Tag: Appetite and ingestive regulation

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StockWatch: Trump Order Lifts Psychedelic Drug Shares

Stocks of most publicly traded psychedelic drug developers jumped when President Donald Trump signed Executive Order 14401, directing the FDA and other federal agencies to accelerate research and improve access to psychedelic drugs, citing their potential as promising treatments for serious mental illnesses.

Among its provisions, the order directs the FDA to provide Commissioner’s National Priority Vouchers (CNPVs) to “appropriate” psychedelic drugs that were granted the agency’s Breakthrough Therapy designation and met the voucher program’s criteria. The FDA’s parent agency, the Department of Health and Human Services (HHS), is required to spend at least $50 million through the Advanced Research Projects Agency for Health (ARPA-H) “to support and partner with” state governments that have enacted or are developing programs to advance psychedelic drugs for serious mental illnesses.

“This is an unmet public health need and potentially promising treatments. That’s why there’s a sense of urgency around this, and why we’re doing it now,” FDA Commissioner Martin A. Makary, MD, said at the ceremony where Trump signed the order. “Applications are about to come in, and this is the perfect timing for this announcement.”

At least one analyst agreed that the timing was right for Washington to spur the development of psychedelic drugs.

“Investor mindshare should rise meaningfully ahead of pot’l approvals in 2027–30,” Andrew Tsai, equity analyst with Jefferies, observed in a research note. “As we approach the first pot’l FDA approval of a psychedelic in 2027, President Trump is providing an official stamp of validation to the class in the form of an executive order, reassuring us that the FDA/HHS/White House’s support of psychedelics is real/actionable (not rhetorical).”

Proving correct

Makary said the FDA planned to issue CNPVs to three serotonin 2a agonists, a class that includes LSD and other psychedelic drugs. While he did not reveal specific companies and drugs by name, market watchers immediately speculated that one of the drugs was COMP360 synthetic psilocybin, the lead clinical candidate of Compass Pathways (NASDAQ: CMPS)—speculation that proved correct when COMP360 won a CNPV on Friday.

COMP360 is expected, according to Tsai, to be the first psychedelic drug to win FDA approval in 2027. In February, Compass announced what it called statistically significant and clinically meaningful data from two Phase III trials assessing COMP360 in treatment-resistant depression (TRD), COMP005 (NCT05624268) and COMP006 (NCT05711940). The data showed positive effects for COMP360 within one day, lasting at least through six months after just one or two doses among those who have a clinically meaningful response.

COMP360 is also in Phase II trials for both PTSD and anorexia nervosa.

Compass fueled speculation about an FDA voucher approval by issuing a statement supporting the executive order: “Today’s announcement aligns regulatory urgency with patient need, and we applaud the Administration for taking this important step forward in accelerating access, without compromising rigorous science.”

Investors celebrated with Compass, whose shares soared 42% from $6.66 to $9.46 on April 20, the first trading day after the order signing. Shares yo-yoed the rest of the week, sliding 7.5% to $8.75 Wednesday before rebounding nearly 5% to $9.15 Thursday and rising another roughly 5% to $9.58 Friday on news of the voucher approval. Year-over-year, Compass shares have more than doubled, soaring about 140% from $5.22 on April 24, 2025.

FDA names additional voucher grantees

The FDA indeed issued three CNPVs on Friday—one to Compass as previously mentioned, one to Usona Institute, a nonprofit medical research organization, for psilocybin for major depressive disorder (MDD), and one to Otsuka Pharmaceutical (Tokyo Stock Exchange: 4578) for methylone (TSND-201) for post-traumatic stress disorder (PTSD). Otsuka is acquiring the methylone program as part of its up-to-$1.225 billion ($700 million upfront) purchase of privately held Transcend Therapeutics, announced last month.

Launched in October by Makary, CNPVs are awarded 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. 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.

“Ultimately, we do not see the FDA’s issuance of the first set of CNPVs as precluding other psychedelic players from also obtaining CNPVs in the future—so we think the FDA’s action today bodes well for the space broadly,” Tsai wrote after the FDA announced the voucher recipients. “Net-net, the macro backdrop for psychedelics is improving.”

