As life expectancy continues to increase around the world, healthy aging is increasingly an area of research focus for the pharmaceutical industry. Aging in good health and adding years that are free of disease and disability to one’s lifetime are important both for individuals and for society as a whole. As a result, repurposing drugs to delay aging and age-related disease is increasingly becoming a source of medical innovation.
One example of age-related medical innovation is the life cycle management of metformin, an API that was approved in 1995 as an antihyperglycemic drug in type 2 diabetes patients. The incidence of type 2 diabetes, closely related to aging and obesity, continues to grow to this day, as do the costs of diabetes treatment. In 2017, the total estimated cost of diagnosed diabetes cases in the United States was $327B, an increase of 26% from 2012 [American Diabetes Association 2018]. Driven by reformulations, metformin has grown in significance as a frontline treatment for type 2 diabetes.
Glucophage (metformin hydrochloride) and its immediate line extension Glucophage XR achieved blockbuster status with $2.3B in sales in 2002 just prior to its patent expiration, and since the original patent expirations there have been numerous NDA 505(b)(1), (b)(2) and ANDA filings using metformin.
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505(b)(1) approvals have included specialized drug delivery of the API, e.g., Glumetza (AcuForm® Technology) and Fortamet (osmotic technology). More importantly, fixed dose combinations have enhanced the performance of metformin in the treatment of diabetes – for example, the Janumet franchise (Janumet and Janumet XR) utilized sitagliptin to more effectively lower blood sugar. Janumet achieved sales of $2.1B in the US in 2017. 505(b)(2) launches have included both combination products and adolescent versions of metformin. Additionally, since the original Glucophage patent estate expiry, numerous ANDA’s have been filed for metformin with extended release, using hydrophilic matrix delivery technologies as well as combination products. Drug repurposing to improve therapeutic outcomes is also a global strategy, for example, the Art. 10.3 (hybrid) regulation in Europe is similar to the US 505(b)(2) pathway.
With the cost of bringing a new drug to market now estimated at around $2.6B over 10 or more years – broken down into $1.4B in out-of-pocket costs and $1.2B in time costs [DiMasi et al 2016] – reformulation pathways offer a cost-effective means of improving treatments with proven active ingredients. And as aging populations worldwide increasingly have the expectation of active and healthy retirement, as well as the financial means to afford treatment, pharmaceutical firms may find further benefits from repurposing drugs that target age-related diseases.
Insights into the aging process
Aging is a process with different trajectories and individual expressions, and healthy aging is a result of both genomic predisposition and lifestyle. While older age is a major risk factor for chronic disease and disability, chronologic age per se is not a cause of disease. Research is ongoing to better understand the different mechanisms of the aging process on a genomic, cellular and molecular level and its relationship to morbidity, disability and frailty. Cellular aging can be triggered by oxidative stress, DNA damages or reduced repair, accumulation of cellular damages and reduced telomere length [Langie et al 2012]. There is evidence that low-grade inflammation developing with older age as a response to cellular senescence is involved in muscle loss and disability [Volaklis et al 2015; Beyer et al 2012], as well as increasing morbidity [Franceschi & Campisi 2014].
Understanding the mechanisms of aging by translational geroscience allows the identification of lifestyle or therapeutic interventions to potentially delay aging and the premature development of morbidity and disability. For example, inhibition of mTOR, reduction of endogenous production of reactive oxygen species (ROS), activation of AMP-activated kinases (AMPK) and inhibition of mitochondrial complex 1 in the electron transport chain have been found to reduce the progression of aging and cellular senescence in vitro. These findings have been confirmed in mouse and dog animal models by a prolongation of life time [Kaeberlein et al 2015]. Even though studies in humans are still inconclusive as to whether aging processes can be influenced by pharmacological interventions, there are observational reports and off-label use that raise these expectations.
