In this article, we will thoroughly examine Akebia Therapeutics: its partnerships, CEO, insider trading patterns, institutional holdings, and financials. Then, we will take a close look at its marketed product in the U.S. - Auryxia. The main focus of this report is the upcoming catalyst for Akebia, the March 22nd 2022 PDUFA action date for vadadustat. We will take a deep-dive to better understand the condition vadadustat targets, the current standard of care, and the patient population. We will then examine how vadadustat works and how it compares to other drugs in the same class. This will allow us to get a better understanding of the landscape and what can happen on March 22nd.
Founded in 2007, Akebia Therapeutics ($AKBA) is a Cambridge-based “fully integrated” biopharmaceutical company with a focus on treating complications of kidney disease. Akebia Therapeutics currently has a market cap of $472.392M.
Akebia Therapeutics merged in 2018 with Keryx Pharmaceuticals, another biotech focusing on kidney disease complications. The merger was a smart move because Keryx Pharmaceuticals already had a marketed product, Auryxia (ferric citrate). Auryxia is indicated for the control of serum phosphorus levels in adult patients with Chronic Kidney Disease (CKD) on dialysis, and the treatment of iron deficiency anemia in adult patients with CKD not on dialysis.
The merger gives Akebia Therapeutics access to Keryx Pharmaceuticals’ commercial capabilities and expertise in the kidney disease complications space, which will be a significant advantage if the company’s New Drug Application (NDA) for vadadustat is approved.
Vadadustat is an investigational oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that is awaiting FDA approval for the treatment of anemia due to CKD in dialysis dependent and non-dialysis dependent adult patients. If approved by the FDA, vadadustat would be a first-in-class drug in the U.S..
Vadadustat is already approved in Japan and is being commercialized by Akebia’s partner Mitsubishi Tanabe Pharma Corporation (MTPC).
The filing for the vadadustat NDA was accepted in June 2021, and the FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of March 29, 2022.
Partnerships
Mitsubishi Tanabe Pharma Corporation (MTPC) is not the only company that Akebia has entered a partnership with.
In 2016, Akebia entered a collaboration and licensing agreement with Otsuka for the development and commercialization of vadadustat in the U.S.. The two companies are to share all costs and potential revenue. In 2017, Europe, China, Russia, Canada, Australia, the Middle East, as well as other unnamed countries were added to the agreement.
Akebia also signed an agreement with Vifor Pharma to provide them an exclusive license to sell vadadustat (if approved by the FDA) to dialysis centers, mostly those operated by Fresenius Medical Care.
In 2017, Akebia entered into a research, development, and licensing agreement with Janssen Pharmaceutica NV (a Johnson & Johnson company).
Concerning its other approved product, Auryxia, Akebia has partnership agreements with Japanese companies Panion & BF Biotech, Inc and Japan Tobacco, Inc.
In 2021, Akebia signed a global licensing agreement with Cyclerion Therapeutics. The deal gives exclusive rights to Akebia to develop and commercialize praliciguat, an investigational oral soluble guanylate cyclase (SGC) stimulator.
John Butler
John P. Butler was appointed in August 2013 as the President and CEO of Akebia Therapeutics. John Butler has a BA in Chemistry from Manhattan College and an MBA from Baruch College. He started his career in Roche, then joined Amgen as a product manager. He spent almost 14 years at Genzyme, first as the president of cardiometabolic and renal disease, and then as the president of personalized genetic health. He then served for more than 1 year as the CEO of hemophilia-focused biotech startup, Inspiration Biopharmaceuticals. John Butler has also served as the president of the American Kidney Fund for almost 10 years. John Butler’s experience in drug development and expertise in commercializing renal products makes him a very valuable asset to Akebia Therapeutics.
As the leader of Akebia, John Butler has been the architect behind many impressive deals that bring considerable value to the company.
Insider Trading and Institutional Holders
In the last 12 months, the largest insider trade executed was by Akebia’s CEO John Butler when he sold almost $170k worth of shares at a price of $3.40 per share - which was above the market price. Over 93k shares were sold during the same period at approximately $316.3k in total. No shares were bought. This is not necessarily a bad sign but it is also not a good sign.
