Biolinerx could mobilise interest in CXCR4 antagonism

A phase 3 win should remind investors about other clinical-stage CXCR4 antagonists.

Trial Results

The clinical success Biolinerx claimed yesterday with its CXCR4 antagonist motixafortide will remind investors that this mechanistic approach could be useful after all. Bristol Myers Squibb’s and Lilly’s discontinuations of similarly acting projects had cast doubt, but Biolinerx could reinvigorate Magenta, X4 and Polyphor.

However, motixafortide scored not in a cancer treatment trial but as an adjunct to autologous stem cell transplantation. And, while Biolinerx has played up motixafortide’s possible pharmacoeconomic benefit, its study did not go head to head against Sanofi’s Mozobil, a soon-to-be generic treatment standard.

The setting in question, stem-cell mobilisation to assist autologous bone marrow transplantation, might seem peripheral, but according to Evaluate Pharma sellside consensus Mozobil is expected to sell $295m this year. This is more than Biolinerx’s market cap, even taking into consideration yesterday’s 53% share price surge.

Stem cell mobilisation aims to increase the number of stem cells that move from the bone marrow to peripheral blood, and thus to enable more to be collected. In autologous transplantation in multiple myeloma the aim is to mobilise six million cells, and this is what Biolinerx’s Genesis trial of motixafortide focused on.

The proportion of patients mobilising at least six million cells in up to two apheresis sessions, the primary endpoint, was 4.9 times higher for motixafortide plus G-CSF versus G-CSF alone (p<0.0001). Looking at the effect in just one apheresis session, the key secondary endpoint, this mobilisation was achieved in 67.5% versus just 4.8% of patients.

Ending repeated apheresis?

This is vital to the pharmacoeconomic case Biolinerx is making: that motixafortide could eliminate the multiple apheresis procedures autologous stem cell transplant patients often need to undergo to allow enough cells to be collected. Five to six cycles is not uncommon, and sometimes the procedure fails for low cell yield.

Mozobil, which like motixafortide is a CXCR4 antagonist, is often used with G-CSF in these apheresis procedures, and the glaring fact is that the Sanofi drug was not used in Genesis. Biolinerx has argued that its project is better, but clearly it has not demonstrated this in a clinical trial.

This is especially pertinent as Mozobil goes off patent in 2023. In litigation Sanofi has managed to keep Zydus Cadila’s approved generic version off the market until then, but once this is launched it would be logical to expect significant price erosion.

Nevertheless, Biolinerx reckons it has shown enough to make motixafortide a new standard of care, and plans a filing next year.

Selected antagonists of CXCR4
Project Company Clinical use/note
Marketed
Mozobil Sanofi (ex Genzyme) Stem cell mobilisation
Tentatively approved generic
Plerixafor Zydus Cadila Generic of Mozobil
Phase 3
Motixafortide (BL-8040) Biolinerx Stem cell mobilisation & oncology
Balixafortide Polyphor Stem cell mobilisation & oncology
Mavorixafor X4 Pharmaceuticals (ex Sanofi) Waldenstrom's macroglobulinemia & WHIM syndrome
Phase 2
MGTA-145 Magenta Therapeutics Stem cell mobilisation; CXCR2 & 4 dual antagonist
Phase 1
AD-214 Adalta Immunosuppressant
...and some discontinued projects
Ulocuplumab Bristol Myers Squibb Academic trials only, no longer in pipeline; MAb
LY2510924 Lilly Ph2 cancer studies terminated; cyclic peptide
LY2624587 Lilly Ph1 cancer study completed; MAb
ALX-0651 Sanofi (ex Ablynx) Volunteer study terminated; nanobody
PF-06747143 Pfizer AML study terminated; MAb
Source: Evaluate Pharma & clinicaltrials.gov.

A separate consideration is what this means for the competition. Magenta’s MGTA-145, a CXCR2 & 4 dual antagonist, is in phase 2 for stem cell mobilisation in allogeneic transplants, while an autologous transplant multiple myeloma setting is the subject of an academic study; both combine it with Mozobil.

A separate idea is that CXCR4 antagonism could have a direct use in oncology, and motixafortide is being studied in combination with Keytruda in pancreatic cancer. Other CXCR4 antagonists in trials in both settings involve X4 Pharmaceuticals, with an asset bought from Sanofi, and the private Swiss firm Polyphor.

However, the approach took a hit when Bristol Myers Squibb discontinued a trial of ulocuplumab, an asset that no longer appears in its pipeline (Bristol failure makes small dent in CXCR4-blocking approach, March 23, 2017). Lilly later scrapped not one but two clinical-stage CXCR4 blockers.

Biolinerx has shown that the field is not dead, but it has not yet proved definitively that its data are strong enough to make motixafortide anything other than a niche drug.

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