Several oral drugs for sickle cell disease have recently earned expedited regulatory designations from the FDA, marking a turning point for a disease that has long been treated with a painfully thin medicine cabinet. Among the most notable developments, Sanofi’s rilzabrutinib received FDA Breakthrough Therapy Designation in February 2026 for warm autoimmune hemolytic anemia — a related blood disorder — while also being studied for sickle cell disease, where it already holds Orphan Drug Designation. Meanwhile, a new class of oral compounds called WIZ molecular glue degraders, developed independently by both Novartis and Bristol Myers Squibb, have entered early-stage clinical trials with preclinical results showing fetal hemoglobin levels jumping from 17% to 45% in red blood cells. These breakthroughs matter because, as of 2024, only four drugs had ever been approved by the FDA for sickle cell disease: hydroxyurea in 1998, L-glutamine (Endari) in 2017, crizanlizumab (Adakveo) in 2019, and voxelotor (Oxbryta) in 2019.
That last one, Oxbryta, was voluntarily pulled from the market by Pfizer in September 2024 after post-marketing studies failed to confirm its clinical benefit on vaso-occlusive crises — the agonizing pain episodes that define daily life for many patients. That withdrawal left an already sparse treatment landscape even more barren. This article examines the oral drugs now racing through clinical development, what breakthrough and fast track designations actually mean for patients, the science behind WIZ molecular glue degraders and pyruvate kinase activators, the cautionary tale of voxelotor’s withdrawal, and what the competitive pipeline looks like heading into late 2026. For the estimated 100,000 Americans and 20 million people worldwide living with sickle cell disease, the stakes could not be higher.
Table of Contents
- Which Oral Drugs for Sickle Cell Disease Have Received Breakthrough or Fast Track Status?
- How WIZ Molecular Glue Degraders Could Transform Sickle Cell Treatment
- Etavopivat and the Pyruvate Kinase Activator Approach
- What Voxelotor’s Withdrawal Means for New Oral Sickle Cell Drugs
- The Crowded Pipeline and Why Most Drugs Will Fail
- Why Oral Therapies Matter More Than the Science Alone Suggests
- What to Watch for in 2026 and Beyond
- Conclusion
- Frequently Asked Questions
Which Oral Drugs for Sickle Cell Disease Have Received Breakthrough or Fast Track Status?
The FDA uses several expedited pathways to speed drugs toward approval when they target serious conditions with unmet need, and sickle cell disease qualifies on both counts. Breakthrough Therapy Designation, the most aggressive of these pathways, requires preliminary clinical evidence showing substantial improvement over existing treatments. Voxelotor earned this designation back in 2019 before its approval and eventual withdrawal. More recently, rilzabrutinib — an oral, reversible Bruton’s tyrosine kinase inhibitor developed by Sanofi — received Breakthrough Therapy Designation in February 2026 for warm autoimmune hemolytic anemia, with ongoing studies in sickle cell disease where it holds Orphan Drug Designation. Etavopivat, now owned by Novo Nordisk after its $1.1 billion acquisition of Forma Therapeutics in 2022, has accumulated FDA Fast Track Designation, Rare Pediatric Disease Designation, and Orphan Drug Designation for sickle cell disease. These designations are not interchangeable.
Fast Track allows more frequent meetings with the FDA and rolling review of the application, while Breakthrough Therapy provides all of that plus intensive FDA guidance on trial design. Orphan Drug Designation, by contrast, offers financial incentives like tax credits and seven years of market exclusivity upon approval. The distinction matters because a Fast Track drug is not necessarily as far along or as promising as a Breakthrough-designated one — it simply means the FDA agrees the disease is serious and the drug addresses an unmet need. Patients and caregivers should be cautious about reading too much into any single designation. Voxelotor had Breakthrough Therapy Designation, sailed through approval, and still failed to hold up in the real world. The designation accelerates the review process, but it does not guarantee the drug works as hoped over the long term. Each of these oral candidates still needs to prove itself in rigorous, placebo-controlled trials before it reaches pharmacy shelves.
