Will FDA Advisors Look Past Hypoglycemia Risk With Once-Weekly Insulin?

 Concerns over hypoglycemia risk with an investigational once-weekly insulin product in patients with type 1 diabetes prompted the FDA to call an advisory committee together

opens in a new tab or window to weigh in on the matter.

On Friday, the Endocrinologic and Metabolic Drugs Advisory Committee will discuss the long-acting insulin icodec by Novo Nordisk, which is seeking an indication for improving glycemic control in adults with both type 1 or type 2 diabetes.

In the phase IIIa ONWARDS 6 trialopens in a new tab or window, insulin icodec was just as efficacious -- but not superior to -- once-daily insulin degludec in type 1 diabetes, yielding a comparable reduction in HbA1c by week 26 (-0.47% vs -0.51%). Both insulins were used in combination with three daily mealtime insulin injections.

However, there was a significantly higher estimated rate of severe or clinically significant hypoglycemia with insulin icodec, marked by a blood glucose under 54 mg/dL (19.93 events per patient year vs 10.37 with the once-daily insulin). The highest risk period for hypoglycemia was around the time of its peak glucose-lowering effect on days 2 to 4 after injection.

This will be the main point of debate for the advisory committee, as briefing documentsopens in a new tab or window stated that while hypoglycemia is "an expected adverse reaction" with exogenous insulin, insulin icodec in type 1 diabetes patients in this trial showed "excess hypoglycemia ... without evidence of any additional glycemic control or other benefit."

The FDA previously told Novo Nordisk during an end-of-phase II meeting that meeting the prespecified noninferiority margin (HbA1c at 6 months) "would not be sufficient to establish a favorable benefit-risk profile" when taking into consideration the risk of hypoglycemia. At that meeting, the FDA recommended the phase III study include a third arm evaluating insulin icodec dosed twice-weekly and assess the possible need for additional bolus dose adjustments.

Novo Nordisk already proposed a few label suggestions and risk-mitigation strategies for type 1 diabetes patients that will be discussed on Friday. First, it was suggested insulin icodec be limited to type 1 diabetes patients wearing a continuous glucose monitor and those without a history of hypoglycemia unawareness or recurrence. This was the same criteria used in the trial. It also suggested that the labeling restrict use to type 1 diabetes patients whose glycemic variability is less than 36% prior to initiation.

Another proposal was an alternative dose titration strategy for this group, like cutting the bolus insulin dose by around 30% between days 2 to 4 when hypoglycemia risk is highest.

During the meeting, hypoglycemia risk will be weighed against the unmet need for a wider range of insulin options for this patient population.

Currently, all basal insulin products on the market are designed for daily dosing, so the main benefit of this product is the convenience of a once-weekly dosing option. This strategy may also help to combat nonadherence to insulin therapy -- a risk factor for hyperglycemia and diabetic ketoacidosis. One recent meta-analysisopens in a new tab or window found that adherence to insulin therapy in adults with type 1 diabetes was fairly low, at around 53%.

ONWARDS 6 was the only trial in the clinical program to include type 1 diabetes patients, as the other five trials only enrolled type 2 diabetes participants. In the ONWARDS 1 trialopens in a new tab or window presented at last year's American Diabetes Association meeting, there was a significantly greater average reduction in HbA1c with icodec compared with glargine U100 in insulin-naive people with type 2 diabetes. In this patient population, there was a numerically higher rate of clinically significant or severe hypoglycemia: 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52.

"Insulin is insulin," lead investigator Julio Rosenstock, MD, of Velocity Clinical Research at Medical City in Dallas, said at the meeting. "When we use insulin, there always will be hypoglycemia, but we only had less than one event per year."

In March, the European Medicines Agency's advisory committee recommended Novo Nordisk's insulin icodec for approvalopens in a new tab or window in both type 2 and type 1 diabetes, though it said that the product "should only be used in patients with type 1 diabetes for which a clear benefit of a once-weekly administration is expected," given the hypoglycemia concerns.

While the FDA isn't required to follow its advisory committees' recommendations, it typically does.

https://www.medpagetoday.com/endocrinology/type1diabetes/110283

Zantac Not a Cause of Woman’s Cancer, Jury Says in First Trial Over Drug

A jury in Chicago on Thursday rejected an Illinois woman’s claim that the now discontinued heartburn drug Zantac caused her colon cancer, in the first trial out of thousands of lawsuits making similar allegations.

The jury in Cook County, Illinois circuit court agreed with arguments from drugmakers GSK and Boehringer Ingelheim that the plaintiff, 89-year-old Illinois resident Angela Valadez, had not proven her colon cancer was at least in part caused by her Zantac use.

