Medicating metabolism

Novel approaches are expanding the focus on both prominent and rare metabolic disorders

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As the new year starts, many of us are still living off the sins of an over-indulgent holiday season of large meals and extreme revelling and yet, for many people, the cheer was subdued or will have longer-term implications than several bouts of indigestion and meagre efforts to lose the holiday version of the freshman-15.
For the growing numbers of people with any of a variety of metabolic disorders, those plates of food and glasses of beverage can be life-debilitating if not outright life-threatening.
Dialing in on diabetes
Diabetes. Obesity. Metabolic syndrome. Pre-diabetes.
Words we hear over and over again, alongside the word “epidemic,” as we read newspapers and magazines and listen to the news. Most of this noise is directed at the onset of and problems related to type 2 diabetes, but diabetes isn’t just one disease.
“Type 1 (T1D) and type 2 diabetes (T2D) have completely different etiologies, but end up in a similar place with regard to glycemic instability and the major micro- and macro-vascular complications arising from chronic hyperglycemia,” explains Randy Anderson, vice president of global product development and therapeutic area leader for metabolics at PPD Inc.
Arising from an autoimmune attack and relatively rapid total destruction of the insulin-producing pancreatic beta cells, T1D requires lifelong insulin replacement via injection. As Anderson explains, however, the continual balance of insulin dose and carbohydrate intake with regard to both timing and magnitude represents a major disease management challenge as patients face high daily risks of hyper- and hypoglycemia.
“Pharma companies are becoming more aware of opportunities in T1D, and there appears to be a substantial increase in products entering clinical development,” he says.
“Some are products already approved for T2D—such as incretin analogs and sodium glucose transporter 2 inhibitors—and others are being developed more concurrently for both T1D and T2D, such as glucose responsive insulins, oral insulins, beta cell regeneration growth factors, stable liquid glucagon and glucagon receptor agonists.”
In early 2013, PPD performed a survey of T1D products in development and identified public references to 94 products or product classes by sponsors (see table Type 1 diabetes products in development). This represents a significant growth, according to Anderson, as a similar survey completed in 2004 noted only 11 T1D products or product classes in development.
Unfortunately, the same period has seen a significant decrease in the number of products being developed for T2D—as Anderson explains it, the decrease is largely due to changes in the regulatory area.
Anderson describes T2D as arising from a perfect storm of factors such as excess caloric intake, low dietary intake of minimally processed fruits and vegetables and sedentary lifestyle, which collectively lead to obesity and insulin resistance.
“Insulin resistance and excess caloric intake tend to stress pancreatic beta cells with overwork and a low-level chronic inflammation that leads to functional beta cell loss,” he adds.
Historically, pharmacologic intervention in T2D focused on improving insulin sensitivity, but more recently, there has been an effort to move the goal posts earlier in the T2D etiologic pathway, in recognition of the major role of incretin hormones in satiety and glucose homeostasis.
“A number of the incretin analogs and probiotics are in development for obesity and T2D,” Anderson says. “Ironically, these treatment interventions broaden our T2D focus to include obesity and impaired glucose tolerance (or pre-diabetes), reminding us of the insulin-resistance continuum of disease first characterized by Gerald Reaven in the late 1980s as metabolic ‘syndrome X’.”
As suggested above, while T1D development enters a period of rapid expansion, T2D development appears to be slowing under the cost and risk burdens extending from improving standard of care and the December 2008 cardiovascular safety guidance from the U.S. Food and Drug Administration (FDA).
“The guidance requires that treatments for T2D must demonstrate non-inferiority in risk of major cardiovascular events relative to standard-of-care treatments for T2D,” Anderson explains. “This requirement has increased the patient-years of follow-up required for marketing approval of moderately effective treatments on the order of six- to eightfold, compared to ICH [International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use] requirements for new chemical entities.”
Anderson acknowledges that in the years immediately after the FDA guidance, there was a moderate increase in the number of products developed for T2D, but he believes that those represented late-stage products already in the pharma pipeline. The present situation seems bleaker.
“There now appears to be a growing backlog of products that have more recently completed Phase 2, but are failing to find financial support for Phase 3 development,” he suggests. “Arguably, there are few large pharma companies that can afford an additional $150 million-plus, three-plus years product-specific investment unless the product has high likelihood of success in multiple indications.”
