PharmaShots Interview: X4 Pharmaceuticals’ Paula Ragan Shares Insights on Mavorixafor for the Treatment of Multiple Immunodeficiencies

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PharmaShots Interview: X4 Pharmaceuticals’ Paula Ragan Shares Insights on Mavorixafor for the Treatment of Multiple Immunodeficiencies

In an interview with PharmaShots, Paula Ragan, Ph.D., CEO, and President at X4 Pharmaceuticals shared her views on the data of Mavorixafor which showed increased immune cell levels regardless of patients having a CXCR4 mutation to treat multiple immunodeficiencies, presented at ASH 2021


  • The ongoing long-term extension arm of the P-II trial evaluates Mavorixafor (CXCR4 antagonist) in patients with WHIM syndrome. The therapy continues to show durable increases in multiple WBC counts, sustained improvements in infections and warts & was well tolerated
  • The P-III trial results are expected in Q4’22. The company also highlights mavorixafor’s ability to raise the spectrum of WBC count across a broad range of diseases with/out CXCR4 mutations including CN
  • The results from the P-I trial in WM, P-I/II trial in ccRCC, P-II trial in WHIM syndrome & ongoing P-Ib trial in CN showed that mavorixafor has the potential to reduce the prevalence or severity of a broader array of immunodeficiencies than previously recognized, regardless of the presence or absence of CXCR4 mutations

Tuba: Can we have a glance at the key points of the mavorixafor’s data for the treatment of immunodeficiency presented at ASH 2021?

Paula Ragan: ASH 2021 was an exciting conference for us, as we presented data updates across a variety of preclinical and clinical programs evaluating the potential of our lead CXCR4 antagonist, mavorixafor, on the rare immunodeficiency disorder WHIM syndrome, the rare cancer Waldenstrom macroglobulinemia (WM) and other chronic neutropenia diseases.

For WHIM syndrome, we presented data that continued to show safety and efficacy in our ongoing long-term extension arm of Phase 2 clinical trial, including durable increases in multiple white blood cell counts (neutrophils, lymphocytes, and monocytes) in addition to improvements in infections and warts, characterized symptoms of WHIM patients.

Our 4WHIM Phase 3 global trial is fully enrolled, and we look forward to reporting top-line data from this 52-week study by the end of the year. Data from 4WHIM and our previous Phase 2 study both will support an NDA submission to the U.S. Food and Drug Administration (FDA).

Additionally, we presented data from ongoing clinical studies demonstrating that mavorixafor increases white blood cell counts across different disease states. The analysis included data from a Phase 1 trial in WM, a Phase 1/2 trial in people with clear cell renal cell carcinoma (ccRCC), the WHIM syndrome Phase 2 trial, and our ongoing Phase 1b trial in chronic idiopathic neutropenia. These results suggest that mavorixafor has the potential to reduce the prevalence and/or severity of a broader array of immunodeficiencies than previously recognized, regardless of the presence or absence of CXCR4 mutations. This effect is likely associated with mavorixafor’s general mechanism of action to impact the three main pillars of white blood cell production: expansion, maturation, and trafficking, through antagonism of the CXCR4 pathway.

Tuba: What is WHIM syndrome? Discuss its epidemiology, symptoms, diagnosis, and treatments.

Paula Ragan: WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare genetic primary immunodeficiency disorder associated with mutations in the CXCR4 receptor, that result in reduced mobilization and trafficking of white blood cells from the bone marrow, leading to neutropenia. Patients with WHIM syndrome typically experience frequent, recurrent infections with a high risk of lung disease, refractory warts from underlying human papillomavirus (HPV) infection, and limited antibody production due to low levels of immunoglobulin, and an increased risk of developing certain types of cancer.

There is no typical path to the diagnosis given the diverse symptoms and people living with WHIM syndrome often experience long diagnosis journeys.

Tuba: How does mavorixafor work in WHIM syndrome and other indications?

Paula Ragan: As a small-molecule antagonist of the CXCR4 pathway, mavorixafor blocks CXCR4 over-signaling, enabling the expansion, maturation, and trafficking of white blood cells into the blood and, as such, potentially improving immune function. 

Tuba: What motivates the company to work on this rare primary immunodeficiency disorder?

