Mickeychiku

Summarizing Biohaven on request: 1. Major amendment by sponsor during NDA review caused 3 months extension (CRL page 1) not because of FDA 2. There are three references by agency of them raising trial design concerns then eventually allowing filing of NDA due to seriousness and rarity of disease. The agency is most likely referring to raising concerns during pre-NDA meeting or before. (CRL page 1-2) 3. The guideline highlights demographic factors, comorbidities and baseline characteristics can affect the trial outcome which also appear to be missing in these trials. Agency concluded these unmeasured confounding eliminates statistical significance in this trial as well (guideline page 3). 4. Agency had concerns with site overlap and selection bias whose outcome are already known and same investigators, examiners and raters assessed both populations with prior knowledge (Guideline page 10). 5. Large missing data in trial was analyzed per the analytical method outlined in guideline page 14 (foot note 31) and it was determined that missingness was not random indicating missing data introduced bias in outcome 6. Guideline mentions that same criteria should be applied for timing of outcome assessment but these studies had discrepancy of up to 90 days at year 3 which accounted for statistically meaningful portion (guidance page 13) 7. Lack of pre-specification and not finalizing protocol and selecting control arms before initiating externally controlled trial (guidance page 4) 8. Agency had similar concerns on secondary analysis as well and raised issues with underreporting and incorrect classification of data which when corrected results in not meeting statistical significance This is the best I can do using my phone. I don’t have a personal laptop, lol! Text in guideline and CRL may not be “exactly”same but try to read the messaging not the language. Just a case study. I don’t have positions nor I intend to have! Good night!

@justkissmyRezpe All good. As you know I share this side of life sometimes. We are actually planning for his 4th birthday this month!

@mickeychiku Hope things are well. Bless you!

There is nothing that can happen in your professional life that will matter if your only child is unhealthy or unwell, physically or mentally. No Michelin star meal tastes good when your Gtube fed child never had a real food. No business class travel feels good when only travel your child can do is between home & hospitals!

$Repl There wasn’t even need to check data. DD here was just regulatory timing!

Abvx jumped 110 to 135 in Feb on antifibrotic data in the same TNBS model in which PDE4 has demonstrated better antifibrotic profile. Pali shockingly got sold on even better antifibrotic data and better CD potential. Ovid went up big on infantile spam indication addition which is likely to fail. Vigabatrin only works in ~25% patients with high relapse. May be works better with prednisolone combo. Hopefully Pali gets due credit now that geopolitics has appear to calm and many PRs lined up in next few days.

Looks like FDA will be adopting CTN model like TGA of Australia. x.com/mickeychiku/st…

@semodough Were holding such good data only to release on worst possible war market crash day. They definitely need some PR lessons.

$PALI CS Robust PALI-2108 Data and Misaligned Stock Reaction Create an Attractive Buy-the-Dip Opportunity believe the P1b FSCD results, together with previously disclosed UC data, provide compelling validation and a strong foundation for PALI-2108’s success. The stock reaction (-7.6% vs. +7.2% for XBI) looks misaligned with fundamentals—more timing-driven than data-driven. With two distinct value-creation paths in UC and Crohn’s, both converging on key inflection points around YE27/1H28, we view the pullback as a compelling buying opportuni

It’s not a new MoA. For UC, we have encouraging apremilast and mufemilast data. Also, Pali preclinical superiority over apremilast (in Pali study) and phase 1 superiority over everyone. For CD, PDE4 showed superiority over prednisolone and nearly comparable or even better to abvx antifibrotic data from Feb in the similar TNBS model. I don’t care about N=5 or placebo. No current treatments can alter stenosis. If it got resolved in Pali trial it’s definitely Pali-2108 that did that. Yes, being behind is the only negative point I see. I think Pali will get much deserved credit after potential abvx BO.

@mickeychiku I definitely think you have been right and correct all this while in your call for fibrosis reversal . But ph2 topline is at least 20 months away. Is the market saying that they want to see ph2 validation first? Not dis-similar to what Abvx went through

$Pali One more Pali post & I will leave you all alone (I will try)! Data most likely Monday morning now. Here are my thoughts: I want Pali-2108 to do (in bowel for now) what I see Prednisolone/Triamcinolone (Steroids), and Eucrisa (pde4 ointment) do temporarily to the inflammation & fibrosis in airway and scar tissue around trach and bowel opening stoma even when they are being used to treat something else in comorbidities. There are interesting details in 10-K released last Friday which I posted earlier! Some additional weekend reads below. ***Not a financial advice..DYODD. jpet.aspetjournals.org/article/S0022-… pubmed.ncbi.nlm.nih.gov/10604928/

@han_seoul_ohno Will grce go up on approval? Lately all approvals leading to sell off

I'm long into two? binaries this April: $GRCE and $CYTK I'm going to go on a VERY long holiday if both miss

@stockdabbler I want another round of noticing

@mickeychiku They’ve already noticed. 81% institutional ownership.

