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StockWatch: enGene Shares Crater on Declines in Complete Response Rates to Bladder Cancer Therapy

enGene (NASDAQ: ENGN) stock suffered an 83% plunge this past week that reflects just how competitive the field is among drug candidates for nonmuscle invasive bladder cancer (NMIBC)—and how questions over clinical data are enough to send investors scurrying to sell their shares.

enGene shares cratered 81% Thursday from $8.85 to $1.72, then fell another 13% Friday, reaching a 52-week low as it finished the week at $1.50.

The sharp falloff followed enGene reporting updated data from its Phase II LEGEND trial (NCT04752722) assessing its nonviral gene therapy candidate detalimogene voraplasmid in high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive NMIBC patients with carcinoma in situ (CIS) with or without concomitant papillary disease (CIS±papillary). The data showed a drop in response rates from a November 2025 readout, falling short of company and Wall Street expectations.

As of the April 21 data cutoff, 67 of 124 evaluable patients treated with detalimogene (formerly EG-70) achieved a 54% complete response (CR) at any time, a rate that fell to 43% (52 of 121 evaluable patients) CR rate at six months. That compares with the 63% CR at any time and 62% CR rate at six months shown for the first 62 patients assessed, as announced by enGene in November 2025.

Also, detalimogene showed a nine-month CR rate of 32.7%, which fell to 13.3% at 12 months after treatment. Engene said it will present its data at the American Urological Association Annual Meeting (AUA 2026), set for May 15–18 in Washington, DC.

“While durability outcomes to date are not what we hoped, these data are preliminary,” enGene president and CEO Ron Cooper stressed in a statement. “We are focused on evaluating the totality of the data as it evolves and plan to continue to engage with the FDA and the medical community.”

Speaking to analysts, Cooper added: “The data are not yet fully mature, and the durability picture is incomplete. We plan to await longer-term durability data for all of Cohort 1 in the second half of the year and continue our ongoing discussion with the FDA regarding both our statistical analysis plans and plans for potential BLA filing.”

“Below key benchmarks”

At least two analysts warned that the updated data will make it harder for enGene to compete with other developers of NMIBC treatments now in the clinic.

“Durability now screens below key benchmarks in the setting, which makes it hard for us to underwrite meaningful commercial upside for detalimogene in what will be a crowded mkt, where ~40% 12‑mo CR is the bar to clear,” cautioned Maury Raycroft, PhD, equity analyst with Jefferies, in a research note.

Raycroft slashed enGene’s 12-month price target 82% from $28 to $5. More ominously, Raycroft chopped Jefferies’ peak sales forecasts for detalimogene by 79%—from the $1.7 billion forecasted for the gene therapy across CIS±papillary, papillary‑only, and BCG‑naïve NMIBC, to $350 million for CIS±papillary alone.

The NMIBC treatment space has expanded in recent years as established drugs like the cancer immunotherapy blockbuster Keytruda® (pembrolizumab), marketed by Merck & Co. (NYSE: MRK), have been joined on the market by newer therapies.

One is Johnson & Johnson (NYSE: JNJ)’s Inlexzo™ (gemcitabine), an intravesical drug releasing system (iDRS) designed to provide sustained local delivery of a cancer treatment into the bladder. Two other newer therapies are Adstiladrin® (nadofaragene firadenovec-vncg), a nonreplicating adenoviral vector-based gene therapy indicated for high-risk BCG-unresponsive NMIBC with CIS±papillary and marketed by privately held Ferring Pharmaceuticals (which licensed the drug from another private company, FKD Therapies, in 2018); and ImmunityBio (NASDAQ: IBRX)’s interleukin-15 (IL-15) receptor agonist Anktiva® (nogapendekin alfa inbakicept-pmln), indicated with BCG. ImmunityBio is part of the privately held NantWorks portfolio of companies.

Those marketed drugs are expected to be joined over the next couple of years by candidates being developed by:

  • CG Oncology (NASDAQ: CGON), which is expected to report topline data from the Phase III PIVOT-006 trial (NCT06111235) of cretostimogene grenadenorepvec, also called CG0070, as an adjuvant therapy in intermediate-risk NMIBC. First results on the combo of cretostimogene with gemcitabine from the Phase II CORE-008 trial (NCT06567743) are to be presented at AUA 2026.
  • Relmada Therapeutics (NASDAQ: RLMD), which will present two abstracts focused on its NDV-01, a sustained-release intravesical formulation of gemcitabine and docetaxel being developed to treat NMIBC at AUA 2026. Relmada plans to present nine-month complete response data from its open-label Phase II trial (NCT06663137) assessing NDV-01 in high-risk NMIBC, as well as discuss its open-label Phase III BOOST trial (NCT07313891), which is evaluating NDV-01 vs. surveillance following transurethral resection of bladder tumor (TURBT).

Mani Foroohar, MD, senior managing director, genetic medicines, and a senior research analyst with Leerink Partners, noted that enGene’s 54% any time and 43% six-month updated CR rates lagged behind those of three competitors: Anktiva (71% and 56%), cretostimogene (75.5% and 64%), and Inlexzo (82% and 59%). However, he added that Adstiladrin was more comparable to detalimogene, which showed rates of 51% and 41%.

Competitive position concern

“Weaker data in recent patient cohorts and lower-than-expected durability trends undermine our confidence in [detalimogene]’s competitive position and essentially foreclose the possibility of closing the efficacy gap with CGON, JNJ, etc., in a later LEGEND update,” Foroohar wrote in a research note.

“With shares trading at a level pricing in program failure, investor focus will center on cohort consistency, data evolution with longer follow-up, and FDA interpretation of the totality of the dataset (questions that will take time to address and will not be resolved prior to full LEGEND data/subsequent regulatory engagement,” Foroohar added.

