Tag: Appetite and ingestive regulation

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Prediabetes Genotyping Identifies Who Benefits from Vitamin D

Genotyping could help identify people who would most benefit from vitamin D supplements to prevent their progression to diabetes, further analysis of a clinical trial suggests.

The genetic association study indicated that individuals with glycemic indicators of prediabetes could benefit from supplementation with 4000 IU/d of vitamin D3 if they carried specific genetic polymorphisms.

Two genotypes of the ApaI vitamin D receptor polymorphism (VDR) were linked to a risk reduction when these vitamin supplements were taken compared with placebo, according to the report in JAMA Open.

“Our exploratory findings, if confirmed, hold promise for high-dose vitamin D3 as a targeted, personalized approach to reducing the risk of type 2 diabetes among selected adults with prediabetes,” reported Bess Dawson-Hughes, MD, from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, and co-workers.

“The magnitude of the observed risk reduction among participants with AC and CC alleles of the ApaI polymorphism, if confirmed in an independent clinical trial, would have clinical implications for the management of prediabetes.”

There are four major polymorphisms in the vitamin D receptor: FokI, BsmI, ApaI, and TaqI. While the FokI polymorphism produces a shorter vitamin D receptor with enhanced transcriptional activity, the BsmI, ApaI, and TaqI polymorphisms influence mRNA stability, posttranscriptional regulation, and translational efficiency.

ApaI is strongly associated with metabolic syndrome and obesity, which are both major risk factors for type 2 diabetes.

In an extended analysis of the Vitamin D and Type 2 Diabetes (D2d) trial, researchers examined whether VDR gene variants modified the results of the trial.

The primary outcome of the original trial, conducted in people who achieved at least two of the three glycemic criteria for prediabetes, did not reach statistical significance in the intention-to-treat analysis. However, further examination revealed that the effect of vitamin D3 depended on the achieved intratrial serum 25-hydroxyvitamin D (25[OH]D) levels.

Dawson-Hughes and team therefore examined common VDR polymorphisms in the D2d trial to see whether these polymorphisms were associated with reduced diabetes risk among participants who achieved higher intratrial mean 25(OH)D level, in a discovery-level analysis.

They then conducted a test phase to determine whether participants’ VDR genetic profile modified the response to vitamin D3 supplementation compared with placebo.

Among 2098 participants in the D2d trial, the 618 carrying the AA alleles experienced no reduction in risk of progression to type 2 diabetes either when achieving higher intratrial 25(OH)D concentrations or when using vitamin D3 4000 IUs per day for a median of 2.5 years after adjusting for race, sex, and body mass index, among other variables.

However, the 1480 participants with ApaI AC and CC genotypes—representing 71% of the study population—had a progressively lower risk of type 2 diabetes at intratrial 25(OH)D levels of 40 ng/ml or higher.

Participants with these genotypes had a 19% reduction in the risk of progressing to type 2 diabetes over the same period (Hazard ratio=0.81).

“If confirmed, a 19% risk reduction in conversion to type 2 diabetes with vitamin D3 supplementation would not be trivial,” the authors concluded, noting that assessment of a single VDR polymorphism is inexpensive and now widely available.

In a Commentary article accompanying the study, Michael Holick, PhD, and Arash Shirvani, PhD, both from Boston University, added: “The enormity of the disease burden of diabetes worldwide and the confirmation that vitamin D supplementation of 4000 IUs per day markedly reduces risk of developing it should be a wake-up call and the impetus for health organizations to develop strategies to improve vitamin D status for children and adults with food fortification programs, implementation of supplementation, and sensible sun exposure recommendations for those who are at risk.”

The post Prediabetes Genotyping Identifies Who Benefits from Vitamin D appeared first on Inside Precision Medicine.

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New ADC Yields Encouraging Clinical Benefit in Platinum-Resistant Ovarian Cancer

Patients with advanced platinum-resistant ovarian cancer whose disease had progressed on standard therapy experienced clinical benefit when treated with the investigational antibody-drug conjugate (ADC) QLS5132.

This finding is according to results from a Phase I clinical trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held in San Diego.

Patients diagnosed with platinum-resistant ovarian cancer face both a poor prognosis and limited treatment options, explained Tao Zhu, MD, chief physician and vice president of Zhejiang Cancer Hospital in China, who presented the study.