If we can efficiently interfere with the aging process through pharmacological targeting, we might be able to delay the negative consequences of aging. Delaying aging to prevent development of chronic diseases and disability might have a huge impact on public health but will also require a rethinking of our disease- and diagnostic-based medicines model. However, this should not discourage our industry. The first study to investigate the effect on aging of a drug in clinical trials has been launched recently in consultation with the FDA [Kaeberlein et al 2015]. The “Targeting Aging with Metformin” (TAME) study will investigate the general decline of age-related disease and specifically the reduction of cancer, enhanced cognitive functions and decreased mortality [Barzilai et al 2016].
Targeting metformin against aging by reformulation
Metformin, discovered about 100 years ago and approved in 1995 as an antihyperglycemic drug in type 2 diabetes patients, belongs to the class of biguanide. The typical dose of an immediate release metformin tablet for the treatment of type 2 diabetes is between 850 – 1.0 mg twice daily, with a minimum daily dose of 1.5 mg and a maximum dose of 2,250 mg. The bioavailability of metformin is only around 50-60 %, with a plasma half-life of 6.2 hours and a blood half-life of 17.6 hours [US FDA 2017].
The pharmacokinetic profile of metformin varies highly among patients and therefore individual dose adjustment is recommended. For example, a lower dose is preferred for patients with kidney impairments and older patients. It is recommended to titrate the patients to the target glucose response by individual dosing regimens. The reason for the low bioavailability is the incomplete absorption from the GI tract, partly due to its pH-dependent dissolution and especially at the pH in the large intestine [Graham et al 2011].
Another issue with metformin products is the high dose and the resulting large tablet size, which are known to cause issues in about one third of the older patients [Stegemann et al 2012]. For the treatment of diabetes, metformin formulations have evolved using the 505(b)(2) regulatory pathway from an immediate release tablet formulation to extended release and fixed dose combination products with gliptins.
When repurposing metformin to delay aging and prevent cancer, mortality and loss of cognitive functions, the actual formulation and dose might not be optimal to eventually target metformin to a specific tissue or more precise plasma levels. Enhancing the bioavailability or reducing the variability of metformin absorption remains a scientific challenge, due to the slow and variable dissolution and low permeability of metformin at physiological conditions. Formulation approaches have shown that modified release pellets targeted to specific intestinal regions could increase the bioavailability and maintain higher plasma levels for over 24 hours [Hu et al 2006].
In addition to this, advanced drug delivery technology, such as micro and nano particulate systems, may have the potential to enhance bioavailability of metformin [Cetin & Sahin 2016]. Using multiparticulate approaches will also allow more dose flexibility and dose adjustment based on the patient factors, as well as circumvent the swallowability issues in special patient populations like geriatric and pediatric patients.
Summary
Targeting and delaying aging is an emerging pharmaceutical field with a high potential to improve public health. Providing clinical evidence of the efficacy by repurposing drugs to delay aging and agerelated diseases is driving innovation in the medical industry. Since science and technology continue to evolve, advanced drug delivery technologies will play a crucial role in achieving new targets for newly developed products or those that were discontinued several decades ago. Effective pathways will continue to involve both NDA 505 (b)(1) and 505 (b)(2), with reliance on enabling technologies for improved bioavailability, modified drug release and fixed dose combinations.
Author Biography
Sven Stegemann, PhD, is director, pharmaceutical business development at Lonza, and professor of patient centric drug design and manufacturing at the Graz University of Technology, Austria. Sven advises major pharmaceutical companies on ways to improve the design, development and manufacture of pharmaceutical products so they better address the individual needs of patients. In his academic role, Dr. Stegemann researches the rational development of patient centric drug products and their associated manufacturing technologies, as well as education and training of students and young scientists. Dr. Stegemann is the founder and chair of the AAPS Focus Group on Patient-Centric Drug Development, Product Design, and Manufacturing as well as the founder and president of theGeriatric Medicine Society e.V..
References
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The information contained herein are believed to be correct. However, no warranty is made, either expressed or implied, regarding its accuracy or the results to be obtained from the use of such information. Lonza disclaims any liability for the use of this information.