How WIZ Molecular Glue Degraders Could Transform Sickle Cell Treatment
The most scientifically exciting oral candidates are a new class of compounds called WIZ molecular glue degraders, which work by an entirely different mechanism than anything previously tried in sickle cell disease. Researchers discovered that a transcription factor called WIZ acts as a repressor of fetal hemoglobin — the form of hemoglobin that naturally protects newborns from sickling but gets silenced in the first months of life. By degrading WIZ, these drugs essentially reawaken the fetal hemoglobin gene, allowing the body to produce a form of hemoglobin that resists the polymerization responsible for the sickle shape. A study published in *Science* in July 2024 showed that an optimized compound called dWIZ-2 raised fetal hemoglobin from 17% to 45% in red blood cells — a magnitude of increase that, if replicated in humans, could be transformative. Both Novartis (with ITU512) and Bristol Myers Squibb (with BMS-986470) are independently racing to bring WIZ degraders to patients. BMS-986470 entered a Phase 1/2 clinical trial in July 2024 under the identifier NCT06481306, edging out Novartis’s ITU512, which is in a Phase I/II study (NCT06546670) evaluating safety, tolerability, and fetal hemoglobin induction in both healthy participants and sickle cell patients.
In preclinical testing, the compound worked when given orally to mice and showed activity in two of three cynomolgus monkeys without apparent side effects. However, preclinical success — even dramatic preclinical success — does not reliably predict human outcomes. The jump from animal models to human patients in sickle cell disease has been notoriously treacherous. The one-in-three failure rate in monkeys, while a small sample, is a reminder that biological variability is real. These trials are Phase 1 and Phase 2, meaning the primary questions are still about safety and dosing, not yet efficacy in large patient populations. If you are a patient or caregiver following these developments, the honest timeline for a WIZ degrader reaching the market, assuming everything goes well, is likely several years away.
Etavopivat and the Pyruvate Kinase Activator Approach
While WIZ degraders aim to reactivate fetal hemoglobin, pyruvate kinase activators like etavopivat take a fundamentally different approach. Pyruvate kinase is an enzyme in red blood cells that plays a critical role in energy metabolism. In sickle cell disease, red blood cells are already stressed and energy-depleted, which contributes to their tendency to sickle and die prematurely. By activating pyruvate kinase, etavopivat aims to improve red blood cell health and survival — reducing hemolysis, increasing hemoglobin levels, and potentially decreasing the frequency of vaso-occlusive crises. Etavopivat is currently the furthest along among the newer oral candidates.
Its Phase 3 trial, called HIBISCUS, is randomizing approximately 380 patients one-to-one to either etavopivat (400 mg once daily) or placebo, with results expected in 2026. Earlier Phase 1 results, published in *Blood Advances*, showed a trend toward reduced vaso-occlusive crises over 52 weeks and increased hemoglobin response at 24 weeks. Novo Nordisk’s decision to pay $1.1 billion for Forma Therapeutics in 2022, largely on the strength of etavopivat’s potential, signals serious pharmaceutical confidence in this mechanism. A related drug, mitapivat, developed by Agios Pharmaceuticals, is another oral pyruvate kinase activator already FDA-approved since 2022 for pyruvate kinase deficiency and now being evaluated in sickle cell disease trials. The existence of two pyruvate kinase activators in development for the same condition is both encouraging and instructive — it means if one fails for safety or efficacy reasons, the mechanism itself is not necessarily dead. But it also means patients may eventually face choices between drugs with similar mechanisms but different side effect profiles, and those distinctions will not be clear until late-stage trial data is available.