Zhu and collaborators tested an investigational ADC, QLS5132, which targets the protein CLDN6. QLS5132 combines a CLDN6-targeting monoclonal antibody with a cytotoxic payload, topoisomerase-1 inhibitor, at a drug-to-antibody ratio of 8:1. CLDN6, Zhu said, makes an ideal target as a protein with very high expression on the surface of ovarian cancer cells and minimal cell-surface expression in healthy tissues.

“The primary purpose of this first-in-human study was to evaluate the safety, tolerability, and pharmacokinetic profile of QLS5132 in patients with platinum-resistant ovarian cancer and determine the recommended Phase II dose for future clinical development,” Zhu said. “Additionally, we aimed to assess preliminary antitumor activity to establish an early signal of clinical benefit in this heavily pretreated population with limited options.”

The Phase I, single-arm, dose-escalation trial enrolled 28 patients with a median age of 57.5 who had been diagnosed with advanced platinum-resistant ovarian cancer and who had experienced progression while on standard therapy. The research team administered QLS5132 as an intravenous infusion every three weeks at dose levels of 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.6 mg/kg, and 6.4 mg/kg.

Treatment-related adverse events (TRAEs) occurred in 26 (92.9%) patients, with nausea, anorexia, anemia, and weakness occurring most frequently. Nine (32.1%) patients experienced TRAEs of grade 3 or higher, and of those grade ≥3 TRAEs, seven were instances of hematological toxicity. No TRAEs led to treatment discontinuation or death, and no patients experienced interstitial lung disease, ocular toxicity, or febrile neutropenia, Zhu said.

After a median follow-up of 2.2 months, nine patients had a partial response at various dose levels. Two of these partial responses occurred in patients who had no detectable CLDN6 expression.

Across all dose levels, 18 evaluable patients experienced an objective response rate of 50% and a disease control rate of 94.4%. When calculated for the 17 evaluable patients who had received dose levels ≥3.2 mg/kg, the objective response rate and disease control rate rose to 52.9% and 100%, respectively. These responses to QLS5132 occurred irrespective of patients’ CLDN6 expression levels at baseline.

“The most encouraging finding from our study was that QLS5132 demonstrated compelling antitumor activity in patients with platinum-resistant ovarian cancer, with an objective response rate exceeding 50%,” said Zhu. “Equally important, at the potential recommended Phase II dose, we observed a favorable safety profile with no reported cases of interstitial lung disease, ocular toxicity, oral mucositis, or febrile neutropenia.”

Zhu also noted that, though more research would be needed to confirm, preliminary data indicated antitumor activity from QLS5132 regardless of CLDN6 expression levels—which, he said, could expand its potential as a treatment option to a broad cohort of patients with platinum-resistant ovarian cancer.

Zhu acknowledged that further research would be needed to fully understand why QLS5132 can have anticancer effects in patients with undetectable CLDN6 tumoral expression. But he suggested the phenomenon may have a few explanations, including tumor heterogeneity, as well as a potent bystander effect resulting in antitumor efficacy even in cells with low or no CLDN6 expression.

“These findings support the advancement of QLS5132 into Phase III studies, with the goal of providing a much-needed new treatment option for these patients,” said Zhu.

Some limitations of this study include a small sample size and an exploratory single-arm design.

This study was funded by Qilu Pharmaceutical. Zhu discloses no conflicts of interest.

The post New ADC Yields Encouraging Clinical Benefit in Platinum-Resistant Ovarian Cancer appeared first on GEN – Genetic Engineering and Biotechnology News.

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Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy

IntroductionDuchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer’s disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.MethodsMale D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.ResultsCompared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.DiscussionThe results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.
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STAT+: Tortugas Neuroscience launches with hopes to develop drugs for brain disorders, other conditions

A new startup has found that the Chinese biotech industry is good for more than obesity drugs and cancer therapies. 

The company, Tortugas Neuroscience, launched Tuesday with plans to develop two schizophrenia and tinnitus drugs licensed from Chinese drugmaker Jiangsu Hansoh Pharmaceutical Group. The startup will also test two other medicines for focal epilepsy and encephalopathies that were originally created by Japanese pharmaceutical company Eisai Co. Ltd. 

Tortugas has $106 million from Cure Ventures, The Column Group, and AN Ventures to begin testing the drugs in mid-stage trials in the U.S. 

Continue to STAT+ to read the full story…

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STAT+: BioAge says experimental pill aimed at reducing heart risks significantly reduced inflammation

BioAge Labs said Tuesday that its investigational pill for cardiovascular risk prevention significantly reduced inflammation in an early study, as more drug companies target inflammation as a way to treat a range of chronic conditions.