Insiders own 1.04% of all shares, which is rather low.
59.64 % of shares are held by institutions, which indicates confidence in the company and its management. Akebia’s largest shareholder is State Street Corporation (9.06%), followed by Blackrock (8.03%), and the Vanguard Group (7.09%).
It is worth noting that hedge funds have no significant ownership in Akebia.
Financials
Data from the latest (September 30th, 2021) balance sheet shows that Akebia Therapeutics had $189.21M of liabilities due within 12 months and long-term liabilities of $275.91M. Akebia Therapeutics also had $207.2M in cash and $53.13M in receivables due within the year. Akebia’s Therapeutics liabilities total to $204.8M more than the sum of its cash and short-term receivables.
Given that Akebia Therapeutics has a market capitalization of $427.62M, it can raise capital if needed - so the $204.8M difference is not that problematic.
Akebia Therapeutics has $97.2M of debt and $207.2M of cash, which results in a net cash position of $110.0M. Over the last year, Akebia Therapeutics burnt through $221.2M of cash and made losses of $299M. Based on their net cash position of $110.0M, it is highly probable that Akebia Therapeutics will need to raise extra capital.
In May 2020, Akebia Therapeutics raised $151.8M via common stock offering, thus growing by 21% the total shares outstanding. A similar scenario occurring soon is not unlikely, with the dilution it comes with.
Auryxia
It has been a rocky road for Akebia’s Auryxia. In 2018, the Centers for Medicare & Medicaid Services (CMS) decided to deny coverage for Auryxia for the treatment of iron deficiency anemia (IDA). This move led to Akebia suing the CMS and the U.S. Department of Health and Human Services. The expensive and messy litigation dragged on for 2 years until Akebia announced on October 25th 2021 that it was dismissing the case, effectively ending this legal battle. It is worth noting that Auryxia is still covered for the treatment hyperphosphatemia in dialysis patients, which represents a considerably larger market than IDA. Akebia is currently interacting with members of the U.S. Congress in order to provide more coverage for Auryxia.
On November 4th 2021, Akebia reported third quarter results with a net revenue for Auryxia of $36.8M, increasing by 7.0% over one year from the $34.4M recorded in the third quarter of 2020. These numbers are encouraging given that the market served has seen an increased mortality rate due to COVID-19. Akebia’s management expects Auryxia’s sales to continue to grow, especially given the fact that the company signed a 5-year $40M supply deal with the Department of Veteran Affairs.
Auryxia’s patent will expire in 2025, which will allow generics to enter the market.
Anemia due to Chronic Kidney Disease
CKD (formerly known as Chronic Renal Failure) is a type of kidney disease characterized by a gradual and permanent decrease of kidney function. There are over 37 million CKD patients in the U.S. and over 800 million worldwide.
A decreased renal function means that the kidneys will produce less erythropoietin (EPO), which is a hormone that signals the bone marrow to produce erythrocytes (red blood cells). Erythrocytes are responsible for transporting oxygen to the tissues in the body. Hemoglobin, a protein in erythrocytes, is what carries the oxygen. Erythrocytes also carry carbon dioxide, the main waste product of tissues, from the tissues to the lungs. A decreased production of EPO thus means a lower rate of production of erythrocytes, which is what causes anemia. Patients with CKD and anemia not only have a decreased erythrocyte production, but their erythrocytes also have a shorter life span.
In function of their Glomerular Filtration Rate (GFR), CKD patients can be classified into 5 different stages of the disease (the lower the GFR, the higher the disease progression stage). As the renal function of a patient deteriorates, they are more likely to experience further complications and thus will be more likely to resort to dialysis.
CKD patients also have significantly lower levels of iron on average, which is mostly due to two factors. The first factor is the increased risk of gastrointestinal bleeding which is yet another complication of CKD, resulting in important iron losses. The second factor is dialysis, with statistics showing that on average dialysis patients lose 1-2 g of iron per year.
Over 50% of CKD patients have an iron deficiency and thus don’t produce enough hemoglobin, the component of the red blood cell that carries oxygen.