What Voxelotor’s Withdrawal Means for New Oral Sickle Cell Drugs
The story of voxelotor is required reading for anyone following oral sickle cell drug development. Developed by Global Blood Therapeutics and later acquired by Pfizer, voxelotor (brand name Oxbryta) was an oral, once-daily hemoglobin S polymerization inhibitor that received both FDA Breakthrough Therapy Designation and approval in 2019. It was hailed as a significant step forward. Then, in September 2024, Pfizer voluntarily withdrew it from the market after post-marketing studies failed to confirm clinical benefit on the outcome that matters most to patients: vaso-occlusive crises. The voxelotor episode illustrates a critical gap between surrogate endpoints and clinical outcomes. The drug improved hemoglobin levels on lab tests — a surrogate marker — but that improvement did not translate into fewer pain crises or hospitalizations in the real world.
For the sickle cell community, which has endured decades of neglect and underfunding, the withdrawal was more than a scientific disappointment; it was a betrayal of hard-won trust. Patients who had reorganized their lives around a daily pill were left scrambling. This history creates a higher bar for every oral drug that follows. Etavopivat’s HIBISCUS trial, for instance, will need to show not just improved lab values but meaningful clinical improvement in vaso-occlusive events, quality of life, or both. For WIZ degraders, the dramatic fetal hemoglobin increases seen in preclinical models will need to hold up through Phase 3 and into post-marketing surveillance. Patients and physicians are right to be cautiously optimistic rather than celebratory — the sickle cell community has been burned before by drugs that looked good on paper.
The Crowded Pipeline and Why Most Drugs Will Fail
The sickle cell disease drug pipeline has never been busier. According to a February 2026 competitive landscape report, over 40 companies are developing more than 50 drugs for the condition. That number sounds promising until you consider the baseline failure rate in drug development: roughly 90% of drugs that enter clinical trials never reach approval. For a disease that currently has just three approved treatments (after voxelotor’s withdrawal), even a 10% success rate from this pipeline could meaningfully expand the pharmacopeia. But patients should understand that most of these candidates will not make it. The drugs in development span multiple mechanisms — fetal hemoglobin induction, pyruvate kinase activation, anti-sickling agents, anti-inflammatory approaches, P-selectin inhibitors, and gene therapies.
This diversity is actually good news, because it means a failure in one mechanism does not sink the entire field. However, it also means the competitive landscape could produce redundant drugs targeting the same pathway, leading to commercial pressures that may not align with patient interests. Companies may abandon promising but less profitable programs in favor of broader-market drugs. One limitation worth noting: most of these oral drugs are being developed primarily for adult patients. Sickle cell disease manifests in early childhood, and pediatric formulations, dosing studies, and safety data lag behind adult programs by years. If you are a parent of a child with sickle cell disease, the timeline for an approved oral therapy your child can take is longer than the headlines suggest.
Why Oral Therapies Matter More Than the Science Alone Suggests
Access is the often-overlooked dimension of sickle cell treatment. Gene therapies like Casgevy and Lyfgenia, approved in late 2023, offer potential cures but carry price tags exceeding $2 million and require myeloablative conditioning — a grueling process that destroys the patient’s bone marrow before reinfusing edited cells. These therapies are available at only a handful of specialized centers, putting them out of reach for the vast majority of the world’s 20 million sickle cell patients, most of whom live in sub-Saharan Africa and South Asia.
An effective oral drug, by contrast, could be manufactured at scale, distributed through existing pharmacy infrastructure, and taken at home without hospitalization. The difference between a daily pill and a one-time gene therapy is not just a matter of medical preference — it is the difference between a treatment that reaches thousands and one that could reach millions. This is why the oral drug pipeline, even with its high failure rate, represents the most practical hope for global sickle cell care.
What to Watch for in 2026 and Beyond
The next twelve to eighteen months will be pivotal. Etavopivat’s HIBISCUS Phase 3 results, expected in 2026, will be the first major readout from the current wave of oral candidates. If the trial meets its primary endpoints, Novo Nordisk could file for FDA approval relatively quickly given the existing Fast Track and Orphan Drug designations.