That improvement, Tsai added, reflects Trump’s endorsement of psychedelic drugs, a collaborative FDA, and growing interest in the space by big pharma giants such as Johnson & Johnson (NYSE: JNJ), which generated $1.696 billion in 2025 sales and $468 million in first quarter sales from Spravato (esketamine), an NMDA receptor antagonist indicated for treatment-resistent depression (TRD) and depressive symptoms in adults with MDD with acute suicidal ideation or behavior in conjunction with an oral antidepressant.

The voucher decision hardly budged Otsuka shares, which dipped nearly 1% Friday from ¥10,870 ($68.18) to ¥10,810 ($67.80).

However, Compass was one of several psychedelic drug companies to see their shares surge on news of the executive order.

AtaiBeckley (NASDAQ: ATAI), formed last November by the merger of atai Life Sciences and Beckley Psytech, jumped 22% from $4.03 to $4.90 on April 20, then plateaued the rest of the week, finishing Friday at $4.63 and a 15% one-week gain. AtaiBeckley shares year-over-year have more than tripled, rocketing 204% from $1.53 a year ago Friday.

Definium Therapeutics (NASDAQ: DFTX) shares rose 5% over two days, from $22.68 the Friday before Trump signed the order to $23.84 on Tuesday, but gave back all the week’s gain, finishing Friday at $22.48. Long-range investors have fared better, as Definium shares have more than tripled, zooming 249% from $6.43 on April 24, 2025.

GH Research (NASDAQ: GHRS) shares climbed 17% from $18.34 to $21.50 the first day after the executive order, only to drop 6% the rest of the week, closing Friday at $20.25 and settling for a 10% one-week gain. GH’s shares doubled year-over-year, growing 101% from $9.50 a year ago Friday.

Showing volatility

The executive order wasn’t enough to boost shares of Cybin, which operates under the name Helus Pharma (NASDAQ: HELP). Helus showed the most volatility in the days following the order signing, tumbling 12% from $5.61 to $4.93 on April 20. The drop followed Helus’ announcement that its CEO, Michael Cola, stepped down immediately at the request of its board, succeeded by interim CEO Eric So, while the board carries out a search for a permanent chief executive.

“It’s like they can’t give investors a break,” fumed “SamZaki320” on a Reddit chat board. “The only positive is that the executive order sentiment is pushing back against a total disaster. Not that it’s a good thing, other companies are up double digits.”

Helus shares bounced back 17% to $5.77 Wednesday and dipping 0.35% to $5.75 Thursday despite the company announcing two powerhouse additions to its scientific advisory board—Robert Langer, ScD, the David H. Koch Institute professor at MIT and a co-founder of Moderna (NASDAQ: MRNA); and Stephen Brannan, MD, a neuroscience drug development expert with over 20 years of experience designing and implementing clinical programs for psychiatric and neurological disorders. Shares fell 2% Friday, closing at $5.61.

In a statement, interim CEO So lauded Trump’s order: “The Executive Order reflects growing recognition of the urgent need for new treatment options in serious mental health conditions and the importance of advancing innovative therapies through rigorous, research-based development.”

Looking beyond Washington

Yet So acknowledged that Washington alone can’t advance psych drug development beyond what its science can accomplish: “Policy momentum is meaningful, but the future of this field will ultimately be determined by the strength of the clinical evidence and the ability to deliver safe, reliable treatments at scale.”

As did Helus and Compass, Definium also praised the executive order: “We applaud the Administration’s recognition that psychedelic medicines may represent meaningful new treatment options for patients,” Definium CEO Rob Barrow stated. He cited his company’s clinical development program for DT120 (lysergide tartrate) for conditions that include generalized anxiety disorder (GAD) and MDD.

At the ceremony where he signed the executive order, Trump acknowledged being asked to address psych drug development by podcaster Joe Rogan and others, which the president said led to talks with Makary as well as HHS Secretary Robert F. Kennedy Jr., NIH Director Jay Bhattacharya, MD, PhD, and Mehmet Oz, MD, administrator for the Centers for Medicare & Medicaid Services.

