New drug sits at the center of this dementia and brain health question.
The headline sounds almost too good to be true — a new drug that cuts sickle cell crises by 45 percent without side effects. And in a sense, it is too good to be true, because the claim actually conflates two separate Novartis-backed developments. One drug, crizanlizumab, demonstrated a 45.3 percent reduction in painful vaso-occlusive crises in a Phase 2 trial but comes with a real list of side effects and a Phase 3 trial that failed to outperform placebo. The other, an experimental compound called dWIZ-2, raised fetal hemoglobin levels to 45 percent in preclinical animal studies without apparent side effects — but it has never been tested in a single human being.
For the roughly 100,000 Americans living with sickle cell disease and the millions more worldwide, parsing these distinctions matters enormously. This article breaks down both developments honestly. We will examine what crizanlizumab actually delivered and where it fell short, what makes dWIZ-2 a genuinely novel approach, why fetal hemoglobin matters so much in sickle cell disease, and what all of this means for patients and families navigating treatment decisions today. For readers of this site focused on brain health and dementia care, the connection is not abstract — sickle cell disease causes silent strokes and cognitive decline, particularly in children and older adults, making advances in crisis prevention directly relevant to neurological outcomes.
Table of Contents
- Did a New Drug Really Cut Sickle Cell Crises by 45 Percent Without Side Effects?
- The Rise and Stumble of Crizanlizumab
- Why Fetal Hemoglobin Is the Holy Grail of Sickle Cell Treatment
- An Oral Pill Versus Gene Therapy — What Patients Actually Face
- The Brain Health Connection — Why Sickle Cell Crises Matter for Cognition
- What Preclinical Results Actually Tell Us
- Where Sickle Cell Treatment Goes From Here
- Conclusion
- Frequently Asked Questions
Did a New Drug Really Cut Sickle Cell Crises by 45 Percent Without Side Effects?
Not exactly. The 45 percent crisis reduction figure comes from the SUSTAIN trial of crizanlizumab, published in the *New England Journal of Medicine*. In that Phase 2 study, patients receiving high-dose crizanlizumab experienced a median of 1.63 vaso-occlusive crises per year compared to 2.98 on placebo — a 45.3 percent reduction. The FDA approved the drug under the brand name ADAKVEO in November 2019 for patients aged 16 and older. But the claim of “no side effects” does not belong to this drug.
More than 10 percent of patients in the trial reported arthralgia, diarrhea, pruritus, vomiting, chest pain, nausea, back pain, and fever. The “without side effects” part likely refers to dWIZ-2, a preclinical compound that works through an entirely different mechanism. In laboratory and animal studies, dWIZ-2 boosted fetal hemoglobin production in red blood cells from a baseline of 17 percent to 45 percent — and did so in mice and in two of three cynomolgus monkeys without apparent adverse effects. It is an oral pill rather than an IV infusion, which would represent a significant practical advantage. But preclinical results in animals routinely fail to translate to humans, and dWIZ-2 has not yet entered human safety testing. Combining the crisis reduction stat from one drug with the safety profile from another creates a misleading picture that patients deserve to see clearly.
The Rise and Stumble of Crizanlizumab
Crizanlizumab is a humanized monoclonal antibody that targets P-selectin, a protein that causes blood cells to stick to vessel walls. In sickle cell disease, misshapen red blood cells clump together and block small blood vessels, triggering the excruciating pain episodes known as vaso-occlusive crises. By blocking P-selectin, crizanlizumab aims to prevent that cellular adhesion before a crisis starts. The drug is administered as an intravenous infusion, initially given at weeks zero, two, and four, then every four weeks thereafter. The SUSTAIN trial results generated genuine optimism, and the FDA approval was celebrated as one of the first targeted therapies for sickle cell patients in decades.
However, the larger Phase 3 STAND trial delivered a serious blow. Neither dose of crizanlizumab outperformed placebo at reducing vaso-occlusive crises that required a healthcare visit. Worse, patients receiving ADAKVEO experienced more serious side effects than those on placebo. The European Commission revoked the drug’s marketing authorization in May 2023, citing the STAND trial failures. In the United States, crizanlizumab remains FDA-approved, leaving patients and physicians in the uncomfortable position of weighing Phase 2 promise against Phase 3 disappointment. This trajectory — encouraging early data followed by deflating confirmatory trials — is unfortunately common in sickle cell research and underscores why cautious interpretation of headlines matters.