CKD is mostly (almost 75% of all cases) caused by diabetes and hypertension, but it can also be caused by glomerulonephritis (inflammation of the glomeruli or renal blood vessels), or polycystic kidney disease. In the U.S., over 30% of adult patients who have diabetes also have CKD.
It is estimated that over 15% of CKD patients have anemia globally. In the U.S. alone, approximately 5.7 million CKD patients have anemia. As mentioned earlier, the more CKD progresses, the higher the risk of complications. A 2014 study found that the prevalence of anemia at Stage 1 CKD was at 8.4%, 12.2% at Stage 2, 17.4% at Stage 3, 50.3% at Stage 4, and 53.4% at Stage 5.
CKD patients with anemia have an increased risk of developing heart conditions or having a stroke. Anemia due to CKD greatly deteriorates the health of patients and is associated with higher mortality and morbidity.
Standard of Care in CKD-induced Anemia
Erythropoiesis-stimulating agents (ESAs) are the established treatment of anemia in CKD patients. ESA proteins are produced using recombinant DNA technology. ESAs were approved for the first time in the U.S. in 1989. In recent years, biosimilar ESAs were approved for clinical use.
The ESAs that are currently used are epoetin alfa (Epogen from $JNJ), epoetin beta (NeoRecormon from Roche), epoetin zeta (Silapo from Stada), darbepoetin alfa (Aranesp from $AMGN), and methoxy polyethylene glycol-epoetin beta (Mircera from Roche). These ESAs are different iterations of the same concept, with different chemical structures, molecular sizes, pharmacokinetics and receptor affinity.
The mechanism of action of these ESAs is intuitive - they stimulate erythropoiesis (the production of red blood cells) by targeting the erythropoietin receptor in a similar way to the EPO hormone in healthy individuals.
ESAs are effective in increasing the production of more erythrocytes, but several studies and clinical trials have shown that they also increased the risk of cardiovascular events and death. The harmful effects were associated to higher doses of ESAs.
These findings led to physicians aiming at target hemoglobin levels of less than 13 g/dL in order to reduce the amount of ESAs administered and thus the risk of increased cardiovascular events or death.
The safety profile of ESAs has always been problematic, creating an unmet need for effective anemia treatment in CKD patients with a favorable safety profile. Another problem with ESAs is the fact that they are injectable, creating discomfort for patients and requiring injections by qualified personnel.
Intravenous (IV) iron therapy is also widely used in CKD patients who have anemia but as a supporting therapy, especially in patients with heart failure.
Vadadustat: Pharmacology
Hypoxia-inducible factors (HIFs) are transcription factors that allow cells to survive a state of hypoxia (when oxygen levels are too low). Transcription factors are proteins that bind to DNA sequences to control the transcription process, which in turn regulates gene expression. In a state of hypoxia, the body’s “protection mechanism” is to activate HIFs (as low oxygen levels can be life-threatening). This in turn induces gene expression changes that increase the production of EPO not only in the kidney, but also in the liver, resulting in the production of more erythrocytes and hemoglobin by the bone marrow. HIFs also enhance intestinal iron uptake, which leads to higher concentrations in the bloodstream and increased erythropoiesis and hemoglobin synthesis. Last but not least, HIFs also act on the bone marrow’s microenvironment to facilitate the production of erythrocytes and hemoglobin.
Akebia’s vadadustat, an oral treatment, works by inhibiting the enzyme hypoxia-inducible factor prolyl hydroxylase (HIF-PH), which is responsible for the degradation of the α subunit of HIF (HIFα). Since the HIFα subunit is no longer being eliminated, it accumulates and binds to another subunit of HIF known as HIFβ, which is constitutively expressed (meaning the gene is being continuously transcribed). The binding leads to new a heterodimeric structure, known as HIFαβ. These new macromolecules bind to hypoxia-responsive elements (HREs). HREs are genetic sequences that are found in the promoters of some genes. When the HIFαβ heterodimers bind to HREs, they regulate the transcription of the concerned genes, such as EPO and factors that impact the intestinal uptake and metabolism of iron. The regulation of the genes leads to increased levels of EPO and iron, which in turn leads to higher production of erythrocytes and hemoglobin.
