Although medical advances and lifestyle educational campaigns have combined to increase life expectancy around the globe, and those same breakthroughs have resulted in the staving off of many midlife diseases, we cannot afford to overlook issues that will affect what will be the fastest-growing segment of the population over the next 30 years.

Emilie Branch, Managing Editor at Pharma's Almanac, discusses the science of aging with Elizabeth Jeffords, Chief Commercial and Strategy Officer for Alkahest.

By the year 2050, we expect the number of people over the age of 65 to double, and with increased age comes a slew of neurodegenerative diseases for which we currently do not have effective treatments or cures. The advocacy for research, trials, and development of therapeutics to combat this huge, unmet need is of paramount importance to prepare for the population surge in this demographic in the years to come.

The Plasma Proteome and the Role of Chronokines

Alkahest is a mid-stage biotech company focused on treating neurodegenerative diseases and diseases of aging by capitalizing on the body’s natural regulatory and communication mechanism, the plasma proteome. CEO and founder Karoly Nikolich partnered with Stanford Professor Dr. Tony Wyss-Coray to study thousands of plasma proteins in people aged 18–70 (even including some centenarian samples) and found that about 15% of those proteins change with age. This research inspired the founding of Alkahest in 2014, with a focus on understanding and targeting these proteins — which the company calls chronokines — to develop clinical candidates that either increase or decrease levels of circulating chronokines with the aim of promoting innate and natural restorative biological processes or to discourage pathological, degenerative processes in age-related diseases, respectively.

Alkahest takes a holistic approach to neurodegenerative diseases by questioning whether failed Alzheimer’s and neurodegenerative treatments are simply not working or are too narrow in scope. Are they personalized enough? Is there a multi-tiered, multi-tooled strategy that addresses the totality of the aging process as it relates to diseases, rather than targeting one specific mechanism within the disease or condition?

Harnessing Chronokines for Neurodegenerative Disease

As Alkahest decoded the plasma proteome, they found that proteins in human plasma that increase with age have been associated with neuroinflammation, tissue damage, and neurodegeneration. Conversely, the proteins that decrease with age carry out regenerative and health-preserving processes. To that end, Alkahest has a two-pronged approach to therapeutics: first, to inhibit the negative actions of the inflammatory and degenerative proteins with traditional biotech approaches like small molecules or antibodies, and second, to enhance or supplement the action of positive regenerative proteins with recombinant proteins or selected plasma fractions.

In preclinical studies, the company has demonstrated that their therapeutic targets activate molecular signaling pathways in older animals that include increased tissue regeneration, reduced age-related cognitive impairment, increased neural activation, and increased memory function. Current clinical trials are testing a variety of therapeutic approaches for a range of age-related medical conditions, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and age-related macular degeneration (AMD), among others. This research informs the clinical trials, and the data gathered from the human trials informs continued research in a virtuous cyclical loop. “We aim to drive closer toward solutions that will potentially decode neurodegenerative diseases and the underpinning biological processes of aging,” says Elizabeth Jeffords, Chief Commercial and Strategy Officer for Alkahest.

Clinical Pipeline

GRF6019 and GRF6021, selected plasma fractions, are in phase II trials as potential treatments for neurodegenerative diseases, including AD and PD with cognitive impairment. These therapeutics are designed to safely replenish regenerative positive chronokines that decrease with age and provide enhancement of both cognition and motor activity while reducing inflammation and restoring neurogenesis. GRF6019 recently completed an open-label, two-dose phase IIa study for the treatment of mild to moderate AD, while GRF6021 is being studied to treat PD with cognitive impairment, with support from the Michael J. Fox Foundation. The first trial results in mild to moderate AD with GRF6019 demonstrated a lack of decline of cognitive and functional domains in patients and encouraged the company to proceed in the design of placebo-controlled studies. Both GRF6019 and GRF6021 are developed and provided by Grifols, a major producer of plasma therapeutics, in partnership with Alkahest.

AKST4290, an oral small molecule, is currently in two phase II clinical trials — one in wet age-related macular degeneration, and one in PD, also supported by the Michael J. Fox Foundation. The drug targets CCR3, which is the GPC-receptor for eotaxin — an immunomodulatory chemokine that is increased in normal aging and in multiple diseases of aging. It has been implicated in AD, PD, retinal diseases, and other aging-related diseases that involve systemic inflammation. Targeting this chronokine may improve conditions for patients via two mechanisms — a broad, anti-inflammatory mechanism and an immune-modulatory mechanism through the body’s innate immune cells. AKST4290 is designed to block eotaxin from binding to its receptor, potentially preventing its detrimental inflammatory effects in macular degeneration and other age-related diseases.

Traditional approaches to treating AMD involve injections in the eye, which are not necessarily as painful as they are burdensome because they require the injections to continue on an ongoing basis. Without a consistent, ongoing cadence for receiving these injection-based treatments, over time patients will cease to see the benefits of their administration. However, Alkahest's current phase II clinical trial begins with three injections but is followed up thereafter with an orally administered small molecule. “Given that wet AMD is the leading cause of blindness in people over 60 in the United States, we are excited at the promise of an oral, small molecule therapeutic which may reduce the need for burdensome injections. Early results show promise, as we have seen visual acuity gains in patients in two open-label phase IIa trials with AKST4290 in both naïve patients and patients refractory to continued use of anti-VEGF injections,” shared Jeffords.

Solutions for the Most Intractable Diseases

Alkahest was born out of a desire to understand whether targeted chronokines drive the biological process of aging, and then to find ways to harness or tweak those chronokines to reverse or inhibit some of the most intractable diseases of late life. “We know that, as baby boomers continue to age, it is important for us to be on the front lines, alongside other researchers, in a parallel effort to grow awareness of the health and societal burdens of an aging population and to make strides for the future. We believe there will be a groundswell of investment in this space in the next few years, especially as we continue to gather more placebo-controlled data to draw even more concrete conclusions about our research and continue to create therapeutics that truly make aging and neurodegenerative diseases more of a chronic and addressable health state,” concludes Jeffords.