurdles that they must leap over. Down-dosing the current anti-amyloids to a very very safe level, charging a highly reasonable treatment fee and making a large amount of money in comparison to the recent clinical trials with maximal dosing would seem to be a walk in the park.

I am not that clear how the FDA would interpret this. Are extensive clinical trials showing "clinical benefit" necessary for this? What "clinical benefit" would actually be involved? It is more preventative medicine. It is removing amyloid which is now understood as a biomarker likely to relate to clinical decline. Why wait until there is irreversible clinical decline necessitating extreme dosing and considerable risk? Run clinical trials --> establish safety and then treat as an off-label? The FDA has showed leadership by approving Aducanumab as a treatment for those in the cognitive decline stage; why not show leadership in allowing treatment as a very safe treatment in the pre-decline stage? Proving such safety should not be overly time consuming.

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

Postby NF52 » Thu Oct 14, 2021 10:05 am

J11 wrote:...The phase 2 from leca has been out there for months now and it is only now that it has hit me: the APOE epsilon 4s had a large response to leca on the highest dose. On the 10 mg/kg biweekly dose the epsilon 4s (n=45) had a change from baseline of 0.096 points on ADCOMS versus a 0.180 change for placebo (n=168). A 47% reduction in decline at 18 months for the e4s? That is more than I had expected might be possible for an anti-amyloid.

Table 2 from the article noted that there was a 97.6% probability of superiority against placebo after 12 months for the highest dose arm....
Lecanemab has shown very impressive results with e4 patients and we should prepare now for the celebration...
Hi J11,

In case you haven't seen it, here's an update from the Sept 10, 2021 issue of ALZFORUM on lecanemab (aka BAN2401), showing that the CLARITY trial, enrolling people with MCI or mild AD, has exceeded its enrollment goal, and the AHEAD 3 and AHEAD45 trials of cognitively healthy people ramping up. AHEAD 3 will enroll people with lower "intermediate" levels of amyloid beta for monthly infusions of 10mg/kg and AHEAD 45 will enroll people with elevated a-beta for biweekly infusions of 10 mg.kg, with an 8-week titration to the full dose for each group.
As of October 2020, Clarity AD had randomized 1,222 participants, with demographic and cognitive scores similar to the Phase 2 study (Nov 2020 conference news). By March 2021, it had exceeded its enrollment goal, at 1,794 patients, the company announced (press release).The trial is set to run until 2024.

In February 2020, the Alzheimer’s Therapeutic Research Institute announced that the Alzheimer's Clinical Trial Consortium (ACTC) would conduct a large BAN2401 study co-funded by the NIH and Eisai (press release). Called AHEAD 3-45, this Phase 3 study started in July 2020. It is a four-year trial that comprises two sub-studies in a combined 1,400 people who are cognitively normal but have elevated brain amyloid. A3 will enroll 400 people with amyloid below the brain-wide threshold for positivity... Their primary outcome is change from baseline on their Preclinical Alzheimer Cognitive Composite 5 (PACC5) Score, also at week 216. Secondary outcomes for A45 include change in brain amyloid PET and cognitive function. Both studies will measure change in tau PET as a secondary outcome. The first person was dosed in this trial in September 2020; as of the July 2021 AAIC, 77 people had been randomized. The trial is expected to run until October 2027.
In June 2021, the FDA designated lecanemab a breakthrough therapy, thus expediting its regulatory review

https://www.alzforum.org/therapeutics/lecanemab
It's worth noting that they are setting the primary outcome as a statistically significant change on the PACC5--a measure of cognitive and daily living skills, not on changes in A-beta and tau. Making a difference in whether or at what rate people with biomarkers of AD pathology can maintain normal cognition would seem to hold far more impact for those with ApoE4 who have a high risk of earlier diagnosis and higher levels of A-beta and tau. One view of why ApoE4's did better on these trials is that they likely started with higher levels of amyloid and more likelihood of tau and so had more to gain.

Here's some support from the lab of Dr. Huang at UCSF's Gladstone Institute for the view that ApoE 3/4 and 4/4 act very differently in the brain than ApoE 3/3. It might also support that our practice of giving separate diagnostic names to symptoms that likely have overlapping genetic causes, and the same name to diseases that likely have widely disparate causes, makes prevention, diagnosis and treatment much more complex. Re: Bumetanide for APOE4 Carriers
The researchers found 8 pathways to Alzheimer's disease (AD) of "perturbed" up-regulated or down-regulated genes that were "uniquely significantly enriched in ApoE4/4 AD". Two other pathways were uniquely significantly enriched in ApoE 3/4 AD and 58 were uniquely significantly enriched in ApoE3/3 AD.
Only seven pathways were shared across all three groups.

