Insulin at 100, Part 3: Insulin’s Uncertain Future

This content originally appeared on diaTribe. Republished with permission.

This is Part 3 of James S. Hirsch’s exploration of the riveting history of insulin, on the occasion of its 100th birthday.

Part 1: The Discovery

Part 2: Failed Promises, Bold Breakthroughs

Insulin’s Uncertain Future

Insulin

Image source: Emily Ye, Diabetes Daily

As further refinements in insulin occurred, the insulin narrative should have become even more powerful – that insulin not only saves people, but in reaching new pharmacological heights, it is allowing patients to live healthier, better, and more productive lives. These should be insulin’s glory days – as well as days of unprecedented commercial opportunity. According to the International Diabetes Federation, in 2019, the global population of people with diabetes had increased a staggering 63 percent in just nine years – to 463 million patients.

Insulin sales should be booming, with a new generation of Elizabeth Evans Hughes and Eva Saxls to tell the story. In fact, insulin sales are declining, and insulin has no spokespeople. Reasons vary for these developments, but one fact is undeniable: insulin has lost its halo.

Insulin is still essential for any person with type 1 diabetes, though even with type 1 patients, insulin is sometimes under-prescribed as doctors fear getting sued over a severe hypoglycemic incident. The belief is that patients are responsible for high blood sugars, doctors for low blood sugars.

Where insulin has lost its appeal is with type 2 patients, which has driven the diabetes epidemic in the U.S and abroad. According to the CDC, from 2000 to 2018, America’s diabetes population surged 185 percent, from 12 million to 34.2 million, and an estimated 90 percent to 95 percent of that cohort has type 2. (The global percentage is similar.) These patients have long had options other than insulin – metformin, introduced in 1995, remains the ADA’s recommended first-line agent. But as a progressive disease, type 2 diabetes, in most cases, will eventually require a more intensive glucose-lowering therapy. Nothing achieves that objective better than insulin, but insulin is delayed or spurned entirely by many type 2 patients.

Some concerns are longstanding; namely, that insulin can lead to weight gain because patients now retain their nutrients. Some type 2 patients wrongly associate insulin with personal failure surrounding diet or exercise, so they want to avoid the perceived stigma of insulin. Some people just don’t like injections. Meanwhile, other patients associate insulin with the medication that an ailing patient takes shortly before they die: insulin as a precursor to death. Some clinicians who care for Hispanic patients refer to insulin pens as las plumas to avoid using a word that carries so much baggage.

What’s striking is how dramatically the cultural narrative has changed, from insulin the miracle drug to insulin the medical curse. And where are the commercials, the movies, the documentaries, and the splashy publicity campaigns about the wonders of insulin? They don’t exist.

The greatest impact on insulin use in type 2 diabetes has been the emergence of a dozen new classes of diabetic drugs. These include incretin-based therapies known as GLP-1 agonists and DPP-4 inhibitors (introduced in the 2000s) as well as SGLT-2 inhibitors (introduced in 2014). diaTribe has covered these therapies extensively, and their brands are all over TV: Trulicity, Jardiance, Invokana, and more. They all seem to have funky names, and like insulin, they can all lower blood sugars but – depending on which one is used – some have other potential advantages, such as weight loss. (Some have possible disadvantages as well, including nausea.)

The expectations for these drugs were always high, but what no one predicted was that GLP-1 agonists and SGLT-2 inhibitors have been shown to reduce the risk of both heart and kidney disease – findings that are a boon to type 2 patients, who are at higher risk of these diseases. These findings, however, were completely accidental to the original mission of these therapies.

Insulin, the miracle drug, has been eclipsed by drugs that are even more miraculous!

Consider Eli Lilly, whose Humalog is the market-leading insulin in the United States. In 2020, Humalog sales fell 7 percent, to $2.6 billion, while Trulicity, its GLP-1 agonist, saw its sales increase by 23 percent, to $5 billion.

That’s consistent with the global insulin market. Worldwide insulin sales in 2020 declined by 4 percent, to $19.4 billion, marking the first time since 2012 that global insulin sales fell below $20 billion.