Why Fetal Hemoglobin Is the Holy Grail of Sickle Cell Treatment
The reason dWIZ-2 has generated so much excitement among researchers has less to do with the specific numbers and more to do with fetal hemoglobin itself. During fetal development, humans produce a form of hemoglobin — fetal hemoglobin, or HbF — that carries oxygen more efficiently across the placenta. After birth, the body gradually switches to adult hemoglobin. In people with sickle cell disease, adult hemoglobin carries the mutation that causes red blood cells to sickle. But fetal hemoglobin does not. Patients who naturally maintain higher levels of fetal hemoglobin into adulthood tend to have dramatically fewer crises and better outcomes overall.
This is why hydroxyurea, the oldest and still most widely used sickle cell medication, works — it boosts fetal hemoglobin production. The gene therapies recently approved by the FDA, including Casgevy and Lyfgenia, also work by reactivating fetal hemoglobin genes or correcting the sickle mutation directly. What makes dWIZ-2 distinct is its mechanism. It is a “molecular glue degrader” that breaks down the WIZ transcription factor, a protein not previously known to play a role in controlling fetal hemoglobin. By degrading WIZ, the drug effectively unlocks fetal hemoglobin production without the DNA-editing machinery of gene therapy or the bone marrow toxicity of hydroxyurea. If it works in humans — and that remains a significant if — it would be the first small molecule to induce fetal hemoglobin without damaging stem cells.
An Oral Pill Versus Gene Therapy — What Patients Actually Face
The practical differences between treatment approaches deserve frank discussion. The approved gene therapies for sickle cell disease, Casgevy and Lyfgenia, offer the possibility of a functional cure. But they require myeloablative chemotherapy to destroy the patient’s existing bone marrow, followed by infusion of modified stem cells and weeks of hospitalization. The process is grueling, carries real risks including infertility and secondary cancers, and costs over a million dollars per treatment. Access is limited to a handful of specialized centers, putting it out of reach for most patients globally — including those in sub-Saharan Africa where sickle cell disease is most prevalent.
A pill like dWIZ-2, if it survives clinical development, would represent something fundamentally different. It would not be a cure — patients would need to take it periodically for life, similar to how hydroxyurea is used now. But it would be oral rather than intravenous, potentially accessible in low-resource settings, and would not require the devastating preparatory chemotherapy of gene therapy. The tradeoff is clear: gene therapy offers a potential one-time fix at enormous cost and risk, while an oral fetal hemoglobin inducer would offer ongoing management at presumably lower cost but with lifelong dependence. For patients who cannot access or tolerate gene therapy — which is most patients worldwide — an effective oral option would be transformative even if it is not curative.
The Brain Health Connection — Why Sickle Cell Crises Matter for Cognition
Readers focused on dementia and brain health may wonder why sickle cell disease belongs in this conversation. The answer is that sickle cell is, among other things, a cerebrovascular disease. By age 20, approximately 37 percent of sickle cell patients have experienced silent cerebral infarcts — small strokes that cause no obvious symptoms but progressively damage brain tissue. These silent strokes accumulate over time, contributing to cognitive decline, executive function deficits, and processing speed reductions that mirror patterns seen in vascular dementia. Vaso-occlusive crises do not only cause pain.
Each crisis represents an episode of blood flow disruption that can affect any organ, including the brain. Reducing crisis frequency is therefore not just about pain management — it is about protecting long-term neurological function. This is particularly important for children with sickle cell disease, whose developing brains are vulnerable to repeated ischemic insults. Any therapy that meaningfully reduces crisis frequency or improves oxygen delivery through higher fetal hemoglobin levels has the potential to preserve cognitive function over a lifetime. However, the evidence connecting specific sickle cell treatments to measurable cognitive protection is still limited, and families should not assume that crisis reduction alone eliminates stroke risk. Regular transcranial Doppler screening and, when indicated, chronic transfusion therapy remain the standard of care for stroke prevention.
