Pramana’s Biotech Discoveries Could Spark a Revolution in Type 1 Diabetes Management
Founder Diane Alexander is revolutionizing drug discovery and development for diabetes from the inside out. At her biopharmaceutical company, she gives scientists freedom to operate with financial equity in their discoveries. She encourages new takes on previous research. The result? Breakthrough possibilities for T1D management.
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Challenge
One hundred eighty decisions. On average, people living with Type 1 diabetes (T1D) make 180 extra decisions about their health each day than someone without diabetes. That’s equivalent to around one decision every five waking minutes. How much and when to inject insulin, what to eat, how and when to exercise, whether to go out with friends, what bedtime rituals are practiced — decisions in the form of manual course corrections are constantly required to curb episodes of high and low blood sugar levels for people living with Type 1 diabetes.
Each health decision is like slicing the rudder of a boat through choppy waters, attempting to course correct a wayward direction. Redirect too much and you end up with too much insulin in your body, risking low blood sugar, or hypoglycemia. When this happens, individuals can experience symptoms like rapid heartbeat, shaking, and sweating. As hypoglycemia worsens, symptoms can include confusion, slurred speech, and even a loss of consciousness or seizures.
One of the most common emergencies for people with T1D, the average person living with Type 1 diabetes experiences about two episodes of hypoglycemia per week, a figure that has not changed substantially in the last 20 years. Additionally, 25% of people living with Type 2 diabetes develop recurring hypoglycemia within four to five years of their diagnosis. Combined, that’s roughly 100 million people living at risk of hypoglycemia. Because of the innumerable combinations of their 180+ health decisions, there are many different regimens for treating hypoglycemia in people living with diabetes.
But what if there was a safe oral once-daily medication that could prevent blood sugar dips and spikes for every person living with diabetes who suffers from hypoglycemia? Something that could eliminate all or most of those 180 extra decisions each day…something that could truly enable the achievement of glycemic control when taken with insulin?
Enter Pramana Pharmaceuticals, Inc., and its boundary-pushing biotechnology. As a part of the company’s impressive portfolio of biological drug candidates, Pramana has driven a molecular innovation that has the potential to give the 100 million individuals who suffer from hypoglycemia back control of their lives.
Origin Story
Pramana’s origin story starts simply — “three senior scientists and a couple of investment advisors meet over coffee..” — but with an outcome that could save lives. In 2015, Diane Alexander, CEO & Co-founder of Canada-based Pramana, met with three medicinal biochemists over a cup of coffee to propose a deal. A serial entrepreneur and senior investment advisor with over 25 years of capital markets experience, Alexander had gathered the accomplished scientists to discuss one of her favorite investment arenas: biotechnology. She says she’s always had a penchant for the field, drawn to the positive impact that biotech innovation can have on health outcomes.
“Along the way, I’ve met some fascinating scientists,” Alexander says. “Particularly, scientists who’ve led medicinal chemistry programs that produced valuable drugs. Drugs that helped millions of people.”
When she met with three such scientists in late 2015, there were several targets of interest, including some low-hanging fruit to be had in molecular research surrounding Type 2 diabetes (T2D). Big pharma had expressed interest in a particular protein receptor that could be developed into a therapeutic to address large, unmet needs in diabetes treatment. The protein, or target, was GPR119. Substantial investment was made in advancing studies that could prove GPR119’s role in managing T2D. While the target proved to be a safe and well-tolerated conduit for T2D management — with some therapeutics advancing to Phase II clinical trials — nothing seemed to catch the eye of big pharma.
“There’s a lot of competition in T2D,” explains Alexander. “It’s more difficult for solutions to go to market, and in the case of GPR119 the historical efficacy data was just not robust enough.”
Sitting across from the scientists at the table, Alexander posed the question, “Why? Why wasn’t GPR119 successful, given it showed such therapeutic promise?” To get to the bottom of it, she proposed a partnership with the scientists. She sketched out a roadmap on the back of a napkin, detailing a timeline and resources to develop a proof of concept for GPR119’s use in managing T2D along with other indications for the target in metabolic disorders. The goal was to discover and develop better molecules than had been previously interrogated. In addition, she offered them equity in the company.
“There was an urgency to our conversation, but I didn’t want them to have scientific boundaries,” Alexander says. “I wanted to enable them to be in an open environment to go after whatever health targets they were interested in.”
Her theory was that if the scientists were given the freedom to research outside of the biases inadvertently introduced in legacy T2D studies, and they were given equity along with capital in the company that was backing them, she could spur a new level of innovation.
In 2016, the scientists began their research under the Pramana banner. By 2017, they’d filed a provisional patent for GPR119 to advance their pre-clinical research. Then, in 2019, Alexander was introduced to a body of work that suggested GPR119 had been misinterpreted. Further discovery of new therapeutics with that molecule would require a significant change of direction — from T2D therapy to an indication prevalent in as many as 90% of people living with T1D and 25% of people living with T2D.
It was the kind of pivot that large corporate research teams struggled to make but that Pramana was designed for. The team shifted directions, leading them to a breakthrough that would not only secure the company’s future but chart a new course of discovery in T1D management and hypoglycemia prevention.
