Tag: Appetite and ingestive regulation

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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…

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MiniMed flexes with next-gen insulin pump after spinning off from Medtronic

Within two weeks of MiniMed’s initial public offering in March, the Medtronic spinoff received FDA clearance for its latest-generation MiniMed Flex automated insulin delivery system. The smaller, screenless pump system is a major milestone for one of the world’s largest diabetes businesses. “We have a long history with durable pumps,” MiniMed EVP, Chief Product and…

The post MiniMed flexes with next-gen insulin pump after spinning off from Medtronic appeared first on Medical Design and Outsourcing.

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Transcutaneous auricular vagus nerve stimulation to alleviate metformin-associated gastrointestinal adverse events and optimize glycaemic control: a randomized, sham-controlled pilot trial protocol

BackgroundGastrointestinal adverse events (GI AEs) are the main dose-limiting side effects of metformin in type 2 diabetes mellitus (T2DM), reducing adherence and compromising long-term glycaemic control. Current strategies (dose adjustment or combination therapy) seldom address both tolerability and sustained metabolic efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that may modulate gut–brain–metabolic pathways—vagal reflexes, inflammation, intestinal barrier function, and enteroendocrine signaling—and thus improve drug tolerance while preserving glycaemic control.MethodsThis single-center, randomized, sham-controlled pilot trial will enroll 60 T2DM patients with metformin-associated GI AEs, randomized 1:1 to either the taVNS group or the sham control group. The intervention lasts 2 weeks with a follow-up at week 4. Assessments at baseline and follow-up include a validated Metformin Symptom Severity Score (total score 0–50; primary outcome), Bristol Stool Form Scale, bowel urgency, glycaemic/metabolic indices [fasting blood glucose (FBG), 2-h postprandial glucose (PG2h), glycated albumin (GA), fasting C-peptide, fasting insulin, HOMA-IR, ISI], and mechanistic biomarkers (GLP-1, 5-HT, IL-6, IL-10, TNF-α, D-lactate, DAO, bile acids). Safety monitoring includes routine hematology, liver and renal function tests.DiscussionBy combining clinical outcomes with targeted biomarker analyses in a randomized design, this pilot study will assess whether taVNS alleviates metformin-associated GI intolerance without impairing glycaemic efficacy, and will provide feasibility data, effect-size estimates, and biomarker selection for future confirmatory trials.Clinical trial registrationTrial registration International Traditional Medicine Clinical Trial Registry (ITMCTR) http://itmctr.ccebtcm.org.cn/, Identifier: ITMCTR2025001086.
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Advances in Stem Cell‑Derived Insulin‑Producing Cells for Type 1 Diabetes

Researchers at Karolinska Institutet and KTH Royal Institute of Technology have developed an improved method for creating insulin-producing cells from human stem cells. In a newly published study, the team demonstrated that these cells effectively regulate blood sugar levels in laboratory tests and can reverse diabetes in mice.

“We have developed a method that reliably produces high-quality insulin-producing cells from multiple human stem cell lines,” said Per-Olof Berggren, PhD, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “This opens up opportunities for future patient-specific cell therapies, which could reduce immune rejection.” Berggren and Siqin Wu, PhD, researcher at Spiber Technologies AB (formerly at Karolinska Institutet), are co-corresponding authors of the researchers’ published paper in Stem Cell Reports, titled “An optimized protocol for efficient derivation of pancreatic islets from multiple human pluripotent stem cell lines.”

Type 1 diabetes (T1D) occurs when the immune system destroys insulin-producing cells in the pancreas, meaning the body can no longer absorb glucose from the blood and regulate blood sugar levels. “In type 1 diabetes (T1D), autoimmune destruction of β cells results in loss of glycemic control,” the authors wrote.

One possible treatment strategy is to replace these cells with new ones. However, previous methods of producing such cells from stem cells have often yielded mixed results. Stem cell therapy for type 1 diabetes is already being tested in several clinical trials. However, a challenge with previous methods is that the stem cells often develop into a combination of the desired and undesired cell types, increasing the risk of complications. Another challenge is that the insulin-producing cells created are often not mature enough to respond well to glucose.