Vadadustat has been approved in Japan under the trade name of Vafseo since June 2020 for the treatment of anemia due to CKD in dialysis-dependent and non-dialysis dependent adult patients. The approval was a result of a partnership between Akebia and MTPC for the development and commercialization of vadadustat in Japan, Taiwan, South Korea, Indonesia and India. The partnership agreement also stated that MTPC is to pay Akebia a royalty of up to 20% on the Japanese company’s total sales of vadadustat. In early 2021, Akebia sold its rights to royalties and sales milestones to HealthCare Royalty Management in a $60M deal.
The U.S. market opportunity within non-dialysis patient population is estimated at $3B with over 250k patients undergoing ESA treatment, with the potential to almost double in size if the number of patients not receiving ESAs is taken into account. On the other hand, the estimated market opportunity within dialysis patient population in the U.S. is $2B with over 510k patients.
A 2016 study showed that 32% of interviewed nephrologists would prescribe HIF-PH inhibitors over ESAs in NDD-CKD patients due to the less invasive administration route. The same study estimated that if approved in the U.S., HIF-PH inhibitors could capture 38% of both the NDD-CKD and DD-CKD market.
Vadadustat is currently being investigated for its possible role in mitigating lung injury in COVID-19 patients. Large randomized controlled trials will start in 2023.
The HIF-PH Inhibitors Landscape
Akebia Therapeutics is not the only company with a HIF-PH inhibitor in its pipeline. Several players currently have similar molecules in phase III/post-phase III studies: roxadustat (FibroGen, Astellas, AstraZeneca), daprodustat (GlaxoSmithKline), molidustat (Bayer), and enarodustat (Japanese Tobacco, JW).
There are also two HIF-PH inhibitors currently in earlier phases: Zydus Calida’s desidustat which recently completed a phase II study and Johnson & Johnson’s JNJ‐429045343 candidate, which is still in pre‐clinical development.
General Safety Concerns
Based on existing preclinical and clinical data, drugs of the HIF-PH inhibitors class have several potential safety concerns: malignancy (cancer), retinopathy, liver dysfunction, hyperkalemia, hypertension, pulmonary hypertension, heart failure, thrombotic events, cyst growth and seizures.
Roxadustat
Roxadustat was widely expected to become the first HIF-PH inhibitor to be approved by the FDA, but FibroGen and AstraZeneca received a Complete Response Letter (CRL) in August 2021 on safety grounds. The rejection was expected as the Advisory Committee (AdCom) voted 13-1 against approval for the non-dialysis population and 12-2 against approval for patients on dialysis unless more clinical data was submitted. The AdCom vote made Fibrogen’s shares plunge 37.60% to reach $15.50.
The pivotal phase III program comprised of 6 non-inferiority trials. The goal of non-inferiority trials is to demonstrate that there are no statistically significant differences between the intervention and the control group in terms of efficacy and safety.
From these 6 trials, 3 of them evaluated the efficacy and safety of roxadustat versus a placebo for the treatment of CKD-induced anemia in non dialysis dependent patients (NDD-CKD). The other 3 trials evaluated the efficacy and safety of roxadustat versus epoetin alfa in dialysis dependent patients (DD-CKD) and in incident dialysis (ID) patients.
These trials had 2 different primary efficacy endpoints; one for the FDA NDA package and one for submissions outside of the U.S.. They were respectively the mean change in baseline hemoglobin values at specific time points regardless of rescue therapy, and the proportion of participants who achieved a positive hemoglobin response after a predefined time period without rescue therapy. Rescue therapy is a type of emergency intervention that is given when patients don’t respond to the usual regimen.
All 6 trials reached their primary efficacy endpoints.
A 2021 pooled meta-analysis of 9 randomized-controlled (phase II/III) trials assessing the efficacy and safety of roxadustat in different populations versus a placebo or ESAs found that the difference of incidence of adverse events (AES) between the roxadustat and the different control groups was not statistically significant. That being said, the difference was statistically significant in terms of serious adverse events (SAEs) in dialysis-dependent patients with an odds ratio of 1.33. An odds ratio higher than 1 means that there is a strong association between the intervention (roxadustat) and the SAEs.