Like Raycroft, Foroohar also now projects $350 million in unadjusted peak year sales for detalimogene, shredding his firm’s projection by 65% from $1 billion.

“From here, investor discussion will center on whether longer follow-up and additional cohort maturation can stabilize efficacy trends ahead of further FDA engagement in 2H26.”

enGene and Cooper insist that detalimogene is more than up to the challenge of competing with other NMIBC treatments. Of the 52 patients who responded at six months, 37 of 44 patients who had a nine-month assessment were in CR (an additional eight patients are pending evaluation), while 13 of 22 patients who had a 12-month assessment were in CR (an additional 11 patients are pending evaluation).

Among patients who showed the 43% six-month CR rate, 14% (6 of 43) successfully converted from non-CR to CR post re-induction.

The company cited other data from the LEGEND trial showing that the progression rate to muscle-invasive or advanced disease was 3.2%, a figure enGene calls low. Detalimogene was generally well tolerated, the company added, with 55% of patients having experienced a treatment-related adverse event (TRAE), mostly mild (Grade 1 and 2), though six patients (4.8%) reported a Grade 3 TRAE.

“These updated data continue to reinforce the favorable safety and tolerability profile of detalimogene and its clinical activity in a heavily pretreated, high-risk NMIBC patient population with limited therapeutic options,” enGene’s Cooper stated. “Importantly, the low rate of progression to muscle-invasive disease leaves patients eligible for other bladder-sparing therapies.”

Detalimogene’s favorable safety profile was also acknowledged by Jefferies’ Raycroft: “We continue to view this administrability/safety profile as a core differentiator vs other intravesical gene/immune constructs (and a key adoption lever), even as durability to date is tracking below expectations.”

IPO roundup: Odyssey raises $304M, drops 9%

Odyssey Therapeutics (NASDAQ: ODTX) raised $304 million in gross proceeds through an upsized initial public offering (IPO) by selling 15.5 million shares priced Thursday at $18 a share, the top of its $16–$18 range, and well above the 13.2 million shares it disclosed in its prospectus just before the offering. Concurrently, an affiliate of TPG Life Sciences Innovations purchased 1.39 million shares at the IPO price, raising another $25 million for Odyssey.

But on their first full day of trading on Friday, Odyssey’s shares fell 9%, closing at $16.42, as investors deemed the upsizing to be aggressive.

Odyssey, a developer of targeted therapies for autoimmune and inflammatory diseases, said it would use approximately $135 million in IPO proceeds to advance its lead candidate, the oral small molecule RIPK2 scaffolding inhibitor OD-001, through 12-week induction readouts from its planned Phase IIa combination trial and Phase IIb monotherapy trial in ulcerative colitis.

Plans also call for using approximately $50.0 million of proceeds to advance Odyssey’s oral small molecule SLC15A4 inhibitor OD-002 through IND-enabling activities and a planned Phase I/IIa trial; and the rest for additional discovery, preclinical, and clinical activities for disclosed or future programs, enabling capabilities, as well as general corporate purposes, working capital, and other capital expenditures.

An option to purchase up to an additional 2.325 million shares at the IPO price is held by Odyssey’s IPO underwriters: J.P. Morgan, TD Cowen, and Cantor are joint book-running managers, while Wedbush PacGrow and Oppenheimer are co-lead managers.

The Odyssey IPO is one of four biotech IPOs emerging in recent weeks:

  • Hemab Therapeutics Holdings (NASDAQ: COAG), based in Cambridge, MA, and Copenhagen, closed its IPO on May 4, having raised $346.7 million by selling 19,262,500 shares at $18 a share—the original offering of 16.75 million shares, plus all 2,512,500 shares for which underwriters held purchase options. Goldman Sachs, Jefferies, and Evercore ISI were joint book-running managers; Wedbush PacGrow was the lead manager. Shares have since jumped 40%, closing Friday at $25.12.
  • Seaport Therapeutics (NASDAQ: SPTX) of Boston garnered $254.88 million on April 30 by selling 14.16 million shares at $18 a share. Seaport’s underwriters have a 30-day option to buy an additional 2.124 million shares at the IPO price less underwriting discounts and commissions. Goldman Sachs, J.P. Morgan, Leerink Partners, Citigroup, and Stifel are joint book-running managers. Shares have since slipped 11%, closing Friday at $16.05.
  • A day earlier, Avalyn Pharma (NASDAQ: AVLN), also of Boston, launched an IPO that garnered $300 million by selling 16,666,667 shares at $18 a share—and revived the market of biotech initial offerings after a lull during March and early April. Avalyn ultimately racked up $345 million in gross proceeds after its underwriters exercised in full their option to buy 2.5 million more shares at the IPO price. Morgan Stanley, Jefferies, Evercore ISI, and Guggenheim Securities were joint book-running managers. Shares have since vaulted 52%, closing Friday at $27.33.

