Akebia Therapeutics Announces Approval of Vadadustat in Japan for the Treatment of Anemia Due to Chronic Kidney Disease in Dialysis-Dependent and Non-Dialysis Dependent Adult Patients

June 29, 2020 at 7:41 AM EDT

First Regulatory Approval for Akebia’s HIF-PHI Marks Beginning of Next Phase of Akebia’s Growth Story

CAMBRIDGE, Mass., June 29, 2020 /PRNewswire/ — Akebia Therapeutics®, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced the first regulatory approval of vadadustat, its oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for the treatment of anemia due to chronic kidney disease (CKD). Mitsubishi Tanabe Pharma Corporation (MTPC), Akebia’s collaboration partner in Japan for vadadustat, has obtained manufacturing and marketing approval of vadadustat as a treatment for anemia due to CKD in both dialysis-dependent and non-dialysis dependent adult patients by the Ministry of Health, Labour and Welfare in Japan on June 29, 2020. Vadadustat will be marketed by MTPC in Japan under the trade name VAFSEO.

An estimated 13 million people in Japan have advanced stages of CKD. Anemia is common in patients with CKD and its prevalence increases as CKD progresses. Injectable erythropoiesis-stimulating agents (ESAs) are currently the standard of care. Vadadustat provides adult patients with a convenient, once-daily oral therapeutic for the treatment of anemia due to CKD in Japan.

“Today’s announcement represents the first regulatory approval of vadadustat and is a significant step forward for patients with anemia due to CKD in Japan,” said John P. Butler, President and Chief Executive Officer of Akebia. “We believe this milestone marks the beginning of the next phase of Akebia’s growth story and we are excited to support our collaboration partner, MTPC, with the expected commercialization of vadadustat in Japan later this year.”

MTPC filed a Japanese New Drug Application for vadadustat in July 2019. The approval was based on data from the vadadustat development program, including MTPC’s two Phase 3 active-controlled pivotal studies, which support the efficacy and safety of vadadustat in treating both adult patients on dialysis and those not on dialysis with anemia due to CKD in Japan. 

Akebia and MTPC entered into a collaboration agreement in 2015 providing MTPC with exclusive rights to develop and commercialize vadadustat in Japan and certain other Asian countries. The regulatory approval announced today triggers a $15 million milestone payment from MTPC to Akebia. In addition, Akebia is eligible to receive up to approximately $190 million in additional milestone payments from MTPC, based upon achievement of certain regulatory and sales milestones. MTPC is also obligated make tiered double-digit royalty payments to Akebia of up to 20% on sales of vadadustat in Japan and certain other Asian countries, subject to regulatory approval of vadadustat. 

About Vadadustat

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor currently in global Phase 3 development for the treatment of anemia due to CKD. Vadadustat is designed to mimic the physiologic effect of altitude on oxygen availability. At higher altitudes, the body responds to lower oxygen availability with stabilization of hypoxia-inducible factor, which can lead to increased red blood cell production and improved oxygen delivery to tissues. Vadadustat is an investigational therapy and is not approved by the U.S. Food and Drug Administration (FDA).

About Akebia Therapeutics 

Akebia Therapeutics, Inc. is a fully integrated biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease. The company was founded in 2007 and is headquartered in Cambridge, Massachusetts.

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Positive Top-Line Results from Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients on Dialysis

CAMBRIDGE, Mass., May 5, 2020 /PRNewswire/ — Akebia Therapeutics, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced positive top-line results from INNO2VATE, the first of its two global Phase 3 cardiovascular outcomes programs. The two INNO2VATE studies evaluated the efficacy and safety of vadadustat, Akebia’s investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), versus darbepoetin alfa for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

