In an interview with PharmaShots, Paula Ragan, Ph.D., President, and Chief Executive Officer at X4 Pharmaceuticals shared her views on preliminary efficacy and safety data of Mavorixafor + Ibrutinib in an ongoing P-Ib study to treat waldenström's macroglobulinemia

Shots:

• The ongoing P-Ib clinical trial evaluates the safety & efficacy of mavorixafor + ibrutinib in patients with WM with both MYD88 & CXCR4 mutations. The trial is being conducted with AbbVie & LLS TAP
• The results showed that patients achieved median reductions of 60%- 75% in serum IgM levels compared to 38%-45% reductions in previously published data of ibrutinib monothx in double-mutation patients @6mos. of treatment; 50% had >50% reduction in serum IgM from baseline; 1 patient achieved normal IgM levels
• Additionally, hemoglobin levels increase with a reduction in the cancer burden in the bone marrow. The combination is well tolerated & no serious AEs were observed

Tuba: Discuss the key results of the Phase Ib clinical study of mavorixafor in Waldenström's Macroglobulinemia (WM).

Paula Ragan: Our ongoing Phase 1b clinical trial is evaluating the safety and initial efficacy of our lead drug candidate mavorixafor, given orally at three different doses (200 mg, 400mg, and 600 mg) in combination with standard of care, ibrutinib, in people living Waldenström's Macroblobulinemia (WM) with confirmed double mutations in the MYD88 and CXCR4 genes. 

WM is a rare blood cancer and a type of non-Hodgkin's lymphoma which leads to an overproduction of a type of immunoglobulin, IgM, resulting in high blood viscosity. Other symptoms include anemia (or reduced hemoglobin), fatigue, and bleeding issues. There is currently no cure for WM and only one approved treatment option, ibrutinib.

About 90% of WM patients present with mutations in the MYD88 gene and 30-40% of patients present with mutations in the CXCR4 receptor gene as well. These patients, referred to as double-mutation patients, have more severe diseases and tend to respond worse than patients with only the MYD88 mutation when receiving ibrutinib. 

Interim data from our Phase 1b trial as of April 15, 2021, demonstrated the potential for mavorixafor plus ibrutinib therapy to be a best-in-class treatment in these double-mutation WM patients. 

Overall, all patients (100%) experienced reductions in serum IgM and no patients disease progressed while on treatment. At 6 months of treatment, patients with double mutations treated with mavorixafor achieved median IgM level reductions of 60%-75%. This compares favorably to published ibrutinib monotherapy reductions of 38%-45% in double-mutation patients. In addition, one patient achieved normal IgM, and two of four patients (50%) had a >50% reduction in serum IgM from baseline.

All patients with hemoglobin levels below normal at baseline (anemia at baseline) had increased during treatment, with a median change in hemoglobin of >20 g/L, approaching normal levels, which suggests a reduction in cancer burden in the bone marrow. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug-drug interactions and no serious adverse events were reported in the Phase 1b study. Results to date include data from 8 patients, with a median study duration of 156 days. 

Tuba: Do you think the therapy will have a large impact on patients with WM?

Paula Ragan: Results from our Phase 1b trial to date demonstrated the potential for mavorixafor plus ibrutinib therapy to be a best-in-class treatment option in these double-mutation WM patients, who generally experience a delayed treatment response, inferior depth of response, and/or shorter progression-free survival, with the standard of care. 

We look forward to presenting longer-term data and an expanded data set from this trial later in the year. If the safety and clinical efficacy continue to be positive, we believe mavorixafor has the potential to improve the standard of care and provide some hope to this difficult-to-treat WM patient population, including potential deeper reductions in IgM levels and improvements in response rates. 

Tuba: What is the importance of reduction in IgM levels in Waldenström's patients?

Paula Ragan: People with WM, and those with the double mutation, in particular, produce large amounts of a protein called immunoglobulin M (IgM), a type of protein that in normal conditions help the body fight infection. However, large quantities of IgM in blood lead to an increased risk of developing a serious emergent condition called symptomatic hyperviscosity syndrome (HVS), characterized by a thickening of the blood, limiting its healthy flow. Increased IgM levels are associated with many symptoms, including fatigue, unexplained weight loss, enlarged lymph nodes or spleen, weakness, and unexplained bleeding. 

As such, reduction of IgM levels in WM patients is one of the most relevant parameters of clinical efficacy, such as an overall response, and improvement in quality of life. 

Tuba: What is mavorixafor (X4P-001)? Discuss its MoA and the importance in WM patients.

