Jordan Alexander

Top Osimertinib Resistance Expert Dr. Zofia Piotrowska Strengthens Credibility of Nuvectis Pharma's NXP900 Combo Study $NVCT $AZN $JNJ open.substack.com/pub/trufflepig… The NXP900–osimertinib combination trial was posted Friday on clinicaltrials.gov The most noteworthy detail was the listing of Dr. Zofia Piotrowska at Massachusetts General Hospital (MGH) as Principal Investigator. It is rare for a clinician of Piotrowska’s stature to lead a microcap-sponsored early combination study unless the biology is compelling and the study is designed with real translational intent. MGH physicians operate under some of the industry’s most stringent institutional oversight regarding industry interactions. Their leadership in a trial is a form of scientific “institutional vetting” that signifies that the protocol has passed a gauntlet of internal reviews and that the PI views the drug as a legitimate potential successor to the current standard of care. Dr. Piotrowska is widely regarded as one of the field’s leading experts on EGFR-mutant NSCLC and was an investigator in AstraZeneca’s landmark FLAURA program. She has since been a definitive voice in mapping the post-FLAURA landscape: a reality where resistance is no longer a simple “on-target” mutation, but a complex web of heterogeneous bypass signaling. This framing is directly relevant here. While Tagrisso (osimertinib) is a ~$7.5B global franchise, nearly all patients eventually progress. Many of these tumors retain EGFR lineage dependence but sustain survival through bypass circuits, including SRC/YES1-mediated signaling. This circuit can stabilize EGFR and maintain downstream survival pathways like SRC–FAK–YAP1 even with ongoing osimertinib exposure. NXP900 is designed to shut down this “bypass hub,” a node active in roughly 80–85% of resistance cases, to restore sensitivity to EGFR blockade. Just as important, this is not a generic all-comers combo. The trial is being genomically enriched by excluding tumors with established non-SRC bypass mechanisms, tightening eligibility around settings where SRC/YES1 biology is most likely to matter. At a site like MGH, where patients are routinely re-biopsied at progression, this improves molecular matching and increases the odds of a clean signal.

I think I’m beginning to feel like $NKTR is the most obvious B/O candidate. My thought is why wouldn’t a BP want to handle the ph3? Given the size of the ph2b and maintenance data there’s got to be comfort and it’s the only truly differentiated approach this far along.

@DrMakaryFDA True cruelty on what you’re doing to the Huntington’s disease community. We will mobilize & make our voices heard during the midterms. Keep in mind we are 200k people strong. @SenRonJohnson @SenRickScott @WhiteHouse @SusieWiles @StevenCheung47 @DanScavino @KushDesai47 @FDA_KyleD

The Q2 Type B meeting between uniQure and the FDA will be the most important conversation about Huntington's disease in a generation. New CBER leadership. New political pressure from Sen. Johnson's investigation. 48-month data coming this summer. The question isn't whether AMT-130 works. p = .003 answered that. The question is whether the FDA's new leadership is willing to evaluate the data honestly, without the baggage of the last regime. 48,000 families are watching. $QURE #HuntingtonsDisease #AMT130

Yeah, the wording is...sus. I'm ecstatic for the Hunter Syndrome community, though! Let's hope the @US_FDA follows suit with #AMT130, especially since the data is actually stronger for it than for the other. @SenRonJohnson we still need you to right those wrongs you talked about. Please don't forget about us! #huntingtonsdisease #raredisease #DyingToLive @adamfeuerstein @SenGillibrand @SenRickScott @SenTedCruz @WhiteHouse @realDonaldTrump @DrMakaryFDA

Below is an (unrelated to $NVCT) #AACR abstract that supports NXP900 as an ideal combo partner for $RVMD daraxonrasib (KRASi) in PDAC, which focuses on the importance of YAP1-FAK axis in KRAS resistance. NXP900, as a rare type 1.5 inhibitor, is the first SRC inhibitor to completely collapse kinase scaffolding signaling (the others type 1 left scaffolding wiring completely intact), including YAP1-FAK axis which is a major resistance hub to many other TKIs. Think of scaffolding as the escape mechanism for acquired resistance. From the abstract: Session PO.CL07.04 - Combination Targeted Therapy 6497 / 15 - Synergistic disruption of KRAS and FAK pathways: A preclinical pipeline for PDAC therapy optimization: "Recent studies suggest that KRAS inhibition may sustain focal adhesion kinase (FAK) activation, implicating the FAK-YAP axis and tumor-associated fibrosis in resistance. FAK, a key regulator of survival and DNA damage repair, has emerged as a promising co-target, with evidence of synergy between FAK inhibition and KRAS blockade, as well as enhanced sensitivity to PD-1 checkpoint inhibitors and radiation. We hypothesize that dual targeting of KRAS and FAK pathways will yield synergistic therapeutic effects in PDAC by disrupting oncogenic signaling and promoting cell death."