Valadez had alleged that her cancer was a result of taking over-the-counter Zantac and generic versions of it from 1995 to 2014. The lawsuits over the drug say its active ingredient, ranitidine, under some conditions turns into a cancer-causing substance called NDMA.

Attorneys for Valadez had asked the jury to award $640 million for her suffering. The judge rejected Valadez's request to seek punitive damages during the trial, according to her attorneys.

Mikal Watts, one of Valadez's attorneys, said he respected the jury's verdict but was confident the companies would be held liable in future Zantac trials. "This is a marathon, not a sprint," he said.

GSK and Boehringer did not immediately respond to requests for comment.

Britain-based GSK, whose predecessor developed the drug but later sold the brand to other companies, and German drugmaker Boehringer Ingelheim, which sold the medicine from 2006 until 2017, were the only defendants in the trial after the other companies settled.

Valadez’s case was the first to go to trial after all cases previously set for trial settled.

Watts said at the trial that began on May 2 that the companies knew that ranitidine would turn into NDMA as it aged or was exposed to extreme temperatures, but did not ensure it was properly handled by transporters, distributors and stores.

Attorneys for GSK and Boehringer countered that Zantac has been repeatedly proven to be safe and effective and that no scientific or medical study has connected Zantac to cancer.

The companies attorneys also argued at trial that there was no evidence to support Valadez's claim that she had taken Zantac for 18 years, and that she had a host of risk factors that made her more likely to develop colon cancer.

First approved in 1983, Zantac became the world's best selling medicine in 1988 and one of the first-ever to top $1 billion in annual sales.

https://www.usnews.com/news/top-news/articles/2024-05-23/zantac-not-a-cause-of-womans-cancer-jury-says-in-first-trial-over-drug

'1 in 9 children now diagnosed with ‘expanding health concern’ ADHD'

 The kids are not all right.

A new report from the Centers for Disease Control and Prevention reveals a staggering uptick in ADHD, or attention-deficit/hyperactivity disorder, diagnoses among American children.

Calling ADHD an “expanding public health concern,” researchers found that 1 in 9 children aged 3-17 had been diagnosed with the disorder, symptoms of which include trouble paying attention, overactivity and impulsive behaviors.

The study, which appears in the Journal of Clinical Child & Adolescent Psychology, found that between 2016 and 2022, ADHD diagnoses among kids jumped by more than one million.

Melissa Danielson, a statistician with the CDC’s National Center on Birth Defects and Developmental Disabilities, attributes the increase to the mental toll of the pandemic. “A lot of those diagnoses … might have been the result of a child being assessed for a different diagnosis, something like anxiety or depression and their clinician identifying that the child also had ADHD,” she said.

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Experts note that ADHD is expressed differently between boys and girls.Studio Romantic – stock.adobe.com
Indeed, the report found that nearly 78% percent of children diagnosed with ADHD had at least one other diagnosed disorder. Common among these additional diagnoses were behavioral or conduct problems, anxiety, developmental delays, autism and/or depression.

Danielson notes that ADHD was originally thought of as a hyperactive disorder that affected boys. While it is now understood to affect both genders equally, symptoms express themselves differently.

She explains, “Boys will often have hyperactive or impulsive ADHD, where they’ll run into the street or jump off things or do things that might make them more likely to be injured. Girls tend to manifest their ADHD in a more inattentive way. They’ll be daydreaming or have a lack of focus or be hyperfocused on a particular task that maybe is not the task that they need to be focused on.”

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The study suggests the pandemic may have played a part in the increase in ADHD diagnoses.amnaj – stock.adobe.com

While the number of children diagnosed with ADHD has risen, the report found that only about half were treating the condition with medication, as opposed to two-thirds in 2016. Danielson explains that this drop-off may be due to shortages in ADHD meds when the data was collected.

Dr. Max Wiznitzer, a professor of pediatric neurology at Case Western Reserve University, suspects the decline in medication may also be the result of parental reluctance. “There’s the myth that it’s addictive, which it’s not,” he said. Wizniter argues that studies have shown people treated with ADHD have no increased risk of drug abuse.

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While ADHD diagnoses are on the rise, the use of medication to treat it has fallen.altitudevisual – stock.adobe.com

Meanwhile, an unrelated study found that between 2000 and 2021, the number of calls to US poison control centers for children’s ADHD medication errors jumped 300%, and a University of Michigan study revealed that 1 in 4 middle and high school students are abusing stimulants prescribed for ADHD. Additionally, ADHD medications are known to cause side effects like headache and loss of appetite.

