Silence RNA Heart Agent Clears First Major Hurdle, Hammering Lp(a)

 The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.

Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45 to 60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.

Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-mg and 600-mg doses.

In addition, for participants receiving the two highest doses, ApoB was reduced was 21% and 24%, respectively, and low-density-lipoprotein cholesterol (LDL-C), by 21% and 26%, respectively.

"The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted," said principal investigator Steven E. Nissen, MD, Cleveland Clinic, Ohio.

The results were presented in a late-breaking clinical trial session at the American College of Cardiology (ACC) 2022 Scientific Session and published simultaneously in the Journal of the American Medical Association.

Elevated Lp(a) is a powerful genetic risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).

SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.

Testing Vacuum

Nissen told theheart.org | Medscape Cardiology that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.

"Someone comes in with an MI in their forties and we measure it and it's 100, 150 (mg/dL), clearly abnormal, and often these patients don't have a lot of other risk factors," Nissen said. "So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it."

During a media briefing, ACC.22 program co-chair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won't be reimbursed because they don't understand it.

"What Dr. Nissen is telling you: it should be measured in everyone at least once, we all believe that, but it hasn't made it into the major guidelines," she added. "I think what we're going to have to do is have the guidelines mandate it and the insurers will follow."

Guidelines currently list elevated Lp(a) as a "risk enhancing factor," which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Nissen. "But we need to go beyond that."

Safety Analyses

The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean ApoB level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.

Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).

At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. Alanine aminotransferase and aspartate aminotransferase levels were elevated three times above the upper limit of normal in one patient at the lowest dose.

One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.

Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.

Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.

But Will It Reduce ASCVD Events?

Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a "holy grail" for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.

She asked Nissen about the observation in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.

Nissen said this kind of analysis wasn't possible because of the small sample size but "because these agents so effectively degrade messenger RNA, it's very likely we will see robust suppression of plasma levels virtually regardless of the baseline level."

Bittner also questioned if "LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?"

"It's a really terrific question that will ultimately need to be answered," Nissen replied. "There's some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that's in lipoprotein(a) and the LDL that is not…. I think it's probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it."

Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. "I don't see it as a long-term limitation."

In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge, United Kingdom, suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it's unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10% to 15%.

He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-L_Rx and has Nissen pulling double duty as study chair.

The study was funded by Silence Therapeutics. Nissen reports consulting for many pharmaceutical companies, but companies are directed to pay any honoraria and speaking or consulting fees directly to charity. He also reports involvement in clinical trials for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, Novartis, Silence Therapeutics, and Pfizer.  Douglas reports research/research grants from Gilead Sciences, Heartflow, Kowa, and Viiv. Bittner reports consultant fees or honoraria from  Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi Aventis; and research/research grants from Amgen and Novartis.  Ference reported receiving research grants from Merck, Novartis, Amgen, Pfizer, and Esperion Therapeutics and receiving personal fees for consulting, advisory, board participation, and lectures from Novartis, Amgen, Regeneron, Sanofi, Merck, Pfizer, Lilly, Novo Nordisk, AstraZeneca, Viatris, The Medicines Company, Mylan, Daiichi Sankyo, DalCor, CiVi Biopharma, Krka Pharmaceuticals, ACC, the European Society of Cardiology, and the European Atherosclerosis Society.

American College of Cardiology (ACC) 2022 Scientific Session. Presented April 3, 2022.

JAMA. Published online April 3, 2022. Full text, Editorial

https://www.medscape.com/viewarticle/971491

Lower dose of insulin-sensitizing drug benefits patients with Type 2 diabetes

 An insulin-sensitizing drug can benefit patients with insulin resistance at lower doses than has typically been prescribed, according to a study co-authored by Paresh Dandona, MD, Ph.D., SUNY Distinguished Professor of Medicine in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

The study, titled "Efficacy of Lower Doses of Pioglitazone After Stroke or Transient Ischemic Attack in Patients With Insulin Resistance," was published March 6 in the journal Diabetes, Obesity and Metabolism.

The study shows that low doses of pioglitazone used to treat diabetes in patients with insulin resistance may be preferable. In this study, patients had a history of previous stroke or transient ischemic attack (TIA).

Pioglitazone is a potent insulin-sensitizing drug with anti-atherosclerotic properties, but adverse effects of weight gain and edema have limited its use.

The researchers assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in a secondary prevention trial who had a history of stroke.

Insulin resistance is a common condition that is closely related to older age, increasing weight and genetic predisposition. And it affects the majority of patients with Type 2 diabetes.