$NVCT NXP900 #AACR2026 Abstract: Session PO.CL07.04 - Combination Targeted Therapy 6497 / 15 - Synergistic disruption of KRAS and FAK pathways: A preclinical pipeline for PDAC therapy optimization NXP900/KRAS data at AACR should be supportive of ongoing NXP900/osimertinib human study with data coming in 2Q, as SRC is also the dominant bypass mechanism for resistance in EGFR (85%). In preclinical NSCLC models, NXP900 showed potent synergy with KRAS inhibitors not only in KRASi-sensitive tumors, but also in KRASi-resistant models. In this dataset, that translated into meaningful combination activity with $AMGN sotorasib in both sensitive and resistant settings, suggesting NXP900 may have real potential as a resistance reversal partner. KRAS-mutant NSCLC is a very large market opportunity (~25% of NSCLC versus ~10% for EGFR) yet KRAS inhibitors have not delivered commercial outcomes commensurate with the size of the population, in part because depth and durability of response remain constrained by resistance. What makes NXP900 interesting is the mechanism. Rather than behaving like a conventional SRC inhibitor (dasatinib), it locks SRC/YES1 in the closed conformation and appears to potently block YAP1-related escape signaling that may help tumors survive targeted therapy. (this allows PD inhibition to remain at peak 90-95% throughout 24 dose interval). That potential applies across oncogene-driven NSCLC. Just as NXP900 is hypothesized to have utility alongside osimertinib in EGFR NSCLC and $PFE lorlatinib in ALK NSCLC, these KRAS data should add to the broader case that NXP900 may be a highly valuable combination backbone in targeted oncology, particularly where acquired resistance limits otherwise important drugs. The near-term focus now shifts to upcoming combination data in 2Q for osimertinib/NXP900. If that reads out well, the proof-of-concept could be substantial. The opportunity is obviously large: $AZN Tagrisso does about $7B in annual sales, despite the fact that resistance emerges in a meaningful portion of patients (25-30%) over time. If NXP900 can help extend response durability or reverse resistance across multiple targeted settings, the strategic value could be significant. Preclinical for now, yes, but clinicial combination data and SRC-driven NSCLC monotherapy data coming in the next 1-3 months. abstractsonline.com/pp8/#!/21436/p…

The FDA approved Kebilidi /Upstaza under exactly the framework they told uniQure was insufficient for AMT-130. Kebilidi/Upstaza received FDA accelerated approval based on data from a single open-label trial of 13 patients compared with an external untreated natural history cohort of 43 patients. Upstaza was approved in the EU in July 2022 as the first gene therapy approved anywhere in the world for direct infusion into the brain.

Sent my DM to @RepAuchincloss informing him of the @uniQure_NV $QURE AMT130 travesty. Text of my message. "Honorable Representative Auchincloss: I hope you read your DM's on X. You need to continue your fight against @DrMakaryFDA and @VPrasadMDMPH who are doing great harm to our once world class and highly respected institution. In particular, their treatment of the HD Community with their reversal of alignment with @uniQure_NV where they had a path forward to submit the one and only HD treatment to show a slowing of this cruel disease AMT130 for approval is criminal. As an investor in uniQure, it is only money for me but for the HD community, it is a miserable AND avoidable death sentence. AMT130 showed a remarkable and unprecedented 75% slowing of disease progression at 3 years. Prior FDA leadership aligned on a plan to allow BLA filing during this quarter as long as data continued to be strong. In September 2025, uniQure shocked the HD world with a 75% slowing of disease progression. What does this mean for patients? Experts in the field such as Dr Sung, Dr Tabrizi and Dr Wild who were involved in the trial have spoken about the potential of this drug in historic terms. They postulate that a 75% slowing means a patient who is expected to worsen a certain amount at 1 year will now have 4 years before experiencing those effects. They have also said that a person who is 20 years old and expected to begin symptoms at age 40 could now live a life without any symptoms if the slowing continues at this remarkable rate. Under Dr Makary's poor leadership, they yanked that hope from those Americans suffering this dreaded disease. Both he and Dr Prasad went on record with lies about the trial and its design. For example, Dr Prasad said to a group of reporters that a placebo controlled sham surgery could be run by "only" requiring sham surgery patients to be under anesthesia for a half hour. This shows he is either lying or NEVER EVEN BOTHERED to read the trial design. The surgery is a 12 hour brain surgery so to imply a 30 minute fake surgery could work as placebo control is ludicrous. Once the patient wakes up, they will know full well they were in the sham arm and the intent is worthless. None of this made sense until you start to follow the money. John Arnold and his Arnold Ventures fund has been supporting Dr Prasad and Dr Makary for years with his extreme views on rare diseases. They are his puppets as Dr Prasad received >$4 million in grants to publish articles that were influenced directly by Arnold. This needs to be investigated quickly. Every day delay is a day HD patients will not recover from. I hope you got to the end of this message and go over these horrible people. Feel free to call me at ###-###-#### to get further opinions on these matters as I have been invested in this company and followed it closely for over 10 years." @SenRonJohnson @SenRickScott @adamfeuerstein @l_e_whyte @laurencurehd @BeckyQuick @MariaBartiromo @docrodwong @LuckyPenguin10 @SECGov @POTUS

its clear @DrMakaryFDA is in @johnarnold pocket both have to go, Makary first

@A_May_MD @AndrewRangeley Never tire of your awesome insights into $NKTR & $ABVX & looking forward to your next big idea!