Other meta-analyses found no statistically significant differences in the incidence of SAEs between the different groups. It is important to note that the results of these pooled analyses are largely dependent on the trials that are being studied and on the choice of statistical analysis tools and methods.
In November 2019, FibroGen presented their own pooled safety analysis of the 6 pivotal phase III trials used for the U.S. submission at an event at the American Society of Nephrology. They had found that roxadustat had a comparable cardiovascular safety profile to the placebo in non-dialysis patients and to the epoetin alfa in dialysis-dependent patients, and a superior profile to the ESAs in the incident dialysis subpopulation.
The hazard ratios FibroGen presented were as follows: 1.08 for non-dialysis patients, 0.96 for dialysis-dependent patients and 0.7 for the incident dialysis subpopulation. Simply put, hazard ratios assess the probability of adverse events in the intervention group when compared to the probability of the same events in the control group. The lower the hazard ratio, the safer the drug.
In theory, these hazard ratios were computed based on pre-defined stratification factors (partitioning of the subject based on multiple characteristics). The idea is to define these factors before the trial begins so this way there is no risk of bias.
In April 2021, in a bombshell revelation, FibroGen’s CEO admitted that they had doctored the phase III trials safety data they had previously presented. FibroGen’s shares dropped 24.8% after the announcement.
What FibroGen did was modify the stratification factors after unbinding the clinical data, in other words, they artificially decreased the hazard ratios by rearranging the patients in new strata based on clinical results.
The real hazard ratios, based on the pre-defined factors were as follows: 1.1 for non-dialysis patients, 1.02 for dialysis-dependent patients and 0.83 for incident dialysis subpopulation. These values clearly indicate that roxadusat is not as safe (no longer non-inferior) as epoetin alfa in incident dialysis patients. Interestingly, FibroGen did not have an agreed-upon non-inferiority statistical margin in terms of safety with the FDA.
For both populations, DD-CKD and NDD-CKD, the FDA found that the roxadustat groups had a statistically higher incidence of all-cause mortality after sensitivity analysis. Sensitivity analysis is conducted to assess how robust the results are. This is interesting because primary analysis of the data showed no statistically significant difference in terms of all-cause mortality. When the results of the primary and sensitivity analysis say different things, it means that the data is inconclusive.
For the DD-CKD populations (versus placebo), the following serious adverse effects were observed (RR=Relative Risk): thrombosis (RR≈1.6), device/shunt thrombosis (RR≈3), seizures (RR≈6). The relative risk is the ratio of the probability of an adverse effect occurring in the intervention group to the probability of it occurring in the control group. RRs higher than 1 mean that the intervention increases the probability of the adverse effect to occur. The higher the number, the higher risk, which is why the RRs computed for thrombosis, device/shunt thrombosis and seizures are very concerning. Myocardial infarction, stroke, and hypertension all had RRs in the 1.2-1.3 range. Although higher than 1, doubt was casted on the clinical significance of the values since a high rate of dropouts was observed in the placebo group.
For the NDD-CKD (versus epoetin alfa), the RRs of the main serious adverse effects were 2.1 for sepsis, 1.3 for thrombosis, 1.5 for device/shunt thrombosis, and 1.5 for seizures. Strokes, hypertension and malignancies were neutral. It is important to note that here the RRs are lower than with the DD-CKD patients because the control is epoetin alfa which is already proven to cause these adverse reactions. The same goes for strokes, hypertension and malignancies.
Other concerning safety signals for roxadustat were serious infections, gastrointestinal bleeding, hyperkalemia and hyponatremia.
FibroGen tried - and failed - to convince the AdCom to endorse the approval in specific subpopulations under the conditions that the doses are lowered, that FibroGen conducts large Phase IV studies, and that label warnings are added to tell patients with an active infection or a history of seizures to use the drug with caution.
Nevertheless, roxadustat is approved in the EU, China, Japan, Chile, and South Korea.