It’s quite stunning. Amid a global diabetes epidemic, and with the purity, stability, and quality of insulin better than ever, insulin sales are falling. (Pricing pressures from insurers and government payers have also taken a revenue toll.) In 2019, Sanofi announced that it was going to discontinue its research into diabetes, even though its Lantus insulin had been a blockbuster for years. More lucrative opportunities now lay elsewhere.

Falling sales may not be the insulin companies’ biggest problem. Public scorn is. Though the insulins kept getting better, the prices kept rising, forcing many patients to ration their supplies, seek cheaper alternatives in Canada or Mexico, or settle for inferior insulins. Some patients have died for lack of insulin. According to a 2019 study from the nonprofit Health Care Cost Institute, the cost of insulin nearly doubled for type 1 patients in the United States between 2012 and 2016 – they paid, on average, $5,705 a year for insulin in 2016, compared to $2,864 in 2012.

Many patients are outraged and have used social media to rally support – one trending hashtag was #makeinsulinaffordable. Patient advocates have traveled to Eli Lilly’s headquarters to protest. In March of this year, nine Congressional Democrats demanded that the Federal Trade Commission investigate insulin price collusion among Eli Lilly, Novo Nordisk, and Sanofi, asserting they “are using their stranglehold on the market to drive up costs.” The letter notes that as many as one in four Americans who need insulin cannot afford it, and at least 13 Americans have died in recent years because of insulin rationing.

The criticism has been unsparing. In April 2019, in a hearing for the U.S. House of Representatives on insulin affordability, Democrats and Republicans alike pilloried the insulin executives. At one point, Rep. Jan Schakowsky (D-Illinois) said to them, “I don’t know how you people sleep at night.”

Insulin is hardly the only drug whose price has soared, but as the Washington Post noted last year, insulin is “a natural poster child of pharmaceutical greed.”

In response, the insulin companies have adopted payment assistance programs to help financially strapped consumers. They also blame the middlemen in the system – the PBMs, or the Pharmaceutical Benefit Managers – for high insulin prices, who in turn blame the insulin companies, and everyone blames the insurers, who point the finger at the companies and the PBMs.

Drug pricing in America is so convoluted it’s impossible for any patient to accurately apportion blame, but the history of insulin explains in part why the companies have come under such attack. When Banting made his discovery, he sold the patent to the University of Toronto for $1. He said that insulin was a gift to humankind and should be made available to anyone who needs it. Insulin was always profitable for Eli Lilly and the few other companies who made it, and critics have complained that the companies found ways to protect their patents by making incremental improvements in the drug.

But for years, those complaints were easily dismissed. The companies were revered for their ability to mass produce – and improve – a lifesaving drug that symbolized the pinnacle of scientific discovery while doing so at prices that were affordable.

When prices became unaffordable – and regardless of blame – the companies were seen as betraying the very spirit in which insulin was discovered and produced, and their fall from grace has few equivalents in corporate history.

Is the criticism fair?

Hard to say, but even the companies would acknowledge that they’ve squandered much good will. Personally, I’m the last person to bash the insulin companies – they’ve kept me and members of family alive for quite some time. Collectively, my brother, my son, and I have been taking insulin for 117 years, so I feel more regret than anger: regret that at least one insulin executive didn’t stand up and say loudly and clearly:

“Insulin is a public good. No one who needs it will be without it. And we will make it easy for you.”

Insulin

Image source: Emily Ye, Diabetes Daily

Whatever that would cost in dollars would be made up for in good will – and such a public commitment would honor the many anonymous men, women, and children, before 1921 and after, who gave their lives to this disease.

The next chapter for insulin? It will almost certainly include continued improvements. Both Eli Lilly and Novo Nordisk are trying to develop a once-a-week basal insulin to replace the current once-a-day options – that would be a major advance is reducing the hassle factor in care. Research also continues on a glucose-sensitive insulin, in which the insulin would only take effect when your blood sugar rises. That would be a breakthrough, but investigators have spent decades trying to make it work.