Under the Hood
In her early conversations with big pharma clients to gauge interest in Pramana’s research, Alexander recalls being told two things: “You’re crazy to go after GPR119 again” and “Go talk to David E. Kelley, MD.” Kelley was a senior leader of Merck Research Laboratories, a renowned multinational pharmaceutical company dating back to 1668. He was known for his novel approaches in drug discovery and early clinical development for diabetes and obesity. Alexander listened to the latter bit of advice. In 2020, she invited Dr. Kelley into Pramana’s fold. She dismissed the naysayers who felt GPR119 research had run its course. In fact, she embraced the notion that perhaps GPR119 was misinterpreted.
Dr. Kelley’s legacy research in GPCRs and insulin ultimately inspired Pramana’s fresh look into the otherwise tired space of T2D molecular inquiry. While other biopharmaceutical labs’ T2D research stated that GPR119 was predominantly expressed in beta cells — the producers of insulin — Dr. Kelley’s studies suggested something very different. By 2021, Pramana’s growing team of medicinal biochemists was able to prove Dr. Kelley’s hypothesis: It wasn’t the beta cell where GPR119 was mostly expressed. It was the alpha cell.
“It was new information in the world of metabolic disease research,” Alexander says. “Proving that GPR119 is mostly expressed in the alpha cell shifted our focus from Type 2 to Type 1 diabetes. It opened the doors for hypoglycemia prevention and potentially to other novel therapies for us.”
As a “g protein,” the GPR119 acts as a molecular switch inside cells, transmitting signals from outside a cell to its interior. In this case, GPR119 monitors mechanisms that make sure glucose (i.e., sugar) amounts stay level. To understand the protein better, scientists studied alpha and beta cells, which are found in the pancreas and play crucial roles in regulating blood sugar levels in our bodies. Beta cells produce insulin, the hormone that plays a vital role in lowering blood sugar levels. Alpha cells, on the other hand, produce glucagon, the hormone that is released into the bloodstream when the body needs to increase blood sugar levels. Together, the two hormones work together to maintain the balance of blood sugar in our body, ensuring it stays within a healthy range.
Like a boat directed by the wind or current, those without diabetes have an intrinsic off-switch; their pancreas can “shut off” insulin production very quickly. For people with T1D, their pancreas doesn’t make insulin, which is the hormone the body needs to convert food into energy. To compensate, they take insulin to manage their blood sugar, staving off potential fainting spells during the day and scary diabetic seizures or even comas at night. But if the amount of insulin they take doesn’t match the amount their body needs, they could end up with too much insulin in their system creating low blood sugar levels, leaving them prone to dangerous symptoms once again.
Alexander’s team has developed what they believe is a “best-in-class” version of the GPR119 molecule that potently activates glucagon when it gets low, working as an adjunctive therapy to insulin injections.
“It has the potential to help those living with T1D maintain that even surf level,” Alexander says. “Not oversteering or overcorrecting, but small adjustments toward the center.”
As an added bonus — based on supportive early research — Pramana’s GPR119 molecule has proven to work autonomously on the alpha cell to control glucagon, so it would not trigger hyperglycemia. And, unlike competing innovations, Pramana’s compound would lend itself toward a pill versus an injectable.
To further validate these early promises, Alexander and the Pramana team are laying the groundwork for future clinical development. They are already designing robust Phase 2 clinical trials, which would also establish expectations for time and range. Ideally, the team wants to show it is possible to take a pill once a day to keep blood sugar levels in check. A couple simple decisions — take a pill and take your insulin — versus 180 health decisions.
Having caught the interest of big pharma to design a clinical study, Alexander is hopeful that as long as their GPR119 compound continues to prove itself, they will be accelerated into a robust clinical program to bring the therapeutic to market “as fast as possible.”
Final Word
Since its launch in 2016, Pramana has developed a broad portfolio of millions of wholly-owned small molecules and multiple issued patents, most recently with patents issued in Europe and China. They’ve also evolved their ownership and management structure to accommodate the company’s success, ensuring each of the scientists’ ‘sweat equity’ aligns with their portion of the company’s financial equity. Part of those evolutions included naming Alexander as CEO in 2018, in addition to adding other esteemed scientists to their company roster: David Kwok, PhD, founder of British-Columbia-based Biopharmaceutical Research, Inc.; Tom Elliott, MBBS, Medical Director of BCDiabetes and faculty member of the University of British Columbia; pharma senior scientists David Kelley, MD, Nigel Beeley, PhD, Susan Hu, PhD, and James Leonard, PhD, who held senior scientific positions at Merck Research Laboratories, Arena Pharmaceuticals (acquired by Pfizer), GSK, Shire (acquired by Takeda), AstraZeneca, and Janssen Pharmaceuticals.
“Giving the scientists equity plays a significant role in Pramana’s success,” says Alexander. “It fuels their passion and creates an equitable environment for mission aligned growth.”
Alexander models the kind of transformational mindset that is needed when challenging antiquated drug therapies in the T1D space. She thinks outside of the box to bridge the gap between R&D and the grueling journey of commercializing and scaling health innovation. With its unique ownership and management structure and wealth of scientific expertise, Pramana is poised to bring a revolutionary drug to market under the T1D Health Moonshot.
Please join us in welcoming Diane Alexander and the rest of the Pramana team to the StartUp Health global community of Health Transformers.
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Published: Aug 17, 2023