In a Phase 1 study of people with obesity and elevated inflammation levels, patients taking a 60-milligram dose of the drug, called BGE-102, experienced an 86% reduction in a measure of inflammation called high-sensitivity C-reactive protein (hs-CRP) after three weeks. That’s a similar level of reduction seen in patients who took a higher 120-mg dose in the study, which the company previously reported. 

Additionally, 87% of patients taking the 60-mg dose achieved hs-CRP levels of less than 2 mg/liter, the threshold thought to be associated with a lower risk of cardiovascular complications.

Continue to STAT+ to read the full story…

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MDMA Assisted Therapy for BN

Conditions: Bulimia Nervosa

Interventions: Drug: MDMA-AT; Drug: MDMA-AT-BN; Behavioral: Standard Treatment (ST)

Sponsors: Icahn School of Medicine at Mount Sinai

Not yet recruiting
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Lilly to Acquire Kelonia for Up to $7B, Expanding Cancer Cell Therapy Pipeline

Eli Lilly has agreed to acquire Kelonia Therapeutics for up to $7 billion, the companies said today, in a deal that would bolster the buyer’s oncology pipeline with an early clinical phase lentiviral in vivo chimeric antigen receptor T-cell (CAR T) therapy under study in relapsed/refractory multiple myeloma.

Kelonia’s lead program KLN-1010 is a one-time intravenous gene therapy designed to generate anti-B-cell maturation antigen (BCMA) CAR T cells, targeting the BCMA protein expressed on the surface of multiple myeloma cells.

In December at the American Society of Hematology (ASH) 2025 Annual Meeting, Kelonia presented positive early clinical data for KLN-1010 from the Phase I inMMyCARTM trial (NCT07075185). The data showed the CAR T therapy to have 100% minimal residual disease (MRD)-negative response rate across four patients, all of whom remained in response through the longest follow up of five months.

Those and other results, according to the company, provided initial clinical validation of KLN-1010 and demonstrated promising tolerability. In January, Kelonia won FDA clearance for an investigational new drug (IND) application for KLN-1010, enabling the trial to expand from Australia into multiple clinical sites across the United States.

“The early clinical data for KLN-1010 are highly encouraging, both as a potential step forward for patients with multiple myeloma and as proof of concept for Kelonia’s platform,” Jacob Van Naarden, executive vice president and president of Lilly Oncology and head of corporate business development, said in a statement.

Investors appeared more sanguine about the Kelonia acquisition as Lilly shares were all but flat in early Monday trading as of 11 a.m. ET, to $927.16 from Friday’s close of $927.03. Kelonia is privately held.

KLN-1010 applies the company’s in vivo gene placement system (iGPS®), which uses engineered lentiviral-based particles designed to efficiently and selectively enter T-cells inside the body, enabling a patient’s own body to generate CAR T therapies designed to treat underlying disease.

Lilly and Kelonia reason that KLN-1010 could transform treatment of multiple myeloma by eliminating challenges associated with both ex vivo patient-specific cell therapy manufacturing, and pre-administration chemotherapy.

“Autologous CAR T therapies have meaningfully improved outcomes for patients with various cancers, but significant manufacturing, safety, and access barriers mean that only a fraction of eligible patients actually receive them,” Van Naarden added. “Kelonia’s in vivo platform has the potential to change that by delivering rapid, durable responses in a far simpler, off-the-shelf format.”

Kelonia marks Eli Lilly’s fourth announced acquisition of a smaller biotech this year:

Behind the deals

Behind all the deals is the pharma giant’s desire to capitalize on the billions of dollars it is generating from sales of its obesity and diabetes drugs based on glucagon-like peptide 1 (GLP-1) receptor analysts alone or in tandem with a glucose-dependent insulinotropic polypeptide (GIP). Lilly markets tirzepatide, a GLP-1/GIP dual agonist, in obesity as Zepbound® ($13.542 billion in 2025 sales) and in diabetes as Mounjaro® ($22.965 billion).

Lilly stands to generate even more in obesity-related sales in coming years once it brings to market its oral obesity drug Foundayo™ (orforglipron), a small molecule GLP-1 receptor agonist—though analysts predict the drug’s 2026 sales will likely be lower than once expected because of the price war Foundayo faces competing head to head with Lilly’s arch-rival in obesity drugs, Novo Nordisk. In December, Novo Nordisk got a jump on Lilly when the Danish biotech giant won FDA approval for oral Wegovy® (semaglutide), a once-daily 25 mg GLP-1 receptor agonist tablet indicated for chronic weight management.

