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Special Report on Metabolic Disease: Intercepting diabetes
Special Report: Metabolic Disease
Researchers target autoimmunity, not hyperglycemia
By Randall C Willis
At the tender age of 11, Elizabeth Hughes Gossett was given a death sentence; she was diagnosed with diabetes. It was 1918.
At the same time, in Canada, Frederick Banting was working on the isolation of a hormone called insulin, first from the pancreases of dogs and later from fetal calves. Between late 1920 and 1921, alongside Charles Best, J.J.R. Macleod and James Collip, Banting was able to reproducibly isolate insulin, and in early 1922, he set up a clinical practice that ultimately saved Gossett’s life.
A century later, insulin still holds center court in the treatment of diabetes and management of hyperglycemia, particularly for patients with type 1 diabetes (T1D). Technical innovations have occurred since those early days, but treatment remains lifelong. Over her remaining 58 years of life, Gossett received approximately 42,000 insulin injections.
Beyond glycemic control
“Obviously, insulin was a revolution when it was first isolated and then later synthesized,” says Francisco Leon, co-founder and chief scientific officer of ProventionBio. “It was a lifesaver and so many people are alive today thanks to insulin.”
It was just natural, he continues, that industry would focus on improvements in insulin—improving how it’s delivered, developing new devices and improving how to measure glycemia.
“But the question is: Alright, we can control T1D, but how well can we really control it?” Leon asks. “When you look at HbA1c levels, they are elevated in 70 percent of subjects despite insulin. So clearly, in the real world, insulin is not offering full satisfactory resolution of the problem.”
He also notes that insulin doesn’t prevent many of the complications—cardiovascular and metabolic, mostly—associated with T1D, complications that shorten lifespans.
Also, patients can expect to have lifespans of 10 to 16 years less than if they didn’t have diabetes, he adds, noting that this, too, “is despite insulin, so there is an unmet need.”
Provention was founded on the question: Can we act earlier in the disease process?
“I talk to patients about this so many times because they always ask us, why haven’t you cured this disease yet or why haven’t you prevented this disease yet?” recounts Chantal Mathieu, head of Clinical Endocrinology at KU Leuven and coordinator of INNODIA, a T1D public-private partnership. “I always say it’s not because of lack of trying.”
She offers several reasons why T1D proves particularly challenging.
Firstly, it affects such a small tissue, the insulin-producing beta cells, which are well hidden within the islets of Langerhans, which are buried within the pancreas, which is buried deep in the abdomen by more predominant organs.
“If you are studying arthritis, you just have to look at the joints to see if they’re inflamed,” Mathieu explains. “You can stick a needle in them and you can get tissue. Beta cell is less than one percent of the whole tissue of the pancreas, and it’s very well hidden away, so we cannot access them.”
Furthermore, by the time clinicians begin to see changes in blood glucose levels, more than 70 percent of the beta cells are dysfunctional or destroyed.
“We need better ways of imaging what is happening with the beta cell,” Mathieu presses. “And we need faster ways of testing interventions that can point the way to what we want to do.”
This was partly the impetus behind INNODIA, which has undertaken integrated biomarker research using peptidomics, proteomics, immunomics and many other omics.
According to Leon, there are 40 to 50 genetic markers for predisposition to autoimmunity and T1D. But even with these markers, disease onset doesn’t typically occur without a second trigger, such as changes in immune regulation or viral infection (more on that later).
“When the immune system tries to eliminate the Coxsackievirus B, which goes into the beta cells that make insulin, the collateral damage is the destruction of the beta cells,” he explains. “And because there is loss of tolerance against the beta cell antigens, there’s also destruction of uninfected beta cells.”
It is this destruction that launches the tetrad of key biomarkers: autoantibodies against insulin, insulinoma-associated protein 2 (IA-2), zinc transporter 8 (ZnT8) and glutamic acid decarboxylase (GAD65).
“Once you have two of the four autoantibodies, you have the disease,” Leon continues. “There’s no way back. There is no restoration of tolerance, and people will progress towards destruction of beta cells and eventually clinical T1D.”
So, how do you treat somebody who doesn’t know they need treatment?
“We believe we are entering a new era in medicine here, when people may be able to be treated before the disease starts,” says Leon, “like [the film] Minority Report, just for medicine.”
