By Melane Sampson
Akebia Therapeutics (NASDAQ: AKBA) is advancing the Nobel Prize-winning science behind hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) through its commercial product, Vafseo, an oral therapy designed for anemia due to chronic kidney disease (CKD), while advancing a pipeline of investigational therapies for rare kidney diseases with significant unmet need.
“Our current strategy is to drive our commercial product, Vafseo, to establish a new standard of care and build a better life for people living with kidney disease,” Mr. John Butler, president and CEO of Akebia, says in an interview with BioTuesdays.
Vafseo is an FDA-approved, oral once-daily HIF-PHI indicated for the treatment of anemia due to CKD in adults who have been receiving dialysis for at least three months. Launched in the U.S. in early 2025, Vafseo is now available in 37 countries.
Mr. Butler explains that HIF-PHIs are designed to mimic the body’s response to reduced oxygen availability, such as when a person is at high altitude. Under these conditions, the body increases hypoxia-inducible factor (HIF), a protein that regulates genes involved in erythropoietin (EPO) production and iron metabolism.
“By inhibiting HIF-PH, Vafseo activates the body’s natural oxygen-sensing pathway to stimulate internal EPO production, increase hemoglobin levels, and improve red blood cell production,” Mr. Butler says.
He clarifies that EPO is a hormone produced primarily by the kidneys that signals the bone marrow to make red blood cells. When kidney function declines, EPO production decreases, resulting in anemia. “Anemia occurs when the body lacks enough healthy red blood cells or hemoglobin to deliver oxygen efficiently. For patients with CKD, this can cause profound fatigue, reduced energy, and a significantly diminished quality of life.”
Akebia estimates that approximately 37 million Americans are living with CKD, a progressive and irreversible disease that can lead to serious complications. Of these patients, roughly 5.7 million are affected by anemia.
Mr. Butler points out that Vafseo offers a differentiated approach to anemia management by activating the body’s natural oxygen-sensing pathway rather than relying solely on injectable therapies. Injectable erythropoiesis-stimulating agents (ESAs) have been the standard of care since the early 1990s, yet unmet needs and undertreatment remain.
To evaluate Vafseo’s potential benefits in dialysis patients, Akebia launched the Vafseo Outcomes In-Center Experience (VOICE) trial—a collaboration with closely held dialysis provider U.S. Renal Care.
The investigator-initiated, multicenter, randomized, open-label, active-controlled, non-inferiority trial enrolled 2,116 patients and evaluated the safety and efficacy of Vafseo administered three times weekly compared with standard of care ESAs in patients receiving in-center hemodialysis for end stage kidney disease.
An interim analysis found that the trial demonstrated statistical evidence of improved safety outcomes for patients treated with Vafseo versus an ESA. Vafseo showed a clinically meaningful reduction in the primary composite endpoint of all-cause mortality and hospitalization, driven by fewer hospitalizations, while rates of death were similar between the two groups.
Beyond Vafseo, Akebia is advancing two investigational therapies for rare kidney disease with significant unmet need—praliciguat and ebribafusp. “We believe we have clear points of differentiation with these two assets in what is becoming an increasingly competitive commercial space,” Mr. Butler says.
Praliciguat is an oral, once-daily drug candidate with potential to treat various kidney diseases. It stimulates the soluble guanylate cyclase (sGC) enzyme, enhancing nitric oxide signalling to address multiple pathways involved in kidney damage.
Akebia is now advancing praliciguat into a Phase 2 study in focal segmental glomerulosclerosis (FSGS), a rare kidney disease characterized by scarring of the kidney’s filtering units, known as glomeruli. This damage can result in protein leakage into the urine, swelling, progressive loss of kidney function, and eventual kidney failure.
Mr. Butler emphasizes that FSGS is a leading cause of glomerular disease-associated end-stage kidney disease in the U.S. It affects approximately 40,000 people in the U.S. and 220,000 worldwide. “The disease is highly heterogeneous, with causes ranging from genetic mutations to unknown origins, and patients may respond differently to available treatments.”
There is currently only one therapy specifically approved for FSGS.
The Phase 2 study is designed to evaluate approximately 60 patients over 12 months. Patients will receive treatment for an initial 24-week placebo-controlled period, after which those assigned to placebo will cross over to praliciguat. The study incorporates dose titration to manage potential blood pressure effects while optimizing treatment exposure.