A Lilly buyout of Kelonia could compel Johnson & Johnson to take a closer look at acquiring Legend Biotech, Kostas Biliouris, PhD, a managing director on the biotechnology research team of Oppenheimer, wrote Sunday in a research note. He cited the fact J&J’s Janssen Biotech successfully partnered with Legend to develop Carvykti® (ciltacabtagene autoleucel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy indicated for adults with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. Carvykti generated $1.877 billion in sales last year, up nearly double (96%) from $963 million in 2024.

Also, Biliouris cited the presence in Legend’s pipeline of LUCAR-G39D, a clinical in vivo CAR T program designed to treat B-cell non-Hodgkin’s lymphoma by targeting CD19xCD20. LUCAR-G39D showed positive first-in-human safety and efficacy data from a Phase I trial (NCT06395870) at ASH last December.

“We believe in vivo CAR T technology has strong potential, as treatment process is fast and circumvents the need for lymphodepletion, but think it will likely take ~6-8years before safety/durability questions are addressed, and regulatory approval is granted,” Biliouris predicted.

Lilly has agreed to acquire Kelonia for $3.25 billion upfront plus up to $3.75 billion in future payments tied to achieving specified clinical, regulatory, and commercial milestones. The acquisition deal is subject to regulatory approvals and other customary closing conditions, and is expected to close in the second half of 2026.

Upon closing, Lilly said, it will determine how to account for the transaction in accordance with Generally Accepted Accounting Principles (GAAP), then reflect the deal in future financial results and financial guidance.

“Kelonia’s leadership in advancing the immense promise of in vivo cell therapy is unmatched, extending its reach and impact beyond the traditional boundaries of personalized medicine,” Kelonia CEO Kevin Friedman, PhD, stated. “We have demonstrated the ability to achieve deep multiple myeloma remissions with significantly reduced complexity and cost relative to ex vivo CAR T-cell approaches.”

“In combination with Lilly’s strengths, our in vivo iGPS platform is positioned to broaden the reach of cell therapy beyond the current CAR T landscape in hematologic malignancies and to transform treatment across a far wider range of cancers and other serious diseases,” Friedman added.

The post Lilly to Acquire Kelonia for Up to $7B, Expanding Cancer Cell Therapy Pipeline appeared first on GEN – Genetic Engineering and Biotechnology News.

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StockWatch: Revolution’s Phase III Pancreatic Cancer Data Dazzles Investors, Analysts

Pancreatic cancer is one of the most difficult cancers to treat, with an overall five-year survival rate of 13%, according to the American Cancer Society, stretching from 3% for metastatic (Stage 4) to 44% for localized (Stages 1 and 2).

Dismal odds such as these explain the enthusiastic response of investors when Revolution Medicine (NASDAQ: RVMD), a developer of RAS-addicted cancer therapies, announced dazzling data from its Phase III RASolute 302 trial (NCT06625320) evaluating its once-daily oral daraxonrasib in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who had been previously treated.

In the trial’s overall (intent-to-treat) study population, daraxonrasib showed a median overall survival (OS) of 13.2 months, nearly double the 6.7 months demonstrated for standard-of-care chemotherapy, with a hazard ratio (HR) of 0.40 (p < 0.0001). Daraxonrasib also presented what Revolution called a manageable safety profile and no new safety signals.

“These results represent a potentially transformative advance for patients and underscore daraxonrasib’s potential to redefine the treatment landscape. We are moving with urgency toward global regulatory submissions and remain committed to rapidly advancing this therapy for patients with a broad range of RAS-addicted cancers, Revolution’s CEO and chairman Mark A. Goldsmith, MD, PhD, said in a statement.

Investors and analysts largely agreed with Goldsmith. Revolution’s stock reacted to the data release by soaring 54% this past week, starting with a 41% surge that sent the share price soaring from $96.43 on April 10 to $136.30 on April 13. Since then, the stock has jumped another 12%, reaching $152.54 at Wednesday’s closing bell. Profit-taking by investors led to a 2% slide on Thursday (to $149.27) and a 0.43% dip on Friday (to $148.63).

“Our base case from stats sim [statistics simulation] was 11 vs. 7 mos, and based on our investor discussions, OS >12 months (and/or >6 mos delta vs. chemo) should drive meaningful stock upside,” Faisal Khurshid, an equity analyst with Jefferies, correctly predicted in an April 13 research note.

A “clear win” scenario, Khurshid explained, would show daraxonrasib with an OS of greater than 11 to 12 months, and/or a daraxonrasib difference vs. chemo of >4–6 months, and/or an HR of <0.5–0.6.

