Pipeline: Multiple potential indications – “Platform in a drug”

MT-001 (Liver – NASH)

NASH has become major problem around the world. In the US fatty liver affects over 65MM Americans. There are many companies developing products for this disease, but to date no product has been approved for this disorder. Many of the drugs being tested were developed for other uses and have been repurposed to try and get to this market quickly, so far unsuccessfully.

Our lead product is targeted for use in the liver to treat NASH. MT-001 has been tested in a variety of NASH models in mice with success. We have demonstrated that MT-001 can also be effective in the treatment of fibrosis, cirrhosis, and primary biliary cholangitis.

We have identified our lead drug and it is effective at reducing MCJ in early testing in nonhuman primates. We expect to file an IND sometime in mid- 2021.

MT-002 (Liver – APAP)

APAP (acetaminophen) poisoning is the principal cause of acute liver failure requiring transplantation. Acetaminophen impairs mitochondrial function (interferes with mitochondrial respiration), which increases ROS and hepatocyte cell death. There are around 100,000 calls to poison centers and 56,000 emergency room visits per year for acetaminophen poisoning in the US. In the UK 45,000 patients are admitted for acetaminophen poisoning (Lee WM, Hepatology, 2004 Jul 40(1):6-9). The only existing treatment is N-acetylcysteine (NAC), which is effective in first 6-8 hours post acetaminophen overdose. Liver transplant is the only remaining option for non-responders.

Our initial work in this area has demonstrated that MT-002 can have significant impact on APAP poisoning in the liver in mouse studies. Using siMCJ delivered with invivofectamine (LNP-based) in a mouse model of acetyl-para-aminophenol (APAP)-induced liver injury we have shown:

Efficacy in treating APAP-induced liver injury when siMCJ was provided 6 h and 24 h after administration of APAP
Lack of effect of N-acetylcysteine (NAC) treatment after 6 h of APAP administration
Treatment with siMCJ increases liver regeneration after APAP-induced liver injury

Studies have been carried out in APAP-induced liver injury mice in which MCJ was knocked out and damage from APAP poisoning was significantly reduced. The formation of super-complexes reduced the production of ROS and subsequent liver damage.

MT-003 (KIDNEY)

The kidneys are an important set of organs that remove waste and extra fluid from the body. The kidneys also helps to maintain pH and a healthy balance of water, salts, and minerals.

We tested wildtype mice versus MCJ knockout mice in the UUO (Unilateral Ureter Obstruction Model) and demonstrated that there is a clear difference between the two in the amount of protein produced in the urine and the amount of fibrosis created in kidney.

The Unilateral Ureteral Obstruction (UUO) model is used to cause renal fibrosis, where the primary feature of UUO is tubular injury as a result of obstructed urine flow. Experimental UUO in rodents is believed to mimic human chronic obstructive nephropathy in an accelerated manner. The kidneys have the second most mitochondria per parenchymal cell after the heart. We are interested in kidney diseases that involve the proximal tubules because delivery of siRNA to that area is sufficient to reduce target protein levels. Mitotherapeutix has a program focused on acute kidney injury resulting from reperfusion that occurs in the kidney following cardiovascular surgery. We believe that knocking down MCJ in these mitochondria will prevent ROS and the subsequent damage in the kidney in the same manner we showed in the liver. In those studies reduction of MCJ led to an increase in beta-oxidation in the mitochondria of the hepatocytes and an increase in ATP and a reduction of ROS and fibrosis.

Mitotherapeutix also has a program focused on Polycystic kidney disease (PKD). Polycystic kidney disease (PKD) is a genetic disorder that causes many fluid-filled cysts to grow in your kidneys. Unlike the usually harmless simple kidney cysts that can form in the kidneys later in life, PKD cysts can change the shape of your kidneys, including making them much larger. PKD is a form of chronic kidney disease (CKD) that reduces kidney function and may lead to kidney failure. PKD also can cause other complications, or problems, such as high blood pressure, cysts in the liver, and problems with blood vessels in your brain and heart.

A breakdown in metabolic function is a key element to the aberration in kidney cell function that occurs in PKD. Recent data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease. (The FASEB Journal. 2020;34:6493–6507) We plan to increase beta oxidation and production of ATP and expect that this change will have positive impact on cyst formation.

MT-004 (Immuno Related-Cancer/CD8 T-CELLS )

Dr. Rincon, a founder in Mitotherapeutix and lead researcher on MCJ has identified CD8 T cells as a cell type that has larger amounts of MCJ than other types of immune related cells. She has also found that knocking out MCJ in CD8 cells can have profound effects on the CD8 T cells. These KO CD8 T-cells are much more active against tumor cells invitro and produce interferon and interleukin II. We expect to explore CD8 T-cells and their role in treating disease including cancer.