It will require screening asymptomatic people at high risk of developing disease, which he suggests is already happening in some European countries—Finland, for example, already screens half their population for T1D autoantibodies—but may see significantly slower uptake in North America.
Even if we do manage to diagnose T1D before it becomes problematic, however, how do we interrupt or reverse the pathology?
Find and replace
Recent efforts to reverse the damage caused by beta cell loss by companies such as Sernova, Sigilon and Viacyte have attempted to leverage both stem cell and cell encapsulation technology to replace the missing cells.
“The strategy here is as long as you can eliminate cell-cell contacts—between the host tissues and your graft cells—you will protect against the adaptive immune destruction, allograft rejection or autoimmunity,” explained ViaCyte’s chief scientific officer, Kevin D’Amour, in the September 2019 DDN Special Report on Stem Cells. “So, the materials we use are blocking cells, but they’re wide open from a molecular perspective, so even large molecules and antibodies can flow through.”
The effort continues to be challenged by finding the right balance between porous enough to allow influx of nutrients and outflow of insulin, while still protecting the cells from attack.
With the support of Altucell, Pai Montanucci and colleagues at University of Perugia recently described their efforts to avoid immune assault by combining pancreatic islet-derived progenitor cells with Wharton Jelly-derived adult mesenchymal stem cells, encapsulating the combo in alginate.
Immunocytochemistry showed that the aggregates produced insulin, glucagon and somatostatin, and the researchers were able to reverse hyperglycemia in NOD mice with recent onset diabetes. They suggested the system was able to “freeze” the autoimmune process as the stem cells promoted Treg expansion, thereby creating a tolerogenic environment.
Other groups, meanwhile, are exploring opportunities to alter the remaining alpha cells—responsible for producing glucagon—to take on the missing beta cell function.
In 2019, Universidad Miguel Hernández’s Ivan Quesada and colleagues reported on their efforts to understand alpha cell development in response to experimental autoimmune diabetes (EAD).
Using the RIP-B7.1 mouse, which they felt better mimicked autoimmune destruction of human beta cells than NOD or STZ-induced mice, the researchers found that diabetes onset led rapidly to an increase in bi-hormonal cells expressing both glucagon and insulin. They likewise noted an increase in alpha cells expressing PDX1, a transcription factor specifically expressed in beta cells, highlighting alpha-to-beta cell transdifferentiation.
“Our findings indicate that, in autoimmune diabetes, alpha cells are facing an intense regenerative state in an effort to maintain alpha cell mass and/or to sustain a cell pool directed to regenerate beta cells,” the authors concluded. “These results also support that pancreatic alpha cells present a significant capability to adapt to EAD, and that this plasticity may be potentially used as an approach to beta cell regeneration in T1D.”
Pursuing a similar goal, Marta Vives-Pi of Autonomous University of Barcelona and colleagues reported they could ameliorate T1D hyperglycemia in mice using the GLP-1 analogue liraglutide, a drug more commonly associated with type 2 diabetes.
Using a systems biology approach to drug repositioning, the researchers curated a library of proteins, seeking those involved in mechanisms of beta cell regeneration, including transdifferentiation, neogenesis from ductal precursors and beta cell replication.
In STZ-induced mouse models, the researchers found that liraglutide improved blood glucose levels and increased beta cell mass, although this effect was lost after treatment withdrawal. They also noted the presence of bi-hormonal islet cells, but again, only during treatment.
“It is reasonable to speculate that the continuous presence of liraglutide is required for the maintenance of islet beta cell mass by promoting the main mechanism responsible for the improvement of blood glucose levels in treated mice, at least during the first 30 days of treatment stages,” the authors suggested.
Moving to autoimmunity
But whether you’re looking at transplantation of ex-vivo-produced beta cells or transdifferentiation of alpha cells to beta, the challenge of autoimmunity is ever present.
“I think that’s the problem also with organoids,” says Astrid Doerner, study director at Crown Bioscience. “I would imagine that even if you transplanted them into the pancreas, and if you even get proper engraftment and vascularization, if it’s still the same individual, you run into the same problem as organ transplantation.”
“You would have to suppress the whole immune system,” she adds. “Otherwise you’ll get similar reaction again.”
Thus, rather than focus on the beta cells, other organizations like ProventionBio are focusing on the immune response and the challenge of autoantigens.
In the 1980s, says Mathieu, clinicians gave cyclosporine to patients newly diagnosed with T1D to modulate autoimmunity. Others have tried bone marrow transplantation to arrest beta cell destruction.