Leaders and laggards

  • Atara Biotherapeutics (NASDAQ: ATRA) shares nearly doubled, leaping 92% from $5.15 to $9.93 Thursday after saying its partner Pierre Fabre Pharmaceuticals (PFP) had a productive Type A meeting with FDA officials to discuss an approval path for tabelecleucel (tab-cel). PFP’s Biologics License Application (BLA) has been rejected twice by the agency through Complete Response Letters, the most recent one in January. The FDA, Atara said, agreed that a single-arm study with an “appropriate” historical control, conducted in a pre-specified manner, “could serve as an adequate and well-controlled study and provide safety and efficacy data in support of a future marketing application.” Atara said PFP intends to submit updated data with longer follow-up from the pivotal Phase III ALLELE trial (NCT03394365) assessing tabelecleucel in adults and children ages 2+ with relapsed/refractory Epstein-Barr virus plus post-transplant lymphoproliferative disease (PTLD) following solid organ transplant or hematopoietic cell transplant.
  • Entrada Therapeutics (NASDAQ: TRDA) shares nosedived 57% Thursday from $16.03 to $6.85 after the genetic medicine developer reported topline data from Cohort 1 of the multiple ascending dose (MAD) portion of the Phase I/II ELEVATE-44-201 trial (NCT07037862) that the company called positive, but which disappointed investors. Entrada said its Duchenne muscular dystrophy (DMD) candidate ENTR-601-44 met the trial’s primary objective by showing favorable safety and tolerability, no discontinuations, and no serious adverse events. But data showed an increase of 2.36% in dystrophin from a baseline of 4.00%—compared to the 10% increase sought by analysts such as Myles R. Minter, PhD, of William Blair. “Management is attributing the miss on biomarker data to lower-than-expected drug exposure,” Minter wrote, “likely due to the transition from dosing adults to juvenile patients.” Entrada cited other positive data, such as lower plasma exposure in Cohort 1 participants ages 6–17 vs. healthy adult volunteers; and markers of kidney function via eGFR, Cystatin C, and magnesium all falling within normal ranges and comparable to placebo.
  • Moderna (NASDAQ: MRNA) shares rose 12% Friday from $48.54 to $54.35 after a news report that the messenger RNA (mRNA)-based vaccine developer was researching vaccines designed to protect against hantaviruses. In a statement, Moderna disclosed that it has carried out early-stage vaccine research on hantaviruses with the U.S. Army Medical Research Institute of Infectious Diseases and is also partnering with the Vaccine Innovation Center at Korea University College of Medicine on a potential jab. “These efforts are early-stage and ongoing and reflect Moderna’s broader responsibility to develop countermeasures against emerging infectious diseases,” Moderna told Bloomberg News. As of Friday, the World Health Organization (WHO) has reported eight cases of hantavirus, including three deaths, among passengers aboard the MV Hondius cruise ship, traveling between Argentina and the Canary Islands in the Atlantic Ocean.
  • Viridian Therapeutics (NASDAQ: VRDN) shares jumped 33% from $14.06 to $18.75 Tuesday after the autoimmune and rare disease drug developer announced positive topline data from the Phase III REVEAL‑2 trial (NCT06625398) assessing elegrobart in chronic thyroid eye disease (TED). Doses of elegrobart given every 4 and 8 weeks achieved what Viridian called “highly statistically significant” 50% and 54% proptosis responder rates (PRR) at week 24, respectively, vs. 15% for placebo. Elegrobart is a subcutaneously delivered, half‑life‑extended monoclonal antibody targeting the insulin‑like growth factor‑1 receptor (IGF‑1R). Viridian said it remains on track to submit a Biologics License Application (BLA) to the FDA for elegrobart in Q1 2027. Viridian cashed in on the news by launching underwritten public offerings of $150 million in convertible senior notes due 2032 and $100 million in Series B nonvoting convertible preferred stock.

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Diabetes Drug Metformin’s Blood Glucose-Lowering Effects Tied to Action on Gut Cells

For decades, physicians and scientists have thought that metformin, a biguanide drug that is prescribed for millions of people worldwide for type 2 diabetes (T2D), mainly targets the liver to suppress glucose production. A Northwestern University-led study in mice has now found that this “wonder drug” instead acts primarily on the gut, and prevents glucose levels from rising in the blood by driving glucose utilization inside cells lining the intestine.

The research found that metformin slows mitochondrial energy production in gut cells by inhibiting mitochondrial complex I in the intestinal epithelium. This then “co-opts” the intestines to function as a glucose sink, forcing the intestine to metabolize extra sugar. The study also found that another biguanide drug, phenformin, and the structurally unrelated supplement berberine, which is known as “nature’s Ozempic,” appear to engage the same pathway in the gut as does metformin.

The preclinical findings could help to explain several gut-related clinical effects in people who take metformin and suggest that modulating mitochondrial metabolism in the gut may represent an effective strategy for controlling blood sugar. “Metformin essentially helps the intestine suck the glucose out of the bloodstream, which further highlights that the gut plays a major role in regulating blood sugar levels,” said corresponding author Navdeep Chandel, PhD, professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

Chandel is senior and co-corresponding author of the researchers’ published paper in Nature Metabolism, titled “Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.” Chandel is also the David W. Cugell, MD, Professor of Medicine (Pulmonology and Critical Care), Biochemistry and Molecular Genetics, and an investigator with the Chan Zuckerberg Initiative. The study’s first author is Zach Sebo, PhD, a postdoctoral fellow in the Chandel lab who will soon start his own research group at the University of Kansas School of Medicine.

Metformin is the most widely prescribed medication for type 2 diabetes and the biguanide class drug approved by the FDA, the authors wrote. However, they noted, “Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear.”

The body relies on glucose as a fast and versatile fuel, but too much glucose can lead to insulin resistance and ultimately damage blood vessels and organs. The newly reported study builds on findings from previous work in Chandel’s lab, which found that metformin lowers blood sugar by blocking a specific part of the cell’s energy-making machinery, mitochondrial complex I, a key enzyme in cellular respiration. The research reported in Nature Metabolism extends that work by pinpointing the specific tissue targeted by metformin.

The study used a mouse model genetically engineered to express a yeast enzyme (NDI1) that mimics mitochondrial complex I but is resistant to inhibition by metformin. By expressing NDI1 specifically in intestinal cells, those gut cells resisted metformin’s effects. In these mice, the drug’s ability to lower blood glucose was significantly reduced, demonstrating that inhibition of mitochondrial complex I in the gut is a key driver of its therapeutic action. “In this study, we show how metformin exerts multiple clinical effects through selective inhibition of mitochondrial complex I in the intestinal epithelium,” they wrote.

