The Leeds, UK headquartered LBP developer announced positive interim results this week from the phase I/II study of the combination of its LPB candidate, MRx0518, and Keytruda (pembrolizumab), the anti-PD-1 therapy of MSD, for patients with solid tumors that have progressed on a prior immune checkpoint inhibitor (ICI).
The renal cell carcinoma (RCC) group met its primary efficacy endpoint ahead of enrollment completion. Part B of the trial has, to date, enrolled 20 patients with RCC, of which four out of the first 16 evaluable patients have achieved clinical benefit, each having achieved at least six months of stable disease, said 4D Pharma.
Part B is scheduled to enroll up to a total of 120 patients: 30 RCC, 30 non-small cell lung cancer (NSCLC), 30 bladder, and an additional cohort of 10 triple negative breast (TNBC), 10 head and neck squamous cell carcinoma (HNSCC), and 10 microsatellite instability high (MSI-H) tumors. So far, the partners have enrolled 20 RCC patients and 27 across the other tumor types.
Patient response
Duncan Peyton, CEO, 4D Pharma, told BioPharma-Reporter: “The primary endpoint for Part B set by 4D Pharma and MSD was for more than three patients out of a total of up to 30 patients per tumor type group to achieve clinical benefit. Out of the first 16 evaluable RCC patients we have already hit four with clinical benefit, achieving the primary in this group. The RCC group and other tumor type groups will continue to enrol so we may see more than four, but we have already achieved that threshold.
“Clinical benefit is defined as complete response, partial response, or stable disease [equal to or greater than] 6 months.
"Including results from the completed Part A previously announced, out of 24 evaluable RCC patients we have achieved clinical benefit in eight. By another common metric - disease control rate - defined as complete response, partial response, or stable disease for at least nine weeks, we have, to date, seen 12/24 (50%).
“In this group of patients, who have had an average of three prior lines of therapy, including a previous immune checkpoint inhibitor, and are not responding to available therapies, this is a meaningful benefit – we now have patients on treatment for over two years.”
He also outlined why it is clear that 4D’s live biotherapeutic candidate, MRx0518, is having an effect: “By definition, to be included on our study, patients must have previously had benefit on a checkpoint inhibitor but then developed secondary resistance and progressive disease. Therefore, you might not expect such patients to respond to a checkpoint inhibitor like Keytruda alone.”
Separately, the contribution of MRx0518 is supported by another study, in which MRx0518 is used as a neoadjuvant monotherapy, he added.
“We have previously published results from this study showing that MRx0518 alone drives changes in the immune system, systemically and in the tumor microenvironment. Importantly these changes are known to be associated with an anti-cancer immune response, and emerging literature is showing that the immune environment being driven by MRx0518 is associated with better outcomes to treatments like checkpoint inhibitors. The data provides preliminary evidence that MRx0518 may help to overcome key mechanisms of resistance to checkpoint inhibitors.”
In terms of next steps in respect of this study, he said it will continue to enrol patients in RCC and the other tumor types to gather more data.
“We are also evaluating options to expand the pool of patients, for example including patients with primary resistance to ICIs, in addition to those with secondary resistance currently being enrolled. We will also be discussing with our partners and Advisory Board potential next steps regarding the development path of MRx0518 and a potentially pivotal study in patients with ICI-refractory RCC.”
LBPs are an emerging class of drugs, defined by the FDA as biological products that contain a live organism, such as a bacterium, that is applicable to the prevention, treatment, or cure of a disease.
Clinical programs
4D pharma has developed a proprietary platform, MicroRx, based on its LBPs, which are orally delivered single strains of bacteria that are found in the healthy human gut.
The company has five clinical programs, the Phase I/II study of MRx0518 in combination with Keytruda in solid tumors, a Phase I study of MRx0518 in a neoadjuvant setting for patients with solid tumors, a Phase I study of MRx0518 in patients with pancreatic cancer, a Phase I/II study of MRx-4DP0004 in asthma, and Blautix in irritable bowel syndrome (IBS), which has completed a successful Phase II trial. A Phase I study of MRx0005 and MRx0029 in patients with Parkinson’s disease is set to get underway mid-2022.
Additional preclinical-stage programs include candidates for CNS disease, immune-inflammatory conditions and cancer. The company also has a research collaboration with MSD to discover and develop LBPs for vaccines.