“And more recently,” she adds, “short-term interventions with compounds like anti-thymocyte globulin or anti-CD3 antibodies like teplizumab have given clinicians the ability to freeze destruction for months or years.”
Teplizumab is at the heart of the disease interception component of Provention’s approach to T1D.
“We believe anti-CD3 is a very logical choice for T cell-driven autoimmunity because CD3 is the main activator of T cells,” Leon explains. “And it was found that you could treat T cell diseases by either depleting the T cell or by providing a deactivation signal to the T cells.”
Numerous earlier efforts to apply anti-CD3 immunotherapies to T1D met with frustration, however, as early promise gave way to impenetrable toxicity issues.
According to Leon, many of those early molecules and the ones still being developed in cancer are immune depletion agents, which trigger cytokine release as they kill immune cells and increase the risks of infection. Teplizumab has a different mechanism of action.
Engineered by Jeffrey Bluestone at the University of Chicago and later at the University of California, San Francisco, teplizumab is designed to provide the deactivation signal, converting autoreactive T cells into inactivated T cells.
“He modified the antibody not to bind to Fc receptors, which are the responsible party for cytokine release and cell depletion,” explains Leon. “So he achieved for the first time an anti-CD3 that was well tolerated and achieved its target results in clinical studies.”
Across three Phase 2 trials, teplizumab demonstrated significant protection of beta cells in newly diagnosed T1D.
Macrogenics licensed the antibody and initiated the Phase 3 PROTÉGÉ study with Eli Lilly. Unfortunately, as Leon presses, the FDA required the primary endpoint of the study to include the change in HbA1c rather than C-peptide, which had been used in Phase 2 studies.
“If you do a trial right, you shouldn’t see a difference in HbA1c between active and placebo because physicians treat to a target of HbA1c by giving more or less insulin,” he continues. “So, what you should see is the same HbA1c with less insulin use, and that’s what was seen with teplizumab in clinical studies.”
PROTÉGÉ missed its primary endpoint, which Leon says was devastating for the field as results supported a positive impact on beta cell protection, based on C-peptide, causing Lilly to step away.
Provention picked up the license and is in the process of repeating the Phase 3 study in newly diagnosed patients (PROTECT) after making improvements in the trial design and going back to C-peptide as the primary endpoint.
Macrogenics had also licensed teplizumab to TrialNet to conduct the TN-10 prevention trial.
The study was performed on nondiabetic relatives of people living with T1D, who had at least two diabetes-related autoantibodies and showed evidence of dysglycemia in an oral glucose tolerance test. And although the ages of the subjects ranged from eight to 50 years, 72 percent were younger than 18 years.
When the study ended, the median time to T1D diagnosis was 48.4 months in the teplizumab group versus 24.4 months in the placebo group. Similarly, roughly twice as many subjects on teplizumab were diabetes-free (57 vs. 28 percent).
In June, at the ADA conference, the researchers announced that another year had been added to the median time to diagnosis. They also suggested that not only did teplizumab slow the decline of C-peptide levels, but in some cases, the decline reversed, indicating possible recovery of dysfunctional beta cells.
“We moved straight into filing a rolling Biologics License Application,” Leon says. “We plan to complete the submission in the fourth quarter of this year for the delay or prevention of clinical T1D in subjects with Stage 2 T1D, who are at risk of progressing.”
Imcyse is taking a different approach with its Imotope platform, using the mechanism of autoimmune targeting against itself by modifying the autoantigen with a thioreductase motif.
In this case, when antigen presenting cells (APCs) deliver the modified autoantigen to naïve CD4 T cells, the thioreductase motif directs T cell maturation toward a cytolytic phenotype. These cells then destroy, in an antigen-specific manner, all APCs presenting the same autoantigen, as well as other effector T cells interacting with the same APCs.
In 2016, Jean-Marie Saint-Remy and colleagues at Imcyse and University of Leuven described the impact of this approach in mice, using the GAD65 autoantigen.
They reported that not only was the diabetes-free survival rate significantly increased in immunized mice (82 percent vs. 38 percent untreated), but also GAD65-induced cells were able to induce apoptosis in APCs presenting the peptide.
Perhaps just as importantly, the researchers also saw signs of the bystander effect in immunized mice as the GAD65-induced cells triggered the destruction of other autoantigen-presenting APCs.