Attacking from either end
As though in response to Anderson’s nod to pre-diabetes, David Platt and colleagues at Boston Therapeutics (BTI) are hoping to influence the development of diabetes in patients by tackling the problems of glucose flux at its source, the gastrointestinal tract.
“My background is not in diabetes or diabetes research,” explains Platt, the company’s CEO. “Our company is about carbohydrate-protein recognition, and we’re dealing with the enzyme in the intestine rather than with systemic mechanisms.”
“You don’t see drugs today in the pre-diabetic arena, which is a new indication, and there are 80 million people for which there is no drug other than perhaps metformin,” he adds. “We think that what we do will eventually end up becoming a prevention medicine for pre-diabetics.”
BTI’s PAZ320 is a dietary supplement, a glucomannan derivative, that works by blocking the enzymes involved in the hydrolysis of carbohydrates—amylase, maltase, lactase and sucrose, for example—in the digestive tract. It also binds to the polysaccharides to slow their absorption to reduce post-meal (post-prandial) glucose fluctuations.
“The idea to block sugar in the intestine is not new, and people have tried to accomplish this with many mechanisms,” Platt suggests. “What surprised me, as a carbohydrate scientist in the field, is that nobody thought to block all of the enzymes with one molecule. We have essentially developed the better mouse trap through allosteric inhibition.”
In a small clinical study by researchers at New Hampshire’s Dartmouth-Hitchcock Medical Center published last summer, approximately half of the T2D patients receiving PAZ320 showed a 40-percent reduction in post-prandial glucose levels. Additionally, the researchers noted few gastrointestinal side effects and no incidents of hypoglycemia, a dangerous side effect associated with some diabetes medications.
“I believe we are around the perfect place where we want to be with the PAZ320, which is around 40-percent to 60-percent enzyme inhibition,” Pratt says. “We’re talking insulin-like activity without doing insulin.”
“That gives you a safety factor as there is no hypoglycemia, because you don’t really lower the glucose levels. If a patient takes a drug that lowers their blood sugar, then we have enough sugar going in to prevent hypoglycemia.”
Approaching the other end of the diabetes patient spectrum and representing T1D development, researchers at Sernova are applying cell-based therapeutic technology to essentially replace the function of the pancreas in the most severely impacted patients.
“Our technologies involve a medical device that is placed under the skin,” explains company CEO Philip Toleikis. “That device is designed so that it actually acts as a scaffold for tissue to form within the device, and basically what we’re doing is forming an organ-like environment for placing therapeutic cells.”
As recently noted by diabetes specialist and cell-transplantation pioneer James Shapiro in a Sernova presentation, the current standard of care for these patients is islet cell transplantation using a method known as the Edmonton Protocol, where cells are introduced to the portal vein of the liver to set up shop in the microvasculature, releasing their endocrinological cargo into the blood stream. The challenge with this protocol, Shapiro explains, is that it is not particularly efficient and can be highly variable. He specifically likened it to a leaking bucket.
Sernova has taken the same principle and simply housed the islets in a different neighborhood, relying on a device they call the Cell Pouch. The pouch, which includes a series of polymer plugs, is inserted subcutaneously, and microvasculature is allowed to infiltrate the device. The plugs are then removed and the spaces are filled with islet cells, which interact with the tissue matrix as they would in the Edmonton Protocol.
“What we are trying to do is create a natural environment where the microvessels actually surround the islets and those islets are sitting in a tissue matrix,” Toleikis explains. “That is much more natural in terms of how the pancreas functions.”
“Not only can we place human donor cells in there but we’re looking forward to when we get a stem cell technology that can read sugar levels and produce insulin, which we can put into our device,” he adds. “And if there is then an issue with those stem cells, the entire device can be removed and another one can be placed in there again.”
That point raises a significant advantage over other methods such as the Edmonton Protocol, where the application of stem cells could be riskier as issues post-transplantation would potentially require removal of the entire liver.
Last September, Shapiro presented the preliminary results of a safety and biocompatibility study of the Cell Pouch in the first two T1D patients.
“The preliminary findings that human islets survive under the skin within the Cell Pouch pave the way for our ongoing studies in patients that will now test how effective this new approach will be,” Shapiro enthused in a press release. “Importantly, the islets were shown to be residing within a natural tissue matrix in the device, and were nicely integrated with microvessels, and stained for insulin, glucagon, somatostatin and polypeptide at the 30-day time point.”