Daprodustat
In November 2021, GlaxoSmithKline announced positive data for its phase III ASCEND program for the evaluation of the efficacy and safety of daprodustat. The ASCEND program is comprised of 5 trials for DD-CKD and NDD-CKD populations.
All ASCEND trials met their primary efficacy (mean changes in baseline hemoglobin levels) and safety endpoints (time to first major adverse cardiovascular event - MACE). MACE is defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke. Daprodustat was non-inferior to the control ESAs.
In terms of safety, the predefined safety margin for non-inferiority was a hazard ratio of 1.25 for MACE.
In the DD-CKD population, the hazard ratio was 1.03 (95% CI; 0.89-1.19) and in the NDD-CKD population it was 0.93 (95% CI; 0.81-1.07) - in both cases within the safety margin.
The data looks very promising, but there are still some safety concerns with regards to the NDD-CKD population. The 2 main safety signals observed in the NDD-CKD population were related to cancer and erosions. Patients in the daprodustat arm had a higher incidence of cancer-related deaths and tumor progression/recurrence with a RR of 1.47 (RR=0.92 in DD-CKD). This observation is not unexpected since HIF-PH inhibitors are known to promote the vascular endothelial growth factor (VEGF) which is a key mediator of angiogenesis in cancer. A more extensive follow up will be required to get a better understanding of the risks related to cancer development. The other safety signal that was observed was a higher rate of gastric and esophageal erosion with a RR of 1.7 in NDD-CKD patients (RR=0.74 in DD-CKD).
These signals are not deal breakers and will probably not solely warrant a rejection. It is not unlikely however that more data will be required to get a better understanding of the risks.
Unlike roxadustat, the risk of seizure in daprodustat (in both NDD-CKD and DD-CKD populations) was negligible, with a rate inferior to 1%.
It is entirely possible that differences in safety profiles between roxadustat and daprodustat are due to the different design of the trials, especially given the fact that for NDD-CKD patients, roxadustat was compared against a placebo. Furthermore, differences in terms of doses could have been a contributing factor.
Daprodustat is approved in Japan.
The PDUFA action date for daprodustat is expected to be in Q4 2022 / Q1 2023.
Molidustat
Bayer’s molidustat program comprised of 5 small-scale phase III trials. Although the data seems encouraging, the trials are in no way pivotal and large-scale trials are needed to fully assess the efficacy and safety of the drug.
Enarodustat
Although approved in Japan, there are only a few small-scale phase III studies assessing the efficacy and safety of enarodustat. Large-scale pivotal trials will be required for FDA approval.
Preclinical Data Overview
In vitro, vadadustat showed inhibition against human HIF-PH inhibitors and stabilized HIF1α and HIF2α (isoforms of HIFα) in cell lines in a time and dose dependent manner. Vadadustat stimulated erythropoietin secretion in the cell lines but did not affect VEGF (VEGF is the protein that contributes to the growth of cancerous tumors). The presence of iron did not affect the activity of vadadustat.
In vivo, a single oral dose of vadadustat administered to rats increased erythropoiesis in a time and dose dependent manner. Repeated doses of vadadustat over a 14-day period led to an increase in haemoglobin levels and erythrocyte count.
Pivotal Phase III Trials
Akebia’s pivotal phase III trials were organized into 2 global programs: INNO2VATE (for dialysis patients) and PRO2TECT (for non-dialysis patients). Each program comprised of 2 trials.
For the INNO2VATE program, one trial was carried out on incident dialysis-dependent patients while the other trial was carried out on prevalent dialysis-dependent patients. For the PRO2TECT program, one trial was carried out on patients previously treated with an ESA, while the other trial was carried out on patients who have never been treated with an ESA. For each program, the data were pooled together for statistical analysis. These trials were the “core package” for both the NDA (FDA) and the MAA (EMA equivalent of the NDA) filings.
In all trials, darbepoetin alfa was used as the comparator. The FDA had explicitly requested Akebia to use an active comparator in their phase III trials. All trials in both programs were noninferiority trials.