Meanwhile, early safety and efficacy signals from the WIZ degrader trials — both BMS-986470 and ITU512 — should begin emerging from their Phase 1/2 studies, giving the field its first human data on whether fetal hemoglobin reactivation via WIZ degradation is safe and effective. For patients and families, the practical advice remains frustratingly familiar: stay connected to a sickle cell specialist, maintain current treatment regimens, and ask your hematologist about clinical trial eligibility. The pipeline is more robust than it has ever been, but hope needs to be tempered by history. The sickle cell community deserves drugs that work in the real world, not just in press releases — and the next round of data will begin to show which of these oral candidates can deliver on that promise.
Conclusion
The sickle cell disease treatment landscape is undergoing its most significant transformation in decades, driven by a wave of oral drugs targeting novel mechanisms from WIZ molecular glue degradation to pyruvate kinase activation. FDA designations including Breakthrough Therapy, Fast Track, and Orphan Drug status are accelerating several of these candidates through development, though the cautionary example of voxelotor’s 2024 market withdrawal serves as a reminder that regulatory enthusiasm does not guarantee real-world success. With over 50 drugs in development across more than 40 companies, the sheer volume of the pipeline provides grounds for cautious optimism.
What matters most now is rigorous data from well-designed trials — particularly the HIBISCUS Phase 3 results for etavopivat and the early human data from WIZ degrader studies. For the 100,000 Americans and 20 million people worldwide living with sickle cell disease, an effective oral therapy would not just be a medical advance but a fundamental shift in accessibility and quality of life. The science is promising. The question is whether it will survive the long, unforgiving road from laboratory to living room.
Frequently Asked Questions
What is FDA Breakthrough Therapy Designation for sickle cell disease drugs?
Breakthrough Therapy Designation is the FDA’s most aggressive expedited pathway, granted when preliminary clinical evidence shows a drug may offer substantial improvement over existing treatments for a serious condition. It provides intensive FDA guidance on trial design, more frequent agency meetings, and rolling review of the application. For sickle cell disease, voxelotor received this designation in 2019 and rilzabrutinib received it in February 2026 for a related blood disorder.
What happened to Oxbryta (voxelotor), the previously approved oral sickle cell drug?
Pfizer voluntarily withdrew Oxbryta from the market in September 2024. Although the drug had improved hemoglobin levels in lab tests — the surrogate endpoint used for its accelerated approval in 2019 — post-marketing studies failed to confirm that it actually reduced vaso-occlusive crises, the painful episodes that most affect patients’ daily lives.
What are WIZ molecular glue degraders and how do they work?
WIZ molecular glue degraders are a new class of oral compounds that target the WIZ transcription factor, which normally suppresses production of fetal hemoglobin in adults. By degrading WIZ, these drugs reactivate fetal hemoglobin production, which resists the sickling process. Preclinical studies published in *Science* showed fetal hemoglobin levels rising from 17% to 45% in red blood cells. Both Novartis (ITU512) and Bristol Myers Squibb (BMS-986470) have compounds in early-stage clinical trials.
How many FDA-approved drugs currently exist for sickle cell disease?
As of early 2026, only three FDA-approved drugs remain for sickle cell disease: hydroxyurea (approved 1998), L-glutamine/Endari (approved 2017), and crizanlizumab/Adakveo (approved 2019). Voxelotor/Oxbryta, the fourth approved drug, was withdrawn from the market in September 2024.
When might new oral sickle cell drugs become available?
Etavopivat is the closest to potential approval, with Phase 3 trial results expected in 2026. If successful, a regulatory filing could follow relatively quickly. WIZ molecular glue degraders from Novartis and Bristol Myers Squibb are still in early-phase trials, meaning they are likely several years from potential approval even in a best-case scenario.
Are these new oral drugs available for children with sickle cell disease?
Most current clinical trials for new oral sickle cell drugs are focused on adult patients. Pediatric formulations, dosing studies, and safety data typically lag behind adult programs by years. Parents of children with sickle cell disease should discuss current treatment options and potential clinical trial eligibility with their child’s hematologist.
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