RESEARCH

We have a portfolio of potent enzyme mimetics which inhibit inflammatory and oxidative injury, with UP1007 as our lead compound.

Selected publications;
chronological order
Implications for human therapy
Carboxyfullerenes as neuroprotective agents (1997)
  • Unify’s early technology provides:
    • Protection against disability in vivo via a mouse model of ALS / motor neurone disease
    • Protection against NMDA-receptor mediated neuronal death in vitro
    • Protection against oxygen & glucose withdrawal dependent neuronal death in vitro
    • Protection against apoptotic neuronal death resulting from withdrawal of serum or exposure to abnormal Alzheimer’s protein Aβ1-42 in vitro
A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties (2004)
  • Lifespan extension of 300% in an in vivo mouse model of mitochondrial superoxide dismutase (SOD) deficiency
  • Unify’s compounds are enzyme mimetics, not conventional anti-oxidants nor conventional free radical scavengers
  • Hence very high potency versus other agents that target oxidative stress and oxidative inflammatory pathways
  • Dismutase activity means that Unify’s compounds mimic the response of the natural enzyme to increasing levels of superoxide; low activity at normal concentrations but high activity at pathological concentrations.
A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice (2006)
  • Lifespan extension in normal mice via oral treatment with Unify’s UP1007 compound from middle age onwards
  • Significantly reduces the risk of death by 46% (hazard ratio of death = 56% versus control mice receiving placebo, p = 0.01) with lifespan increase of ~11%
  • Increase in lifespan was not associated with caloric restriction
  • Furthermore, aged mice chronically treated with UP1007 had significantly:
    • Lower markers of oxidative damage (DHE oxidation) in the brain than untreated aged mice
    • Lower brain mitochondrial superoxide production than untreated aged mice
    • Better performance in spatial memory tasks than untreated aged mice
Ketamine-Induced Loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase (2007)
  • Ketamine induces an increase in brain superoxide radicals via the enzyme NADPH-oxidase. Superoxide is, in turn, toxic to certain neurons
  • Unify’s UP1007 protects neurons both in vitro and in vivo from ketamine-induced toxicity
  • Relevance for a range of pathologies in humans that are mediated via NADPH-oxidase and oxidative stress
SOD Activity of carboxyfullerenes predicts their neuroprotective efficacy: a structure-activity study (2008)
  • Study of six different carboxyfullere derivatives
  • Correlation between superoxide dismutase activity in vitro and protection against NMDA-receptor mediated neuronal toxicity (believed to be mediated by reactive oxygen species)
  • Unify compounds far more potent than conventional antioxidants in protecting neurons
Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates (2014)
  • Randomized double-blind placebo controlled trial in macaque monkeys with unilateral Parkinson’s induced by MPTP. Treatment with Unify’s UP1007 began one week after Parkinson’s was induced
  • After 2 months, UP1007 treated monkeys had significantly better outcomes than control monkeys:
    • Motor symptoms including validated Parkinson’s rating scale and kinematic analysis of movements
    • In vivo brain imaging (PET) of dopamine levels
    • Post-mortem measures of histology of the substantia nigra
Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates (2018)
  • For mice:
    • Plasma half-life of UP1007 was around 8 hours, wide tissue distribution and uptake into the brain, with clearance dominated by hepatic and renal routes
    • Wide therapeutic index, with single lethal IP dose around eighty times lowest effective daily dose tested during in vivo efficacy studies
    • Lifespan extension in normal mice with treatment of ~2 years
  • For primates:
    • Well tolerated at therapeutic dose in Parkinson’s model for 2 months
    • No evidence of renal, hepatic, electrolyte, or hematologic abnormalities
    • Serial ECGs demonstrated no alteration in cardiac electrical activity
Reduction of Leukocyte Microvascular Adherence and Preservation of Blood-Brain Barrier Function by Superoxide-Lowering Therapies in a Piglet Model of Neonatal Asphyxia (2019)
  • Asphyxia is the most common form of brain damage in new-born infants
  • Reactive oxygen species formed during reperfusion, once asphyxia eases, are believed to contribute to damaging inflammation. White blood cells (leukocytes) accumulate in the brain during such inflammation.
  • Unify’s UP1007, and the native enzyme it mimics, superoxide dismutase, both reduce the number of white blood cells that adhere to blood vessels and protect the blood brain barrier following asphyxia in a piglet model.

UP-1007

‘UP-1007’ is a derivatized fullerene (60 carbon ball). Unify’s unique product can be taken by mouth and spreads throughout the body – including the brain. It is envisaged that this product will be used to target major diseases which currently have clinically unmet needs.

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Parkinson’s Disease​
Acute macular degeneration​
Mild Cognitive Impairment​
Alzheimer’s Disease​
Heart Attacks​
Strokes
Traumatic brain and spinal cord injuries​

EFFECTIVE IN BRAIN:​
PRE-CLINICAL PRIMATE DATA IN PARKINSON’S DISEASE​

Fig. 1 Brain PET imaging of Parkinsonian monkeys: 80% protection by UP1007, none by placebo

Modified from Dugan et, Ann Neuroll., 2014. Unify Pharmaceuticals has obtained permission for the use of these figures from the Annals of Neurology.

FIGURE 2: Dynamic functional assessment of Parkinson symptoms. Animals rated on an 18-point scale that assesses severity of symptoms. *UP1007 significantly better than placebo.

FIGURE 3: Parkinson motor scores in primates at the end of the study. Data are the mean scores after 8 weeks of drug treatment.

A pre-clinical study in 2014 showed the marked efficacy of C3 on primates afflicted with Parkinson’s (PD). This test was particularly significant for the nature of the subjects; most trials in this area are conducted on animals such as mice which are not biologically similar enough to humans to fully prove efficacy against PD. Statistically significant differences between UP1007 and Placebo groups began to appear after 30 days. No toxicity from UP1007 was observed (Hardt et al., 2018)

INTELLECTUAL PROPERTY

Unify Pharmaceuticals holds intellectual property in the US, protecting its proprietary research.

Patent Number Description Date Granted
7,145,032; 7,511,075 Therapeutic malonic acid/acetic acid C.sub.60 trl-adducts of buckminsterfullerene and methods related thereto December 5, 2006; March 3, 2009
9,035,057 Dihydroethidine analogues and uses thereof May 19, 2015
9,550,827 Methods for ameliorating and preventing central nervous system inflammation January 24, 2017
10644_058PV1_2017_11_15 Methods and compositions for the improvement of lysosomal function and treatment of neurodegenerative diseases. Pending: Submitted November, 2019