In terms of efficacy, the primary endpoint was the mean change in hemoglobin levels between baseline and after 36 weeks. The primary safety endpoint was time to first MACE.
For the NDD-CKD trial, the mean difference between the vadadustat and control (darbepoetin alfa) groups in terms of change in hemoglobin levels was 0.05 g/dl at weeks 24 through to 36 for patients not previously treated with ESAs and was -0.01 g/dl with ESA-treated patients. The predefined noninferiority margin was -0.75 g/dl, which means that vadadustat achieved noninferiority in terms of efficacy when compared to darbepoetin alfa in NDD-CKD patients.
In the DD-CKD trial, the mean difference in hemoglobin levels between the vadadustat and the darbepoetin alfa group at weeks 24 through to 36 was -0.07 g/dl for incident dialysis patients and -0.17 g/dl in prevalent patients while at weeks 40 to 52 it was -0.31 g/dl in incident dialysis patients and -0.18 g/dl in prevalent dialysis patients. Vadadustat also achieved efficacy noninferiority in the DD-CKD trial.
In the DD-CKD trials, a first MACE was reported in 18.2% of patients in the vadadustat group and in 19.3% of patients in the darbepoetin alfa group. The difference is nonsignificant statistically. The hazard ratios for MACE were 0.96 (95% CI; 0.83-1.11) for both the intervention and the control group. Vadadustat achieved noninferiority in terms of safety.
In the NDD-CKD trials, a first MACE was reported in 22.0% of patients in the vadadustat group and in 19.9% of patients in the darbepoetin alfa group. The hazard ratio of MACE in the vadadustat group was 1.17, which fails to meet the predefined 1.25 noninferiority criteria when taking into account the 95% confidence interval [CI] (1.01-1.36), meaning that vadadustat did not achieve noninferiority in terms of safety when compared to darbepoetin alfa in NDD-CKD patients.
The missed safety endpoint made Akebia’s share plunge 73% when the top-line results were announced.
Interestingly, the cardiovascular safety signals detected in the PRO2TECT trials (NDD-CKD) had never been observed before in smaller scale vadadustat trials and did not occur in the INNO2VATE (DD-CKD) program.
One point to consider is that in the PRO2TECT trials, the hemoglobin target levels were different for subjects in the U.S. (8-11 g/dl) and abroad (9-12 g/dl). In the U.S. subpopulation (with the lower hemoglobin target range), the hazard ratios for MACE and expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event) were consistent with what was observed in the INNO2VATE trial in terms of safety. On the other hand, subjects outside the U.S. in the vadadustat groups had considerably higher MACE and expanded MACE when compared to the darbepoetin alfa group. It is too early to say if there is a correlation between the higher hemoglobin target levels and higher cardiovascular risk observed in NDD-CKD subjects outside of the U.S., but it is a viable hypothesis. The higher overall MACE risk in the vadadustat groups was largely due to a high number of nonfatal myocardial infarctions and incidence of death from non-cardiovascular causes. Other than these safety signals, both the intervention and control groups had similar adverse effects distributions.
SAEs traditionally associated with HIF-PH inhibitors such as cancer or pulmonary hypertension were evenly distributed between the vadadustat and darbepoetin alfa groups.
Safety signals observed in the roxadustat trials such as thrombosis, seizures or serious infections were also not seen in both the INNO2VATE and PRO2TECT programs.
FDA Approval
For the last number of years, everyone - including Akebia’s management - operated under the assumption that FibroGen’s roxadustat will be the first HIF-PH inhibitor to be approved by the FDA. The recent developments concerning daprodustat and roxadustat have drastically changed the HIF-PH inhibitor landscape and will have a direct impact on the likelihood of FDA approval for vadadustat.
There is no doubt that clinical data has clearly demonstrated that roxadustat, daprodustat, and vadadustat are noninferior in terms of efficacyto the current standard care, ESAs.
In clinical practice, efficacy is not the only factor to be considered when assessing if an intervention is beneficial for a patient of a specific population. Without a benefit-risk assessment, any decisions would not only be highly unethical, but counterproductive as well.