“The success of cell therapy for type 1 diabetes (T1D) depends on reliable differentiation of stem cells into functional pancreatic islets,” the authors noted. They pointed out that previous protocols have exhibited variable efficiency across different human pluripotent stem cell (hPSC) lines. “Differentiation beyond the stage (S) 4 pancreatic progenitor (PP) stage frequently yields heterogeneous cultures containing proliferative non-endocrine cells and immature endocrine cells … increasing the risk of cyst or tumor formation,” the team further commented.

The newly optimized production process reported by Berggren and colleagues yields more mature and purer insulin-producing cells than previous methods. In a laboratory setting, the cells were able to secrete insulin and responded strongly to glucose. When the researchers transplanted these cells into streptozotocin (STZ)-induced diabetic mice, the animals gradually regained the ability to regulate their blood sugar. “By adjusting the culture steps and allowing the cells to form three-dimensional clusters themselves, many unwanted cell types are eliminated and the cells gain a better ability to respond to glucose, according to the researchers. “Single-cell analyses show that the SC-islets are free of non-endocrine cell populations before and after transplantation,” the team stated.

The transplantation was performed in the anterior chamber of the eye (ACE) which provides a transparent and accessible site for noninvasive monitoring of engrafted SC-islets through the cornea, the team pointed out. Transplantation into this compartment is also straightforward and minimally invasive.  In their paper, the team noted, “Intraperitoneal glucose tolerance tests (IPGTT) at three, four, and six months post-transplantation showed improved glucose handling over time … SC-islet transplantation reversed hyperglycemia by three months, and by five–six months blood glucose levels fell slightly below pre-STZ baselines.”

Berggren commented, “This is a technique we use to monitor the development and function of the cells over time in a minimally invasive way. We observed that the cells gradually matured after transplantation, retaining their ability to regulate blood sugar for several months, which demonstrates their potential for future treatments.”

Fredrik Lanner, PhD, professor at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and last author of the paper, added, “This could solve several of the problems that have previously hindered the development of stem cell-based treatments for type 1 diabetes. Building on this, we will work towards clinical translation aiming at treating type 1 diabetes.” In their report the authors concluded, “Our protocol generated glucose-responsive SC-islets from all eight hPSC lines tested … demonstrating potential for autologous applications … Our efficient differentiation protocol represents a key step toward autologous cell therapy, though further work is required to realize this goal.”

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STAT+: Researchers behind GLP-1 obesity drugs advance new approach: Drop GLP-1 as a target

The scientists whose work spurred the development of powerful obesity drugs like Eli Lilly’s Zepbound are now raising a provocative hypothesis: Perhaps targeting the GLP-1 hormone is actually not necessary to achieve effective weight loss.

A group of researchers led by Richard DiMarchi and Matthias Tschöp has created an experimental drug that activates receptors of the GIP and glucagon hormones. They propose — based on rodent and monkey studies — that this kind of molecule, when administered at high enough doses, may result in weight loss comparable to the weight loss seen with drugs that include GLP-1 as a target, and without the tolerability issues like nausea and vomiting that often come with the approved treatments, according to a peer-reviewed draft paper published this week.

The research, funded by a biotech called BlueWater Biosciences, would still need to be confirmed in humans; oftentimes results seen in animals don’t translate in the clinic. But the proposed approach, outlined in the journal Molecular Metabolism by some of the most well-known scientists in the field, is likely to stir controversy, as it challenges a central notion underpinning not just the development of approved obesity products but also next-generation versions. 

Continue to STAT+ to read the full story…

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Pregnancy Sickness Study Identifies New Genetic Links

The University of Southern California (USC) research team that identified the hormone-encoding gene GDF15 as a key driver of pregnancy sickness has identified nine additional genes linked to its most severe form, hyperemesis gravidarum (HG). Six of the identified genes had not been previously linked to the condition.

The Keck School of Medicine of USC team and international collaborators conducted a genome-wide association study (GWAS), scanning the entire genome for differences between women who developed HG during pregnancy and those who did not. They analyzed data from more than 10,000 women with the condition and more than 450,000 controls across European, Asian, African, and Latino ancestries. Their findings offer new clues about the condition and new hope for those affected.

Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, led the present study and earlier research linking GDF15 to HG. Fejzo told GEN, “The study is much larger than previous studies and on a more diverse population allowing for identification of new genes associated with HG … The new genes give us new directions to explore for prediction, diagnosis, treatment, and response to therapies.”

Fejzo is first author of the team’s published report in Nature Genetics (“Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting”), in which the team stated, “Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.”

HG, which affects about 2% of women, causes nausea and vomiting so severe that eating can become extremely difficult. “Most pregnancies are affected by nausea and vomiting (NVP), but in 0.3–10.8% of pregnancies the symptoms can be severe enough to cause maternal weight loss and adverse maternal and fetal outcomes,” the authors wrote. HG in its most severe form can even be life threatening.

HG was long misunderstood and often dismissed as psychological, growing evidence shows that it has a strong biological and genetic basis and can lead to severe malnourishment, putting both mother and baby at risk. Current treatments for HG are frequently ineffective in improving patient symptoms, the authors further pointed out, and so increase the risk of pregnancy termination, postpartum depression, and suicidal ideation, along with other maternal and offspring comorbidities. “Therefore, understanding of HG etiology is critical to begin to address the negative impact severe NVP has on maternal and child health.”

While historical hypotheses have previously centered around human chorionic gonadotropin (hCG), recent large-scale genetic studies have implicated the GDF15 gene encoding growth differentiation factor-15—a hormone associated with nausea and vomiting, the authors further pointed out. Earlier research by Fejzo and an international team had shown that the link between HG and GDF15 lies in women’s sensitivity to the hormone. They found that women exposed to lower levels of the hormone before pregnancy because of a mutation in the gene experience more severe symptoms, while women exposed to higher levels of the hormone before pregnancy have less severe nausea and vomiting symptoms.

“GDF15 was identified as the greatest genetic risk factor for HG in both a genome-wide and an exome-wide association study, and a rare mutation in GDF15 was associated with a greater than tenfold increased risk for HG,” the scientists noted in their newly reported study. Fejzo explained to GEN, “The mutation in GDF15 is rare. People who carry the mutation have abnormally low levels of GDF15 when they are not pregnant and that increases their risk of being hypersensitive to it during pregnancy when it is produced in massive amounts by the placenta.”

Commenting on their prior work implicating a role for GDF15 and HG, Fejzo further explained to GEN, “In our first GWAS study we found the association between the GDF15 gene and HG. Next, we published a whole-exome sequencing study that identified a mutation in GDF15 associated with HG. Then we published our study in Nature which provided strong evidence that hypersensitivity to the rise of GDF15 in pregnancy (due to low pre-pregnancy GDF15 in circulation) is the main driver of the condition.”

For their newly reported study the researchers carried out a multi-ancestry genome-wide association study of 10,974 HG/excessive vomiting in pregnancy cases and 461,461 controls across European, Asian, African, and Latino ancestries from nine contributing studies.

The results identified 10 genes that were linked to HG, including four that had previously been identified, and six new genes. “Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” said Fejzo. “The fact that we’ve studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population.”

The four genes previously identified were growth differentiation factor 15 (GDF15), GFRAL, which produces the receptor for the GDF15 hormone of the same name, and IGFBP7 and PGR, both of which are involved in development of the placenta. The strongest link by far was to GDF15, which rises sharply during pregnancy. “We know that GDF15 and it’s receptor GFRAL are the main drivers and are in a signaling pathway that causes aversions, nausea, and vomiting,” Fejzo told GEN. “More work needs to be done to explore the other associations, but since studies suggest manipulating progesterone and/or IGFBP7 may not be safe in pregnancy, current studies are focusing on the GDF15 pathway.”

The six newly identified genes offer further clues that might help explain the basis of HG or point to new ways of treating it. They include FSHB, TCFL72 SLITRK1, SYN3, IGSF11, and CDH9. “Now that we’ve more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it,” Fejzo said. Speaking to GEN, the researchers noted, “Because the new associations are novel, we need to understand the roles they may play in normal pregnancy and then compare that to pregnancies affected by HG.”

Of the newly identified genes, TCF7L2 stands out because it is one of the strongest genetic risk factors for type 2 diabetes and is also associated with gestational diabetes. “This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo said. In further commentary to GEN, Fejzo added, “The TCF7L2 gene is a type 2 diabetes-associated gene and a transcription factor that may control glucagon-like peptide-1 (GLP-1) expression and has been associated with liraglutide effects resulting in greater weight loss in obesity. So understanding its role in that rapidly evolving therapeutic arena has potential.”