According to the article, Bumetanide has been studied for autism, schizophrenia, seizures and depression, "suggesting brain penetration and potential effectiveness in the central nervous system" by "flipping" genes back from an up-regulated or down-regulated state to a more normal state. In the experiments using a mouse model with ApoE4, the Bumetanide "rescued" neuronal plasticity in the hippocampus and spatial learning. Three pathways that appeared to be significantly affected by the drug were the "GABAergic synapse, circadian entrapment and morphine addiction pathways."
As for those many relatives who relied on silence and other methods to avoid difficult topics, I suspect we all have families that practiced that to some extent. So in addition to knowing more about genetics, I choose to forgive them what they didn't understand, while I still wish they had shared difficult truths: “Tout comprendre c’est tout pardonner.”
4/4 and still an optimist!

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

Postby J11 » Thu Oct 14, 2021 9:59 pm

Thank you for posting NF52!

Sorry everyone, but I am in a grumpy mood. For some reason my internet has hit a traffic jam and I am not totally sure what to do. It is super S---L----O----W . I know I know first world problem, yeah well how are you supposed to get over an internet crisis? It usually involves a dreaded interaction with technical support and perhaps there is some very odd something or other happening with software or something. We have upgraded to fiber optic internet, though I had been happy up till now with staying with WiFi and just switching to the 5 GHz signal. Not sure now what getting high speed will entail.

The prayers and best wishes from the thread will be greatly appreciated; somehow we will have to live through this slow web.

NF52, I have looked on alzforum for the lecanemab article on September 10, though I was unable to find it. Might you supply a url?
I do though believe that I can recall reading this article. From what I remember there seemed to be some confusion about the enrollment from China into Clarity. They were continuing to enroll Chinese, even when the trial had apparently completed enrollment? Making Alzheimer's trials more international can be a benefit, though I am somewhat worried that it could also add in complexity. When Eastern European clinical sites were added into the large dementia trials there seemed to be problems with clearly defining what was meant by Alzheimer's etc.. As much as you want to be all scientific and objective there is this unfortunate truth that people often do not all line up in a row like lab mice. Medicine is a social science. It could keep you up late at night worrying about all the potential unanticipated confounders that China might add into Alzheimer clinical science. Culture can be confusing.

NF52, if I remember correctly you have close contact with the lecanemab trials. I am interested in the titration schedule for the phase 3. It is only recently that I have encountered the idea that there might be a minimal (non- existent titration)? Basically, patients are at full dose after ~2 months? This then resulted in the phase 2 leca trial showing such strong results after only one year of treatment.With aducanumab titration required ~6 months plus. What I only recently realized was that lecanemab could possibly readout much sooner than I had thought. This is compounded by the fact that the APOE epsilon 4s appeared to do so much better than the non 4s in the phase 2. It certainly has me wondering whether at some not distant time in the future the trial could simply be stopped for success. 45 patients on high dose in the phase 2 with e4 genotype had a large response. Perhaps it will be acknowledged that the non 4s are not receiving that much benefit from treatment and then the large results from the 4s can be given on the top line. It will likely be not that easy to overlook the e4 non e4 difference when all of these large phase 3 trials are now approaching shore.


Yes, with the 3-45 Phase 3, I can see the logic in moving to the next generation of psychometric tests. Most of the current AD clinical tests are fairly hopeless. With our loved one, we were aware for years and years that there was a problem before it showed up on the MMSE etc. Our loved one went home -- down home ~10 years before a clinical AD diagnosis- no one knew who are loved one was. These were direct family and friends who really knew all of the ridiculous pranks that real people in the country seem to get up to when they growing up. They had lots of fun and lots of memories. However, it was immediately apparent to them that our loved one was not the same person that they remembered. That's what happens with Alzheimer's: your complete personness shifts -- it typically starts to become fluid. If you haven't made contact in a few years, the person that you knew is no longer the person that is in front of you. As long as you maintain constant direct contact, though you don't notice it as much. You just accept a day and another day and another day and it all seems like a continuous movie. You don't dwell on how much the person has changed over a length of time. People without neurodegenerative illness are expected to maintain their personhood essentially forever.

This of course is directly related to anti-amyloid treatment. AD does not magically start when you hit 30 MMSE. It can happen decades before this. We probably witnessed the decline over a multi-decade time period. The brain imaging clearly shows how AD brains neurodegenerate years before final cognitive decline. This is the time interval that we really want to see some clinical intervention. Low dose aducan should reasonably be expected to be quite helpful then. What I am unsure about is how much clinical evidence might be expected to demonstrate this? Proving that anti-amyloids stop neurodegeneration at the early stage might take 5-10 years. At a certain point one might think that simply accepting the obvious would be regulatory stance. However, I am not clear on this point.

I think the best outcome here might be something like a 5,000 preclinical trial with low dose aducan over ~1 year months that demonstrated safety. Then dosing could go off label. Really nice and low dosing; no titration and very safe. People would then have the confidence to try very early prevention. The clinical ratios of those helped versus those with possible side effects would overwhelmingly favor treatment.