Paula Ragan: Mavorixafor is a molecule that binds and antagonizes the CXCR4 receptor resulting in reduced signaling. In 30-40% of WM patients, the CXCR4 receptor has a gain-of-function mutation which leads to overactivation of the CXCR4 pathway by its ligand chemokine ligand 12 (CXCL12). Over-signaling of the CXCR4 pathway immobilizes the CXCR4-mutated cancer cells in the bone marrow enabling them to grow and produce excessively high levels of IgM. This growth ultimately crowds out the healthy bone marrow cells resulting in anemia and contributing to the other severe symptoms that are the hallmark of WM disease. 

By blocking the CXCR4 receptor from being stimulated by its ligand CXCL12, mavorixafor increases mobilization and trafficking of cancerous B cells from the bone marrow. At the patient level, this reduces the crowding effects of cancer on the bone marrow which leads to improved hemoglobin levels (reducing anemia) and decreasing IgM (lowering cancer burden). The results of our Phase 1b study of mavorixafor plus ibrutinib demonstrate this proof of mechanism in our initial 8 patients treated at the low to mid doses.  

Tuba: Highlight the pipeline of X4 Pharmaceutical.

Paula Ragan: At X4 Pharmaceuticals, we are advancing a variety of therapies for the treatment of diseases resulting from dysfunction of the CXCR4 pathway. In addition to our Phase 1b trial currently investigating our lead asset, mavorixafor, in combination with ibrutinib for the treatment of WM, we are advancing a Phase 3 trial, 4WHIM, evaluating mavorixafor in people with the immunodeficiency WHIM syndrome. 

In addition, we are evaluating mavorixafor in a Phase 1b clinical trial in patients with severe congenital neutropenia (SCN) and are exploring additional indications for mavorixafor's use across larger chronic neutropenic populations given its demonstrated effect of increasing total white blood cell levels with both acute and chronic dosing. 

We believe that inhibition of the CXCR4 receptor creates the potential for mavorixafor to provide therapeutic benefit across a wide variety of rare diseases, including primary immunodeficiencies and certain types of cancer. We are evaluating additional preclinical candidates to expand our pipeline to address additional rare diseases.  

Tuba: When you are expecting your first approval for mavorixafor?

Paula Ragan: Our most advanced program is the Phase 3 clinical trial evaluating mavorixafor in people with WHIM syndrome, a rare primary immunodeficiency disorder characterized by low white blood cell counts, severe recurrent bacterial infections in multiple organ systems (lung, ears, and skin) and warts (alterations/ulcers in the skin caused by the HPV virus) that can turn into cancer over time. WHIM syndrome patients are born with gain-of-function mutations in CXCR4, leading to over-signaling of the receptor; mavorixafor, administered as an oral once-daily capsule, has the potential to correct the root cause of this debilitating disease. 

Data from our Phase 2 trial to date has demonstrated the potential of mavorixafor to become the first disease-modifying therapy for people with WHIM. This includes improving circulating levels of white blood cells and reducing infections rates and wart burden, with a positive safety profile in patients treated for more than 2 years. 

With 23 patients now enrolled, we have surpassed the 18-patient minimum enrollment needed in our Phase 3 trial for primary endpoint analyses and assessment of clinical benefit and enable a U.S. regulatory filing (if supported by the Phase 3 data). We anticipate enrollment will conclude in Q3 of this year and we expect to have top-line data from the trial in Q4 2022. Mavorixafor has been granted Breakthrough Therapy Designation, Fast Track Designation, and Rare Pediatric Disease Designation in the U.S., in addition to Orphan Drug Status in the U.S. and EU. We hope to make mavorixafor available to WHIM patients as soon as possible.

Tuba: What motivates the company to work on rare diseases such as WM?

Paula Ragan: Thousands of genetic rare diseases affect small patient populations who lack treatment alternatives and have little to no prospects of future options due to the small patient populations affected.  

X4 was founded to make a difference and provide hope for this and other rare populations by hearing the patients voices and advancing disease-modifying treatments that target the cause of disease, with the potential to improve their quality of life and, and in some cases, offer a dramatic change for the better, for the very first time. Every patient deserves to feel hope. 

Source: Touch Oncology

About Author: Paula Ragan is the President and CEO of X4 Pharmaceuticals. She has more than 18 years of experience building companies in the biotechnology industry. Dr. Ragan received her B.S. from Tufts University and her Ph.D. from Massachusetts Institute of Technology and completed post-doctoral studies at Harvard Medical School

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