Paula Ragan: X4’s work and culture are grounded with a “patient-focused grit”. The team is committed to delivering disease-modifying treatments that could forever change the quality of life and fate of many patients living with rare genetic diseases, such as WHIM syndrome. There are millions of people around the world living with a rare disease and research and therapeutic development for the more than 6,000 rare diseases currently identified is scarce. We are happy and proud to be one of the companies leading the way in the development of potential therapeutics for a number of these diseases and are excited to potentially make the first disease-modifying therapeutic available for people with WHIM syndrome in the next couple of years.

Tuba: Discuss mavorixafor’s broader market potential to benefit a larger immunodeficient population in need.

Paula Ragan: Dysregulation of white blood cells contributes to a broad range of serious immunodeficiencies with significant unmet needs, independent of CXCR4 mutation status. Primary immunodeficiencies alone represent an estimated $3.3 billion in prescription sales worldwide, and patients currently rely on few injectable options such as intravenous immunoglobulin therapy (IViG) or granulocyte-colony stimulating factor (G-CSF), with significant drawbacks such as regular injectable administration and lack of reduction in severe bacterial infections in a large percentage of patients. Given our initial data to date, showing mavorixafor’s ability to increase white blood cell counts across a variety of disease states, in addition to its daily oral administration, we believe mavorixafor has the potential to reduce the prevalence and/or severity of a broader array of immunodeficiencies than previously recognized.

Tuba: What are the other indications in which you are evaluating mavorixafor?

Paula Ragan: We are currently evaluating mavorixafor in a Phase 1b trial in people with the rare type of non-Hodgkin lymphoma Waldenstrom macroglobulinemia (WM), who carry the CXCR4 mutation.

About 90% of WM patients present with mutations in the MYD88 gene and about 30-40% of WM patients present with mutations in the CXCR4 receptor gene as well. These patients, referred to as double-mutation patients, have more severe diseases, associated with crowding of cancerous immune cells in the bone marrow, anemia, and higher levels of the blood protein IgM, which leads to severe thickening of the blood. CXCR4 mutations also respond worse than patients with only the MYD88 mutation to the currently approved drug, ibrutinib, leading to delayed and less efficacious responses.

Interim data presented at ASH demonstrated the potential of mavorixafor in combination with Ibrutinib to improve clinical responses in patients with mutations in both CXCR4 and MYD88 and with a positive safety profile to date. Of evaluated double mutant patients (n=10), 100% achieved an overall response (>25% reductions in IgM), including four Major Responses (>50% reduction in serum IgM) and one Very Good Partial Response (VGPR) of >90% reduction in serum IgM. IgM levels were lower in the combination treatment than with Ibrutinib alone, in a refractory subset of the population. Responses are beginning to mirror the previously published reductions in serum IgM levels achieved by Ibrutinib monotherapy in refractory, non-CXCR4-mutation patients, suggesting that CXCR4 antagonism by mavorixafor may eliminate some, or all, of the negative impacts of CXCR4 mutations in this higher-risk double mutant WM sub-population. We look forward to reporting further data from this during the second half of 2022.

Tuba: When can we expect the approval of mavorixafor in WHIM?

Paula Ragan: For the WHIM indication, mavorixafor has been granted Breakthrough Therapy Designation, Fast Track Designation, and Rare Pediatric Designation in the U.S., and Orphan Drug Status in both the U.S. and European Union. We expect top-line data from our 4WHIM Phase 3 trial evaluating mavorixafor in people diagnosed with WHIM syndrome by the end of the year. Should the data continue to be as positive as it has been to date, we will work to compile all final data and file an NDA thereafter in 2023.

Tuba: When are you planning to enter into the clinical stage with your preclinical candidates?

Paula Ragan: We continue to advance our preclinical pipeline of additional CXCR4 inhibitors with the potential to treat additional diseases. We anticipate our next IND filing of our lead preclinical drug candidate towards the end of 2022.

Tuba: What are your coming year plans in terms of collaborations, licensing agreements, new funding, etc?

Paula Ragan: To keep the best interest of our shareholders, we remain nimble and thorough in our approach to business development. X4 will provide updates as our intentions for collaborations and licensing agreements progress. In the meantime, we remain steadfast in our mission to rapidly advance our lead candidate, mavorixafor, for people living with WHIM and other rare diseases that result from immune system dysfunction, such as other chronic neutropenia diseases and rare cancers.

Source: AllerVie Health

About Author:

Paula Ragan is the CEO and President 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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Tuba was Senior Editor at PharmaShots. She was curious, creative, and passionate about recent updates and innovations in the life sciences industry. She covered Biopharma, MedTech, and Digital health segments. Tuba also had an experience in digital and social media marketing and ran the campaigns independently. She can be contacted at [email protected].

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