Corresponding author Navdeep Chandel in his lab in Chicago. [Kristin Samuelson, Northwestern University]
Corresponding author Navdeep Chandel, PhD, in his lab in Chicago. [Kristin Samuelson, Northwestern University]

Metformin is currently the only FDA-approved biguanide drug, but the team found that another biguanide, phenformin, which had previously been used to control blood glucose but was then withdrawn, also lowered blood glucose through the same mechanism. The findings suggest that directing drugs or supplements to the gut could be an effective strategy for controlling blood sugar, Chandel said. Sebo added, “Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works.”

The study revealed unexpected parallels with berberine, a popular plant-derived OTC supplement that is often used to control blood sugar. Berberine has recently gained attention on social media as “nature’s Ozempic,” though experts caution that evidence is still limited, and it should not be used as a substitute for approved medications. The study by Chanel and colleagues has now found that berberine appears to engage the same pathway as metformin in the intestine. “Thus, we identify mitochondrial complex I in intestinal epithelium as a shared and essential therapeutic target for metformin, phenformin, and berberine,” the authors stated.

“Metformin has decades of clinical evidence behind it, whereas supplements like berberine are far less rigorously tested,” Chandel said. “If you’re going to use berberine, you may as well use the real deal.”

The study results may help to explain clinical observations among people who take metformin. According to Chandel, individuals who take metformin tend to have lower blood sugar after meals, and the study suggests that metformin turns the gut into a “sponge” that soaks up extra sugar. Individuals taking metformin also tend to have lower levels of circulating citrulline, which is made only by mitochondria in small intestine cells. If metformin inhibits mitochondria, citrulline production drops. Taking metformin also increases levels of GDF15, a hormone linked to reduced appetite and weight loss. The gut senses energy stress and sends out GDF15, which tells the brain to eat less and adjust metabolism.

“In addition to enhanced intestinal glucose utilization and blood glucose clearance, this mechanism accounts for metformin-induced citrulline depletion, improved postprandial glycaemia, and elevated lactoyl-phenylalanine (Lac-Phe) and growth differentiation factor 15 (GDF15) levels—all of which are definitive clinical outcomes caused by metformin treatment,” the authors wrote in summary.

“People have always wondered how one drug can do 10 things,” Chandel said. “Well, it can do that if the drug is hitting a big node in a cell, and hitting mitochondria in a cell is a big node. So, if you can get into those cells and inhibit mitochondria, it’s going to have huge effects.”

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Musk v. Altman week 2: OpenAI fires back, and Shivon Zilis reveals that Musk tried to poach Sam Altman

In the second week of the landmark trial between Elon Musk and OpenAI, Musk’s motivations for bringing the suit were under scrutiny.

Last week, Musk took the stand, alleging that OpenAI CEO Sam Altman and president Greg Brockman had deceived him into donating $38 million to the company. He claimed that they’d promised to maintain it as a nonprofit dedicated to developing AI for the benefit of humanity, only to later accept billions of dollars of investment from Microsoft and restructure the company to operate a for-profit subsidiary.  

This week, Brockman fired back with his side of the story, arguing that Musk had actually pushed for OpenAI to create a for-profit arm and fought a bitter battle to have “absolute control” over it. OpenAI has argued that Musk is suing because he didn’t get his way and is now trying to undermine a competitor to his own AI company, xAI.

Shivon Zilis, a former OpenAI board member and the mother of four of Musk’s children, also testified, revealing that Musk tried to recruit OpenAI CEO Sam Altman to lead a new AI lab at his electric-car company, Tesla. 

Musk cofounded OpenAI in 2015 with Altman, Brockman, and others but left in 2018. Now, he’s asking the court to remove Altman and Brockman from their roles and to unwind the restructuring OpenAI undertook last year, which converted its for-profit subsidiary into a public benefit corporation. He is also seeking as much as $134 billion in damages from OpenAI and Microsoft, OpenAI’s investor. 

The outcome of the trial could upend OpenAI’s race toward an IPO at a valuation approaching $1 trillion. Meanwhile, xAI, which Musk founded in 2023, is now a division of his rocket company, SpaceX; the combined companies are also expected to go public as early as June, at a target valuation of $1.75 trillion.

On Monday, Brockman walked into the courtroom in a blue suit and tie, holding hands with his wife, Anna Brockman. On the stand, he was serene, even chipper, as he recalled OpenAI’s early days. But he grew agitated under impassioned questioning from Elon Musk’s lawyer, Steven Molo. Altman listened in silence, while Anna Brockman sat behind him, fidgeting. Outside the courthouse, protesters rallying against the AI race sang hymns over the voices of lawyers giving press conferences.

Two days before trial began, according to Brockman, Musk messaged him to ask if he would be interested in settling. When Brockman suggested that both sides drop their claims, Musk texted back: “By the end of this week, you and Sam will be the most hated men in America. If you insist, so it will be.”

Musk stormed out with a Tesla painting

Last week, Musk testified that he’s suing to save OpenAI’s nonprofit mission to develop AI safely, but he said he was open to seeing OpenAI become a capped-profit company with moderate investments from Microsoft. 

This week, Brockman told the jury that Musk was never truly committed to keeping OpenAI a nonprofit. In the summer of 2017, when an AI model that OpenAI built beat the world’s best players in a video game called Dota 2, Musk hosted a gathering at his “Haunted Mansion” near San Francisco. The house was splattered with confetti and cups, Brockman recalled, and the actress Amber Heard, who was Musk’s girlfriend at the time, served whiskey.

“Time to make the next step for OpenAI. This is the triggering event,” Musk wrote in an email—having said weeks earlier that if OpenAI made a major public achievement, it would be “time to create a for-profit,” Brockman told the jury.