“Research has been going on for quite some time. But usually with things like this, nothing ever happens, no matter how the research ends up. We’re changing that,” Trump said. “Why would we wait three or four years to get it done? Or 10 years? Frankly, let’s get it done immediately—and that’s what happened.”

Leaders and laggards

  • Daiichi Sankyo (Tokyo Stock Exchange: 4568) shares slipped 10% from ¥2,790 ($17.50) to ¥2,499 ($15.67) on Friday after the drug developer announced it was delaying the release of its annual earnings results for the fiscal year that ended March 31, from April 27 to May 11,  “as additional time is required to finalize the financial figures.” May 11 is the day when Daiichi Sankyo plans to release its five-year business plan. “The company is currently reviewing the supply plans for its oncology products portfolio and development pipeline in light of rapidly changing business conditions. As a result, additional deliberation is required to reasonably estimate the amount of loss provisions to be recorded in connection with contracts with contract manufacturers,” Daiichi Sankyo added in a statement.
  • Inhibrx Biosciences (NASDAQ: INBX) shares leaped 37% from $84.08 to $115.09 Wednesday after Reuters reported, citing unnamed sources, that Merck & Co. (NYSE: MRK), Merck KGaA (XETRA: MRK), and Ono Pharmaceutical (Tokyo Stock Exchange: 4528) were in talks with Inhibrx for a joint spinoff of two precision-engineered cancer candidates, INBRX-106 and ozekibart (INBRX-109). The treatments could have a combined value of more than $9 billion if their clinical trials prove successful, the report stated. Inhibrx declined to comment, while the other companies cited did not respond to Reuters queries. INBRX-106 is a hexavalent sdAb-based, OX40-targeting candidate being studied as monotherapy and in combination with Merck & Co.’s cancer immunotherapy blockbuster Keytruda® (pembrolizumab). Ozekibart is a tetravalent death receptor 5 (DR5) agonist antibody designed to exploit the tumor-biased cell death induced by DR5 activation. On Tuesday, Inhibrx announced ozekibart showed positive data in a Phase I/II trial (NCT03715933) assessing the drug plus Folfiri in patients with locally advanced or metastatic, unresectable colorectal cancer.
  • Organon (NYSE: OGN) shares surged 31% from $8.60 to $11.26 Friday after the Indian news outlet The Economic Times reported that Sun Pharmaceutical Industries (NSE: SUNPHARMA and BSE: 524715) had submitted a $13 billion offer for the women’s health drug developer spun out of Merck & Co. (NYSE: MRK) in 2021. The deal would be Sun’s largest ever merger-and-acquisition (M&A) deal—if Sun can prevail over at least two other would-be suitors for Organon, German-based private family-owned drug developer Grünenthal, and EQT (Nasdaq Stockholm: EQT), a Swedish-based global investment organization. The latest surge comes two weeks after Organo shares zoomed 28% on an April 10 Economic Times report stating that Sun Pharma had submitted a $12 billion all-cash offer for Organon.
  • Spruce Biosciences (NASDAQ: SPRB) shares tumbled 26% from $69.89 to $51.69 Tuesday after the neurological disorder drug developer priced a $69 million offering of common stock and pre-funded warrants that generated $64.4 million in net proceeds. The offering consisted of 1.15 million shares of common stock priced at $50 per share and pre-funded warrants to purchase 50,000 shares at $49.99 per share. Al shares and pre-funded warrants were sold, and underwriters of the offering exercised in full their option to purchase up to an additional 180,000 shares at the public offering price on Tuesday. “We intend to use the net proceeds from this offering to advance the company’s pre-commercial and launch activities, for planned clinical trials, and for working capital, capital expenditures, and other general corporate purposes,” Spruce stated in its prospectus supplement filed Tuesday. Leerink Partners, Guggenheim Securities, and Oppenheimer & Co. acted as joint book-running managers, while Jones and Craig-Hallum acted as co-managers for the offering.

The post StockWatch: Trump Order Lifts Psychedelic Drug Shares appeared first on GEN – Genetic Engineering and Biotechnology News.