Insulin resistance is also an established independent risk factor for vascular disease, including stroke and myocardial infarction, and partly explains the association between diabetes and increased risk for these diseases. 

Dandona says pioglitazone is currently used to treat patients with Type 2 diabetes. The most recent American Heart Association/American Stroke Association guidelines on secondary stroke prevention list the drug as a Class 2B recommendation in patients with stroke who have insulin resistance and elevated glycated hemoglobin.

Dandona says this recommendation stems directly from the findings of the Insulin Resistance Intervention in Stroke (IRIS) trial.

"Unfortunately, many clinicians are reluctant to use pioglitazone because of adverse effects, particularly weight gain and edema, and the drug is seldom prescribed by neurologists in their stroke patients," he says.

Low doses provide cardiovascular protection

Dandona says he instigated the reanalysis of the IRIS study because he has been prescribing pioglitazone over the past decade at a low dose of 15 milligrams with excellent results of glycemic control without the side effects of weight gain and edema.

"When I looked at the previous analysis of the IRIS trial, it occurred to me that the low dose may be as effective as the high dose, but with fewer side effects," he says.

Dandona asked J. David Spence, MD, professor of neurology and clinical pharmacology at the Robarts Research Institute at the University of Western Ontario, the first author of the new paper, to further analyze the data to look at the lower doses.

Spence, who has focused his research on the prevention of stroke, then asked Dandona to join as a co-author.

The IRIS study demonstrated that pioglitazone not only reduced the cardiovascular complications, but also reduced the progression of prediabetes to diabetes, Dandona says.

"Since most of the patients in the study were treated with the high dose of 45 milligrams daily, which has frequent side effects of weight gain and edema, it was important to reanalyze the data to focus on the effects of the two lower doses (15 and 30 milligrams daily) of the drug, he says.

"The IRIS study reanalysis clearly demonstrates that while the two lower doses provide cardiovascular protection similar to that of the higher dose, the side effects of edema and weight gain are significantly lower.

"A more frequent use of this drug at lower doses in diabetes and prediabetes by physicians would contribute to significant improvements in glycemic control and cardiovascular complications," Dandona adds.

Benefits include improved diabetic control

Furthermore, since pioglitazone is a generic drug, it is inexpensive compared to insulin.

"Hence, pioglitazone must be used prior to insulin, especially since subcutaneously injected insulin has no protective effect on cardiovascular complications," Dandona says.

"The health benefits are an improvement in diabetic control, as well as a reduction in the incidence of myocardial infarction and stroke," he adds.

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Explore further

Greater benefit for pioglitazone in high-risk patients post stroke

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More information: J. David Spence et al, Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance, Diabetes, Obesity and Metabolism (2022). DOI: 10.1111/dom.14687

https://medicalxpress.com/news/2022-04-dose-insulin-sensitizing-drug-benefits-patients.html

A prune—or six—a day may keep inflammation at bay

 A study in postmenopausal women suggests eating nutrient-rich prunes every day may be beneficial to bone health, reducing inflammatory factors that contribute to osteoporosis. The research will be presented this week in Philadelphia at the American Physiological Society's (APS) annual meeting at Experimental Biology 2022.

An estimated 13.6 million people in the U.S. over the age of 50 will develop osteoporosis—a loss of bone strength caused by reduced mineral density of the bones—by the year 2030. Osteoporosis increases the risk of fracture, especially in older adults. People who experience menopause have lower levels of estrogen, which trigger an increase in inflammation in the body, which can also contribute to bone loss.

Previous research has shown that polyphenol extracts—plant compounds that act as antioxidants and reduce inflammation—in prunes promote lower levels of oxidative stress and inflammation in a type of bone cell called osteoclasts. In a new study, researchers from the Integrative and Biomedical Physiology Program and the Departments of Nutritional Sciences and Kinesiology at The Pennsylvania State University explored the effects of prunes on bone health after menopause.

Postmenopausal women with a bone mineral density score that was defined as low—a marker of osteoporosis—were divided into three groups:

• One group ate 50 grams (g) of prunes (about six prunes) daily for 12 months.
• A second group ate 100 g of prunes (about 12 prunes) daily for 12 months.
• A control group ate no prunes.

The research team looked at blood samples taken from all volunteers before and after the trial and found significant reductions in inflammatory markers in both of the prune-eating groups compared to the control group.

"Our findings suggest that consumption of six to 12 prunes per day may reduce pro-inflammatory mediators that may contribute to bone loss in postmenopausal women. Thus, prunes might be a promising nutritional intervention to prevent the rise in inflammatory mediators often observed as part of the aging process," said Janhavi Damani, MS, first author of the study.