Over the next six weeks, Brockman said, Musk and the other cofounders had intense discussions about creating a for-profit entity to raise enough capital to build artificial general intelligence—powerful AI that can compete with humans on most cognitive tasks. Musk wanted to have majority equity in the entity and the right to choose a majority of the board members. He also wanted to be its CEO, said Brockman. 

Brockman testified that in August 2017, he and other cofounders gathered to hash out the terms of the for-profit structure. Ilya Sutskever, OpenAI’s chief scientist at the time, arrived bearing a painting of a Tesla as a “token of goodwill” in return for the actual Teslas Musk had given them days earlier. “It felt a little bit like [Musk] was buttering us up, right,that he wanted us to feel indebted to him,” Brockman told the jury.

When Brockman and Sutskever proposed that they all have equal shares of equity, said Brockman, Musk fell silent and finally said, “I decline.” Musk then stood up and “stormed around the table,” he said. “I actually thought he was going to hit me.” Musk grabbed the painting and walked out. 

Brockman said that afterwards he struggled to decide whether to continue building OpenAI with Musk or break away. “There was a fork in the road,” he said. “Do we accept Elon’s terms? Or do we reject the terms, he quits to create his own, and then we create our own?”

“The one thing we could not accept was to hand him unilateral, absolute control, potentially, over the AGI,” Brockman told the jury.

What was Brockman thinking?

In his theatrical baritone, Molo argued that Brockman was motivated by greed rather than a commitment to OpenAI’s nonprofit mission to develop AI that benefits humanity. He noted that while Brockman never invested money in the company, he now owns a stake worth close to $30 billion. 

“Solving for the mission has always been my primary motivation,” Brockman said, pushing back on Molo’s characterization of him. “It remains so today.” 

Molo pulled up Brockman’s electronic journal on a screen in the courtroom, trying to show the jury what Brockman was really thinking behind the scenes. In 2017, while negotiating with Musk about the future of OpenAI, Brockman wrote about wanting to become a billionaire: “Financially what will take me to $1B?” 

“Why didn’t you take the $29 billion and donate it to the nonprofit that you had a fiduciary duty to, for the good of humanity?” Molo asked Brockman, raising his voice to dramatize moral indignation. 

Molo then pulled up a journal entry Brockman had written in November 2017, while he was torn over whether to turn OpenAI into a for-profit without Musk: “it’d be wrong to steal the nonprofit from him. to convert to a b-corp without him. that’d be pretty morally bankrupt.” Brockman and Musk had previously considered creating a b-corp, which is a for-profit company that pursues a social mission.

Brockman explained, “I meant it would actually serve the mission, but it’d be hard to look at yourself in the mirror.”

Molo also tried to undermine Brockman’s credibility by revealing that he holds a stake in multiple companies with business ties to OpenAI, including the AI company Cerebras, the cloud provider CoreWeave, and the nuclear fusion startup Helion Energy. Altman has tried to steer OpenAI into deals with companies that he invests in, including Helion and the rocket maker Stoke Space, drawing scrutiny over potential conflicts of interest.

Former OpenAI chief technology officer Mira Murati and former OpenAI board member Helen Toner both appeared in video depositions. They addressed the brief firing of Altman in 2023, saying that they could not trust him because of his alleged history of lying. Murati’s text messages with Altman from that time, which were introduced as evidence, revealed his desperate attempts to understand what was happening and regain control. 

Musk plotted a rival AI lab at Tesla

After Brockman’s two days of testimony, Shivon Zilis, who left OpenAI’s board in 2023, took the stand in a black jacket and black jeans, appearing composed but with a flicker of nerves. OpenAI’s lawyer Sarah Eddy asked her in a deceptively soothing voice whether she acted as a conduit for Musk as he tried to poach OpenAI’s cofounders to work at a new AI lab within Tesla. Eddy argued that Musk is suing OpenAI only to undermine a competitor in the AI race. 

Zilis said she met Musk while working at OpenAI as an informal advisor in 2016, and that they had a “one-off” romantic encounter. In 2017, she joined Tesla and Musk’s brain-implant company, Neuralink. In 2020, she joined OpenAI’s board of directors. She became pregnant with Musk’s children through IVF but did not disclose her ties with Musk to OpenAI until Business Insider reported them in 2022. 

By late 2017, Musk had concluded that OpenAI was unlikely to build AGI and pivoted to building an AI lab at Tesla, according to an email sent to Zilis. 

Eddy pulled up a draft of an FAQ document that Zilis emailed a colleague at Tesla in 2017 about an event the company was organizing at the NeurIPS AI conference: “The purpose of this event is to share that Tesla is building a world leading AI lab(?) which will rival the likes of Google/DeepMind and Facebook AI Research.” 

Zilis told the jury that when Musk was still on OpenAI’s board, he tried to recruit Altman to lead that prospective AI lab. Musk had asked Andrej Karpathy, an OpenAI research scientist he’d recruited to work at Tesla, “to send a list of top OpenAI people to poach,” according to a text message by Zilis. 

“There is little chance of OpenAI being a serious force if I focus on TeslaAI,” Musk texted Zilis in 2018, just before he left OpenAI. Tesla’s AI lab never came to fruition.

Eddy pressed Zilis about whom she was loyal to when she was working for OpenAI and Musk at the same time. “I had an allegiance to the best outcome for AI for humanity,” Zilis told the jury.

What’s going on next week?

Next week, Ilya Sutskever will testify, as will Microsoft CEO Satya Nadella. The lawyers for both Musk and OpenAI will deliver their closing arguments. The jury will begin deliberating the week after and deliver an advisory verdict guiding the judge to decide the case.

This story is part of MIT Technology Review’s ongoing coverage of the Musk v. Altman trial. Follow @techreview or @michelletomkim on X for up-to-the-minute reporting.

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Opinion: RFK Jr. allegedly ‘collected’ a dead raccoon’s penis. Was it bioethically justifiable?

