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Focusing on the Key Drivers of Disease

AllRock Bio’s lead drug, ROC-101, is an orally administered, potentially best-in-class pan-ROCK inhibitor. ROC-101 is being investigated in pulmonary arterial hypertension (PAH) and pulmonary hypertension with interstitial lung disease (ILD-PH). ROC-101 potently inhibits both ROCK isoforms, ROCK1 and ROCK2. This pan-ROCK inhibition results in an anti-proliferative, anti-inflammatory and anti-fibrotic mechanism of action that potentially enables the treatment of PAH and ILD-PH. This mechanism for ROC-101 targets the pathologic process of pulmonary arterial remodeling seen in PAH and ILD-PH, and it also targets the pulmonary fibrosis seen in ILD-PH.

The diagram depicts a stylized cell membrane and nucleus. At the top, outside of the cell membrane are oval shapes depicting ligands, such as collagen, cytokines, growth factors, lysophosphatidic acid (LPA) and growth hormones. They are all binding to their distinct receptors, including integrins, G protein coupled receptors (GPCRs), receptor protein kinases, and the TGF beta receptor. All of these kinases are shown to stimulate RhoA activation, allowing RhoA to bind to ROCK 1/ 2 enzymes, which then leads to either 1) phosphorylation of STAT3 or 2) TGF beta induced pro fibrotic gene expression or 3) extracellular matrix deposition or 4) cytoskeletal remodeling. There is then an arrow drawn from the cytosol where ROCK1&2 are present to the nucleus where an arrow denotes that ROCK1 and 2 activation leads to the binding of transcription factors to pro fibrotic genes and to pro-inflammatory cytokine genes. And this results in the up regulation of genes such as CXCL10, ICAM-1, COL1A1, Alpha – SMA, COL3A1, and CTGF.

Adapted from Hartmann 2015. Frontiers in Pharmacology 6:276.

Leading the Way in Developing Novel Therapies

Pulmonary Arterial Hypertension (PAH) is a severe condition characterized by elevated blood pressure in the pulmonary arteries, impacting both the lungs and the right side of the heart.

Heart and lungs on the right and individual regions of pathogenesis in the lung on the left. In the upper left-hand portion of the graphic there is a box numbered “1” which displays a normal small peripheral artery with the wall of the artery being depicted as lined with an endothelial cell. An arrow points down to an abnormal peripheral artery that displays muscularization and medial hypertrophy with hypertrophy of the smooth muscle much greater than that of the external elastic lamina or the internal elastic lamina, which are also shown. An arrow leads from this abnormal artery to a box on the left, showing neointimal formation and arterial occlusion with the neointimal space depicted in red and narrowing the lumen of the small peripheral artery, even further. The abnormal artery from the upper left hand box also has an arrow going to a third boxed area showing the evidence of plexiform lesion formation. There the architecture of the small peripheral artery is almost completely ablated with elastic fibers and inflammatory cells leading to a heterogeneous occluded lumen designate a plexiform lesion. Red-colored cells labeled inflammatory cells are present, and below this there is an arrow leading to fibrotic alveoli which are in contrast to the healthy alveoli shown in an arrow leading from the lung space.

Adapted from Dunmore BJ, Jones RJ, Toshner MR, Upton PD, Morrell NW. Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus. Cardiovasc Res. 2021;117(11):2309-2325. doi:10.1093/cvr/cvaa350.

In PAH, the small pulmonary vessels undergo narrowing, obstruction, or destruction, leading to elevated arterial pressure. This heightened pressure impedes blood flow through the lungs, necessitating increased effort from the right ventricle to maintain adequate circulation, ultimately placing significant strain on the heart.

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is a complex condition characterized by elevated blood pressure in the pulmonary arteries, occurring concurrently with chronic lung diseases that induce scarring and inflammation of lung tissue. This dual pathology presents significant clinical challenges. In ILD patients, the lung parenchyma becomes thickened and fibrotic, impairing oxygen diffusion into the bloodstream. The resultant chronic hypoxemia can trigger vasoconstriction and vascular remodeling in the pulmonary arteries, leading to increased pulmonary arterial pressure.

Our lead drug, ROC-101, an investigational oral pan-ROCK inhibitor, is intended to promote vasodilation, reduce vascular remodeling, and improve endothelial function, leading to improved hemodynamic parameters.

PAH and ILD PH

Pulmonary arterial hypertension (PAH) is a complex disease characterized by several pathological mechanisms.

One of the key aspects of PAH is the intrinsic proliferative potential and cellular accumulation within the pulmonary arteries. This is due to sustained proliferative signaling, which allows cells to continuously divide and grow.

Impaired blood vessel formation and vasoreactivity are critical features of PAH. This is because it induces the formation of new blood vessels, which can be abnormal and dysfunctional. Impaired vasoreactivity, or the inability of blood vessels to properly constrict and dilate, further complicates the disease, leading to increased blood pressure in the pulmonary arteries.

Many therapies on the market may be effective at relieving symptoms, but they fail to modify the progression of the disease. AllRock Bio is striving to address this with ROC-101, which targets increased ROCK activity in PAH patients. Increased ROCK activity in patient cells correlates significantly with the duration of PAH in patients, suggesting its association with disease progression (Antoniu 2012).

Furthermore, inhibiting both the ROCK1&2 isoforms (schematic shown below) has been shown in animal studies to reduce muscularization and thickness of pulmonary vessel walls and to reduce right-sided heart pressures. ROC-101 lowered collagen deposition in the fibrotic lungs, improved fibrotic lung histology, reduced immune cell infiltration, and decreased phosphorylation of target proteins in the lung. These functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis.

The schematic is a linear representation of the ROCK1 (top) in comparison to the ROCK2 (bottom) enzyme. Starting at the top is a line that stretches 1354 amino acids in length and encompasses the end terminal left portion of the ROCK1 molecule that contains a kinase domain with 90% identity between ROCK1 and ROCK2. This is followed by the mid portion of the schematic containing a coiled-coil region with 55% identity to ROCK2 containing at a RhoA binding domain (where RhoA is bound to a GTP) and in between this and the pleckstrin homology domain, which also has a CRD domain there is a caspase-3 cleavage site. The pleckstrin homology domain has a 65% identity to ROCK2 and then there is the carboxy terminus of the enzyme at amino acid 1354. Below this is the ROCK2 schematic with an amino terminal kinase domain, a middle region with a coiled-coil region and then between the contiguous RhoA binding domain and the pleckstrin homology domain is a Granzyme B cleavage site and the entire ROCK2 amino acid is 1388 amino acids in length.

Adapted from Hartmann 2015.

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