Identifying a small-molecule drug that can effectively treat (or potentially cure) patients with sickle cell disease (SCD) around the world is something of a Holy Grail in hematology research and drug discovery more broadly. After more than a decade of effort, researchers at the Novartis Biomedical Research report the identification and extensive testing of a small-molecule drug candidate that has the potential to treat SCD patients by boosting the levels of fetal hemoglobin (HbF).
The research, published today in Science in a report entitled “A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction,” was led by Pamela Ting, PhD, associate director of hematology at Novartis Biomedical Research. Ting leads a team of 40 co-authors, including Jay Bradner, MD, PhD, the former president of Novartis Institutes for BioMedical Research, who left the company in 2022 and joined Amgen late last year. Developing small-molecule drugs for SCD has been a long-standing interest of Bradner’s, dating back almost 15 years to research he performed on histone deacetylase inhibitors in collaboration with Stuart Schreiber, PhD, and colleagues at the Broad Institute.
Over the past decade or more, predating her own arrival at the company in 2015, Ting estimates that Novartis has screened some two million compounds in the search for a promising compound to take to the clinic. Along the way, the company briefly pursued its own CRISPR gene editing strategy, following a similar path to the approach that Vertex Pharmaceuticals took in developing Casgevy by boosting HbF production. (Although Novartis and collaborators published promising initial clinical data last year, the company decided to shelve the gene editing program.)
Despite the remarkable clinical success of the CRISPR ex vivo approach—the first American patient in the Vertex trial, Victoria Gray, celebrated the fifth anniversary of her stem cell transfusion earlier this week—it is clear that this demanding (and expensive) ex vivo strategy will not help the millions of patients in Africa and beyond—a point that Ting and colleagues hit home in their report in Science.
“Regrettably,” Ting and her co-authors write, “substantial challenges exist for [hematopoietic stem and progenitor cell] therapies to reach most SCD patients, who live in medically underserved communities and low and middle-income countries. Safe, efficacious, and globally accessible HbF-inducing medicines therefore remain an important unmet need.”
Fyodor Urnov, PhD, director of technology and translation at the Innovative Genomics Institute, told GEN that the 2023 approval of Casgevy provided definitive clinical evidence that the strategy of upregulating HbF is “a safe and effective approach to resolve major symptoms of sickle cell disease.” The new work builds on the theme of modulating a transcription factor to upregulate HbF, but this time using a small molecule. “Even people who live and breathe CRISPR will agree that, on balance, such a small molecule could have a wider global reach than gene editing,” Urnov said.
“There is a pressing need for oral agents that can more effectively induce fetal hemoglobin,” agreed hematologist Vijay Sankaran, MD, PhD, professor of pediatrics at Harvard Medical School. (Sankaran played a key role in cementing the HbF upregulation strategy to treat SCD 15 years ago.) He called the new Novartis report impressive and “exciting work and identifies a promising new target for fetal hemoglobin induction.”
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The Novartis study falls into a category known as “molecular glue pharmacology.” The researchers recognized that very small modifications to the chemical structure of a class of drug compounds that mediate targeted protein degradation (TPD) could profoundly affect the choice of protein for degradation. (A good example was work published by Novartis colleagues last year on the discovery of selective glue degraders for cancer immunotherapy).
“This was a big conceptual leap,” Ting explained. “You could do just a little bit of work around a fundamental structure and then broadly look for changes to the substrate selectivity.”
She added: “We decided, if this [chemical] library is capable of drugging a new class of transcription factors, then we should think about how we can apply it to an age-old problem that, at the root, is really a question of how do we regulate genes? And can we target transcription factors to regulate gene expression?”
Ting’s team embarked on a screen of a library of almost 3,000 compounds that target cereblon, a component of the E3 ubiquitin ligase complex that is involved in targeted protein degradation. Using a cellular assay that detected the upregulation of HbF) in erythroblasts, Novartis researchers identified scores of candidate molecules before whittling down the list and focusing on “compound C” for further study.