During one of health secretary Robert F. Kennedy Jr.’s recent appearances on Capitol Hill, Rep. Adelita Grijalva (D-Ariz.) brought up an unusual allegation: that in 2001, he collected a dead raccoon’s penis. The incident was first described in the new book “RFK Jr.: The Fall and Rise” by Isabel Vincent, which quotes from a journal of Kennedy’s: “I was standing in front of my parked car on I-684 cutting the penis out of a road killed raccoon, thinking about how weird some of my family members have turned out to be.” According to Vincent, Kennedy cut off the penis “to study [it] later.”

While Kennedy did not respond to Grijalva about the raccoon incident, focusing instead on the National Institutes of Health budget and DEI, it has been widely treated as sensational news. But the jokes about it obscure an important question: whether his described actions meet fundamental standards of bioethical judgment.

Read the rest…

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Phenotype, Genetics, and Interpretation: Further Considerations on Atypical Depression

We read with great interest the recent article by Shin et al. (1). The authors leveraged the substantial Australian Genetics of Depression Study (AGDS) cohort to provide compelling evidence for the clinical and biological validity of the atypical depression subtype. Their integrative analysis of clinical features, polygenic scores (PGSs) for mental, metabolic, and circadian traits, and self-reported treatment outcomes is a significant contribution to the field. The particularly robust finding of an association between a genetic predisposition for eveningness (lower-chronotype PGS) and atypical depression, which persisted after adjustment for body mass index (BMI), is noteworthy and points to a potentially core, BMI-independent pathway.

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Medical Marijuana Initiation and Simulated Driving Performance Among Mid-to-Late-Life Adults With Chronic Pain: Prospective Observational Feasibility Cohort Study With Matched Controls

Background: Marijuana initiation among adults aged 50 years and older has increased substantially. Although acute tetrahydrocannabinol exposure can impair psychomotor function, less is known about how real-world medical marijuana initiation relates to functional tasks such as driving in mid-to-late life. Objective: The objective of our study was to evaluate the feasibility of recruiting and retaining adults aged 50 years and older, who are newly registered for medical marijuana, and matched non–marijuana-using controls, into a longitudinal high-fidelity driving simulator protocol, and to explore preliminary associations between medical marijuana initiation and simulated driving performance. Methods: This prospective, nonrandomized feasibility cohort study enrolled adults aged 50 years and older who are newly registered in the Florida Medical Marijuana Use Registry, along with age-, race-, and sex-matched controls. Assessments occurred at baseline (T1; preinitiation) and at 1 month (T2). Primary feasibility outcomes included recruitment, retention, simulator completion and tolerance, and exposure verification. Exploratory outcomes included reaction time and divided attention (DA) performance, which are measured using an immersive, high-fidelity driving simulator. Results: Recruitment and exposure verification procedures were feasible, but simulator sickness contributed to substantial missing data. Exploratory analyses suggested group differences in select DA outcomes at T2. At T2, reaction time to DA situation 3 (DA3) was significantly shorter in the medical marijuana group (n=14, mean 2.57, SD 1.63) than in the control group (n=7, mean 5.79, SD 4.32; =−2.50, =.02, =−1.11, 95% CI −2.04 to −0.16). These findings should be interpreted cautiously, given the small sample size, missing data, and multiple comparisons. Conclusions: A prospective protocol examining medical marijuana initiation and simulated driving among mid-to-late-life adults is feasible, but future studies should incorporate design and analytic refinements to address simulator sickness and missing data and to better characterize exposure timing and patterns. Trial Registration: ClinicalTrials.gov NCT04629716; https://clinicaltrials.gov/study/NCT04629716
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Communication-Based Teaching on Childhood Obesity and the Planetary Health Diet in Medical Education: Proof-of-Concept Study Comparing 4 Information Sources

Background: Childhood obesity constitutes a complex medical and psychosocial challenge that requires both nutritional knowledge and sensitive, relationship-oriented doctor-patient communication. The Planetary Health Diet links individual health promotion with environmental sustainability and represents a relevant framework for contemporary medical education. Objective: This proof-of-concept study investigated how different information sources influence medical students’ acquisition, structuring, and application of knowledge on childhood obesity and the Planetary Health Diet within a communication-based teaching setting, including the exploratory use of artificial intelligence–based tools. Methods: A total of 359 second-year medical students participated in a mandatory communication seminar during the 2023‐2024 academic year. Following a precourse knowledge assessment and a brief theoretical introduction, students worked on a standardized counseling scenario addressing childhood obesity. In small groups, students used only 1 assigned information source (ChatGPT, Google Search, scientific papers, or instructional videos) to prepare a counseling approach. Group outcomes were assessed using a predefined scoring system based on a sample solution, complemented by thematic content analysis. Results: All information sources enabled students to acquire relevant knowledge on childhood obesity and the Planetary Health Diet. However, groups differed with regard to the depth, differentiation, and structuring of their responses. The ChatGPT group achieved the highest conformity scores with the sample solution and provided the most additional information, followed by the Google and video groups, while the paper group achieved the lowest scores. Prior to the course, students reported limited knowledge of the Planetary Health Diet and little practical experience in counseling children with obesity and their families. Conclusions: Communication-based teaching formats provide an effective framework for introducing medical students to complex topics such as childhood obesity and sustainability-related nutrition early in their training. Easily accessible digital tools, including artificial intelligence–based systems, may facilitate knowledge acquisition and elaboration; however, their use requires explicit didactic framing, critical source evaluation, and reflection on the complexity of chronic conditions to support responsible and realistic learning outcomes in future physicians.
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Feasibility of Integrating Wearable Devices and Ecological Momentary Assessment for Real-Time Environmental Exposure Estimation: Proof-of-Concept Study