“The present technology using a single epitope of a single beta cell antigen potentially prevents responses toward alternative epitopes and perhaps even alternative antigens, provided the latter are presented by the same APC,” Saint-Remy and colleagues wrote. “This condition is easily achieved considering that the main site at which the cCD4+ T cells control the immune response is in the lymph nodes draining the diseased organ, a location at which much of the autoantigens released into the affected organs are processed for presentation to the immune system.”
Last September, Jean Van Ramplebergh, vice president of clinical and regulatory at Imcyse, presented the results of a Phase 1b trial of the insulin-based Imotope IMCY-0098 at the EASD congress in Barcelona. These data suggested that IMCY-0098 was safe in patients.
The company is currently preparing for its follow-on clinical trial IMPACT, which Van Ramplebergh says will have an adaptive design, allowing the company to adjust study parameters as new results come in or milestones are achieved.
A key focus for this study will be the search for biomarkers, which was not as successful as expected in earlier studies, in part because of the status of the appropriate technologies at the time.
“Now, we can benefit from other and more precise, more specific techniques to really go and look at what is the immune response after a certain number of injections, after a certain dosing, and based on that, decide what to move forward and how to test then more adults and adolescents,” Van Ramplebergh continues.
An additional motivation for the biomarker analysis is Imcyse’s participation in INNODIA, which, he presses, has led the company to collect many more samples that they would never collect if left to their own devices.
“This will allow [INNODIA members] to build a biobank through all the different studies and add on this collection to be able to follow all these all these markers,” he explains. “That’s something that you would probably not do or not so extensively on your own, because you would probably not elaborate on so many aspects.”
Also looking to turn the immune system against itself, City of Hope’s Bart Roep and colleagues at Leiden University Medical Center recently reported on their efforts to transform tolerogenic dendritic cells with proinsulin peptide.
“We want to negotiate with the immune system rather than bombard it into submission, because the latter may affect your chances of fighting off cancer and infections, including coronavirus,” Roep explained in an announcement. “In addition, this is the first time that physicians tried to intervene in T1D years after diagnosis.”
In a small Phase 1 study in patients with long-standing T1D, the researchers found that both beta cell function and overall diabetic control remained stable throughout the six months of monitoring.
“Most importantly, there were no signs of systemic immune suppression, no induction of allergy to insulin, no interference with insulin therapy, and no accelerated loss in beta cell function in patients with the remaining C-peptide,” the authors reported. “Our results warrant subsequent clinical testing in patients with a shorter diagnosis of T1D and with preserved C-peptide production, to assess whether this novel immune intervention strategy is able to delay or halt progressive loss of beta cell function.”
Taking the vaccine concept one step further, Provention is targeting one of the other factors believed to be involved in the onset of T1D pathology: infection with Coxsackievirus B.
The infectious disease work started in Finland, explains Leon, which struggled with elevated rates of autoimmune disease compared to neighbouring Russia.
“Finland created a national program called DIPP—Diabetes Prediction and Prevention—which followed 220,000 consecutive newborns,” Leon recounts. “They collected samples from the mothers and from the babies every three months, and followed those with genetic predisposition to T1D until they were at least 15 years of age.”
The researchers then examined the samples from those who developed clinical T1D and found that 60 percent of those children had experienced a persistent infection with Coxsackievirus B within the six to 12 months preceding onset of clinical T1D.
The later TEDDY study of 400,000 children performed a complete virome analysis to look for infections associated with T1D, and Coxsackievirus B came to the top.
“A consortium called nPOD—Network for Pancreatic Organ Donors—collected pancreases from patients who donated their organs to science, and found 60 percent of those subjects had Coxsackie B inside their beta cells,” Leon continues.
Other work showed that the virus uses a cell receptor expressed in insulin granules, closing the loop on why Coxsackievirus B infects beta cells.
A vaccine against Coxsackievirus B being developed by Vactech caught the eye of Provention co-founders Leon and CEO Ashleigh Palmer, who were then focused on celiac disease through their previous company Celimmune. They licensed the vaccine as Provention’s first asset.
In May, Karolinska Institutet’s Malin Flodström-Tullberg and colleagues described their evaluation of Provention’s polyvalent Coxsackievirus B vaccine candidate in non-human primate and mouse models.
