An anti-inflammatory drug used to treat severe rheumatoid arthritis was among experimental therapies given this year to some Covid-19 patients, but such an off-label approach is hardly a novel idea.
A University at Buffalo pediatric endocrinologist has spent two decades considering a similar medication for those diagnosed with Type 1 diabetes.
Her latest clinical trial – reported Wednesday in the New England Journal of Medicine – found that an 11-year-old drug used to treat other autoimmune conditions can preserve insulin-making power for at least a year in some children and young adults newly diagnosed with the condition.
“Golimumab can be a disease-modifying agent and that's very significant,” Dr. Teresa Quattrin told The Buffalo News.
The biologic, brand named Simponi, was approved to reduce swelling, discomfort and joint pain in those with ulcerative colitis and some forms of arthritis.
It worked much the same way in the study to disrupt tumor necrosis factor, or TNF, a protein that causes inflammation, from killing beta cells that help produce insulin in the pancreas.
Because many patients in the study were able to continue to produce some insulin on their own, they relied on less daily synthetic insulin and more easily controlled blood sugar.
“The burden of this disease, it's unbelievable,” said Quattrin, a pediatric endocrinologist at Oishei Children’s Hospital in Buffalo and senior associate dean for research integration in the University at Buffalo Jacobs School of Medicine and Biomedical Sciences.
Type 1 diabetes, a progressive disease, develops in three stages. It starts when the immune system mistakenly attacks and starts to destroy healthy beta cells that foster insulin production, the hormone needed to get glucose (sugar) from the bloodstream into other cells to provide energy for the body.
“This process starts many years before Type 1 is diagnosed,” Quattrin said.
Blood sugar rises during the second stage, usually without symptoms, until the third stage, where increased thirst and urination, unexplained weight loss, blurred vision and fatigue often signal a dangerous rise in glucose levels.
Those it strikes have a genetic predisposition – though not necessarily a family history – and the cause has nothing to do with behavioral and nutritional choices.
Type 2 diabetes, by far the most common form, is a metabolic disorder that prevents the pancreas over time from making enough insulin to keep blood sugar levels in the normal range. It, too, can run in families, though a poor diet, lack of exercise and obesity are considered major risks regardless of heredity.
Complications for both types are serious. Elevated or low blood sugars cause immediate and long-term challenges. Higher blood sugar levels can lead to blindness, heart disease, kidney failure, neurologic problems and a shorter lifespan.
Researchers, including Quattrin, are working to better diagnose and treat Type 1 diabetes in the first two stages.
“Why wait?” she said.
Standard treatment pushes manufactured insulin into the body through injections or a pump that at some point puts the pancreas into a state of partial remission. Some human insulin production continues for three to six months until it stops almost completely.
The randomized study Quattrin led showed many who received golimumab extended that period to a year.
Two-thirds of the 84 participants, ages 6 to 21, got the drug by injection twice a week for 12 months while the others got a placebo, starting within 100 days from diagnosis.
Of those who received golimumab, nearly 41% remained in partial remission, known as the "honeymoon period," at the end of the of the 52 weeks compared to 11% in the placebo group.
No serious drug side effects were reported.
Results at this point look more promising than for a similar drug given emergency authorization for use last spring as a treatment for Covid-19. Drug-maker Regeneron Pharmaceuticals reported over the summer that sarilumab showed no statistical benefit for those critically ill with the disease.
There is no cure for Type 1 diabetes but researchers inch forward taking three approaches to address the disease: an engineered closed-looped system that can automatically produce insulin and maintain proper levels in the body – in other words, an artificial pancreas – finding ways to protect and preserve insulin-producing beta cells, or figuring out how to implant them.
“As we speak today, there's actually no FDA approved therapy to preserve beta cells. I think that's part of the excitement here,” said Dr. Stephen Gitelman, professor of pediatrics and head of the pediatric diabetes program at the University of California at San Francisco, and a study co-investigator.
“As with most medical problems, engineered solutions and replacement parts just aren't as good as what nature gave you,” Gitelman said. “The question becomes, ‘Why can't we just find a way to preserve the cells that are there?”
Quattrin and other researchers don’t know who among their patients received golimumab because they weren’t told by drugmaker Janssen Research & Development, which funded and tracked the 27-site, double-blind study. She believes at least half of six participating patients in Buffalo got golimumab.
“I had two teenagers who did incredibly well throughout all the treatment period and even a little bit after, when we stopped the study drug,” Quattrin said.
Researchers completed the treatments last year and are following participants for a second year to learn if those who received golimumab got a lasting effect after treatment stopped.
A post-study analysis showed that those younger than 18 had 36% fewer episodes of hypoglycemia, or low blood sugar, which can cause lightheadedness and fainting, and become fatal if left untreated.
Quattrin grew up and attended medical school in Naples, Italy. She came to Buffalo in 1985 for additional pediatric endocrinology training and stayed.
She started conducting anti-TNF animal studies using Enbrel – the first in the class of such drugs – a year after it hit the market in 1998. Seven years later, she released a pilot study of 18 patients that showed they relied on less insulin through injections or a pump and had better blood sugar control after six months on the drug.
“It took a long time because a TNF blocker had never been used this way,” Quattrin said. “A lot of patients would say, ‘No, we don't want to do it.’ ”
Other diabetes researchers took note of the small study and Janssen approached her three years ago with the idea of building on that study with golimumab.
Both groups in the latest study achieved good blood sugar control, Quattrin said, and those who got golimumab did so with about one-third to one-half less injected insulin. She described that as “a critical benefit.”
It will mostly be up to Janssen, the drug-maker that funded the clinical trial, to move to a final study phase that might lead to FDA approval for its use in diabetes treatment.
The federal government typically helps underwrite research and development costs of drugs that address more common conditions. That includes heart disease, which imperils one of every two Americans, and prediabetes, the precursor to Type 2 diabetes, which impacts one of every three.
Federal agencies often encourage pharmaceutical companies to shoulder most of those costs to find breakthroughs for less common diseases.
An estimated one in 11 people in the U.S. have Type 2 diabetes.
About 1 in 300 people have Type 1 diabetes.
Quattrin and Gitelman are among those seeking better ways to screen for and treat it, in part through Diabetes TrialNet, which helps support related research.
Potential costs to patients also might come into play in terms of future study. Simponi injections run about $18,000 per year, according to the National Center for Biotechnology Information, though Quattrin said they could come down with wider use.
Several TNF-blocking drugs are being investigated, Gitelman said, and important questions still need to be answered with golimumab and others.
Can they be studied when used further upstream in diabetes development? When used by those younger than 6 and older than 21? If used in combination with each other or complementary treatments, as is the case with asthma, cancer and other therapies?
Researchers are curious and hopeful.
“With the handful of these other drugs that we have now, we're kind of at the end of the beginning” of important breakthroughs, Gitelman said. “We have to figure out now, ‘Where do we go from here?’ ”
Golimumab study co-authors included Drs. Michael J. Haller of the University of Florida, Andrea K. Steck of the University of Colorado, Eric I. Felner of Emory University, and seven researchers with Janssen.