The ultimate goal of the Cell Pouch, Toleikis explains, is to make patients insulin-independent.
“It has been shown with the Edmonton Protocol with islet transplantation that when the patients are insulin-independent, the incidence of the diabetes side effects also starts to drop,” he says. “The side effects don’t develop because the sugar levels are controlled quite tightly.”
“We’ve shown in our preclinical studies that we can use a significantly smaller number of islets to be able to achieve glucose control relative to the Edmonton Protocol, which shows that we have a very efficient system.”
Key to that success will also be the development of the company’s Sertolin anti-rejection platform, based on Sertoli cells.
“Naturally, Sertoli cells line the seminiferous tubules of the testes in males,” Toleikis says. “They are there to protect and allow the sperm to survive as they grow. We can actually take those Sertoli cells and mix those in with the islets or other therapeutic cells and they will release factors into the area and allow those cells to be protected in a natural kind of way.”
By having that local immune protection, he adds, it eliminates any potential toxicities related to the antirejection drugs and therefore allows for the treatment of a much larger population of patients who are not necessarily the sickest. This move, he figures, would potentially transform the cell-transplantation arena from treating thousands of patients per year to millions of patients.
Caring for the orphans
Of course, where diabetes, obesity and metabolic syndrome form the three pillars of the most predominant metabolic disorders, there are dozens if not hundreds of other conditions that impact smaller numbers of patients worldwide, many considered orphan diseases.
“These diseases tend to affect much smaller numbers of patients,” says David Aviezer, CEO of Protalix Biotherapeutics. “We’re talking about a few thousand patients per disease. Thus, the level of focus and public attention on these disorders is not huge.”
“This is more of a niche avenue for pharma, which requires a different kind of marketing,” he adds. At the same time, he suggests, interest in orphan indications in general are becoming an important part in pharma development.
Many of these conditions are the result of deficiencies in or the complete lack of a key enzyme in a metabolic pathway, resulting in the build-up of different compounds within various tissues throughout the body. What was a harmless metabolite under normal circumstances becomes a metabolic toxin that can significantly slow physical and neurological development. For that reason, many of the most severe forms of these diseases are seen in childhood and can lead to severe developmental difficulties or early death.
Typical methods to treat these conditions, aside from symptom alleviation, involve dietary restrictions or enzyme inhibitors to limit production of the offending metabolite, enzyme stabilizing therapies (such as chaperones) to help bolster or correctly fold a deficient enzyme or outright enzyme replacement therapy (ERT). Depending on the disease, cell transplantation therapy (such as bone marrow transplantation) may also be an option.
Last January, BioMarin Pharmaceuticals announced its acquisition of Zacharon Pharmaceuticals with an eye to the latter’s significant expertise and portfolio of candidates targeting glycan and glycolipid synthesis. In particular, BioMarin looked to add Zacharon’s inhibitors of enzymes involved in different mucopolysaccharoidoses (MPS) as well as Tay Sachs and Sandoff disease.
“Zacharon’s lead program, focused on reducing the accumulation of heparan sulfate, offers the exciting prospect of treating both the CNS and peripheral manifestations of MPS III, and potentially other MPS disorders, with an orally bioavailable small molecule,” explained BioMarin EVP and Chief Medical Officer Hank Fuchs. “In general, reducing the synthesis of the target substrate alleviates the burden on the compromised lysosomal system, and this therapeutic approach has been clinically validated with other enzyme inhibitors.”
A month later, Genzyme announced new data from its two Phase 3 studies of oral inhibitor eliglustat tartrate in the treatment of type 1 Gaucher disease. In the first study, the drug was shown to improve spleen and liver size in Gaucher patients while also improving platelet and hemoglobin levels. In the second study, the compound was shown to be non-inferior to imiglucerase infusion, an ERT designed to replace the function of the enzyme missing in Gaucher patients.
Also in February, Amicus Therapeutics presented findings of their Phase 3 efforts with oral migalastat HCl monotherapy in patients with Fabry disease. Developed with GlaxoSmithKline, migalastat is designed to stabilize the endogenous but faulty alpha-galactosidase A in patients to prevent metabolite accumulation and therefore disease pathology. At the time of reporting, migalastat did not show statistically significant improvement over placebo but numerical superiority in most study endpoints.