After mass spectrometry experiments showed that this chemical targeted the WIZ transcription factor, Ting’s group renamed the drug candidate dWIZ-1. The WIZ target was emphatically confirmed by CRISPR gene knock-out experiments. All told, these results suggested that WIZ was a previously unrecognized repressor of HbF expression. dWIZ-1 could recruit WIZ to the cereblon-ubiquitin ligase complex to trigger targeted protein degradation. The Novartis researchers continued experiments with a modified molecule termed dWIZ-2.
The Science report is packed with multiple types of experiments—molecular assays, mouse and non-human primate models, protein modeling using AlphaFold, and X-ray crystallography. Part of the rationale, Ting says, “was to convince ourselves that by every measurement that we could think of, we could see a reproducible effect.”
Some of the most important data in the report are results administering dWIZ-2 in a trio of cynomolgus monkeys. This in vivo study monitored the animals for 28 days and showed robust up-regulation of the γ-globin gene and HbF production in virtually all peripheral reticulocytes. “We saw almost pan-cellular HbF expression, which is very promising,” Ting said, and no signs of cytotoxicity. Curiously, one of the three animals was termed a non-responder. Ting calls it “the coolest monkey, because I feel like it must be telling us something and I don’t know what it is!”
The Novartis team found evidence for WIZ binding directly at the β-globin locus, which was unexpected. “Seeing WIZ for the first time is quite surprising for such a deeply studied locus,” Ting said. “For whatever reason, the globin locus seems to be highly sensitive to the loss of WIZ.” What is striking, she adds, is that “there is relatively strong overlap with binding sites for BCL11A,” the transcription factor that Vertex successfully targets in its Casgevy cell therapy.
“That’s where we leave it in the paper, as a bit of a teaser, something that we hope that we can further study in the future and that others will be inspired to study.”
Dealbreaker
As Ting readily acknowledges, there are still many unanswered questions, including the specificity of the inhibition. WIZ naturally binds at many spots in the genome, including a dozen or more in the β-globin gene cluster. “For whatever reason, when we modulate WIZ, the effects are fairly moderate and fairly mild,” Ting said. And the results in the non-human primates bode well. “We hope with these new chemical probes that this is something that we can continue to study and understand in the long run,” Ting says.
“I think the [Novartis] approach is promising, but with the current data it’s difficult to know what degree of HbF induction a human would experience,” said Vivien Sheehan, MD, PhD, associate professor and director of Sickle Cell Translational Research at Emory University School of Medicine in Atlanta. Sheehan, who first heard these results presented at the American Society of Hematology conference late last year, would like to see additional quantification data including HbF measurements using high-performance liquid chromatography. She also observes that “the lack of myelosuppression is promising for a potential combined therapy with hydroxyurea.”
Sankaran cautions that the non-specific effects of targeting WIZ lead to expression changes of hundreds of genes in erythroblasts. “More studies are needed before and during human clinical studies,” he said. A rigorous assessment of the safety of systemic WIZ degradation will be needed. “That could be a dealbreaker,” Sheehan says.
Understandably, Ting would not be drawn on a timeline for progress into the clinic, but her closing comments underlined her team’s belief in the program. “What we’re really focused on now is making sure that we’ve found a molecule that can really go all the way to patients,” she said. “We are highly committed to sickle cell patients around the world. We see the unmet need,” she said. “We’re progressing as quickly as possible, and we really have our eye on a medicine that will reach patients where they are.”
Nevertheless, while a small-molecule drug should prove both more affordable and accessible in the countries where most SCD live, IGI’s Urnov cautions that access to drug therapies outside the U.S. is by no means guaranteed. For example, a decade ago, Gilead slashed the price of its drug Solvadi by almost 99 percent in order to provide meaningful access to hepatitis patients in Egypt. The Novartis study, Urnov says, offers “an important opportunity to think ahead to how to solve this challenge when and if a medicine based on this work is approved in the U.S.”