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New Low-Toxicity Transplant Method Reverses Type 1 Diabetes in Mice

Researchers at Stanford Medicine say they have developed a combination treatment method that cured or prevented type 1 diabetes in mouse models by pairing blood stem cell transplantation with pancreatic islet cell transplantation under a substantially reduced preconditioning regimen. The approach creates a mixed immune system from both donor and recipient cells, which stopped autoimmune destruction of insulin-producing cells while also producing long-term tolerance to the transplanted tissue. The findings, published in the Journal of Clinical Investigation Insight, show that reversing type 1 diabetes can be accomplished without chronic immunosuppression or the toxic conditioning via radiation or chemotherapy currently used for hematopoietic stem cell (HCT) transplantation.

“The possibility of translating these findings into humans is very exciting,” said senior author Seung K. Kim, MD, PhD, a professor of developmental biology at Stanford. “The key steps in our study—which result in animals with a hybrid immune system containing cells from both the donor and the recipient—are already being used in the clinic for other conditions. We believe this approach will be transformative for people with type 1 diabetes or other autoimmune diseases, as well as for those who need solid organ transplants.”

Type 1 diabetes is an autoimmune disease that attacks pancreatic islet cells. While islet transplantation can restore insulin production, it typically requires immunosuppressive drugs that carry risks including infection, malignancy, and organ damage. The Stanford team’s approach reduced these negative effects by inducing immune tolerance through mixed hematopoietic chimerism, a state in which donor and recipient immune cells coexist.

“Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues,” the researchers wrote. “However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance.”

The current findings by the Stanford team builds on a series of research initiatives beginning with work published in 2022, in which the researchers showed they could cure toxin-induced diabetes in mouse models using antibody-based immune conditioning combined with moderate radiation (200–300 cGy), followed by transplantation of donor-matched blood stem cells and islets. This study served as a proof of concept but used radiation at levels that are potentially toxic.

A November study published in JCI, along with the new research addressed two significant challenges for developing an effective transplantation protocol: autoimmune diabetes, in which the immune system targets islet cells, and the need to reduce conditioning toxicity. In the November study, the researchers added an immune-modulating drug used in autoimmune disease to their regimen. This change enabled the formation of a hybrid immune system that both accepted donor islets and prevented autoimmune attack. All treated mice were protected from developing diabetes, and those with already possessing the disease were cured.

To further reduce toxicity, the April study added additional agents, baricitinib, venetoclax, and an αCD47 antibody, to go with αCD117 antibody and transient T cell depletion. These agents were selected because they target distinct biological pathways involved in immune regulation and bone marrow niche clearance. Baricitinib, a JAK1/2 inhibitor, reduces inflammatory signaling and supports donor cell engraftment. Venetoclax promotes apoptosis of specific immune cells, and αCD47 disrupts a signaling pathway that normally protects cells from clearance, which helped in the removal of host stem cells to make space for donor cells.

“We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and αCD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT,” the researchers wrote. “Combined with αCD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of [graft-versus-host disease].”

This new combination allowed researchers to reduce radiation exposure to 10 cGy, a fraction of the levels used in conventional bone marrow transplantation. Mice treated using this regimen showed stable engraftment of donor cells, maintained fertility, and experienced no graft-versus-host disease. They also remained insulin-independent for the duration of the study.

The findings provide a potential pathway toward clinical adoption, which could be speedier than usual since many of the agents used for this approach are already approved or under evaluation in humans.

Work at Stanford will continue in this area and will focus on testing the reduced-intensity regimen in autoimmune diabetes models, refining conditioning strategies, and exploring alternative sources of islet cells, including those derived from stem cells.

If successfully, translated to the clinic, this treatment regimen could reduce or eliminate the need for lifelong insulin therapy, while expanding the use of transplantation-based therapies across a wider set of patients.

The post New Low-Toxicity Transplant Method Reverses Type 1 Diabetes in Mice appeared first on Inside Precision Medicine.

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Epigenetic Mapping in Pancreatic Cells Identifies New Diabetes Target

Researchers at Lund University in Sweden have conducted the first study looking at epigenetic changes associated with type 2 diabetes in alpha and beta pancreatic cells. Published today in Nature Metabolism, their findings show that the ONECUT2 gene plays a key role in the development of type 2 diabetes by altering insulin production. 