BioMarin also reported last March on their progress in Phase 1/2 studies with BMN-701, a fusion of insulin-like growth factor 2 and acid alpha-glucosidase in the treatment of late-onset Pompe disease, with particular interest in the impact of treatment on pulmonary function and strength.
In the announcement, Benedikt Schoser of the Friederich-Baur Institute explained the importance of the findings.
“More than half of late-onset Pompe patients require ventilatory assistance, and many more patients have impairments directly related to weakness of breathing muscles. This means that a therapy that improves respiratory muscle function substantially would be important and welcome and could help delay premature death in Pompe disease.”
Similarly, by summer, Ultragenyx Pharmaceutical announced approval to initiate a Phase 1/2 study of UX003, a recombinant human beta-glucuronidase, for the treatment of MPS VII, a disease for which there is currently no approved drug therapy.
Planting the flag
The key to any of these treatments, explains Protalix’s Aviezer, is to reverse the patient’s physiological situation back to the way it would have been if there was no disease. Unfortunately, that process is rarely an easy one, and even many of the current marketed ERT products have limitations and drawbacks.
“It goes way beyond just taking the sequence of the missing enzyme and expressing it as in many cases that just doesn’t work.”
Like Genzyme (imiglucerase) and Shire (velaglucerase) before it, Protalix is putting its energies into ERT for Gaucher disease with taliglucerase alfa, but it differs significantly from the others in how it produces the enzyme. While the others use mammalian culture, Protalix relies on plants using its ProCellEx platform.
Aviezer uses the analogy of raising dogs and cats versus raising house plants.
“The level of maintenance and expense is dramatic,” he explains. “And the same is correct when you go down to the cellular level. Growing plant cells is much less expensive than growing mammalian cells.”
Using ProCellEx, there is a built-in advantage on the cost of production because the plant cells are that much more robust, and growth media is very simple, inexpensive and well-defined.
“Furthermore, regarding the post-translational modifications, the enzyme for Gaucher disease requires a very specific sugar moiety to be present on its surface, which is a mannose,” he continues. “Only that will enable the enzyme to bind to its target cells, the macrophages in the patient.”
“When you use mammalian cells, you get additional sugars that actually block the mannose from being exposed. They mask the required mannose.”
Thus, he suggests, the additional sugars must be clipped off enzymatically following purification or methods must be devised to inhibit their processing in the cell culture.
“What we are able to do with the plant cells is actually engineer the cells in a way that the product they make is already ready to go with the correct mannose structure.”
The impact of the differences in glycosylation patterns—at least between imiglucerase and velaglucerase—was recently examined by Gregory Grabowski and colleagues at the University of Cincinnati College of Medicine, who performed microarray and RNA sequencing transcriptome analysis in a mouse model of Gaucher.
Despite both being produced in mammalian cells, the two ERTs have distinct glycosylation patterns. Although both drugs displayed similar efficacy in mice, there were clear transcriptome pattern differences between the two treatments, suggesting the drugs may not function in identical ways.
A similar study by Seng Cheng and colleagues at Genzyme on acid alpha-glucosidase (GAA), the ERT for Pompe disease, showed that changing the glycosylation of GAA could have significant impacts on the efficacy of the biotherapeutic as well as its ability to reverse disease pathology if initiated early enough. The researchers cited a fivefold higher efficacy in clearing tissue glycogen.
“This improved clearance of glycogen resulted in a corresponding increase in muscle strength and motor function in mice treated starting at five to six months of age,” they wrote.
The next stage in development for Protalix is a move to an oral formulation; all current Gaucher ERT formulations are infusion. The company recently completed Phase 1 studies of the oral version.
“The obvious advantage of moving to an oral is patient compliance, making it much easier for treatment particularly for patients who are hesitant to start this lifelong commitment to infusions every two weeks,” Aviezer explains, suggesting that an oral option will have immediate benefits in patient quality of life.
But it is also trying to reproduce the physiological picture in normal unaffected human beings, he adds.
“Theoretically we would like to infuse the patient every day, which is impossible because quality of life would not be existent. Therefore, doing this once every two weeks is a compromise, but it is clear that giving a bolus once every two weeks is far from being similar to the physiological status.”