$pali Snaps from study link I provided below earlier. Just look at PDE4 (Rolipram) performance against prednisolone in TGF-B1, collagen content, morphological score (histological) in TNBS mouse model. Then look into Phase 1 data released on Monday. Then collectively compare above with aSMA, histologic (fibrosis) score, and collagen data in TNBS mouse model data of…….yes, you got it right…that’s the one! How long before big funds notice?

@WassimLaroussi3 Did you see who liked your video today?

Just wasted 20 min of my life - would have rather watched $ABVX chart while the market is closed 😂

@BioLobotomy @plainyogurt21 So far……Best case >85% reduction in two very severe patients with 15+ years of active disease > 60% best case reduction in mouse model where fibrosis induced only 20 days before treatment..

@plainyogurt21 wouldn't pali take a beating if ABVX shows good anti fibrotic activity in CD, near the year-end? But if it's at all disappointing I think the PALI runup into CD data will be crazy.

$PALI $CCCC probably both good (70% odds) for a 4x by EO27. r u patient enough

@jayabacus Possible to get slides? I guess not

$PALI "Dr. Jones will present “Targeted PDE4 Inhibition Using PALI-2108 Prodrug as a Novel Therapeutic Strategy in Fibrostenotic Crohn’s Disease”, highlighting how gutrestricted pharmacology and translational biomarker science are converging to redefine the treatment of fibrostenotic IBD." web.hansonwadegroup.com/rs/355-DOS-429…

@Respekchemistry @plainyogurt21 They said good till 2029 (for two phase 2) at Oppenheimer on 02/26.

Probably this one. Thousands of patients live with tracheostomy cause airway is obstructed and need frequent LTR surgeries! Thousands of patients live with frequent bowel resection cause bowel is obstructed! Thousands live with both. If what Pali said during the call “non-passable obstruction (stenosis) became completely or almost completely resolved in 2 weeks” is definitely true, then Pali needs to non-stop PR this everywhere all over the place!

@mickeychiku I don‘t have a transcript. Just listened to the webcast and watched the presentation. I am referring to the CMOs answer to a question starting at ca. min 45:30.

After listening to $PALI's webcast on the Phase 1b FSCD data disclosed this morning, I would say my computational model didn't age poorly. Five patients with confirmed ileal stenosis received 14 days of once-daily PALI-2108 at doses of 20 to 30 mg. Four of five were on concomitant biologics with a mean disease duration of 15.4 years. No serious adverse events and no PDE4 class effects. Ileal cAMP increased 41% in four of five patients with no decreases in the fifth, exceeding the 27% colonic cAMP signal from the UC cohort. Fecal calprotectin fell 59% with a tight inverse correlation to cAMP (r = -0.93, p = 0.023). Mean SES-CD dropped from 8.0 to 4.2, a 47.5% reduction, with two of five patients achieving endoscopic remission at just two weeks. In my article from February I identified prodrug activation in the terminal ileum as one of the gating pharmacokinetic uncertainties. This is now substantially de-risked with reported ileal tissue concentrations above IC90. During the webcast Q&A (starting around minute 45:30) the President & CMO Mitch Jones was asked how far the patients were from surgery and answered that at least one patient's impassable stricture became passable after 14 days. This is the first data point that speaks to structural stenosis rather than mucosal inflammation alone. Anecdotal in a single patient at two weeks, but if PALI-2108 can actually resolve stenosis that would be a huge breakthrough.

@Respekchemistry @plainyogurt21 Recently said good to run 2 phase 2 without further dilution.

@plainyogurt21 Yes, Pali high probability bet if not taken by Boehringer Ingelheim before that which is even better.

@BioLobotomy Yes, I head that too. When it becomes passable, patient becomes eligible for balloon dilation instead of resection which is incredible!

$PALI no transcript yet but if I'm not mishearing an incredible detail was just disclosed. Paraphrasing: "endoscopic confirmation of the resolution of a fibrotic lesion (n=1)" They also claim inflammation was reduced to the extent an impassable stricture became passable (n=1)

@BioLobotomy @MattB79569101 If this is really shrinking or elimination of stricture, this is scientific breakthrough. Hope someone asks.

@mickeychiku @MattB79569101 I'm well aware it was pre-clinical data ofc! But that's kind of what expectations are built upon, and PALI simply has less extensive evidence in their pre-clinical models. I think we agree, ANY actual anti-fibrotic sign tomorrow would be amazing considering the time-point.

$PALI Hopefully the webcast reveals baselines, plasma concentrations, and AEs (all of which we should automatically assume are drug related, to be as cautious as possible). That's make or break. Even if baselines are a little fudged, low plasma would validate their masking tech