Thanks to @AndrewRangeley for having me on Yet Another Value Podcast! Mostly chatted about $NKTR and $ABVX, which I know someday people will get tired of hearing me talk about, if they aren’t already 😅

Wild how you can just… find public evidence of the conflicts people like @AnilMakam have in their views. Maybe add a disclaimer as you tweet re: AMT-130 so HD patients on X understand you’re just parroting your sponsor’s views? What actual engagement with the science have you done here besides spreading FUD?

Great find. This should get a lot of attention. Clear and obvious @johnarnold stalled @uniQure_NV life saving therapy bc he is upset about drug prices and was in the ear of Prasad. Zero independence under Prasad and AMT-130 needs to be reversed and approved now $QURE @DrMakaryFDA

$qure $clpt $rgnx Woah, Gets worse each and every day for Vinay. Marky Mark, Scientist Andrew and now Resource Allocator aka @AnilMakam It’s time to step down Marky Mark, you hired Mr. 30 minute Sham control not once but twice! That is worthy of immediate termination on your end. Not to mention, you are also getting paid from AV. @RepAuchincloss @SenRonJohnson @SenRickScott @SenGillibrand @WhiteHouse @FrankLuntz @SusieWiles @BeckyQuick @HDSA @HDBuzzFeed @Help4HDI @adamfeuerstein @MartinShkreli @laurencurehd

Follow the money and it will make everything clear. Every @uniQure_NV $QURE investor was wondering how/why the FDA could have changed alignment on filing BLA this qtr back in that fateful November day. As time goes on, it is becoming very clear to me. @VPrasadMDMPH and @DrMakaryFDA are bought and paid for by @johnarnold and his Arnold Ventures fund. Various reports have come out over the years, and it is past time for journalists to further investigate the relationships between Vinay and John Arnold and his wife. Here are some snippets from a 2018 WSJ article that should alarm anyone who cares about not only US healthcare but worldwide healthcare if the FDA continues to be the clown show it is under @DrMakaryFDA. Hopefully @POTUS will actually do something for Americans and the rest of the world. wsj.com/articles/a-bil… Make sure you read the last snippet. That sums up what has happened to the once prestigous US FDA. It is bought and paid for by none other than John Arnold. Come on Senators and Congressmen and Congresswomen, time to get John Arnold, Vinay Prasad and Marty Makary in front of Congress to answer questions and FOLLOW THE MONEY. Journalists, please don't let up. Go after these scum and don't stop reporting about their control and abuse of the system. Instead of creating new treatments to help people, John Arnold is instead using his fortune to prevent care to those among us who lost the ovarian lottery and were born with a heinous genetic ailment. Get the HD Community the help they need AND deserve. @SenRonJohnson @SenRickScott @RepAuchincloss @adamfeuerstein @l_e_whyte @laurencurehd @BeckyQuick @MariaBartiromo @docrodwong @LuckyPenguin10

The FDA launched its Plausible Mechanism Framework in February 2026, specifically designed to fast-track rare disease therapies using biomarkers and natural history data. AMT-130 has biomarker data. It has natural history comparisons. It met its primary endpoint. The FDA built this door. AMT-130 fits through it. Open it. $QURE #HuntingtonsDisease #AMT130 #RareDisease

Arnold Ventures, the main financial backer of #Prasad, hates #genetherapies...essentially based on price and proposed making development and access impractibly onerous. These ideas are either hopelessly simple-minded or outright evil. $qure

All, and I say ALL the evidence points towards targeting HTT1a transcript as the sine qua non in addressing HD via huntingtin modulation. $qure just lucked out IMO, got early strikingly promising data and the death panels want to delay access for another 5 years. Also wrote about it 15 months ago: rnaitherapeutics.blogspot.com/2025/01/huntin…

@mike98572986 @AnilMakam oh is this the same Dr. Makam who contributes as an Evidence Author for the Institute for Clinical and Economic Review (ICER), described as a key voice in evaluating the value of new medical therapies. The same ICER that Arnold Ventures funds. How odd profiles.ucsf.edu/anil.makam

Good morning from Blue Water Key RV resort outside of Key West FL. Hope the walls start closing in on Arnold and @VPrasadMDMPH for what they did to @uniQure_NV $QURE AMT130 and HD patients. This is OUR sunrise for HD.

“Some patients are too costly to treat and to expensive to save” sounds familiar?