Longevity and ongoing Clinical Trials (part 1)

Cover photo by Science in HD

The still early-stage longevity industry has grown in the past 4 years from a neglected and underfunded domain of R&D into what is now claimed a trillion-dollar industry, spanning thousands of active companies across almost every continent.

Right now, anti-aging therapies are already being tested in human patients, and different strategies are being tried, some summarised here A Review of Every Single Longevity Therapy in Clinical Trial Today by Nathan Cheng.

So, let’s see some of these trials: 

Lorecivivint (STRIDES-1): Samumed is a private regenerative medicine company that targets the Wnt signalling pathway (also involved in stem cell differentiation and renewal). They are also one of the few aging-focused companies to make it to Phase 3 (data 2021, link), with their drug Lorecivivint, a small molecule modulating the signalling Wnt pathway, in patients with Osteoarthritis (knee). 

UBX1325 – Unity is back in the clinic with a second phase 1 trial (Data 2021, link) with a new senolytic drug, a small molecule that is a Bcl-xL inhibitor (UBX1325). Namely a repurposed cancer drug licensed from Ascentage Pharmaceuticals that induces apoptosis, and re-tested in order to ameliorate various diseases of the eye (Age-related Macular Degeneration). 

Dasatinib + Quercetin: Mayo Clinic is targeting one of the oldest senolytic therapies by running a phase 2 trial (link) with: 1) Dasatinib (small molecule), a cancer drug that is able to remove senescent cells in vitro and likely in humans, and 2) Quercetin, a natural flavonoid found in kale and other plants that is believed to act as a senolytic by targeting the Bcl-xL apoptosis pathway. By clearing senescent cells they hope to improve kidney diseases. 

AKST-4290 and GRF6021- Alkahest (owned by Grifols) is the largest company actively pursuing the young blood factors/parabiosis strategy for aging, and also running trials for Parkinson’s, Alzheimer’s, inflammatory skin disease, using the small molecule Eotaxin inhibitor or a proprietary plasma fraction. 

Eotaxin is a chronokine (plasma fractions) whose levels increase in blood plasma as we age. It may be a signalling molecule that modulates aging, and its inhibitor is tested on a phase 2 trial (Data April 2021) targeting altered intercellular communication during Neovascular Age-related Macular Degeneration (link).

They are also running a second phase 2 trial GRF6021, targeting altered intercellular communication in patients with Parkinson’s Disease (trying to improve their cognitive function), by using young blood containing young blood factors identified by Alkahest’s chronokine screening (link).

TRIIM (somatropin, DHEA, metformin): Intervene Immune is attempting to reverse aging and immunosenesence through thymic regeneration and is running now the phase 2 TRIIM-X trial (somatropin, DHEA, metformin), an expansion of the original TRIIM trial (HGH + DHEA only on small group of men). They are trying to reverse immunosenesence by re-growing the thymus with somatropin (human growth hormone) and suppress insulin effect with DHEA and metformin (Data October 2022). They measure epigenetic aging, thymus size and density and naive T cell function (link).

DNL151: Denali Therapeutics has a number of therapies targeting neurodegenerative diseases using different strategies. Current treatments for Parkinson’s are based on increasing levels of dopamine and not treating the underlying biology. So, clearing out intracellular aggregates may be key to overcoming neurodegenerative disease. For this reason their phase 1b trial (Data December 2020) is interesting because it improves the garbage collection function of the lysosomes to remove intracellular aggregates. They are using a LRRK2 inhibitor (small molecule), because high levels of LRRK2 (also known as dardarin) cause neurodegeneration via lysosome dysfunction and build up of Lewy bodies (Trial link).

OpRegen: Lineage Cell Therapeutics (formerly BioTime) is a stem cell therapeutics company that is targeting Dry Age-related Macular Degeneration (dry AMD), spinal cord injury and cancer using cells derived from allogenic embryonic stem cells. In particular in their phase 2 trial (Data December 2020, link), they are trying to improve vision by using embryonic stem cells. 

FX-322: Frequency Therapeutics (FREQ) has demonstrated the first sustained therapeutic improvement in human hearing loss. The initial sample size was relatively small but the breakthrough was promising. In their current phase 2 trial (link) targeting hearing loss (old age hearing loss from cell loss), they are trying to stimulate progenitor cells to divide and differentiate into hair cells in the inner ear via GSK3 inhibitor and histone deacetylase inhibitor in order to improve hearing. 

GS010: Gunsight Biologics has demonstrated allotopic expression of mitochondrial genes in the cell nucleus to treat a rare genetic disease that causes blindness (LHON). Mitochondrial DNA is subject to harmful mutations as we age due to the reactive environment of the mitochondria, leading to mitochondrial dysfunction and age-related diseases. The gerontologist Aubrey de Grey has suggested that the 13-14 mitochondrial genes that encode for proteins must be protected and the best way to do this is to copy the genes into the cell nucleus. GS0101 is proof of concept that this can be done for at least one of the genes. For this reason, Gensigth’s phase 3 trial (Data June 2024) is using allotopic expression of mitochrondrial genes with recombinant adeno-associated virus that delivers wild type ND4 mitochondrial gene to cell nucleus, trying to improve eyesight (trial).

CB4211: Cohbar (CWBR) is attempting to use naturally occurring mitochondrial peptides to treat various age-related diseases associated with mitochondrial dysfunction. In the case of CB4211, they are targeting the AMPK / insulin pathways. Their phase 1 trial (Data 2021) using analog of the natural MOTS-c mitochondrial peptide, believed to regulate AMPK pathway and or insulin pathways to treat non-alcoholic fatty liver disease (NAFLD) / nonalcoholic steatohepatitis (NASH) can be found here trial.

RTB101: resTORbio is doing one last phase 2 trial (despite having merged with CAR-T therapy company Adicet Bio) in collaboration with the National Institute on Aging studying whether the RTB101 mTORC1 inhibitor (small molecule licensed from Novartis) is capable of protecting older adults from developing COVID-19 after exposure. mTORC1 inhibition is one of the most studied anti-aging pathways. Their phase 2a (Data 2021) is targeting altered intercellular communication and immunosenescence (Trial link). 

Elamipretide: Stealth BioTherapeutics has a number of planned trials targeting age-related diseases caused by mitochondrial dysfunction and most use the peptide Elamipretide. Unfortunately, their first attempt at treating Primary Mitochondrial Myopathy failed in December 2019. Stealth does however have an ongoing Phase 2/3 (Data June 2021) targeting mitochondrial dysfunction (Barth Syndrome) aiming to improve aerobic capacity, by using the peptide Elamipretide that binds to cardiolipin in the inner membrane of the mitochondria and stabilises it. By doing so, it improves mitochondrial respiration and reduces damage from reactive oxygen species (link).

In the second part of this blog I will continue the analysis with other longevity clinical trials. 

Thanks for reading.

*Disclaimer: This information is for educational purposes only.