What Preclinical Results Actually Tell Us
The phrase “preclinical studies” can sound like a minor qualifier, but it represents a vast gulf between laboratory results and proven medicine. dWIZ-2 worked in mice and showed activity in two of three cynomolgus monkeys — one of the monkeys did not respond.
Published in *Science* in 2024, the results are genuinely promising from a mechanistic standpoint, but the drug has not undergone Phase 1 safety testing in humans, let alone the efficacy trials that would be required for approval. Historically, roughly 90 percent of drugs that enter clinical trials fail to reach approval, and the attrition rate for compounds still in animal testing is even higher. Crizanlizumab’s own journey — from encouraging Phase 2 results to a failed Phase 3 trial and European withdrawal — illustrates how unpredictable the path from promising data to reliable treatment can be.
Where Sickle Cell Treatment Goes From Here
The sickle cell treatment landscape is more active than it has been in decades. Between the approved gene therapies, ongoing work on crizanlizumab and related anti-adhesion approaches, the early-stage promise of molecular glue degraders like dWIZ-2, and continued optimization of hydroxyurea use in underserved populations, patients have more reason for cautious hope than at any point in the disease’s history. The critical word is cautious.
Headlines that merge the best numbers from different drugs in different stages of development do patients a disservice by inflating expectations. What would genuinely change the game is an oral medication that reliably raises fetal hemoglobin to therapeutic levels without significant toxicity — and that can be manufactured and distributed affordably to the regions where sickle cell disease exacts its greatest toll. Whether dWIZ-2 or a successor compound proves to be that drug remains an open question. For now, patients and caregivers should work closely with their hematologists, stay current on clinical trial opportunities, and treat dramatic headlines with the skepticism they usually deserve.
Conclusion
The “45 percent without side effects” headline is built from two real but separate findings. Crizanlizumab reduced vaso-occlusive crises by 45.3 percent in a Phase 2 trial but carries documented side effects and failed its Phase 3 confirmatory study — leading to revoked approval in Europe while remaining available in the United States. dWIZ-2 raised fetal hemoglobin to 45 percent in animal models without apparent adverse effects, but it is years away from potential human use. Neither drug, on its own, delivers what the combined headline promises.
For patients with sickle cell disease and for families concerned about the neurological consequences of repeated crises, the honest picture is still one of incremental progress rather than a single breakthrough. Hydroxyurea remains the backbone of treatment for most patients. Gene therapies offer transformative potential for those who can access them. And the next generation of oral therapies, including molecular glue degraders, represents a genuinely new approach worth watching — from a safe distance, with expectations grounded in the evidence rather than the headlines.
Frequently Asked Questions
Is crizanlizumab (ADAKVEO) still available in the United States?
Yes. Despite the Phase 3 STAND trial failure and the European Commission revoking its marketing authorization in May 2023, crizanlizumab remains FDA-approved in the United States for patients aged 16 and older to reduce the frequency of vaso-occlusive crises.
What is dWIZ-2 and can patients access it now?
dWIZ-2 is a preclinical oral compound developed by Novartis that degrades the WIZ transcription factor to reactivate fetal hemoglobin production. It has only been tested in mice and monkeys and has not entered human clinical trials. It is not available to patients.
How does sickle cell disease affect brain health?
Sickle cell disease causes silent cerebral infarcts — small strokes without obvious symptoms — that accumulate over time and contribute to cognitive decline. By age 20, approximately 37 percent of sickle cell patients have experienced at least one silent stroke. Reducing vaso-occlusive crises may help protect brain function, though direct evidence linking specific treatments to cognitive preservation is still limited.
Would dWIZ-2 be a cure for sickle cell disease?
No. Unlike gene therapies that aim for a one-time correction, dWIZ-2 would need to be taken periodically for life. It would manage the disease by maintaining elevated fetal hemoglobin levels rather than fixing the underlying genetic mutation.
Why did the Phase 3 trial of crizanlizumab fail when the Phase 2 trial showed a 45 percent reduction in crises?
Phase 2 trials are smaller and can produce results that do not hold up under the larger, more rigorous conditions of Phase 3 studies. The STAND trial found that neither dose of crizanlizumab outperformed placebo at reducing crises requiring a healthcare visit, and patients on the drug experienced more serious side effects than those on placebo.
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For more, see NIH MedlinePlus — cognitive testing.