Since its discovery, the ultimate goal of insulin has been to make it disappear, as that would mean diabetes has been cured. It turns out that insulin therapy may indeed disappear someday, even if no cure is found. Since its discovery, the ultimate goal of insulin has been to make it disappear, as that would mean diabetes has been cured. It turns out that insulin therapy may indeed disappear someday, even if no cure is found.

Stem-cell therapy has long held promise in diabetes – specifically, making insulin-producing beta cells from stem cells, which the body would either tolerate on its own (perhaps by encapsulating the cells) or through immunosuppressant drugs. Progress has been halting but is now evident. Douglas Melton began his research in this area in 1991, and in 2014, he reported that his lab was able to turn human stem cells into functional pancreatic beta cells. The company that Melton created for the effort was acquired by Vertex Pharmaceuticals, and earlier this year, Vertex announced that it had received approval to begin a clinical trial on a “stem-cell derived, fully differentiated pancreatic islet cell therapy” to treat type 1 diabetes. Another company, ViaCyte, also announced this year that it will begin phase 2 of a clinical trial using encapsulated cells in hopes that they will mature into insulin-secreting beta cells.

It may take 10 to 15 years, but leaders in the field are cautiously optimistic that a cell-based therapy will someday provide a better option than insulin.

Diabetes would survive, but the therapy once touted as its cure would be dead.

Because I have a soft spot for happy endings – and because so much of own life has been intertwined with insulin – I have my own vision for insulin’s last hurrah.

A group of researchers in Europe are conducting a clinical trial to prevent type 1 diabetes. Called the Global Platform for the Prevention of Autoimmune Diabetes, the initiative began in 2015, and researchers are testing newborns who are at risk of developing type 1 to see if prevention is possible.

And what treatment are they using?

Oral insulin.

Like the discovery of insulin itself, this effort is a longshot, but if it works, insulin will have eradicated diabetes – a fitting coda for a medical miracle.

I want to acknowledge the following people who helped me with this article: Dr. Mark Atkinson, Dr. David Harlan, Dr. Irl Hirsch, Dr. David Nathan, Dr. Jay Skyler, and Dr. Bernard Zinman. Some material in this article came from my book, “Cheating Destiny: Living with Diabetes.”

About James

James S. Hirsch, a former reporter for The New York Times and The Wall Street Journal, is a best-selling author who has written 10 nonfiction books. They include biographies of Willie Mays and Rubin “Hurricane” Carter; an investigation into the Tulsa race riot of 1921; and an examination of our diabetes epidemic. Hirsch has an undergraduate degree from the University of Missouri School of Journalism and a graduate degree from the LBJ School of Public Policy at the University of Texas. He lives in the Boston area with his wife, Sheryl, and they have two children, Amanda and Garrett. Jim has worked as a senior editor and columnist for diaTribe since 2006.

Source: diabetesdaily.com

Breakthroughs in Pancreatic Cell Replacement: The ViaCyte Interview

I recently had the opportunity to sit down with Manasi Sinha Jaiman, M.D., M.P.H., Vice President of Clinical Development, and Mark Daniels, Senior Director of Clinical Development, of ViaCyte, “a regenerative medicine company focused on delivering novel stem cell-derived cell replacement therapies as a functional cure for all type 1 diabetes and a next-generation treatment for insulin-requiring type 2 diabetes.”

They have amazing things coming down the pike, so I was super excited to speak with them:

Tell our readers about ViaCyte. What’s the company’s mission and story?

Dr. Jaiman: ViaCyte is at the forefront of regenerative medicine approaches to develop a functional cure for type 1 diabetes (T1D). We have cell replacement therapies for pancreatic islet cells contained in a small retrievable pouch implanted under a patient’s skin.

The therapy is designed to enable insulin and glucagon (the counter-regulatory hormone that treats low blood glucose) production with the implanted cells to effectively control blood glucose levels, decrease the risk of hypoglycemia, and mitigate short-term and long-term diabetes-related complications for patients.

