Background

GRF6019 is a proprietary plasma fraction of about 400 proteins, developed by Alkahest and manufactured by Grifols. It represents a second-generation product of earlier clinical research infusing young adult plasma to treat age-related neurodegenerative disease (see Young Plasma). This treatment approach grows out of mouse parabiosis studies indicating a rejuvenating effect of young blood on the aging brain (e.g., Nov 2009 news; May 2014 conference news). The rationale behind GRF6019 is that the components of young blood that counteract inflammatory and other age-related degenerative processes in the brain can be enriched and delivered as a plasma-derived product that does not require matching donor and recipient blood types.

In February 2019, responding to reports of commercial delivery of young plasma as a purported treatment for various conditions including memory loss, the FDA issued a statement warning the public of the potential risks of this practice. GRF6019 is a plasma fraction from which clotting factors and immunoglobulins have been removed to reduce those risks. 

Findings

In April 2018, Alkahest started a Phase 2 trial in 47 people with clinical diagnoses of mild to moderate AD; biomarkers to confirm underlying molecular pathology were not required. The study compared two doses of 100 ml or 250 ml GRF6019, given as five once-daily intravenous infusions in week one, and again in week 13, primarily on safety measures. Secondary outcomes include six-month change on some widely used cognitive and clinical batteries—MMSE, ADAS-Cog11, CDR-SB, ADCS-ADL, ADCS Clinical Global Impression of Change, NPI Questionnaire—as well as on some individual tests, e.g., the Grooved Pegboard and Category Fluency tests. There was no placebo group for comparison. The trial ran at nine U.S. sites, and finished in May 2019. In August, top-line data were announced. According to the company press release, GRF6019 was safe and well-tolerated, participants showed no decline on the ADAS-Cog11 or MMSE, and "negligible decline" on the CDR-SB and ADCS-ADL over six months. Results were published after peer review (Hannestad et al., 2020).

From January to December 2019, Alkahest ran a placebo-controlled Phase 2 trial in 26 people with clinically diagnosed AD and advanced dementia, i.e., an MMSE score below 10. Participants received infusions of 250 ml GRF6019 or placebo daily for five days, followed by a month of observation. Primary outcomes were safety and tolerability; secondary outcomes included change in MMSE, ADCS-ADL, and other measures of cognitive impairment and neuropsychiatric symptoms. According to a presentation at CTAD 2020, the treatment was safe and well-tolerated. Neither treatment nor placebo groups worsened on secondary cognition and functional endpoints, and there were no differences between the groups. In a plasma proteome biomarker analysis, the company reported post-treatment changes in proteins involved in complement and coagulation, nervous system development, apoptosis, axon guidance, and synapse function, that were not detected after placebo treatment. Results were subsequently published (Hannestad et al., 2021).

Alkahest is developing a second plasma fraction, GRF6021, for Parkinson's disease dementia.

In 2021, Alkahest became a wholly owned subsidiary of Grifols.

For all clinical trials of GRF6019, see clinicaltrials.gov.

Clinical Trial Timeline