“The study shows that many genes central to insulin and glucagon production are regulated by differences in DNA methylation,” says Charlotte Ling, PhD, professor of epigenetics at Lund University and lead author of the study. “It has made it possible, for the first time, to describe detailed, cell-specific epigenetic patterns.”

The number of people living with diabetes is rapidly increasing worldwide, with approximately 95% of cases attributed to type 2 diabetes. This condition develops gradually and is characterized by a reduced ability to use insulin effectively, leading to elevated blood sugar levels. Over time, high blood sugar can lead to a range of complications that significantly impact the patient’s quality of life. 

Lifestyle factors like diet and physical activity are major drivers of this condition; however, genetics can also contribute to the development of type 2 diabetes, increasing the risk for some people over others. While genome- and epigenome-wide studies on diabetes have identified genetic and epigenetic mechanisms involved in type 2 diabetes, previous epigenetics studies had only looked at whole tissues and none had investigated epigenetic changes within specific cell types that are involved in blood sugar regulation. 

Ling’s team focused on alpha and beta pancreatic cells, which secrete insulin and glucagon hormones, respectively, to regulate blood sugar levels. By analyzing hundreds of thousands of cells from 24 people, with and without diabetes, the researchers created the most detailed epigenetics mapping of pancreatic cells to date. This allowed them to discover over 22,000 regions in nearly 8,000 genes that were differentially methylated between alpha and beta cells. 

“Here, for the first time, we show exactly which regions regulate insulin and glucagon production through DNA methylation, which gives us the opportunity to develop future treatments based on epigenetics,” says Ling.    

They then used CRISPR epigenetic editing to alter DNA methylation around the genes encoding for insulin and glucagon, which revealed that levels of the ONECUT2 transcription factor were elevated in beta cells from type 2 diabetes patients. This epigenetic upregulation was found to impair the ability of beta cells to release insulin, which in turn disrupted glucose regulation and reduced energy production within the cell.

Based on their findings, the researchers developed a web tool intended as a comprehensive resource available to researchers investigating the impact of age, sex, and type 2 diabetes on DNA methylation and gene expression in alpha and beta cells. 

“We now want to understand which of these changes can actually be reversed, and whether this can help beta cells regain their function in diabetes,” says Ling. “A key aspect is to see whether the effects of editing DNA methylation can be sustained in the cell over time.” 

The post Epigenetic Mapping in Pancreatic Cells Identifies New Diabetes Target appeared first on Inside Precision Medicine.

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<![CDATA[Explore GLP-1 agonists and their “truly transformative” role in psychiatry in this podcast. ]]>
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From the discovery of GLP-1 to today’s diabetes/obesity therapy and beyond

Glucagon-like peptide-1 was discovered as an insulinotropic peptide from the gut during a search for candidates for the incretin effect. It turned out to also inhibit glucagon secretion and is now considered an important regulator of glucose metabolism. In further investigations of its physiological effects, it also inhibited gastrointestinal secretion and motility and inhibited appetite and food intake. Because of these effects, it was eventually demonstrated to be able to improve glucose control and beta cell function in T2DM patients and was even associated with weight loss.

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Medical Students and Clinicians’ Perceptions of Social Media Direct-to-Consumer Advertising and Medication Requests

This study examines how medical students and clinicians report experiencing patient medication requests associated with prescription drug direct-to-consumer advertising on social media; survey data from 98 respondents indicate that those providing both in-person and virtual care encounter more frequent requests for medications advertised online, particularly branded glucagon-like peptide-1 (GLP-1) weight loss drugs.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/bbfc17dfe52bad6c4dfff581bd0c8095" />

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Vitamin D Linked to Lower Diabetes Risk in People with VDR Gene Variant

A genetic analysis of a large U.S. clinical trial suggests that vitamin D supplementation may reduce the risk of progression from prediabetes to type 2 diabetes, but only for those people who harbor specific variants of the vitamin D receptor gene. The study, led by researchers at Tufts University and published in JAMA Network Open, found that daily high-dose vitamin D lowered diabetes risk by 19% in participants with certain genotypes, opening the possibility of using vitamin D as a diabetes prevention strategy.