What is exciting is that ViaCyte is the first company to advance human stem cell-derived islet cell replacement therapy capable of producing insulin in the clinic, backed by two decades of research and expertise.

We are further augmenting our therapies by optimizing both the delivery device and the cells through collaborations with industry leaders, including W. L. Gore & Associates (the makers of GORE-TEX) and CRISPR Therapeutics.

Our mission is to develop cell replacement therapies offering long-term treatment to decrease the burden of the constant management needed with T1D.

What led you to your work at ViaCyte?

Dr. Jaiman: A significant focus of my medical career has been the integration of technology and medicine to advance treatments that can change the paradigm of diabetes disease management.

My experiences both in research and actively seeing patients with T1D have given me first-hand experience in seeing the daily work required to achieve any form of glycemic control as well as the burden patients and families face from complications from hypoglycemia or DKA.

I have also been able to see the importance of innovative approaches in addressing their needs. When I looked at the ViaCyte technology, I immediately saw great potential in their regenerative medicine approach to lessen the burden of disease and improve quality of life.

Mr. Daniels: Throughout my time in the industry I have been extremely fortunate to be able to work with innovative companies advancing potential, game-changing therapies for difficult-to-treat diseases. I was attracted to ViaCyte because the bar is set high; ViaCyte is looking to develop functional cures for diseases and is not just treating symptoms.

I also believe in the potential of cell replacement therapies and that these will be a meaningful new chapter in the advancement of medical treatments.

In ViaCyte, I have also found a team of extremely gifted and dedicated scientist-coworkers who are all generous with their knowledge and completely aligned in the mission to deliver a functional cure to the type 1 diabetes community.

It is exciting to be the first company to evaluate human stem cell-derived islet cell replacement therapy for its potential to functionally cure type 1 diabetes in the clinic.

Manasi Sinha Jaiman, M.D., M.P.H., Vice President of Clinical Development and Mark Daniels, Senior Director of Clinical Development

Manasi Sinha Jaiman, M.D., M.P.H., Vice President of Clinical Development and Mark Daniels, Senior Director of Clinical Development

What exciting new developments is ViaCyte currently working on?

Dr. Jaiman: Currently, ViaCyte has two clinical cell replacement therapy candidates. First, VC‑02 PEC-Direct is a treatment comprised of pancreatic islet cells in a pouch designed to allow blood vessels to enter the device and directly interact with the implanted cells to produce insulin and glucagon.

This treatment candidate is targeted for those with high-risk type 1 diabetes (hypoglycemia unawareness) able to tolerate immunosuppression.

In contrast, our groundbreaking VC‑01 PEC-Encap device is an advanced treatment comprised of pancreatic islet cells in a pouch that fully encapsulates the cells preventing immune cells from interacting with the implanted cells, which eliminates the requirement for immunosuppressants.

We are collaborating with W. L. Gore & Associates to optimize their innovative membranes which encapsulate the cells in our implanted devices. We expect to share clinical data in the second half of 2021.

Anything new in the pipeline that people with diabetes should be especially excited about?

Dr. Jaiman: One of the challenges with cell replacement therapies is to protect against adverse reactions and rejection of implants by the body’s immune system, which serves as a defense mechanism against foreign bodies.

In collaboration with CRISPR Therapeutics, we are employing gene-editing technology to engineer cells to avoid recognition by the immune system. Our partnership is focused on advancing gene-edited allogeneic stem cell-derived therapies from discovery through commercialization with the goal of developing a potential next-generation functional cure for all insulin-requiring type 1 and type 2 diabetes.

Mr. Daniels: With our preclinical candidate, VCTX210 PEC-QT, pancreatic islet cells would be in the same pouch as PEC-Direct, allowing the implanted cells to interact directly with blood vessels, an approach intended to enable robust and consistent engraftment.

Yet by designing the cells to be immune-evasive through CRISPR Therapeutics’ gene editing we would expect to eliminate the need for immunosuppressants as are required with PEC-Direct. We look forward to sharing more about this unique program in the future.

