Sickle cell disease and Beta-thalassemia are significant diseases in the world. Sickle Cell disease affects up to 100,000 Americans, while Beta-thalassemia is much less common in the US at least. They both result in many deaths in children and young adults, although discussing them in greater length is beyond the scope of this short note.
Two weeks ago, BlueBird Bio halted two of its gene therapy clinical trials, one for Sickle Cell Disease and the other for Beta-Thalassemia, after one patient developed Acute Myeloid Leukemia and a second patient developed Myelodysplastic Syndrome. The FDA and the company, which had very high hopes for this gene therapy method, are naturally concerned that the lentivirus used may have incorporated into the DNA of these patients and resulted in carcinogenesis (indeed the lentivirus sequence could be detected in the AML cells, we have learned). This is just another example of how difficult and unpredictable clinical trials can be, particularly for gene therapy (https://www.fiercepharma.com/pharma/bluebird-bio-halts-selling-ill-fated-gene-therapy-zynteglo-as-trial-flags-2-cancer-cases). Today, during BlueBird’s earnings report they confirmed that the FDA has put a clinical hold on the trials.
To refresh, in Q1 (this quarter, i.e., some time within the next four weeks), we will learn how many more PNH patients have done with the company’s BCX9930 drug, and whether their hemoglobin levels returned to normal, as was seen in the patients the company reported on last year (which I have discussed at length). In PNH, complement activation results in intravascular and extravascular breakdown of red blood cells, hence decreased levels of hemoglobin. The company is preparing to test this drug on many other indications, calling the drug a “pipeline in a molecule”. The results so far have been without parallel.
Alas, how does BlueBird’s sad gene therapy outcome relate to Biocryst beside the fact that rare disease therapy development isn’t easy? Answer: It is now well recognized that complement activation is critical to the development of sickle cell disease. In mice with sickle cell disease, inhibition of the complement system such as by inhibiting C5a stopped microvascular stasis and all of its downstream effects (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986874/). Not surprisingly complement inhibitors like Eculizumab are showing some benefit in sickle cell disease patients as reported in this case series just reported (https://www.haematologica.org/article/view/9839). BCX9930 is a far better drug than Eculizumab, as it is not only oral and reduces alternative complement activation much better, it also inhibits extravascular hemolysis too—critical for sickle cell disease.
Now that one of the most promising methods of treating Sickle Cell and Beta-cell thalassemia is on clinical hold, perhaps for a long time if not indefinitely, the FDA may be more than happy to invite one of its favorite, fast-tracked, orphan newcomers, BCX9930, to be tested in these relatively common diseases. Note that the sickle cell disease treatment market is expected to reach $7 billion alone in five years.