The primary endpoint is change from baseline in urine protein-to-creatinine ratio at 24 weeks, with a target reduction consistent with regulatory expectations for FSGS development programs.
“We chose FSGS because proteinuria is a clear measure of disease activity, and we believe it provides an opportunity to demonstrate the impact of praliciguat,” Mr. Butler says.
He notes that regulatory progress in rare kidney diseases has created a more defined pathway for drug development. “The FDA has been incredibly focused on rare kidney disease.”
The PARASOL Project, an international collaborative effort co-sponsored by several leading organizations in kidney health, including the FDA, NephCure, the Kidney Health Initiative (ASN), and National Kidney Foundation, has assessed clinical trial endpoints for FSGS including proteinuria reduction as a potential basis for accelerated and traditional approval.
“In diabetic kidney disease, praliciguat has already demonstrated it can reduce proteinuria,” Mr. Butler says. “While biology always carries uncertainty, we believe the existing safety and efficacy data significantly reduce the risk as we move into this study.”
Akebia’s second rare kidney disease program is ebribafusp (AKB-097), a next-generation anti-C3d–factor H fusion protein designed to target complement-mediated kidney diseases. C3d is a protein fragment generated when the complement system becomes overactive.
AKB-097 is a once-weekly subcutaneous therapy designed to target complement activation within the kidney. The molecule combines a factor H-based complement regulatory component with a targeting antibody designed to bind C3d deposits, allowing localized inhibition of the alternative complement pathway.
“We licensed this product in late 2025, and we believe it has tremendous potential to make a meaningful difference in multiple rare kidney diseases,” Mr. Butler says. “We view this as a next-generation complement inhibitor.”
He explains that the complement system is an essential component of the immune system that helps protect the body from infection. Excessive complement activation, however, contributes to tissue damage in several kidney diseases.
The key differentiation of AKB-097 is its ability to target complement activity at the site of disease rather than broadly suppressing complement throughout the blood.
“Most current complement inhibitors work systemically,” he says. “You need to deliver enough drug into the bloodstream to ultimately reach the kidney, which means you are also affecting complement where you actually need it to function—throughout the body to help prevent infection.”
Systemic complement inhibition can increase the risk of infections, and several approved complement inhibitors carry boxed warnings related to this risk.
“With AKB-097, our goal is to deliver the drug directly to the tissue where complement is being overactivated,” Mr. Butler says. “The antibody component targets the kidney, while the factor H component helps break down the activated complement pathway at the disease site.”
By concentrating activity in the kidney, Akebia believes AKB-097 may offer the potential for comparable efficacy with reduced systemic exposure, potentially improving safety and convenience.
“We believe this could represent a significant differentiation from current complement inhibitors,” Mr. Butler says. “Instead of requiring high systemic exposure, long infusions, or frequent administration, our goal is to provide targeted delivery directly to the site of disease.”
Akebia is evaluating AKB-097 in a Phase 2 basket study across multiple complement-mediated kidney diseases, including C3 glomerulopathy, IgAN, and lupus nephritis and dosed its first patient in September.
The basket study design will allow Akebia to evaluate AKB-097 across diseases sharing the same underlying biology. “We think this approach provides an opportunity to demonstrate the broad potential of this platform,” Mr. Butler says.
The Phase 2 study will evaluate several biomarkers, including proteinuria, urinary levels of the membrane attack complex, and alternative complement pathway activity in the bloodstream.
“We believe this is a very interesting opportunity,” Mr. Butler says. “There are significant players in the complement space, but we believe our approach, targeting the sites of complement activation, has the potential to offer meaningful advantages in efficacy, safety, and convenience.”
Beyond its rare kidney disease programs, Akebia is also exploring additional applications of HIF biology through earlier-stage programs.
The company is developing AKB-9090, a novel HIF-PHI candidate being evaluated for cardiac surgery-associated acute kidney injury. Akebia is also exploring AKB-10108, another HIF-PHI compound with potential applications in retinopathy of prematurity, a leading cause of blindness in newborns.
Looking ahead, Mr. Butler says Akebia’s commercial portfolio and pipeline reflect its strategy to continue building a fully integrated biotechnology company focused on improving outcomes for people living with kidney disease.
“We have a leadership team with a proven track record of developing and commercializing therapies. We have a commercial product, Vafseo, with the potential to become the standard of care. We also have a robust pipeline of mid- and early-stage programs that we believe can create meaningful value for patients and shareholders.”
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