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Explore further

Eating prunes may help protect against bone loss in older women

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More information: Abstract: "A randomized controlled trial of dietary supplementation with prunes (dried plums) on inflammatory markers in postmenopausal women" experimentalbiology.org/

https://medicalxpress.com/news/2022-04-pruneor-sixa-day-inflammation-bay.html

New York City Will Mandate Masks For Children Under 5 Years Old

 by Jack Phillips via The Epoch Times (emphasis ours),

New York City Mayor Eric Adams said that the city would mandate children aged 2 to 4 to continue wearing masks after a judge issued an order in favor of his administration.

“Every decision we make is with our children’s health and safety in mind. Children between 2 and 4 should continue to wear their masks in school and daycare come Monday,” the Democrat mayor said on Twitter on April 1.

It came after State Supreme Court Justice Ralph Porzio earlier that day struck down the city’s mask order for young children. However, an appellate court issued a stay in the lower court’s ruling, allowing the mask mandate to remain intact amid the appeals process.

Porzio stated that the mandate was “absurd” after it was lifted for children aged 5 and older, and characterized it as “arbitrary, capricious, and unreasonable.” That ruling was handed down in response to a lawsuit from a group of parents who sued Adams and New York City agencies.

“Universal masking, therefore, presents one of the strongest, if not the strongest defense against COVID-19 for settings with children ages two to four,” New York City attorneys said in court papers, although numerous studies have shown that young children have exceedingly low COVID-19 death and hospitalization rates compared with other age groups—even compared with older children.

“For these reasons,” the city added, “throughout the pandemic, both the City and New York State had more stringent rules in place for this setting.”

Amid the appeals process, it’s not clear how much longer New York City, which has employed some of the strictest COVID-19 rules in the United States, will keep the mandate intact. Dr. Ashwin Vasan, New York City’s health commissioner, said at a news conference on Friday that officials are “recommending to wait a little bit longer before making masks optional for this age group,” referring to young children.

Over the past several months, federal and state data have shown hospitalizations, cases, and deaths from COVID-19, the illness caused by the CCP (Chinese Communist Party) virus, have fallen dramatically. In response, other Democrat-led states and municipalities have dropped mask and vaccine mandates while some Democrats have even voiced criticism about those rules.

Michael Chessa, an attorney who represents the group of parents suing Adams, said they were pleased when Porzio agreed with their arguments. However, they were disappointed when his ruling didn’t go into effect pending the appeals process, he told Gothamist.

“On Monday morning when parents send their children to school, they won’t have that choice,” Chessa said, adding that the appellate court hasn’t set a date for arguments.

https://www.zerohedge.com/covid-19/new-york-city-will-mandate-masks-children-under-5-years-old

Teens faced emotional abuse at home during the pandemic: CDC

 A majority of teenagers say they endured insults, put-downs and other forms of emotional abuse from a parent or other adult at home during the height of the pandemic lockdown in 2020, according to a survey released Thursday by the Centers for Disease Control and Prevention.

The findings offer a stark appraisal of how high school students have fared during the pandemic. 

"These data echo a cry for help," Dr. Debra Houry, the CDC's acting principal deputy director, said in a statement. "The COVID-19 pandemic has created traumatic stressors that have the potential to further erode students' mental wellbeing."

In a call with reporters Thursday, Kathleen Ethier, director of the CDC's Division of Adolescent and School Health, said the survey results underscored "the degree to which families were experiencing stress" during the pandemic.

"Our data make it clear that young people experienced significant disruption and adversity during the pandemic and are experiencing a mental health crisis," Ethier said.

The survey findings, which were published as a series of reports Thursday, are based on the responses of a group of 7,705 nationally representative high school students. Participants were asked to complete the Adolescent Behaviors and Experiences Survey in the first half of 2021, though the questions asked about experiences from the previous year, 2020.

In general, 66 percent found it difficult to complete their schoolwork during the pandemic. 

More than half of the high school students — 55 percent — said they were on the receiving end of cursing or other verbal insults from an adult in the home during pandemic lockdown. Nearly three-quarters of those students identified as lesbian, gay or bisexual, and 63 percent were young women.

More than 1 in 10, or 11.3 percent, said they suffered physical abuse, such as hitting, beating or kicking.

It remains unclear how significant a role lockdown played in such reports. "There is no way to know specifically whether our findings reflect something new due to the pandemic or existing levels of abuse from prior to the pandemic," Ethier said.

