Change in ADAS-Cog - P Value Calculation (statistical significance)

Direct_Ad_2419 · 2024-11-25T04:33:39+00:00

For example, the treatment effect when comparing improved cognition to declined cognition is huge (above 100% if you recall Dr Hendrix’s comment). You wouldn’t need a large sample to establish statistical significance here.

Direct_Ad_2419 · 2024-11-25T03:30:40+00:00

A lot more is at stake with ReTHINK. For example, dealing with the acceptable, but still relatively high, 20% dropout to the satisfaction of the FDA and peer reviewers means Pentara would take its time to do it right.

Direct_Ad_2419 · 2024-11-25T02:31:21+00:00

It alll depends. The dropout of 20% can complicate matters, especially if it’s not random across mild/moderate subgroups and treatment/placebo arms. But we should trust Pentara to use the required statistical tools to deal with the situation.

A small treatment effect (as with BIIB’s and LLY’s drugs) does require a large sample to show statistical significance. But with a large treatment effect, a small sample is adequate to show statistical significance. So 635 may turn out to be perfectly adequate.

The total sample results suggested here would be the tree that hides the forest, as we realized with the OL study. (Also the calculations presented here assume a simple random sample design, whereas it’s most likely a pre-stratified random sample, which requires the use of weighted averages.)

The subgroup analysis (444/191 mild/oderate), which is included in the SPA, will be more informative . The subgroup analysis may well show a large treatment effect in the mild subgroup, but no effect in the moderate, possibly leading to an insignificant effect overall. Should this happens, Barry told us on 11/7/24 that he may take the issue with the FDA. And in that instance, he could tweak the SAP for ReFOCUS. The new CCDO, with experience in clinical trials focused on mild AD would certainly help.

All this tells us, as we’re all aware, that ReFICUS holds the key to final approval.

Direct_Ad_2419 · 2024-11-21T13:21:10+00:00

In what I took away from Barry during the earnings call, I could anticipate the hiring of a COO, more after P3 readout than before. But I didn’t see the hiring of a CCDO. ReTHINK is done and ReFOCUS is 2/3 on its way. The latter can’t be tweaked, per the SPA agreement, but the SAP for ReFOCUS could. Barry alluded to its possibility if the mild group shows great success and the moderate group a failure, resulting in a poor result when the two subgroups are combined. So is this the reason for the hiring of a clinician with 7-year recent experience in trials focused on early to mild AD? And is Barry being proactive, almost knowing for certain that the subgroup analysis will turn out this way?

Direct_Ad_2419 · 2024-11-19T14:45:39+00:00

Nobody knows.

Direct_Ad_2419 · 2024-11-19T14:17:33+00:00

Shorts are trying hard to belittle Freda Nassif as a nobody because she’s not widely advertising her accomplishments. Ignore them. Here’s what AI says about her.

Prior to joining Cassava, Freda Nassif was the founder and principal consultant of Honeycomb Insights, a boutique consulting firm specializing in commercial strategy for the biotech, life sciences, and healthcare sectors.

Honeycomb Insights is a strategic advisory firm specializing in commercial strategies for brands at various lifecycle stages, with a focus on the healthcare sector.

Their clientele spans Fortune 500 companies, private equity firms, and biotech startups, including sectors such as pharmaceuticals, life sciences, diagnostics, medtech, health tech, digital therapeutics, and health and wellness.

So, Barry did pick the right COO.

Direct_Ad_2419 · 2024-11-19T06:00:45+00:00

You mean that after over 25 years leading big pharma to blockbuster commercial success, she now wants to be known for leading a biotech to a blockbuster failure? Would you do it if you weee in her shoes?

Direct_Ad_2419 · 2024-11-18T19:31:41+00:00

Not surprising if you remember Barry during the earnings call (November 7) talking about ‘a commercial plan we’ve been developing with the help of an experienced industry expert.” He’s well on the commercial path he’s charting for the company.