The phase III results for roxadustat have highlighted considerable safety issues that are more or less consistent with the predicted pharmacological effects of the HIF pathway activation. Roxadustat’s safety data raised important concerns with regards to the viability of the entire HIF-PH inhibitor class - regardless of regulatory approvals outside the U.S..
It is important to note that most of the safety concerns observed in the roxadustat pivotal trials, such as seizures and infections, were not seen in the vadadustat pivotal trials. The designs of the roxadustat and vadadustat pivotal trials were very different - the vadadustat trials were considerably superior in terms of methodology.
The daprodustat phase III data significantly changed the general sentiment regarding the safety of the HIF-PH inhibitor class. The results were clearly challenging the hypothesis that the safety issues observed in the roxadustat trials were a class issue. With experts exploring the idea that the different safety outcomes were due to different trial designs, prospects for vadadustat were looking more promising.
But the situation is not binary. Although clinical data from the daprodustat pivotal trials might have shown that the safety signals observed in the roxadustat trials were not necessarily a drug class problem, it also showed that daprodustat was noninferior to ESAs in terms of cardiovascular safety (unlike vadadustat in the NDD-CKD population) and thus had a more favorable safety profile than vadadustat.
It is important to understand that the pivotal trials demonstrated that vadadustat was not worse than the standard of care in terms of efficacy. It may or may not be superior to ESAs, but the design of the pivotal trial does not allow us to answer this question. Regardless of the fact that ESAs have a suboptimal cardiovascular safety profile, it would not make sense for the FDA to approve a new drug that is not worse than the standard of care in terms of efficacy but worse in terms of cardiovascular safety (for the NDD-CKD population), especially with the data showing daprodustat being non-inferior to ESAs both in terms of efficacy and safety in both the NDD-CKD and DD-CDD populations. If the daprodustat cardiovascular safety data had not demonstrated non-inferiority, the FDA might have had more incentive to potentially consider vadadustat for the NDD-CKD population since the medical need would still be unmet. We are not saying that had the daprodustat safety data been different, vadadustat would have a higher chance of FDA approval, we are merely trying to explain the FDA’s rationale.
It is also important to remember the rationale for developing vadadustat as an alternative to ESAs: a more optimal safety profile and more convenient administration (and thus better patient adherence).
In short, we think that it is highly unlikely that vadadustat would receive approval for the NDD-CKD population based on the safety data. On the other hand, an approval for the DD-CKD population is rather likely but the overall safety profile of the molecule could delay FDA approval.
Akebia Therapeutics: the Bottom-Line
Strong points:
Vadadustat achieved non-inferiority in terms of efficacy when compared to marketed ESAs in both NDD-CKD and DD-CKD patients
Vadadustat also achieved safety non-inferiority in DD-CKD patients
Serious adverse effects such as seizures and infections reported in the roxadustat trials were not significantly observed in the vadadustat pivotal trials
FDA approval is likely for DD-CKD patients (but not guaranteed due to overall safety profile)
Vadadustat could be the first HIF-PH inhibitor to be approved by the FDA - very significant market opportunity, especially given the unmet need in non-dialysis patients
Daprodustat data showed that cardiovascular safety issues were not a class problem
Vadadustat is already approved in Japan
Roxadustat is already approved in the EU as well as in other countries
EMA approval for vadadustat is likely (at least in DD-CKD patients, but also not completely unlikely for NDD-CKD patients if certain conditions are met)
Akebia already has a marketed product (Auryxia) generating revenue
Significant expertise and experience in the renal complications space
Partnerships with big players
Experienced and capable management
Confidence from institutional investors
Recent licensing deal with Cyclerion Therapeutics to expand pipeline
Concerns:
Likelihood of FDA approval for vadadustat in NDD-CKD patients almost null
FDA approval for DD-CKD patients is also not completely guaranteed - overall safety profile might be an issue
Akebia might need to raise capital through common stock offering, thus diluting shareholders
Physicians have important safety concerns with regards to HIF-PH inhibitors
Auryxia’s patent is expiring in 2025
Auryxia’s CMS coverage was decreased
Insider’s stake in the company is not particularly high
This article originally appeared in The Biotech Report