Not only did the vaccine protect the animals from infection, but also completely protected permissive mice from developing virus-induced diabetes. Unlike in the unvaccinated controls, the islets of immunized mice showed strong staining for insulin and glucagon.
“Our results provide a solid scientific basis for human trials with Provention’s PRV-101 vaccine,” said study co-author Tampere University’s Heikki Hyöty, who is also a co-founder of Vactech, in announcing the findings. ”Our observation showing that this prototype works in macaques is highly important since their immune system closely resembles the immune system of humans.”
According to Leon, Provention is in the process of initiating a first-in-human clinical trial, which will start by the end of the year in Finland.
“This is potentially the first ever vaccine for Coxsackie B and is also potentially the first ever vaccine designed for autoimmunity,” he says. “In addition to preventing the acute infection by Coxsackievirus B—which can cause myocarditis, pericarditis, meningitis—the virus has these potential complications of celiac and T1D, which we want to prevent.”
Viruses are unlikely to be the only microbes influencing the autoimmune process and subsequent glycemic control.
“Microbiome in diabetes research has been the focus for our group for many, many years,” says Jim Wang, senior vice president at CrownBio. “People realize that gut microbiome impacts the glucose regulation and also impacts the pancreas function.”
And as Bernat Olle, CEO of Vedanta Biosciences, suggested in the DDN Special Report on Microbiomics in January 2019, the microbiome also significantly influences the immune system.
“It turns out that about 80 percent of the immune cells in the body are in the gut,” said Olle. “They have to patrol all of the populations of microbes that are sending signals to the body and make sure that they’re behaving themselves properly.”
Accessing and profiling the gut microbiome in the experimental setting continues to be a challenge, Wang adds, and this is vital to understand the impact of therapy or diet in these models.
“One conventional method is to use the endoscope to insert into the gut to take some samples to measure and profile those microbiomes,” he says. “But that’s invasive and difficult and expensive. It’s not quite feasible to do that in humans and in the animal models.”
Thus, CrownBio and its CVMD group have been collaborating with a company to develop a simple capsule-like device that a patient or test animal—right now, nothing smaller than a monkey—can swallow.
Another issue raised by Doerner is experimental and model consistency.
“We moved facilities in San Diego and that was a huge challenge for our team,” she recounts. “We had to make sure that we had a working IBD [irritable bowel disease] model and other models. So, we basically tried to transfer the microbiome.”
Part of that effort, she describes, involved moving old bedding to the new facilities, simply to maintain continuity.
“Unfortunately, the vendor is not always having a consistent microbiome either,” she adds. “So, we we’ve had issues that literally had to try my some different vendors to get a reliable model.”
Doerner gives the example of their collagen-induced arthritis model, where changes in the microbiome can translate to 30 percent of mice getting disease or 80 to 90 percent of mice.
“We had to do a lot of tweaking to make sure that it keeps consistent, so we can actually offer that to our clients,” she says. “If it only works in 30 percent of the mice, that’s not a good starting point for [clients].”
Another significant challenge comes in making sure you are studying the microbiome that matters most to drug development: the human gut microbiome.
According to Doerner, companies have expressed interest in establishing human microbiomes in mice for their IBD models, but, she adds, that is not an easy task.
“First of all, you have to have mice that don’t have a microbiome or get rid of the microbiome they have,” she says. “And then, how stable is the microbiome from a human in a mouse over time? So, I think there are a lot of challenges.”
Those challenges aside, microbiota profiling has started to show subtle differences between the microbiomes of subjects with islet autoimmunity and T1D and those without.
As was recently reviewed by Emrah Altindis and colleagues at Boston College and Linköping University, two studies performing metagenomics sequencing of stool samples from the TEDDY study identified several bacteria that weakly correlated with T1D onset.
Similarly, the DIABIMMUNE study of approximately 1,000 children followed from one month to three years of age observed diminished microbial diversity and reduced bacterial gene content in autoantibody-positive children as they progressed toward T1D.
“A functional analysis found that bacterial metabolism in autoantibody-positive subjects is characterized by a higher prevalence of genes involved in sugar transport and a lower prevalence of genes associated with amino acid biosynthesis compared to subjects that did not seroconvert,” recounted Altindis and colleagues.
The authors are quick to note, however, that despite the growing catalogue of microbes identified as more prevalent in T1D, any causal relationship is poorly understood. And in fact, the identity of the microbe may be less important than its function in the gut ecosystem.