Several of the other genes identified are involved in appetite and nausea, as well as brain plasticity, or how the brain learns and adapts to new information. Fejzo suggests the brain may learn to associate certain foods with feeling sick, leading to strong, lasting aversions during pregnancy. More research is needed to explore this possibility. “Other genes are associated with learning flexibility so we hypothesize that they may play a role in conditioned taste aversion and may provide new targets to alter or dampen learned aversions,” Fejzo told GEN. Historically, people believed the pregnancy hormone hCG was the cause, but we found no evidence to support that and instead, fascinatingly, we found a link to the follicle stimulating hormone receptor.”

Of the ten candidate genes six—GDF15, GFRAL, IGFBP7, PGR, TCF7L2 and SYN3—have been linked with cachexia—a wasting condition with similar symptoms to HG, including loss of appetite, weight loss and muscle wasting, the scientists noted. “Manipulation of GDF15, GFRAL, IGFBP7, PGR and TCF7L2 in animal models has shown effectiveness in reducing symptoms of cachexia. Thus, assuming analogous functions for these factors in HG, there is both genetic and biological support for causal and potentially reversible contributions for these genes in NVP.”

The researchers also found that some genes linked to HG were associated with other pregnancy outcomes. “This study also identified individual associations between risk genes and adverse outcomes including shorter pregnancy duration, pre-eclampsia, and birth weight,” they noted.

Several medications are available for treating HG, but even the most effective, Zofran, only partly relieves symptoms for about half of patients. The new findings reveal new potential treatment targets and could possibly also help match existing medications to patients based on their genetic profiles. “The ten genetic associations provide intriguing avenues to advance our understanding and pursue therapeutic pathways for a common pregnancy condition that in its most severe form is associated with substantial morbidity and even mortality for mothers and exposed offspring,” the scientists concluded.

Fejzo and her team just received approval to launch a clinical trial of metformin, a widely used diabetes medicine that increases GDF15 levels. The study will test whether taking metformin before pregnancy can desensitize women to the hormone, potentially reducing nausea and vomiting or preventing HG in women who have had it before. GEN was told, “We will be initiating a clinical trial to increase GDF15 prior to pregnancy in patients with a history of HG and planning to conceive to desensitize them to the hormone’s rapid rise in early pregnancy. We and others have shown preliminary evidence that this approach may work as in our retrospective study pre-pregnancy metformin use was associated with a significant reduction in HG risk.”

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DNA Tests to Predict GLP-1 Drug Response to Launch in 2026

PrecisionLife and Ovation.io have signed a commercialization agreement to bring GLP-1 response genetic tests to the market. Today, the partners announced plans to launch both direct-to-consumer and laboratory developed tests later this year. 

The companies had entered a collaboration at the end of last year, leveraging Ovation’s multi-omics and longitudinal clinical data and PrecisionLife’s advanced analytics platform to uncover genetic mechanisms of response to GLP-1 medication. Earlier this year, they reported the identification of a series of biomarker signatures that can quantitatively predict which patients are most likely to respond to GLP-1 therapies and sustain that response over time. 

The partners are now actively working on translating this discovery into noninvasive genetic tests for patients to make informed decisions about the likely risks and benefits of these increasingly popular drugs, as well as for drug developers to stratify patients in clinical trials.

“Our teams have generated the world’s most detailed insights into why patients respond differently to these medicines,” said Steve Gardner, chief executive officer of PrecisionLife. “We will make these insights clinically actionable via noninvasive DNA tests supported by our results reporting platform and CLIA lab partners.”

PrecisionLife stressed that their findings go beyond the GLP-1 genetic predictors reported last week by 23andMe. “While that study highlighted a handful of variants associated with modest differences in outcomes, this work identifies combinatorial biomarker signatures that stratify patients and quantitatively predict response—and is already being translated into tests designed for use in real treatment decisions,” a company representative told Inside Precision Medicine. 