The big breakthrough that has emerged for me of late are these polygenic scores. There has been so many years of these studies with ever larger sample sizes. We now can describe a great deal about human behavior based upon these scores. It is helping to reveal the inner workings of people and I think people will derive large benefit from knowing the truth about themselves. It will create much stronger communities with people who have much stronger commonalities.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby dee » Fri Oct 15, 2021 1:28 pm

I have almost no idea what most of this says. But it sounds very promising. Thank you! I needed some hope today. In fact, I joined the forum instead of just being my normal lurker self so I could say thank you. :)



J11 wrote:The phase 2 Lecanemab results for the APOE epsilon 4s were stunning. Admittedly this is a delayed headline (almost reading history than your newspaper as this result was published in April), though it is still worthwhile to highlight these results.

The bottom figure from the above post is an attempt to convey the information in Supplementary Table 16 of the article in a more easily understandable graphical format. What we can see is that the APOE epsilon negatives did not appear to have much of a response relative to placebo on ADCOMS for any of the doses. However, the APOE epsilon positives appeared to have a quite large % response versus placebo. At the highest SUVR on the left ~ -0.31, the percentage reduction in decline was ~50%. That is worth repeating:

There was a ~50% reduction in decline on ADCOMS at 18 months for APOE epsilon 4s in the phase 2 clinical trial for the highest treatment arm of 10 mg/kg twice monthly (n=45 treatment; n= 168 placebo).

Slowly Alzheimer's progression in epsilon 4s by ~50% in this population of early mild AD patients constitutes a near functional cure. This represents a substantial treatment advance. Extrapolating this result forward one could imagine that with such a magnitude of slowing of progression the most severe stage of AD would likely not manifest for those somewhat younger than their expected age of cognitive decline onset. It is startling to recognize that for the ~50 million American epsilon 34s, the vast majority could have a clinically proven treatment option that would prevent their manifesting AD.

Nevertheless, this is somewhat speculative as the highest dose that achieved nearly 50% reduction in decline only had 45 APOE + patients. Nonetheless, the next lower dose of 10 mg/kg once monthly with n=218 recorded a 23% reduction in decline. Table 2 from the article further notes that the Bayesian ADCOMS at 12 months for the combined group of APOE epsilon plus and minus had a 32% decline in progression versus placebo. One has reason to assume that much of this benefit would also be driven by the e4+s as they demonstrated almost all of the benefit at 18 months. 1200 of the Phase 3 patients in Clarity now have 12 months data, though perhaps only half would be epsilon 4s.

This is extremely positive news!

The lecanemab results appear to be driven almost entirely by the epsilon 4s. They are not receiving a benefit of ~20% as reported with Aducan, but closer to 50%. Perhaps with some data filtering these numbers would increase. For example, what were the results for the patients with more amyloid clearance? How could the placebo be corrected for the hidden placebo treatment effect? or the rapid progressors or non-progressor placebo? ...

The upper figures in the previous post highlight the superior performance that was also noted in the 302 Aducan trial for e4+s. It is becoming increasingly unclear whether epsilon 4s actually do receive benefit from anti-amyloids. Combining these two subgroups merely obscures the large difference in response. If Clarity had pre-specified e4+s as a top-line result, the trial might have already been halted for success. The e4 results are large. It does seem that some of the e4-s are likely benefiting though it could take some effort to determine exactly the covariates that determine their response.

Also highlighted in the figure for the 302 results is the consistent statistical significance across all measures for the high dose arms for the e4+s, while all of the high dose arms in the e4-s are far wide off such significance. Also the 0.53 CDR-sb gain versus placebo for the high dose for the e4+s is somewhat better than the overall 0.39 gain for the 302 high dose arm. Yet, 0.53 reflects closer to a 30% gain for Aducan versus ~50% gain for the high dose e4+s on Leca in the phase 2. Perhaps this difference relates to the higher SUVR result for Leca and possibly as well as the cleaner trial results due to reduced side-effects etc..

Given the above, It would be very helpful if we could find an early approval mechanism for leca. There is a large dominance of naysayers in the regulatory process. Considering the near perfect 100% failure rate of AD drugs for almost 20 years this is possibly inevitable. However, the results above suggest that we need some more yea sayers. Leca has shown some large positive benefit for epsilon 4s and realistically this would seem to offer substantial benefit. Perhaps let Clarity run to March which would be 12 months of full enrollment of 1800 patients; then begin the up titration for the epsilon 4s who were on placebo while maintaining randomization and then open up Right to Try on a profit neutral basis until full approval were granted. Of course, Depending upon what the regulatory time line is this might not be needed. It is not clear to me whether the plan is to approve leca even while Clarity is ongoing. The rolling submission for leca only mentioned including safety data for Clarity.


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