XinThera is focused on well-validated targets with a mission to rapidly create and advance fast-follower programs with best-in-class potential in areas of high-unmet need. The company capitalizes on its strength in chemistry as it designs the next generation of medicines with superior properties and efficacy. Its first two programs are in immunology inflammation and precision oncology.
PARP1 Program Summary
Clinically approved inhibitors of PARP inhibit both the PARP1 and PARP2 isoforms and have demonstrated efficacy in cancer cells with homologous recombination deficiencies (HRD) through synthetic lethality both by inhibiting the enzymatic activity of PARP and by locking or “trapping” the enzyme on DNA, disrupting replication. These agents have become a standard of care therapy for ovarian, breast, prostate and pancreatic cancer patients harboring HRD, but the utility of these inhibitors has been limited by off-target effects and activity against PARP2, the predominant PARP isoform in the hematopoietic system, resulting in hematological toxicity.
Xinthera has developed highly selective inhibitors for PARP1 and have found they demonstrate selective anti-tumor activity in HRD cancer models while mitigating the hematological toxicities seen in first generation PARP inhibitors. These inhibitors both selectively inhibit the enzymatic activity of PARP1 at picomolar concentration and promote trapping of PARP1 on DNA while not trapping PARP2. The reduced hematological toxicity seen with PARP1 selective inhibition will allow for a greater depth of PARP1 inhibition and trapping in patients and provide an option for patients found unable to tolerate currently approved PARP inhibitors. PARP1 selective inhibition will also allow combination therapy with traditional chemotherapy and novel agents, unachievable with current PARP inhibitors due to overlapping hematological toxicities. Current approved PARP inhibitors also lack the ability to enter the central nervous system (CNS). Xinthera has developed CNS available PARP1 selective inhibitors for the treatment of HRD tumors that have metastasized to the brain, and for the treatment of primary CNS malignancies. Phase 1 clinical trials are expected to start in first half of 2023.
MK2 Program Summary
Small molecule options are extremely appealing to patients living with chronic and debilitating inflammatory diseases. JAK inhibitors, through their mechanism of action (MOA), namely the inhibition of multiple cytokines, have achieved at least biologic-like efficacy in a pill, highlighted by rapid and durable clinical benefit, however, safety concerns have emerged.
Alternative oral treatments, with new MOA are desired and the MK2 pathway represents such an exciting therapeutic option for patients living with multiple inflammatory conditions including PsA, RA, AS and IBD. Targeting the P38-MK2 pathway directly inhibits multiple therapeutically relevant cytokines such as TNF, IL-6, IL-17 and IL-1β, all of which are indirectly impacted by JAK inhibitors, while sparing other cytokines and growth factor which are impacted by JAK inhibition.
Inhibitors of p38 did not advance in the clinic as they were associated with tachyphylaxis/ lack of a sustained and durable clinical response, and it is hypothesized that this is because p38 has many substrates, including anti-inflammatory pathways and negative feedback loops. XinThera has two MK2 assets moving through IND-enabling studies with the objective of starting Phase 1 clinical trials in the first half of 2023.