Wiznitzer is a proponent of ADHD medication because he believes it can help control the symptoms of overactivity and inattention and aid focus. Left untreated in childhood, ADHD is known to raise the risk of diabetes, heart disease and shortened life span in adults, which is why Wiznitzer advocates for increased awareness and diagnosis.

ADHD is typically treated with a combination of behavior therapy and medication, but the report found less than half of kids and adolescents diagnosed with ADHD were getting behavioral therapy.

Recent research suggests that beyond medication, the use of behavioral therapy, in conjunction with nonpharmacological treatment, including noninvasive brain stimulation, may very well be the wave of the future for treating ADHD.

https://nypost.com/2024/05/23/lifestyle/1-in-9-us-children-diagnosed-with-adhd/

GoodRx upped to Outperform from Sector Perform by RBC

 Target to $10 from $8

https://finviz.com/quote.ashx?t=GDRX&p=d

Melugin: Many Predominantly Mid East, Asian Men Illegally Crossed Border, "Special Interest Aliens"

 FOX News national correspondent Bill Melugin at the U.S.-Mexico border in Jacumba, California on Wednesday reported that "masses of predominantly Middle Eastern and Asian men" illegally crossed the border overnight.

JESSE WATTERS, FOX NEWS: Southern California has become America's hottest migrant magnet. San Diego County officials say the shelter system is completely overrun. Nearly 150,000 migrants have been released on the streets just since September and they come from every corner of the globe. South America, China, the Mideast. National correspondent Bill Melugin caught up with a group of them in the middle of the night. Here's how that went down.

BILL MELUGIN, FOX NEWS: You can see adult men from all around the world are showing up here in sanctuary state California to cross our border illegally in the middle of the night.

Take a look at this video we shot right here in Jacumba, east of San Diego, 2:00 am overnight as masses of predominantly Middle Eastern and Asian men crossed illegally here, very nonchalant. Many of them special interest aliens, meaning they are coming from countries with potential national security concerns. We talked to a lot of them, there was not a single Mexican out here. Take a listen.

MELUGIN: Where are you guys from? What country?

MIGRANT: Pakistan.

MIGRANT: Pakistan.

MIGRANT: India.

MIGRANT: Turkey.

MIGRANT: India.

MELUGIN: Where are you guys from?

MIGRANT: Turkey.

MIGRANT: Turkey.

MELUGIN: Where you guys from?

MIGRANT: China.

MIGRANT: Ecuador.

MELUGIN: Where you guys from?

MIGRANT: India.

MIGRANT: India.

MIGRANT: India.

MIGRANT: India.

MIGRANT: India.

MIGRANT: India.

MELUGIN: All India?

MIGRANT: India.

MIGRANT: Iran.

MELUGIN: Iran? Why did you come?

MIGRANT: No freedom.

MELUGIN: No freedom?

MIGRANT: No freedom in iran. Iran is a dangerous country. No freedom for speaking, for writing, for singing, or thinking.

MELUGIN: We met up with a local resident our here, former U.S. military, he goes out and collects all these discarded passports and IDs that illegal immigrants drop as soon as they cross into Jacumba illegally. He has hundreds from China, from Afghanistan, Pakistan, Saudi Arabia, Turkey, many others. Some of them are burned, cut, shredded as these migrants try to destroy some of the documents to hide who they are and where they've been. Take a listen.

MAN: They are just dropping this stuff on the ground to come here and assume a new identity. So it's a little bit scary. From my military background and seeing the people who are coming across, male, male, male, these are all military-aged males. People keep saying that. I've got the proof right here.

MELUGIN: And if you're wondering how some of these people from halfway around the world arrive here at the San Diego border, we have talked to a lot of them, using translator apps. They told us they fly into Turkey, then fly into Mexico, then take a bus up the Tijuana, and then they cross somewhere in this area.

https://www.realclearpolitics.com/video/2024/05/22/bill_melugin_masses_of_predominantly_middle_eastern_and_asian_men_illegally_crossed_the_border_special_interest_aliens.html 

Merck builds in cell, gene therapies with Mirus Bio deal

 Germany’s Merck KGaA has agreed to acquire Mirus Bio, a specialist in transfection reagents used in the production of cell and gene therapies (CGTs), in a deal valued at around $600 million.

If completed, the acquisition will make Mirus Bio part of Merck’s US and Canadian life sciences division MilliporeSigma, which provides a wide range of products used in the production of CGTs, as well as operating as a contract development and manufacturing organisation (CDMO).