“Best-case outcome”

“The disclosed data materially exceeds these expectations,” Khurshid declared. “This is by any measure a best-case outcome for RVMD [emphasis in original]. Darax’s performance was roughly in line with the Ph1 experience, and chemo only slightly outperformed historical benchmarks.”

Revolution’s positive data sets the bar high for other cancer treatment developers—including Erasca (NASDAQ: ERAS), which is expected by the end of the first half to announce initial monotherapy data from its Phase I trial (NCT06983743) assessing ERAS-0015, a RAS-targeting molecule, in patients with RAS-mutant solid tumors.

Khurshid’s colleague at Jefferies, Maury Raycroft, PhD, noted Erasca has said it believes a >10% improvement in response rates in PDAC or non-small cell lung cancer compared to daraxonrasib could support ERAS-0015 as being differentiated from Revolution’s candidate, as would improvement in two or more safety/tolerability attributes, such as rash, gastrointestinal diseases, and stomatitis.

“Given the efficacy seen in ERAS’ 8 mg cohort and escalation to 40 mg, we remain (+)ve on the pot’l for stronger activity at higher doses,” Raycroft wrote in an April 13 research note. “That said, improved safety may be a key differentiator, particularly to enable combinations, especially as the competitive benchmark in PDAC continues to move higher.”

At Leerink Partners, Jonathan Chang, PhD, senior managing director, emerging oncology, and a senior research analyst, raised the firm’s 12-month share price target 28%, from $115 to $147, “to reflect greater conviction in pipeline opportunities.”

“Although RAS pathway drug development is highly competitive, we continue to believe encouraging clinical data from the innovative RAS(ON) platform, coupled with the large addressable population of RAS-dependent cancers, support a positive long-term outlook for RVMD,” Chang wrote.

Leerink colleague Andrew Berens, MD, senior managing director, targeted oncology, and a senior research analyst, observed that daraxonrasib could set a standard for positive data that several RAS-based cancer drug developers are working to improve upon, citing:

  • Adlai Nortye (NASDAQ: ANL): Its panRAS inhibitor AN9025 shares the same method of action as daraxonrasib but with potentially greater potency and durability. The company’s pipeline also includes AN4035, a panRAS antibody-drug conjugate.
  • BridgeBio Oncology Therapeutics (NASDAQ: BBOT): Its BBO-11818, a pan KRAS ON/OFF inhibitor, has shown efficacy signals in early PDAC clinical studies. “The more targeted ON/OFF approach may lead to greater potency and less toxicity.”
  • Immuneering (NASDAQ: IMRX): Its atebimetinib showed 64% OS at 12 months as a first-line pancreatic cancer treatment in updated data announced January 7.

“Not insurmountable”

“Dara[xonrasib] sets a high bar that is not insurmountable. The data for dara look encouraging, with a clear benefit over SOC [standard-of-care] chemo, but could leave room for other novel approaches to improve on efficacy and/or tolerability,” Berens wrote. “We think dara could be the first targeted therapy for RAS mutant PDAC patients and potentially become the 2L SOC, establishing RAS inhibitors as key backbone therapies in PDAC.”

That could lead to more RAS-based combination therapies, which Berens said has favorable implications for Tango Therapeutics (NASDAQ: TNGX)’s vopimetostat, an oral, selective PRMT5 inhibitor being studied in combinations with either daraxonrasib and another Revolution RAS(ON) cancer candidate, zoldonrasib, in a Phase I/II trial (NCT05732831).

Revolution said it plans to present its data at the American Society of Clinical Oncology’s 2026 ASCO Annual Meeting, set for May 29–June 2 in Chicago. Data will also be presented to regulators as Revolution files a New Drug Application (NDA) with the FDA, which has selected daraxonrasib for its Commissioner’s National Priority Voucher (CNPV).

Launched in October by FDA Commissioner Martin A. Makary, MD, CNPV is a pilot program that awards vouchers to drug developers whose work is deemed to address a health crisis in the United States, deliver more innovative cures, address unmet public health needs, and increase domestic drug manufacturing as a national security issue. In return, the vouchers entitle companies to reviews of their final applications within a target timeframe of 1–2 months rather than the current 10–12 months.

The stock surge boosted Revolution’s market capitalization (share price times the number of outstanding shares) to approximately $30 billion. That’s the midpoint of the $28 billion to $32 billion acquisition that Merck & Co. (NYSE: MRK) was pursuing for Revolution in January, according to the Financial Times. That prospective deal reportedly collapsed after the companies failed to agree on the value of daraxonrasib and Revolution’s other cancer-fighting candidates.