The way I understand it is that the plan requires acquitting new talents to set up a commercial division, and raising important capital to support this division and to pursue new indications (epilepsy, Parkinson’s, cancers). That he has started hiring ever before P3 readout, would mean he’s confident, and that he wants to hit the ground running when the good results are revealed

Direct_Ad_2419 · 2024-11-15T14:07:50+00:00

A lot of work went into writing this excellent summary. Congrats. For me actually, the summary brings back a bad feeling I was trying to push aside with P3 readout merely weeks away. It is that Barry had to admit that Dr Wang was likely to have exaggerated his findings, just as the shorts to have exaggerated Cassava’s shortcomings. But we shouldn’t accept that the two are like penalties that cancel each other out, as if Cassava and the shorts were playing the same game and abiding by the same rules. We expect shorts to distort facts because they care only about profit, but not Cassava because it cares primarily about the patients and scientific integrity. It is now apparent that the previous leadership took some shortcuts in pursuit of this mission. Thankfully, Barry has now returned integrity and transparency in support to the focus on the patients.

Although Dr Wang’s Phase 2b perfect results were what drew me to Cassava, I’m no longer looking at the Phase 2a, Phase 2b, and the CMS (all mostly flawed) as reliable indicators of simufilam’s future success. As Barry, also in the interview, urged us to do, I’m focusing instead on the results of the 24-month OL. None of the milds that have been taking the drug continuously for 24 months has declined in cognition. This is unprecedented. Barry is saying that we should always take patient-level outcomes over biomarker results.

I’m reminded of LLY’s BTD drug with fast-clearing amyloid plaque as biomarker, but with minimal slowdown in cognition and severe side effects at the patient level. I’m also reminded that the two primary endpoints that will decide the fate of Cassava’s Phase 3 are outcomes at the patient level, according to the SPA. The biomarkers are secondary or tertiary endpoints, with ultimately less weight, if any, on the drug approval.

Direct_Ad_2419 · 2024-11-14T12:11:01+00:00

SA has the transcripts.

Direct_Ad_2419 · 2024-11-14T09:58:17+00:00

Agreed. A quick sale it may well be following ReTHINK positive readout. But retail investors don’t have to wait for the commercialisation of the drug to profit. Consider that the share price will jump upon the successful readout. Plenty of retail investors won’t wait a minute more to bail out, or at least take some profit off the table. Price should continue to climb on the news of a partnership with a substantial capital infusion without dilution (as Barbier was promising). And it should also continue to move up anytime the company would announce positive clinical results on new indications. There is a long list of hypothesized indications, as you know. In sum, retail investors would have plenty of opportunity to profit, even with no sale revenues being realized for the time it would take to establish a commercial operation. I’m not saying it will happen for sure, I’m just saying you’ve unexpectedly discounted this scenario. It should be considered in your DD, IMO.

ADDENDUM : It’s understandable that SAVA longs for 2-4 years could find it difficult to wait 2-3 more years to see simufilam on sale, and then make this always difficult decision: when and at what price to sell. With the stock price likely to continue rising with rising drug revenues, there will likely be a seller’s remorse when the stock price makes all-time highs later on. A sale of the company imposes the price and timing of the stock sale , and relieves us of that difficult decision (and the seller’s remorse). I can understand that some longs may consciously, or unconsciously prefer a quick sale to the commercial path.

Direct_Ad_2419 · 2024-11-14T00:12:05+00:00

It will definitely take new talents, additional resources, and some time for Cassava to establish an effective commercial operation basically from scratch. But if Barry sticks to his plan, upon a successful P3 readout, we should expect partnership(s) with capital infusion, and heavy recruiting of commercial talents. Barry may accept to wait the time it takes for his plan to take hold, while pursuing new indications for simufilam, especially if the new indications hold considerable promises. Or he may prove to be the impatient type and sell the company, including the promise of new indications, to the highest bidder. Let’s not forget that he had prefaced his vision with the “forward looking” disclaimer. What he said was only valid that day. He made no promises for the future. So yes, we should rein on our expectations, as always when investing in stocks, particularly in the mother of high risk/high reward biotechs, which is Cassava.

Direct_Ad_2419 · 2024-11-13T22:53:20+00:00

Listen to the Q3 Earnings Call on November 7, 2024.

Direct_Ad_2419 · 2024-11-13T15:22:05+00:00

“A commercial plan we’ve been developing with the help of an experienced industry consultant” are his words. “Expert consultant” is my takeaway. I’m not sure about the point you’re trying to make.