Looking to turn a possible hazard into a weapon, KU Leuven’s Conny Gysemans and colleagues reported on their efforts to restore immune tolerance using Lactococcus lactis as a delivery vehicle for the proinsulin antigen as well as the cytokine IL-10 and combining that therapy with low-dose teplizumab. For their study, they used mice with long-duration T1D that received insulinitis-free syngeneic islet transplants and monitored return of hyperglycemia.
They noted disease recurrence within about 8 days for untreated mice, whereas 32 percent of anti-CD3-treated mice and 48 percent of mice receiving combined treatment were normoglycemic until six weeks after treatment initiation. As well, sustained tolerance was associated with reduced autoreactive CD8+ T cells and increased insulin-reactive Foxp3+ CD4+ Tregs, particularly around the islet grafts.
“An important observation is that longer disease duration, specifically to the point of lacking measurable beta cell function, before therapy initiation diminished therapeutic success,” the authors noted. “However, [complete treatment] mice were significantly better at avoiding disease recurrence, and therapeutic success was less influenced by disease duration.”
In August, Precigen ActoBio, the company responsible for the L. lactis component (AG019) of the study through its ActoBiotics program, announced completion of the Phase 1b portion of its ongoing clinical trials of AG019 monotherapy versus early-onset T1D.
Aside from showing good safety and tolerability, AG019 slowed C-peptide decline in 67 percent of adult subjects and in some cases, C-peptide stabilization at six months. As well, collaborators showed the monotherapy increased the frequency of islet-specific Tregs.
“These preliminary data for the Phase 1b monotherapy portion of the study are very promising,” said Pieter Rottiers, CEO of Precigen ActoBio and co-author of the preclinical study. “In particular, the encouraging trend we are seeing in C-peptide levels indicates potential treatment-related disease modification over time. We look forward to providing expanded data in the coming months for both the AG019 Phase 1b monotherapy and the Phase 2a combination with teplizumab.”
Although most of these interventions are still early-stage, perhaps we are finally ready—a century on—to make headway against the onset of T1D, providing therapies equally as transformative as insulin to the next Elizabeth Hughes Gossett.
People who need people
Given the current treatment options, a diagnosis of type 1 diabetes represents a lifelong burden of glycemic control efforts and constant concerns about secondary, possibly life-threatening complications. For this reason, a key feature of Chantal Mathieu’s involvement as coordinator at INNODIA is the role of the patient advisory committee in helping the organization to decide where its T1D research should go.
“I’ve done for 30 years clinical trials and sometimes when I try to recruit people, they look at me and they ask: What is this?” she recounts. “This is not feasible. This is too much blood. This is too frequent.”
Too often, she says, when patients ask clinicians what something means, the clinicians misinterpret the request as the desire for clarification, for the same information using different words. Instead, patients are asking why something is being done. What value the therapy brings. What will be different at the end of the day.
“I have learned so much from them, because they look at this very critically,” she acknowledges. “So, I really like having these people living with the disease involved in our projects.”
The co-founder and chief scientific officer of Provention Bio, Francisco Leon, offers a similar perspective on the importance of patient involvement.
“We have colleagues who have T1D in their families,” he explains. “And they remind us every day what it is to live with T1D and the practical realities of the disease and celiac as well. So, we really try to consider and take into account patient preferences and needs as much as possible in our trials.”
And being responsive can come in the smallest gestures.
The dosing schedule for teplizumab was originally 14 days, says Leon, but families found that burdensome as it meant losing two weekends.
“We found a way, doing PK/PD modeling, to compress the 14 into 12 days so that it’s only one weekend, but giving exactly the same amount of drug by increasing the dose a little bit,” he explains. “And we found that this method, which we are using in PROTECT, gives patients better quality of life by not having to worry about the second weekend.”
Imcyse’s vice president of clinical and regulatory, Jean Van Ramplebergh, shares their enthusiasm.
“Even when I was at Sanofi, I’ve always been a big fan of involving patients and patient committees,” he says. “I have experienced just over the last two, three months how helpful [the committee] was and how proactive they are when we reach [out] to them.”
When it comes to recognizing that all of this work—mechanism of action, dosing strategy, formulation, etc.—is meaningless in the absence of the unique perspectives of those living with T1D, the researchers speak with one voice: the patient’s.