Merck never commented on its pursuit of Revolution, while AbbVie (NYSE: ABBV) flatly denied an earlier report that it sought to acquire the cancer drug developer. All the acquisition talk surrounding Revolution landed the company on GEN’s updated A-List Top 10 Takeover Targets of 2026, published March 9.

Cashing in

Revolution quickly cashed in on its positive data and stock surge, first proposing a $1 billion public offering of stock and debt, then doubling the size to $2 billion. The $2 billion offering consisted of concurrent public offerings of 10,563,381 shares of common stock at $142 per share (approximately $1.5 billion in gross proceeds) and $500 million of 0.50% convertible senior notes due 2033. Revolution also granted underwriters of the common stock offering a 30-day option to purchase up to an additional 1,584,506 shares.

J.P. Morgan, TD Cowen, and Guggenheim Securities are book-running managers for the stock and note offering, with LifeSci Capital acting as lead manager.

Daraxonrasib (formerly RMC-6236) is an oral RAS(ON) multi-selective, non-covalent inhibitor designed to target cancers driven by a variety of common RAS mutations, including PDAC, non-small cell lung cancer (NSCLC), and colorectal cancer. It is now under study in four global Phase III registrational trials—three in PDAC, the other in NSCLC. Daraxonrasib has been granted the FDA’s Breakthrough Therapy and Orphan Drug designations for the treatment of patients with previously treated metastatic PDAC harboring G12 mutations.

The RASolute 302 trial is a 501-patient global, randomized, registrational clinical study designed to evaluate the efficacy and safety of daraxonrasib as a monotherapy in patients with previously treated metastatic PDAC. Patients were randomized to receive either an oral dose of 300 mg daraxonrasib once daily or investigator’s choice of standard of care cytotoxic chemotherapy. The trial enrolled patients with metastatic PDAC harboring a wide range of RAS variants, including those with RAS G12 mutations (such as G12D, G12V, and G12R), as well as patients without an identified tumor RAS mutation (wild type).

Primary endpoints of RASolute 302 are OS and progression-free survival (PFS), as well as OS in patients with tumors harboring RAS G12 mutations. Secondary endpoints include PFS and OS in all enrolled patients (the intent-to-treat population) encompassing patients with and without identified tumor RAS mutations, as well as objective response rate, duration of response, and patient-reported quality of life.

Kailera makes history with $625M IPO

The “sign of life” StockWatch reported on last week when Avalyn Pharma filed paperwork for an initial public offering (IPO) is blooming this spring into a full blown comeback for IPOs, paced by what market watchers called the largest-ever public offering for a U.S. biotech—the eye-popping $625 million IPO carried out by Kailera Therapeutics—with at least two other companies submitting paperwork for filings of their own.

Kailera is a developer of therapies for obesity and weight management based on glucagon-like peptide receptor 1 (GLP-1) agonists, alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. The company priced an IPO on Thursday that generated $489.7 million in net proceeds through the sale of 39,062,500 shares of common stock at $16 per share—the high end of the pricing range of $14–$16.

On Kailera’s first full day of trading on Friday, investors showered the company with buys, propelling a 72% leap that sent shares to a high of $27.50 before the stock settled for a 62.5% gain, closing at an even $26.

The company earlier anticipated $458.7 million in net proceeds based on a $15 per share IPO price—though any $1 increase to the IPO price would increase what Kailera netted from the offering by an additional $31 million, according to an amended Form S-1 registration statement filed April 13 with the U.S. Securities and Exchange Commission (SEC).

Net proceeds could ultimately be even higher, since Kailera has granted its underwriters a 30-day option to purchase up to an additional 5,859,375 shares at the IPO price minus underwriting discounts and commissions. J.P. Morgan, Jefferies, Leerink Partners, TD Cowen, and Evercore ISI are joint book-running managers for the offering, with William Blair acting as lead manager.