“Being able to give the drug every day and be able to maintain a steady state level of enzyme in the patient’s blood stream is much closer to what you would expect in the physiological treatment. Therefore, the hope is that from an efficacy point of view, patients will be doing better due to the fact that they’re maintaining a steady state level of enzyme in their circulation.”
With the Phase 1I results proving the oral taliglucerase safe, the company expects to move into a short Phase 2 study later this year.
Despite an ever-shifting and evolving landscape, recent advances in metabolic disease should prove fateful for patients who hope to see their qualities of life approach normal.

Metabolic disease digest
Although diabetes and metabolic disorder tend to grab most of the headlines, several other orphan disease affect thousands of people worldwide, often children.
Gaucher disease (Types 1-3)
Cause: Deficiency of glucocerebrosidase leads to fatty buildup in organs such as spleen, liver, kidneys, lungs, brain and bone marrow.
Prevalence: 1 in 100,000
Symptoms: Liver and spleen enlargement, skeletal disorders, pain, neurological complications, anemia
Treatment: Enzyme replacement therapy (ERT); substrate reduction therapy; bone marrow transplantation (BMT)
Niemann-Pick disease (Types A-D)
Cause: Deficiency in sphingomyelinase or NPC1/NPC2 proteins leads to fat and cholesterol accumulation in organs such as liver, spleen, bone marrow, lungs and possibly brain.
Prevalence: 1 in 100,000 to 1 in 1,000,000 (based on type)
Symptoms: Liver and spleen enlargement, brain damage leading to ataxia, difficult walking or swallowing, spasticity
Treatment: No cure, only supportive treatment
Fabry disease
Cause: Alpha-galactosidase deficiency leads to fatty buildup in autonomic nervous system, eyes, kidneys and cardiovascular system
Prevalence: 1 in 10,000
Symptoms: Enlarged heart and circulatory issues, peripheral burning pain, corneal clouding
Treatment: ERT; supportive treatment for pain, gastrointestinal distress
GM1 gangliosidoses (early/late infantile, adult onset)
Cause: Deficiency in beta-galactosidase results in build-up of acidic lipids in central and peripheral nervous system
Prevalence: 1 in 150,000 births
Symptoms: Neurodegeneration, liver and spleen enlargement, seizures, blindness, muscle atrophy
Treatment: Substrate reduction therapy (clinical trials); supportive therapy
GM2 gangliosidoses (Tay-Sachs, Sandhoff)
Cause: Beta-hexosaminidase deficiency leads to neurological accumulation of fatty materials
Prevalence: 1 in 130,000 (Sandhoff) to 1 in 320,000 births (Tay-Sachs)
Symptoms: Progressive mental degeneration, dementia, loss of hearing, blindness, spasticity, seizures
Treatment: No specific treatment; supportive care includes diet, hydration and airway assistance
Pompe disease (early/late onset)
Cause: Acid alpha-glucosidase deficiency promotes glycogen accumulation, with significant involvement of heart and skeletal muscles
Prevalence: 1 in 40,000 births
Symptoms: Muscle weakness, poor weight gain, respiratory distress and failure
Treatment: ERT
Cause: Absence or deficiency of alpha-L-iduronidase causes build-up of glycosaminoglycans in skeletal and connective tissues
Prevalence: 1 in 115,000 births
Symptoms: Progressive mental decline, slowed physical maturation, possible spleen, liver or heart enlargement
Treatment: ERT; BMT; umbilical cord blood transplantation (UCBT)
MPS II (Hunter syndrome)
Cause: Absence of iduronate sulfatase promotes skeletal and connective accumulation of glycosaminoglycans
Prevalence: 1 in 125,000 births
Symptoms: Similar to MPS I but milder
Treatment: ERT; BMT; UCBT
MPS IV (Morquio syndrome)
Cause: Absence or deficiency of N-acetylgalactosamine 6-sulfatase (Type A) or beta-galactosidase (Type B) prevents breakdown of the keratin sulfate sugar chain
Prevalence: 1 in 200,000 births
Symptoms: Diminished physical development, neurological complications, progressive skeletal malformations, restricted breathing, heart disease
Treatment: Supportive surgical treatment of bone disorders
For more information on these and other orphan diseases, visit

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