Over the course of the next six months, PrecisionLife will reproduce, refine, and validate their findings using additional datasets provided by Ovation, including studies to confirm the predicted response to GLP-1 drugs including semaglutide and tirzepatide in a real-world context. 

The launch of a consumer DNA test is expected to enable patients to understand their individual safety, efficacy, and tolerability profile for GLP-1 drugs before starting treatment. This could also offer providers a clearer basis for selecting therapies and help payors make more sustainable coverage decisions. The collaborators have stated they will evaluate the opportunity of using these tests to inform reimbursement decisions and expand coverage of certain health plans based on an individual’s predicted response. 

For drug developers, laboratory developed tests (LDT) could open up opportunities for more precise patient stratification, improving the probability of success in clinical trials evaluating the expansion of GLP-1 drugs into new indications. The companies are currently in discussions with various stakeholders and sponsors to deploy the LDTs as stratification tools in a clinical setting. 

“We’re confident that together we can translate those insights into commercial outcomes and products in GLP-1s and other diseases with huge clinical impact,” said Curt Medeiros, chief executive officer of Ovation.io. 

Going forward, the partners will continue to validate their findings and expand the scope of the studies, including identifying additional markers of safety and tolerability to GLP-1 drugs as well as pinpointing further efficacy and safety signals for individual molecules. 

The post DNA Tests to Predict GLP-1 Drug Response to Launch in 2026 appeared first on Inside Precision Medicine.

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Syncing Exercise to Body Clock Maximizes Cardiovascular Benefits

Timing exercise according to a person’s natural propensity towards being a “morning lark” or an “night owl” could maximize its cardiovascular benefits, a randomized trial suggests.

Matching exercise according to individual body clocks maximized the sleep quality and several parameters of cardiovascular health of middle-aged adults with preclinical risk factors.

The findings highlight the added value of incorporating circadian biology into exercise plans to optimize health outcomes.

Reporting their findings in Open Heart, the researchers suggest that assessing for chronotype—the predisposition towards morningness or eveningness—should be considered when prescribing exercise for those at risk of cardiometabolic disease.

“Our study shows that when you exercise may be just as important as how you exercise,” researcher Arsalan Tariq, PhD, from the University of Lahore, explained to Inside Precision Medicine.

“Aligning workouts with an individual’s biological clock significantly amplifies cardiovascular and metabolic benefits, offering a simple way to personalize prevention and improve adherence.”

A person’s chronotype affects their sleeping patterns, hormonal secretion, and energy levels during the day through an internal timing mechanism.

This is regulated by the circadian clock in a system that influences various physiological processes including blood pressure, heart rate, glucose metabolism, and vascular function.

Tariq and team examined how timing exercise affected key indicators of cardiovascular health among at-risk middle-aged adults.

Participants were aged 40 to 60 years and had at least one cardiovascular risk factor, such as high blood pressure, overweight, or obesity. The group also included those with a family history of premature cardiovascular disease.

Participants were randomly assigned to exercise at a time that either matched or did not match their chronotype, between 8am and 11am or between 6pm and 9pm.

This consisted of five, 40-minute sessions per week of supervised moderate intensity aerobic exercise such as brisk or treadmill walking for 12 weeks.

Of the 134 participants who completed the 60 sessions, 70 were larks—34 of whom had exercise matched with chronotype—and 64 were owls, with 30 matched to chronotype.

Measurements taken at the start of the trial and three days after it finished showed particular improvements in sleep and systolic blood pressure among those matched with chronotype.

Sleep quality improved by 3.4 points in matched participants versus 1.2 in the unmatched on the Pittsburgh Sleep quality Index. Systolic blood pressure dropped by 10.8 mmHg compared with 5.5mmHg in matched versus unmatched groups, respectively.

Chronotype-aligned exercise also led to significantly greater improvements in diastolic blood pressure, heart rate variability, peak oxygen consumption, low-density lipoprotein, and fasting glucose compared with misaligned exercise.

“Personalized, time-matched exercise interventions may become a practical strategy in clinical and public health settings, potentially leading to better outcomes and improved engagement,” the researchers reported.

“Future research and guidelines may consider circadian factors as a core component of lifestyle-based disease prevention.”

The post Syncing Exercise to Body Clock Maximizes Cardiovascular Benefits appeared first on Inside Precision Medicine.