Pipeline development

Kailera said the IPO plus its cash, cash equivalents, and marketable securities would give the company resources that it intended to spend on developing its four clinical-phase pipeline candidates, all in-licensed for $100 million upfront from Jiangsu Hengrui Pharmaceuticals (Shanghai Stock Exchange: 600276):

  • Ribupatide, the company’s lead product and a once-weekly injectable GLP-1/GIP receptor dual agonist peptide, including to fund three ongoing global Phase III KaiNETIC clinical trials into the second quarter of 2028 (more than $625 million, the estimate based on the $15 share price)
  • Oral ribupatide, a once-daily oral tablet formulation of ribupatide, including the funding of planned Phase III trials into the second quarter of 2028 (more than $150 million)
  • KAI-7535, a once-daily oral small molecule GLP-1 receptor agonist, including through the completion of a planned Phase II clinical trial (more than $50 million)
  • Other R&D activities, including development of KAI-4729, a once-weekly injectable GLP-1/GIP/glucagon receptor tri-agonist, as well as for working capital and other general corporate purposes (Remaining proceeds, not quantified)

Kailera gained exclusive global rights outside Greater China to Jiangsu Hengrui’s GLP-1 portfolio in 2024. That year, Kailera was launched with a $400 million Series A financing co-led by Atlas Venture, Bain Capital Life Sciences, and RTW Investments. Last October, Kailera garnered an additional $600 million in Series B financing led by a new investor, Bain Capital Private Equity.

“Our obesity-first approach seeks to capitalize on and improve upon proven science to advance product candidates which have the potential to maximize weight loss and address other critical needs in the current therapeutic landscape and to provide options, including oral options and alternative mechanisms, for people living with obesity no matter where they are in their treatment journey,” Kailera stated in its amended registration statement.

Kailera has adjusted the value of its cash and equivalents plus marketable securities from $652.728 million to a pro forma $1.142 billion in assets, reflecting the conversion of all outstanding preferred shares into common stock upon closing of the offering, plus an amended and restated certificate of incorporation.

Kailera’s IPO has surpassed the previous record-high among U.S. biotechs, the $604 million offering of Moderna (NASDAQ: MRNA) in December 2018, two years before the messenger RNA (mRNA) vaccine developer won FDA emergency authorization for its COVID-19 vaccine.

In the works

At least two other biotechs have filed Form S-1 registration statements for future IPOs in recent days, without disclosing how many shares they plan to raise or their offering prices.

  • Seaport Therapeutics is a developer of treatments for depression, anxiety, and other debilitating neuropsychiatric disorders based on its GlyphTM platform, a lymphatic-targeting prodrug technology designed to enhance a drug’s oral bioavailability and reduce side effects by bypassing first-pass metabolism. “Through our differentiated approach, we identify clinically validated mechanisms with established efficacy and safety profiles that have historically been limited by high first-pass metabolism, low bioavailability, and/or side effects,” Seaport stated in its Form S-1
  • Hemab Therapeutics, a developer of subcutaneous treatments for rare blood coagulation disorders, said its lead candidate, sutacimig (HMB-001), is a bispecific antibody in Phase I/II trials for the prophylactic treatment of Glanzmann thrombasthenia and Phase II studies for the prophylactic treatment of Factor VII deficiency. Another therapeutic candidate, HMB-002, is a monovalent antibody in Phase I/II trials for the subcutaneous prophylactic treatment of Von Willebrand disease. “We are building a franchise designed to address select coagulation disorders where we believe advances in biology, drug modality, and care delivery have the potential to meaningfully improve disease management,” Hemab stated in its Form S-1.

Leaders and laggards

  • MeiraGTx (NASDAQ: MGTX) shares yo-yoed, rising 26% from $8.97 to $11.29 Tuesday, after the company announced plans to present three-year data from its Phase I AQUAx trial (NCT04043104) evaluating AAV-hAQP1 in Grade 2/3 radiation-induced xerostomia. MeiraGTx reported “clinically meaningful” improvements in xerostomia symptoms, such as the average XQ score improving by 17 points (39.5%) at month 12, bilaterally treated participants reporting greater improvement than those treated unilaterally (21 points vs 13 points), and 75% of bilaterally-treated patients reporting transformative (≥10 point) improvement at month 12. After dipping 0.4% to $11.25 Wednesday, shares slumped 16% to $9.48 Thursday as MeiraGTx priced an approximately $100 million offering of 11,111,111 shares at $9 per share. Proceeds plus existing cash and cash equivalents are expected to fund commercial launches of AAV-hAQP1 and botaretigene sparoparvovec (“bota-vec”), a gene therapy for XLRP that MeiraGTx agreed to acquire from Johnson & Johnson (NYSE: JNJ) for $25 million cash upfront, a $50 million one-time payment tied to achieving specified regulatory and commercial milestones, plus a “mid-teens” royalty on global net sales starting on or after July 1, 2029.
  • Travere Therapeutics (NASDAQ: TVTX) shares soared 37% from $30.70 to $42.13 Tuesday after the rare disease drug developer won full FDA approval for Filspari® (sparsentan) in a second rare kidney disease. Filspari has become the first and only treatment for focal segmental glomerulosclerosis (FSGS), specifically to reduce proteinuria in adults and younger patients ages eight years and older with FSGS without nephrotic syndrome. Filspari won FSGS approval based on positive data from the Phase III DUPLEX trial (NCT03493685), where researchers reported a statistically significant 46% reduction in proteinuria from baseline to Week 108 in patients treated with Filspari vs. 30% for those treated with standard of care maximum labeled dose irbesartan, marketed by Sanofi (Euronext Paris: SAN) as Avapro®. Filspari first won FDA approval in 2023 to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression.