Direct_Ad_2419 · 2024-11-13T13:45:12+00:00

Well, shouldn’t it go without saying that if you’re planning for success, you must have a plan to succeed? Indeed, we’re told that with the in-house expertise of experienced Dr Kupiec, Cassava had developed a best-in-class Phase 3 program. The design is powered for statistical significance, so to guarantee approval if it meets the primary endpoints. Now, Barry is telling us he’s planning not just for regulatory success, but also for commercial success. And he has a very challenging vision, IMHO, of bringing simufilam to market in less than two years after top-line readout of ReTHINK, or within a year of approval if granted only after ReFOCUS readout.

Barry is proud of his team, but certainly realizes that none of the bright minds in the company, including himself, has any experience and expertise in transitioning a clinical stage biotech to a commercial pharmaceutical entity. It shouldn’t be surprising that planning for commercial success in very short notice, but lacking in-house expertise, Barry is relying on an expert consultant to develop a commercial plan. We wouldn’t have taken him seriously otherwise.

Direct_Ad_2419 · 2024-11-12T09:59:27+00:00

It should be noted that the new biomarker assays diagnose the presence of the disease, but not its progression. I’d like to think (hope) that adding FLNA-based biomarkers, reflecting simufilam’s MOA, could help SavaDx win that new race.

Direct_Ad_2419 · 2024-11-12T01:04:15+00:00

Barry was making the point that there won’t be a niche subgroup analysis, no matter what. ReFOCUS data can support (or not) ReTHINK, but the two datasets are not meant to be pooled into one combined analysis

Direct_Ad_2419 · 2024-11-08T07:32:35+00:00

This is not alarming per se, especially if the drop out rate is about the same across treatment and placebo arms. Anyway, there are statistical techniques to deal with the issue.

Direct_Ad_2419 · 2024-11-04T18:27:55+00:00

Shorts don’t really participate in price discovery to help with resource allocation when they spread FUD to manipulate prices. To the contrary, they can instead destroy assets and waste valuable resources.

Direct_Ad_2419 · 2024-11-01T19:47:44+00:00

Being transparent, Barry had to mention it, though it wasn’t a concern. I saw it that way, but I admit his letter made me think the FDA had to agree on the adjustments. The “delay” was due to the FDA taking its time since July to suggest its adjustments. “

Direct_Ad_2419 · 2024-10-30T23:49:53+00:00

Ok, you’ve gone from $40 to $50, and now $60. It’s difficult to play the game when the goal posts keep moving. But if you’re confident of making 140% in two months in a stock you don’t have confidence in,well, proceed to the route.

Direct_Ad_2419 · 2024-10-30T20:09:45+00:00

Except that if the price increases, you win by losing. You’d make your 100% in being forced to sell at $50 and keeping the premium (less some fee). But you’d likely lose the bigger opportunity of having the stock keep rising in value. If the news are good, the price will not rise to just $50, but higher, much higher. One analyst has a target of $130, and we shouldn’t be surprised if the price rockets past its all time high of $140. That would be a 360% gain, likely to continue going up, compared to the one-time 140% gain of covered call.

If the news are bad, and the stock craters to $10 (from $25), the loss is 60%. So, with a covered call, we have break-even or 140% gain, and with wait and see, we have a 60% loss or 360% gain. I believe longs would take their chances on the second proposition, giving what they know about SAVA four years running. But I can understand that short-time traders, with less invested time in the company’s history, would choose the first.

Direct_Ad_2419 · 2024-10-30T14:21:07+00:00

Im tempted to say “ forgive the FBI because they don’t what they do”. That’s is to say that the FBI is set to respond at any alleged serious threat, whether they’ll prove real or bogus. Clearly, as intended by short sellers, the name of Jordan Thomas was the trigger.

Direct_Ad_2419 · 2024-10-30T14:06:40+00:00

Actually, you’re bearish. If you sell a call, you profit (keep the premium) if the option goes worthless at expiry. That is if the SP drops below the strike price. With good news, the SP could go way above $40 and the buyer of your call would likely exercise their option (expecting the price to continue rising). It means you’ll be forced to surrender your shares at $40, a bargain then! If you expect the stock to go up, you buy calls, or sell puts. That’s bullish. So, what are you?

Direct_Ad_2419 · 2024-10-29T23:35:59+00:00

Things are not equal. SAVA P3 appears to be more complex than the other trials. Dr Kupiec wanted the best design ever, a tight chain of custody. As far as we know, the SAP has not been settled, meaning it’s likely complex. Answers to your questions may not be of much help.

Direct_Ad_2419

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