Ariana Hoet, a pediatric psychologist, noted that caregivers, including parents, were also very stressed during the pandemic, and that may have resulted in verbal and emotional outbursts within the home.

"This study gives a voice to children, and shows a little bit of what we've been seeing in clinic," said Hoet, who is also the clinical director of On Our Sleeves, a national program that aims to reduce stigma around children’s mental health. "We know that kids — especially teens — can feel parents' stress."

A separate CDC study released in February found that mental health issues among American youth were increasing even before the pandemic.

From 2013 through 2019, that report found, 1 in 5 teenagers had at some point experienced an episode of major depression: unshakeable and worrisome feelings of sadness and hopelessness lasting for at least two weeks.

The CDC report published Thursday found that 44 percent of students said that during the previous year, they felt an ongoing sense of hopelessness, so much so that they were unable to engage in regular activities, Ethier said.

Nearly 20 percent had seriously thought about dying by suicide.

The survey also asked students about their drug use during the pandemic. Nearly a third, 31.6 percent, said they had experimented with some kind of drug, including nicotine, or alcohol.

About 1 in 3 said their use of such substances increased during the pandemic — perhaps mirroring worrisome trends also observed among adults in lockdown.

Nearly 20 percent of surveyed teens said they drank alcohol, and just over 15 percent reported using e-cigarettes.

Vaping and marijuana use were more prevalent than use of painkillers and cigarettes, the survey found.

Overall reports of substance use and misuse were more prevalent among older teens and those in largely marginalized groups, including American Indian students and those identifying as gay, lesbian or bisexual.

https://www.nbcnews.com/health/health-news/teen-mental-health-pandemic-cdc-report-finds-troubling-trends-rcna22357

Ukraine War Hastens Investor Migration to Private Markets

 Much of the commentary about the Ukraine war’s implications for the investment-management industry has tended to be both immediate and narrow, particularly in discussions about the spillovers for different segments. By zooming out, however, some longer-term ramifications become more apparent for both public and private markets.

The war is amplifying and accelerating six important secular evolutions that were already taking place well before the first Russian troops invaded Ukraine. Indeed, on the eve of the invasion:

Inflation was already a problem; the Federal Reserve was already behind the curve; it was losing control of the monetary policy narrative; and the days of massive liquidity injections were ending.

With many policy options virtually exhausted by the enormous response to the pandemic, the possibility of stagflation for the global economy was already a risk; and, at the other end of the probability distribution of potential outcomes, the upside scenario of high growth and transitory inflation was declining.

Persistent China-U.S. tensions, together with the pronounced politicization and weaponization of trade sanctions during the Trump administration, were serving as headwinds to continued globalization and liberalization of both economic and financial cross-border interactions.

The need to intensify the battle against climate change was urgent, as was the realization of the complexities of the transitional issues, including the orderly replacement of fossil fuels.

China and some other countries were looking for more ways to build bigger pipes around the Western-dominated core of the international monetary order.

Driven by an enlarged set of stakeholders, companies were being pushed to take more seriously their social and environmental responsibilities, including starting to self-sanction themselves more away from harmful activities.

In addition to speeding up and intensifying these developments, the war has also increased the scope for their interactions, making the universe of potential outcomes not just much broader but also more path dependent.

Ironically, the complexity of potential outcomes has a powerfully simple implication for the investment-management industry: a bigger migration from public markets into private ones such as private equity, venture capital, private credit and real assets.

The drivers here go well beyond the irony that, in public markets with still-repressed bond yields and the certainty of sizable negative real return on cash, equities remain the asset of choice despite the deteriorating outlook for economic and corporate fundamentals. Indeed, much of the essence of “risk-free assets,” and the comforting correlations associated with them, has been eroded.

Private markets offer the potential for flexibility that is needed in this more uncertain world. This includes a broader range of investment techniques, the scope for structural resilience that comes with explicit collateralization and smart structuring, a more appropriate pricing of liquidity, and the greater structural ability to stay in the trade during periods of unsettling volatility.

The increase in demand for private markets will need to be met by a broader and better choices set offered by the industry. Investment-management firms will need to bring to the table a greater degree of cognitive diversity, more of a multidisciplinary mindset, a more global footing (including in more developing countries), and good local presence and solid execution capabilities. Legal jurisdictions will matter much more, as will the compliance infrastructure to navigate a world of ballooning primary and secondary sanctions.