Background: Environmental exposures such as heat and air pollution are critical determinants of health, yet traditional assessment methods rely on stationary monitors or residential address proxies that fail to capture the exposures that individuals experience throughout the day. Objective: This pilot study aimed to assess the feasibility of integrating ecological momentary assessment (EMA), wearable devices, and continuous GPS tracking to capture real-time environmental exposures and to explore associations with concurrent health outcomes. Methods: In total, 7 young adults (aged approximately 16 to 24 years; 5/7, 71% female) wore Fitbit Charge 6 watches from July 2025 to August 2025 (mean 28.1, SD 1.1 days), recording sleep quality and duration, resting heart rate, breathing rate, heart rate variability, and physical activity. GPS location measured at up to 5-minute intervals (mean 19.7, SD 25.8 measurements per day) was linked to ambient temperature, humidity, and air pollution data (particulate matter <2.5 um or <10 um in diameter, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide) derived from monitoring stations, satellites, and climate models using data-integration algorithms accessed via an application programming interface. EMA surveys administered 3 times per day captured participants’ emotional states and location (inside or outside). Feasibility targets were ≥3 GPS measurements per day, ≥1 survey completed per day, and complete sleep data on ≥50% of days. We examined exploratory bivariate correlations between environmental exposures, physiological measures, and self-reported mood, adjusting for multiple comparisons using false discovery rate correction. Results: Of the 7 participants, 5 (71%) met predefined feasibility targets. Mean compliance included 565 (SD 457) GPS coordinates per participant, 1.4 (SD 0.2) EMA surveys per day, and complete Fitbit sleep data on 64% (SD 27%) of days. Surveys identified barriers to compliance, including perceived complexity of the system and forgetting to put the Fitbit watch back on after removing it. Exploratory correlations (6/7, 86% of participants with complete Fitbit data) revealed associations between nitrogen dioxide and heat exposure and reduced heart rate variability (a marker of parasympathetic tone), and between air pollutants (sulfur dioxide) and increased negative emotions. Heat exposure showed a paradoxical pattern of lower self-reported sadness but reduced heart rate variability with higher levels of heat exposure. Given the small sample size, these correlations should be considered preliminary and hypothesis generating rather than definitive findings. Conclusions: This study demonstrates that the multimodal integration of wearable devices, GPS tracking, and EMA is feasible for capturing real-time environmental exposures and concurrent health outcomes in young adults. This approach addresses critical exposure misclassification issues in environmental health research that relies on residential addresses as proxies. Preliminary patterns suggest complex relationships between environmental exposures and both physiological and emotional outcomes, warranting further investigation in larger, more diverse samples. This approach could inform future personalized environmental health interventions.
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Leukemia Stem Cell Diversity Drives Treatment Resistance in AML

Scientists from the German Cancer Research Center and HI-STEM have uncovered a major reason why acute myeloid leukemia (AML) frequently returns after treatment. Their findings, published in Cell Stem Cell, reveal that leukemia stem cells, the rare but critical cells that sustain the disease, exist in multiple biologically distinct forms, each with different vulnerabilities and resistance mechanisms.

The discovery helps explain why venetoclax, one of the most important targeted therapies in AML, often loses effectiveness over time. More importantly, it provides a framework for designing personalized combination therapies that could prevent relapse by targeting resistant stem cell populations before they expand.

Why AML remains difficult to cure

Acute myeloid leukemia is an aggressive blood cancer characterized by the rapid accumulation of abnormal myeloid cells in the bone marrow. Although newer targeted therapies have improved outcomes, relapse remains the central clinical challenge.

One of the most transformative advances in AML treatment has been the introduction of venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2. Combined with hypomethylating agents or low-dose chemotherapy, venetoclax has substantially improved responses, particularly in older patients who are unable to tolerate intensive chemotherapy.

Yet despite these advances, most patients eventually relapse.

Researchers have long suspected that leukemia stem cells are responsible. These rare cells possess the ability to self-renew indefinitely and survive therapeutic pressure, allowing the disease to regenerate even after apparently successful treatment.

Not one leukemia stem cell—but four

In the new study, researchers analyzed samples from more than 150 AML patients to better understand how leukemia stem cells respond to therapy.

Their findings challenge the idea that AML stem cells represent a single uniform population. Instead, the team identified at least four distinct leukemia stem cell subtypes, each resembling different developmental stages of normal blood cell formation.

This developmental identity turned out to be critically important because it determined which survival pathways the cells depended on—and therefore how sensitive they were to venetoclax.

Some stem cell subtypes were highly dependent on BCL-2 and responded well to treatment. Others relied on alternative survival programs that rendered them intrinsically less sensitive to the drug.

Cancer stem cells adapt under therapeutic pressure

One of the study’s most significant findings was that leukemia stem cells are not fixed in a single state. Instead, they can dynamically reprogram themselves in response to therapy.

Venetoclax works by blocking BCL-2, a protein that protects leukemia cells from programmed cell death. When BCL-2 is inhibited, susceptible leukemia cells undergo apoptosis.

However, the researchers found that under treatment pressure, many leukemia stem cells transition into more resistant cellular states. Rather than relying on BCL-2, these resistant cells switch to using a related survival protein known as BCL-xL.

This adaptive shift effectively allows the cells to bypass venetoclax and survive treatment.

The findings strengthen a broader principle increasingly recognized across oncology: cancer is not only genetically heterogeneous but also highly plastic. Tumor cells can alter their identity to evade therapeutic pressure, making durable treatment responses difficult to achieve with single-agent therapies.

Combination therapies may overcome resistance

The study also points toward potential strategies for overcoming this resistance.

By identifying which survival pathways individual leukemia stem cell subtypes depend on, researchers showed that resistant populations could potentially be targeted with rational drug combinations. In particular, combining venetoclax with inhibitors targeting BCL-xL emerged as a promising approach.