Photo credit: ViaCyte

Where do you envision ViaCyte and people’s lives affected by diabetes in five years? Ten years?

Mr. Daniels: This year marks the 100th anniversary of the development of therapeutic insulin to regulate blood glucose, yet dependency on tedious insulin injections are still a common course of treatment for many living with type 1 diabetes.

Within the next five years, we envision delivering significant progress in later clinical-stage studies with increased time in range, reduction in hypoglycemic events, and reduction in (or elimination of) the need for insulin injections in patients following our cell replacement treatments as we move toward making these therapies more widely available.

Dr. Jaiman: Within five years, we expect to be moving through the final phases of our regulatory process for our human stem cell-derived islet cell replacement therapy enabling availability more broadly for patients with type 1 diabetes.

It is our hope that within a decade, cell replacement therapy will offer longer-term treatment, easing the burden of constantly monitoring blood glucose. A functional cure will no longer be a dream, rather, a reality.

Is the ever-elusive cure on the horizon? A functional cure?

Dr. Jaiman: Yes, we believe a functional cure is on the horizon!

ViaCyte is focused on advancing cell replacement therapies toward a functional cure with a combination of implanted cells and device engineering.

This cell replacement therapy could represent insulin production protected from the immune system in a way that totally mitigates the underlying disease. Our technology is designed to safely implant the missing cells that make insulin and glucagon – that’s the breakthrough that gets us to the functional cure.

How can people with diabetes get involved or learn more?

Mr. Daniels: As ViaCyte is advancing novel treatments for type 1 diabetes, our team has been very fortunate to collaborate with multiple incredible research and advocacy organizations, including the Juvenile Diabetes Research Foundation (JDRF), Beyond Type 1, and California Institute for Regenerative Medicine (CIRM).

These organizations are focused on education and support for finding a cure for diabetes with resources for both patients and researchers on their websites. A great resource is the website www.clinicaltrials.gov – by typing “ViaCyte” into the search window, you can find more details regarding our ongoing clinical trials.

This includes details about the entry criteria to participate as well as the geographical locations of the sites (to find the one closest to you) and contact details necessary to reach out and connect with the study site team to learn more about what is involved in the study participation.

Photo credit: ViaCyte

Anything else you’d like to share?

Dr. Jaiman: Insulin treatment has largely transformed type 1 diabetes from a fatal illness to a chronic one, yet it is not a cure. At ViaCyte we recognize the long journey in the evolution of diabetes management, and we are keen to deliver a solution that offers real hope for a functional cure for type 1 diabetes.

Every single member of our team is passionate and dedicated to this endeavor. Managing diabetes can be difficult at any time, however, this past year has highlighted the need for accelerating therapeutic advancements to help reduce COVID-associated morbidity and mortality in the vulnerable population with diabetes.

With the pandemic still ever-present, we believe our mission of realizing a functional cure is even more critical for patients as they navigate living with a chronic disease during this very trying time. Our leadership team is wholly focused on improving patient care with an eye to the future.

Mr. Daniels: I am very appreciative of the Diabetes Daily team for providing this forum to connect to their community. The stories of family member’s and loved one’s experiences (including those of some of our own coworkers) with T1D resonate clearly within us and fuel our motivation behind the work we do.

It is only through the support of the T1D community and especially the valued study participants that we are able to advance this important research.

We are proud to be part of the biotech and biopharma community advancing some of the world’s most promising medical devices and therapeutic treatments. We look forward to sharing more details regarding the value of these treatments in the clinic.

Source: diabetesdaily.com

Is a Functional Cure for Type 1 Diabetes on the Horizon?

Have you heard about the ongoing research on cell-based therapies for type 1 diabetes? Dr. Paul Laikind is the President and CEO of ViaCyte, a company that aims to develop “a product that can free patients with type 1 and type 2 diabetes from long-term insulin dependence.” Hear more about the novel research and the recent […]
Source: diabetesdaily.com

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