In the world in which massive liquidity injections shielded investors from virtually any and all headwinds, public markets offered significant potential, especially when levered. Meanwhile, the breakdown in the traditional correlation matrix for stocks and bonds, together with the repression of volatility, only enhanced the upside.

Russia’s invasion of Ukraine is speeding up the move away from this world, a process that had already begun. Increasingly, investors will need to consider larger allocations to private markets, both to maximize returns and contain risks. And the industry will have to adapt in both offerings and management.

Mohamed A. El-Erian is a Bloomberg Opinion columnist. He is president of Queens’ College, Cambridge; chief economic adviser at Allianz SE, the parent company of Pimco where he served as CEO and co-CIO; and chair of Gramercy Fund Management. His books include "The Only Game in Town" and "When Markets Collide."

https://www.bloombergquint.com/gadfly/ukraine-war-hastens-investor-migration-to-private-markets

ACC: Lexicon hopes sotaglifozin cardio data will set its drug apart from SGLT2 rivals

 As the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes, Lexicon’s sotagliflozin has tantalizing potential. But getting the pill to pass muster with the FDA has been problematic.

The latest setback with the U.S. regulator came five weeks ago when Lexicon pulled back a submission for approval in Type 2 diabetes patients with heart failure. That came on top of an FDA rejection for sotagliflozin in 2019 in Type 1 diabetes.

All the while, sotagliflozin has generated promising data. On Saturday, at the American College of Cardiology in Washington, D.C., Lexicon highlighted results from a trial of sotagliflozin in Type 2 diabetes and kidney disease patients that showed the drug not only reduced heart failure by 26%, but that it also provided a reduction in the risk of heart attack and stroke.

A follow-up analysis of the trial revealed consistent reductions in major adverse cardiovascular events (MACE) in two subgroups—a 21% reduction in MACE in patients with cardiovascular disease and a 26% reduction in MACE in those without CVD.

For Lexicon chief medical officer Craig Granowitz, the benefit of sotagliflozin in heart failure is no surprise. It’s a class effect that has been shown for other SLGT2 inhibitors, such as Eli Lilly and Boehringer Ingelheim’s Jardiance. But the heart attack and stroke findings could prove an advantage for the medicine against its rivals, Lexicon figures.

“What was seen in this study, which hasn’t been seen with SGLT2 inhibitors, is a benefit in reducing heart attack and stroke, whether or not that patient has had a prior heart attack or stroke or has another diagnosis related to cardiovascular disease,” Granowitz said. “That is why the ACC selected this as a presentation today.”

The study chair for the Scored trial, Deepak Bhatt, a professor at Harvard Medical School, also noted a consistent benefit for sotagliflozin in three other vascular disease groups—coronary artery disease, cerebral vascular disease and peripheral artery disease.

“The data are very strong,” Bhatt said. “I hope (sotaglifozin) gets approved. I think it might be the best in class.”

Bhatt said it’s too early to tell if there are added benefits from sotaglifozin because of its dual action. But upcoming studies will leave no doubt.

“Is there anything beyond SGLT2 from the SGLT1? Bhatt asked. “There’s some randomization data that suggests there might be independent benefits.”

By pooling data from phase 2 and phase 3 trials testing sotaglifozin in more than 20,000 combined patients in both Type 1 and Type 2 diabetes, Lexicon has shed more light on the drug’s benefits.

“If you look at those (other) studies, which were not designed to look at cardiovascular events—they were just designed to look at blood sugar management—you still see a reduction in stroke and heart attack,” Granowitz said. “That’s never been seen before. That’s pretty remarkable.”

In the field of diabetes candidates, sotagliflozin is distinguished by its ability to block SGLT2 in the kidneys and SGLT1 in the intestines. Sanofi recognized the drug’s potential in 2015, paying Lexicon $300 million up front and committing $1.4 billion in milestone payments to get a piece of the action.

But in 2019, while Lexicon gained approval in Europe to treat Type 1 diabetes patients who can’t achieve adequate control of their blood sugar with insulin, it had no such luck in the same indication with the U.S. regulator.

After an advisory committee deadlocked 8-8 on whether to recommend a nod, the FDA rejected it twice—in March of 2019 and upon appeal nine months later, citing the risk of diabetic ketoacidosis.

Also in 2019—after some mixed trial results—Sanofi bailed on the project, paying $260 million to return full rights to Lexicon.

Three years after losing the Type 1 bid, Lexicon has not given up on an approval in that indication, Granowitz said. 

https://www.fiercepharma.com/pharma/acc-lexicon-points-data-could-set-diabetes-drug-sotaglifozin-apart-other-sglt2-inhibitors