In mouse models transplanted with patient-derived leukemia cells, these subtype-specific combination therapies were significantly more effective than current standard approaches.

This suggests that future AML therapy may require simultaneous targeting of multiple stem cell states to prevent resistant populations from emerging during treatment.

Biomarkers could guide precision medicine in AML

Another key advance from the study was the identification of biomarkers capable of distinguishing the different leukemia stem cell subtypes.

These biomarkers could eventually enable clinicians to determine, at the time of diagnosis, which resistance mechanisms are most likely to arise in a particular patient.

“This means that in the future, it may be possible to determine at the time of diagnosis which patient will benefit most from which therapy,” said Alexander Waclawiczek, PhD, first author of the study.

Such an approach would represent a major shift away from treating AML as a largely uniform disease and toward truly individualized therapy guided by stem cell biology.

A new framework for AML treatment

The findings also reinforce the growing importance of cancer stem cell biology in therapeutic design. Rather than focusing exclusively on eliminating bulk tumor cells, future strategies may increasingly aim to eradicate the specific stem cell populations capable of regenerating disease after therapy.

“The results should help to align AML therapy in the future more closely with the biological characteristics of individual AML cases and, in particular, their leukemia stem cells, rather than treating all patients according to a similar protocol,” said Andreas Trumpp, PhD, who led the study.

The next major step will be translating these findings into clinical trials testing personalized combination therapies tailored to leukemia stem cell subtype composition.

The post Leukemia Stem Cell Diversity Drives Treatment Resistance in AML appeared first on Inside Precision Medicine.

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Lymphoid Cancer Risk Linked to Long Telomeres and POT1 Mutations

Researchers at the Johns Hopkins Kimmel Cancer Center and the Telomere Clinic at Johns Hopkins have identified an inherited cancer predisposition syndrome that results in unusually long telomeres that allow lymphocytes to stay in a biologically more youthful state for extended periods, increasing the risk of lymphoid malignancies. The findings, published the journal Blood, showed that inherited loss-of-function mutations in the POT1 gene disrupt normal telomere regulation and alter the aging dynamics of immune cells. The investigators found that because of this longer cellular lifespan cancer-associated mutations are persistent and expand over time, creating favorable conditions for the development of lymphoma and related blood cancers.

“The spectrum of lymphoid cancers was striking,” said senior author Mary Armanios, MD, a professor of medicine at Johns Hopkins. “Family members developed childhood leukemia, multiple forms of lymphoma, and adult-onset chronic lymphocytic leukemia—cancers often considered biologically distinct and associated with different inherited risks. Yet within the same families, multiple lymphoid malignancies appeared across generations. Some individuals developed melanoma before lymphoma, while others developed as many as five cancers over a lifetime. The good news is the cancers tended to be slow-growing and usually curable.”

Telomeres are protective caps at the ends of chromosomes that normally shorten with age and as a result of cell division, which limits the lifespan of cells that accumulate damage. POT1, or protection of telomeres 1, normally regulates telomere length by binding single-stranded telomeric DNA and restricting telomerase-mediated elongation. The researchers said that  “POT1 binds single-stranded telomeric DNA and is essential for telomere protection, but POT1 heterozygous loss of function is permissive of telomerase elongation in the absence of a detectable DNA damage response.”

For their initial research the investigators focused on 51 people from 24 families that were know to carry mutant POT1 variants. The surveyed the participants to evaluate family cancer histories and collected biological samples to define the range of cancers associated with the mutations with the aim of examining how telomeres influenced lymphocyte aging. The data showed that among this small cohort, hematologic malignancies were the second most common cancers after melanoma, occurring in 27% of participants, with lymphoid cancers accounting for approximately three-quarters of blood malignancies found.

As a result, the researchers noted that “our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma, explaining its syndromic association with solid tumors and, in some cases, myeloproliferative neoplasms.”

The investigators also found that telomeres responded differently that is typically observed as people aga. In those people with the POT1 mutation telomere length remained stable over time and in some cases lengthened rather than shortening with age. The findings indicated that lymphocytes retained prolonged replicative capacity, allowing cells with oncogenic mutations to survive instead of being eliminated through senescence.

To find out whether these findings extended beyond the studied families, the researchers then analyzed data from 210 adults with POT1 variants enrolled in the UK Biobank and found that people carrying pathogenic POT1 variants had an eightfold increased risk of lymphoma, and 45% developed lymphoid malignancies by age 80.

The research also examined asymptomatic POT1 mutation carriers to understand how lymphoma develops before clinical diagnosis. Among carriers without lymphoma, 12 of 20 had evidence of B-cell or T-cell clonality, a precursor state associated with lymphoma development. After age 65, all studied carriers showed detectable clonality. Sequencing and cytogenetic analyses revealed lymphoma-associated mutations in nearly all mutation carriers older than 60 years.

The study was prompted by earlier research which has shown evidence linking long telomeres to tumor development. Work in animal models had shown that long telomere length can bypass cellular senescence checkpoints and increase tumor incidence. Other  research had also found POT1 mutations in melanoma, papillary thyroid cancer, glioma, sarcoma, and chronic lymphocytic leukemia. But, the prevalence and natural history of these mutations across hematologic malignancies had remained uncertain.

The findings may influence future approaches to cancer surveillance and genetic evaluation in individuals with POT1 variants. The researchers said that ultralong lymphocyte telomere length could help identify pathogenic variants and distinguish variants of uncertain significance. They noted, however, that telomere length testing may have limitations because advanced clonality can interview with the ability to accurately measure baseline telomeres.

“Our data suggest that, for now, telomere length clinical testing should be reserved for individuals with variants in the gene that have unclear significance,” Armanios said.

The post Lymphoid Cancer Risk Linked to Long Telomeres and <i>POT1</i> Mutations appeared first on Inside Precision Medicine.