Life sciences is a major arm of Merck’s business – contributing around €9.3 billion out of the group’s total net sales of €21 billion last year – but has been under pressure since the end of the pandemic as a result of a steep fall-off in COVID-19-related revenues and volatility in the CDMO market.

Last week, the life sciences division reported first-quarter sales down nearly 14% to €2.1 billion, mainly as a result of inventory destocking by customers in Merck’s process solutions business, which focuses mainly on consumables used in the research and manufacturing of biologics, like filtration devices, chromatography resins, single-use equipment, and processing chemicals and excipients.

According to Matthias Heinzel, chief executive of the division, buying Mirus Bio and products like its TransIT-VirusGEN transfection platform will build up Merck’s expertise and capacity in the manufacturing of viral vectors used to make CGTs.

“Viral vector-based cell and gene therapies have demonstrated their potential with more than 20 approvals over the last 10 years and will continue to advance, with a projected growth of 30% until 2028,” he said.

“Combining Mirus Bio’s leading technology with Merck’s bioprocessing expertise and portfolio allows us to provide solutions for almost every step of viral vector development and manufacturing.”

Merck has previously said that supporting companies developing novel therapies like CGTs is a key pillar of its life sciences growth strategy. A recent GlobalData analysis found almost 700 candidates in the industry pipeline, including almost 50 in late-stage development.

“This strategic acquisition is a further building block for accelerating growth in the break-through technologies of the future,” said Merck group CEO Belén Garijo. “As a leader in the production of viral vectors, our goal is to make the significant potential of cell and gene therapy available for patients worldwide.”

The takeover is expected to be completed in the third quarter of this year, subject to the usual regulatory clearance and other closing conditions.

https://pharmaphorum.com/news/merck-builds-cell-gene-therapies-mirus-bio-deal

Appeals Court Sides With Drugmakers in 340B Case, Allows Limits on Discounts Under Program

 The U.S. Court of Appeals for the District of Columbia on Tuesday ruled in favor of pharmaceutical companies, finding that drugmakers are allowed impose limits on the discounts that they may give under Section 340B of the Public Health Service Act.

In a 21-page opinion, Circuit Judge Gregory Katsas wrote that the appellate court holds that 340B “does not categorically prohibit” drugmakers from applying certain restrictions on the distribution of covered drugs to specific entities. Katsas ruled the specific restrictions in the case at hand—between Novartis and United Health versus the Health Resources and Service Administration (HRSA) and the Department of Health and Human Services (HHS)—do not violate section 340B “on their face.”

Still, the judge noted that the ruling does not “foreclose the possibility that other, more onerous conditions” might violate 340B in the future, or that the restrictions named in the case could indeed be in violation of the statute “in particular circumstances.”

Established by Congress in 1992, the 340B Drug Pricing Program provides incentives for pharma companies that give healthcare providers discounts on certain drug products, which are prescribed to patients below the federal poverty level.

To facilitate access to these discounted drugs, healthcare providers work with third-party distributors—such as contract pharmacies—to help ship the 340B medicines and bring them to their intended communities.

However, in 2020, Novartis and United Health started imposing restrictions on these external service providers. With regard to its beneficiary hospitals, Novartis restricted work only to contract pharmacies within 40 miles while United Health would only allow contract pharmacies that the beneficiary had already worked with, or otherwise select only a single contract pharmacy.

In response, HHS released an advisory opinion that allowed the beneficiaries could choose which third-party entities to partner with, and that drugmakers are required to deliver covered drugs to the contract pharmacies.

For its part, HRSA sent enforcement letters to Novartis and United Health, along with other large drug manufacturers, asserting that the companies’ duty under Section 340B are “not qualified, restricted or dependent on how the covered entity chooses to distribute the covered outpatient drugs,” according to Tuesday’s court opinion.

Novartis and United Health filed separate lawsuits asking the court to vacate the enforcement letter, declare that their restrictions were lawful and prevent future enforcements. The district court sided with the companies in 2021 but declined to enjoin potential enforcement in the future.

A lawsuit filed by the Pharmaceutical Research and Manufacturers of America (PhRMA) failed to block an Arkansas law that empowers hospitals to use outside pharmacies to dispense discounted drugs. In March 2024, the U.S. Court of Appeals for the Eighth Circuit ruled against PhRMA, upholding an Arkansas law that enables healthcare providers to dispense drugs—obtained at a discounted price via the 340B Drug Pricing Program—through certain pharmacies.

https://www.biospace.com/article/appeals-court-sides-with-drugmakers-in-340b-case-allows-limits-on-discounts-under-program/