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Experiences From an Internet-Delivered Treatment Program for Individuals With Obesity: Pilot Study

Background: The prevalence of obesity is a global health challenge, as obesity is associated with various comorbidities, reduced quality of life, and increased mortality. Providing effective treatment to improve health and quality of life for people with obesity is a major health care concern. Internet-delivered treatment (IDT) is an alternative treatment that increases patient accessibility and reachability; however, pilot testing is required before such interventions are evaluated in full-scale studies or implemented. Objective: This study aims to investigate the feasibility and user-friendliness of an IDT program for obesity (IDT-O); to evaluate body weight, dietary habits, physical activity, psychosocial functioning, and experiences of treatment in those who completed the 6-month treatment; and to investigate the dropouts’ experiences of the treatment. Methods: A prospective 1-year observational approach, evaluated through a multimethod research design, was adopted. Inclusion criteria were age 18 years and older, BMI of ≥30 kg/m, or BMI of 28‐29.9 kg/m with obesity-related comorbidity. Participants were offered a 6-month therapist-assisted IDT-O program providing evidence-based obesity treatment, behavioral and lifestyle support, and strategies to address weight stigma. BMI, participants’ dietary habits, self-reported physical activity, psychosocial functioning, experiences of treatment effects, and treatment satisfaction were measured before treatment and after 6 and 12 months. Dropouts were followed up through qualitative interviews. Results: A total of 20 participants (17 females and 3 male; mean age 44.2, SD 16.4 years) started the IDT-O program, and 35% (7/20) completed all 12 modules. Ten (8 females) out of 13 dropouts were interviewed. Both quantitative and qualitative findings showed that participants were generally satisfied with the content and design of the intervention. Those who completed the IDT-O lost some weight (mean 2.0%, 95% CI −1.09 to 5.13), reported improved dietary habits (effect size [ES] 0.25, 95% CI −0.51 to 1.00), increased physical activity (ES 0.93, 95% CI −0.08 to 1.87), and improved psychosocial functioning (distress: ES 0.43, 95% CI 0.‐0.37 to 1.19; avoidance: ES 0.67, 95% CI −0.18 to 1.48), 6 months after completing the treatment. The qualitative analysis of the interviews revealed “The programme was OK, but it does not suit everyone” as the main theme. The main themes were based on the 3 subthemes: “It wasn’t for me,” “There were good things,” and “There are things to improve.” Conclusions: The findings indicate that the IDT-O holds potential as a treatment for people with obesity, although one limitation is that only 35% (7/20) of the participants completed the pilot program. Improvements in lifestyle habits and psychosocial functioning were observed in those who completed the IDT-O, but these findings are preliminary and need to be confirmed in a more comprehensive study. The issue of nonadherence underscores the importance of both thoroughly assessing patients before treatment and further development of IDT-O programs. Trial Registration: ClinicalTrials.gov NCT04150445; https://clinicaltrials.gov/study/NCT04150445
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STAT+: FDA eyes expanding testosterone therapy for libido

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Hellooooo, friends. Psychedelics and testosterone are front and center today, but also we note that GLP-1’s dominance in obesity may not be as inevitable as it looks. Early animal data from GLP-1 pioneers suggest that pathways like GIP-glucagon offer effectiveness and better overall tolerability. 

The need-to-know this morning

  • Kailera Therapeutics raised $625 million in an initial public offering — the largest-ever Wall Street debut for a drug company. Kailera is developing obesity drugs licensed from China. 

Do we even need GLP-1 anymore? 

The scientists whose work helped spur the development of GLP-1-based obesity drugs are now questioning whether that target is necessary at all. Instead, they’re proposing that using GIP-glucagon as a dual target could deliver comparable — or even superior — weight loss, without the nausea and dosing limitations that come with current therapies.

Continue to STAT+ to read the full story…