With Type 1 Diabetes Delay Possible, Focus Now on Screening

The recent approval of teplizumab-mzwv (Tzield, Provention Bio) for the delay of type 1 diabetes by the US Food and Drug Administration is expected to advance efforts to increase screening to cost-effectively identify those at risk for the condition who would be eligible to receive the new treatment.

The anti-CD3 monoclonal antibody was approved November 17 as the first disease-modifying therapy for impeding progression of type 1 diabetes. In a clinical trial, teplizumab delayed the onset of clinical (stage 3) type 1 diabetes by approximately 2 years, and longer in some cases.

It is administered by intravenous infusion once daily for 14 consecutive days and is expected to cost in the region of $200,000 for the course of treatment.

The specific indication is "to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes." In stage 2 type 1 diabetes, the individual has two or more islet autoantibodies and abnormal glycemia but is as yet asymptomatic. It is associated with a nearly 100% lifetime risk of progression to clinical (stage 3) type 1 diabetes and a 75% risk of developing the condition within 5 years.

Currently, most people who are screened for type 1 diabetes autoantibodies are first-degree relatives of those with the condition through TrialNet, other local programs, or more recently, a $55 test offered by the research and advocacy organization JDRF.

But because 85% to 90% of people who develop type 1 diabetes don't have first-degree relatives with the condition, broader population screening will be necessary to identify eligible candidates for teplizumab.

During an investor call on November 18, Provention Bio chief commercial officer Jason Hoitt said that among the company's "strategic initiatives" were "advancing awareness and screening for autoantibodies in at-risk individuals, and ultimately, routine screening during pediatric well visits for the general population," as well as "[healthcare provider] belief in teplizumab and desire to prescribe it for their patients."

Without broad population-based screening, first-degree relatives of people with type 1 diabetes are likely to be the first to be screened and those with stage 2 identified for receipt of teplizumab. Today, that population is estimated at about 30,000 in the United States, Hoitt said, adding, "with this approval we hope that more stage 2 patients can be readily identified so the course of the disease can be changed."

During the call, Hoitt also announced that the wholesale acquisition cost of Tzield would be $13,850 per vial, which translates to $193,900 per 14-vial continuous regimen, anticipated to be a sufficient dose for most patients. The company also launched a program called COMPASS to help patients navigate insurance reimbursement, as well as provide some with financial assistance.

Cost aside, JDRF CEO Aaron Kowalski, PhD, told Medscape Medical News that clinicians shouldn't doubt the value of delaying type 1 diabetes onset, even if not completely preventing it.

"This is the first drug ever to treat the underlying disease. There is this undercurrent that insulin is enough. Why would you undertake an additional risk of an immunotherapy? Type 1 is hard to live with. I think sometimes the clinical community doesn't appreciate that insulin is not enough. It's very difficult, and opening this door is important…We believe very strongly that the delay of onset of type 1 diabetes is clinically meaningful. We hear that from every family we've talked to. Clinicians should appreciate this and not discount it."

How Would Screening Happen?

While the path to universal screening for type 1 diabetes risk isn't yet clear, quite a bit of thought and research has gone into it even before teplizumab and other immune-modulating agents showed promise in forestalling the condition.

Data from a universal screening program of schoolchildren implemented in Bavaria, Germany, and a screening program in Denver, Colorado, suggest that even without such an intervention, identifying people at high risk for developing type 1 diabetes could be cost-effective by allowing for education of the individual and family members about the signs of type 1 diabetes, thereby reducing the likelihood that the person would progress to developing diabetic ketoacidosis (DKA) prior to diagnosis.

Another study that used data from the United States and Western Europe, found that screening children for type 1 diabetes-associated islet autoantibodies at ages 2 and 6 years would identify most of those who go on to develop the disease by mid-adolescence.

However, using a genetic risk score at birth to identify those who would go on to autoantibody testing is potentially a more cost-effective approach, William A. Hagopian, MD, PhD, director of diabetes programs, Pacific Northwest Research Institute, Seattle, Washington, told Medscape Medical News.

The score — based on human leukocyte antigen (HLA) haplotypes and their interactions as well as non-HLA genes — can stratify nearly 80% of childhood type 1 diabetes within the top 10% of all newborns. Thus, only the top 10% would then go on to receive the more expensive autoantibody testing.

"I've been working with UK colleagues for the past 3 to 4 years to develop a strategy using genetic risk scores followed by autoantibody screening. I feel strongly that that's the cost-effective way to go. It's relatively inexpensive, scalable, and can be applied commercially in newborn screening labs. To be successful an approach must be cost-effective. Payors are willing to pay for newborn screening, but not so much on testing 100% of kids for antibodies," Hagopian said.

He is now working with Washington State newborn screening labs to demonstrate feasibility of the approach using dried blood samples from actual neonatal screening after obtaining informed consent from the mothers in postpartum wards in several hospitals. Those found to be at high risk using the genetic risk score are contacted for follow-up with autoantibody screening. The program will continue for another year and a half. "I think it actually has a chance of being accepted into their regular program," he said.

And then, he hopes, other states will follow, and eventually, the strategy will be added to the Recommended Uniform Screening Panel (RUSP) for universal newborn screening programs, as recommended by the US Department of Health and Human Services.

"New newborn screenings for additional diseases are implemented regularly. Most are far less common than type 1 diabetes. So even if our approach is less than 100% sensitive, this condition is a lot more common than the many inborn errors of metabolism, so we're still going to be identifying a lot of cases…This is my hope for how universal type 1 diabetes screening will unfold. I see a way this may work quite well."

A Two-Pronged Approach to Screening Could Work Best

Meanwhile, JDRF, which supported the teplizumab research as well as others working in the space, is focusing on both genetic and autoantibody screening, Kowalski said.

"JDRF is working on both pathways — testing kids at birth for genetic predisposition and also antibody screening. We have huge programs focused on general population antibody screening."

Kowalski said that while the two-pronged approach certainly is worth exploring — and JDRF is doing that — he also thinks that universal autoantibody screening could be cost-effective if done efficiently, such as with less expensive assays than the one used in TrialNet.

"We have programs where you do the genetic screening and keep an eye on people. We also have programs, like the one we're funding in Germany, that are doing broad autoantibody screening of all kids. We're hopeful that will be very cost-effective if we move to cheaper assays."

He noted that the proportion of children with new-onset type 1 diabetes who present in DKA rose from 40% pre-COVID-19 to 50% during the early days of the pandemic. On the other hand, "With screening you can get that to near-zero, like they did in Bavaria. Here [in the US], one ICU visit for DKA [costs] $100,000."

While JDRF and others have been working on this for years, the new availability of teplizumab will be "multifold in helping things along...I think you're going to see a lot of work on the cost-effectiveness of teplizumab. I think the case will be pretty straightforward that there's huge upside to delaying the disease from a near-term and a long-term cost perspective. This is the first time we've had a drug out there with a price attached to it."

But it may not happen quickly, Kowalski cautioned. "I feel there's a...series of events that has to happen to drive towards universal screening. Here in the US it's complicated because we have a very discrepant healthcare system with all these different payers, public and private."

During the investor call, Hoitt said that Provention Bio is also exploring use of Tzield in younger patients and newly diagnosed patients, and the potential benefit of re-dosing or combining with other treatments.

Hoitt is an employee of Provention Bio. Kowalski is an employee of JDRF. Hagopian has reported receiving study funding from Janssen.

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.

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