The new findings build on data from the Vitamin D and Type 2 Diabetes (D2d) clinical trial, a multi-site randomized study that enrolled more than 2,000 U.S. adults with prediabetes. Study participants were assigned to receive either 4,000 IU of vitamin D3 daily or a placebo. The subjects were then followed for a median of 2.5 years to assess progression to diabetes. The original trial did not show a statistically significant reduction in diabetes risk across all participants.

“But the D2d results raised an important question: Could vitamin D still benefit some people?” said lead author Bess Dawson-Hughes, MD, a senior scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “Diabetes has so many serious complications that develop slowly over years. If we can delay the time period that an individual will spend living with diabetes, we can stop some of those harmful side effects or lessen their severity.”

In their follow-on research, the Tufts noted that subsequent analysis of the D2d trial data showed that outcomes varied based on achieved blood levels of vitamin D in participants. The new study also found a genetic link to those who had improved outcomes.

To explore the role genetics might play, the investigators conducted a post hoc analysis of 2,098 D2d participants who consented to genetic testing. They focused on three common polymorphisms in the vitamin D receptor (VDR) gene: ApaI, BsmI, and FokI. The researchers first examined how vitamin D levels correlated with diabetes risk across genotypes, then evaluated how genetic variants influenced response to supplementation.

The data showed that the ApaI polymorphism is a key determinant of response. Participants with the AA genotype, which was about 30% of the cohort, did not experience a reduction in diabetes risk with vitamin D supplementation. By comparison, those with the AC or CC genotypes, the remaining 70% of participants, showed a 19% lower risk of developing diabetes when treated with vitamin D compared with placebo.

The biological basis for this effect is linked to the role the VDR gene plays in pancreatic β cells, where it influences insulin secretion and glucose regulation. Variations in the receptor may alter how effectively vitamin D exerts these effects, explaining why some individuals benefit from supplementation while others do not.

Earlier research has suggested there is a connection between vitamin D and diabetes risk. In earlier analyses of the D2d trial, participants who maintained higher blood levels of vitamin D experienced substantial reductions in diabetes incidence. These findings were supported by meta-analyses and observational studies, including research from the UK Biobank, which found that genetic variation in VDR could modify its activity.

“We hypothesized that VDR gene variants modify the association between achieved intratrial 25-hydroxyvitamin D (25(OH)D) level and diabetes risk and may modify the effect of vitamin D3 supplementation on the risk of developing diabetes,” the researchers wrote. 25(OH)D is the main form of vitamin D circulating in the blood.

The current study broadens knowledge on the role vitamin D can play in diabetes prevention by identifying the specific polymorphisms at play. The overlap between ApaI and BsmI variants provides further evidence of the role of VDR genetics, although the researchers noted that ApaI alone may be sufficient to identify likely responders.

“This genetic association analysis of the D2d study suggests that genetic variation in the VDR, specifically the ApaI polymorphism, is associated with diabetes risk at higher intratrial 25(OH)D levels and is associated with response to 4000 IU/d of vitamin D3 supplementation among adults with prediabetes,” the researchers wrote.

The implications for clinical care include the potential use of genetic testing to guide preventive treatment. A single test for the ApaI polymorphism could help identify patients with prediabetes who are most likely to benefit from higher-dose vitamin D supplementation.

While the results have established a link between variations in the VDR gene and diabetes development, the research noted that the study was not designed to assess the mechanisms underlying the genetic effects. Further, its sample size limited subgroup analyses by race and ethnicity.

“Our findings suggest we may eventually be able to identify which patients with prediabetes are most likely to benefit from additional vitamin D supplementation,” Dawson-Hughes said. “In principle, this could involve a single, relatively inexpensive genetic test.”

Next steps in this line of research include replicating the findings in independent cohorts and conducting prospective trials designed to test genotype-guided supplementation strategies.

The post Vitamin D Linked to Lower Diabetes Risk in People with <i>VDR</i> Gene Variant appeared first on Inside Precision Medicine.

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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.

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