Vadadustat achieved the primary and key secondary efficacy endpoint in each of the two INNO2VATE studies, demonstrating non-inferiority to darbepoetin alfa as measured by a mean change in hemoglobin (Hb) between baseline and the primary evaluation period (weeks 24 to 36) and secondary evaluation period (weeks 40 to 52). Vadadustat also achieved the primary safety endpoint of the INNO2VATE program, defined as non-inferiority of vadadustat versus darbepoetin alfa in time to first occurrence of major adverse cardiovascular events (MACE), which is the composite of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke across both INNO2VATE studies. Each analysis was measured against non-inferiority (NI) margins agreed upon with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

“The INNO2VATE study results are very compelling,” stated Glenn Chertow, M.D., M.P.H., Professor of Medicine, Chief, Division of Nephrology at Stanford University, and Co-Chair of the independent Executive Steering Committee for INNO2VATE. “The greatest strength of the INNO2VATE data is the consistency across both efficacy and all MACE components. The nephrology community has been eagerly awaiting straightforward, high-quality data evaluating the treatment of anemia due to CKD with a novel HIF-PHI. Based on these two randomized trials comparing vadadustat to the active darbepoetin control, I am confident that vadadustat has the potential to be a safe and effective option for the treatment of anemia due to CKD in adult patients requiring dialysis, upon approval.”

John P. Butler, President and Chief Executive Officer of Akebia Therapeutics stated, “We are thrilled to be sharing positive top-line data from INNO2VATE, the first of our two global Phase 3 programs studying vadadustat to treat anemia due to CKD. It is extremely rewarding to see this program yield clear, consistent, straightforward results. We believe our data uniquely positions vadadustat as a potential new oral standard of care for treating all populations of dialysis patients, including both incident and prevalent dialysis patients, with anemia due to CKD, subject to approval.”

“We look forward to sharing these compelling data with regulators, as well as with physicians, dialysis providers and payers. We are more confident than ever that the clinical success we’ve demonstrated with INNO2VATE supports vadadustat’s potential for regulatory and commercial success, upon approval.” Butler continued, “The team is already at work on vadadustat’s New Drug Application (NDA), which we expect to file as quickly as possible following the top-line data readout of PRO2TECT, our global Phase 3 program studying vadadustat in adult patients not on dialysis with anemia due to CKD, which we expect in mid-2020, as planned. We believe that the INNO2VATE data will be highly informative for physicians, patients, dialysis providers and payers, as they make important decisions about patient care, once vadadustat is approved.”

Global Phase 3 INNO2VATE Program
Akebia’s global INNO2VATEprogram is a cardiovascular outcomes program that includes two separate Phase 3 studies (Correction/Conversion and Conversion), which collectively enrolled 3,923 adult patients on dialysis with anemia due to CKD. Both INNO2VATE studies are global, multicenter, open label (sponsor blinded), active-controlled (darbepoetin alfa – an injectable erythropoiesis stimulating agent (ESA)), non-inferiority studies. In both studies, patients were randomized 1:1 to receive either vadadustat or darbepoetin alfa. Vadadustat was initiated at a starting oral dose of 300 mg once daily and adjusted over time in increments of 150 mg within the range of 150 to 600 mg daily using a dose adjustment algorithm, while darbepoetin alfa was dosed per the US package insert (USPI) or summary of product characteristics (SmPCs) in appropriate geographies.

The INNO2VATE Correction/Conversion study evaluated 369 incident dialysis patients (181 and 188 patients randomized to vadadustat and darbepoetin alfa, respectively) who initiated chronic dialysis (either peritoneal dialysis (PD) or hemodialysis (HD)) for end-stage renal disease (ESRD) ≤ 16 weeks prior to screening and had limited exposure to recombinant erythropoiesis stimulating agents (rESAs). The INNO2VATE Conversion study evaluated 3,554 dialysis patients (1,777 and 1,777 patients randomized to vadadustat and darbepoetin alfa, respectively) currently receiving rESA who were converted to either vadadustat or darbepoetin alfa.

In both INNO2VATE studies, the primary efficacy endpoint was the mean change in Hb between baseline and the primary evaluation period (weeks 24-36). NI was achieved if the lower bound of the 95% confidence interval for the between-group difference of the mean Hb change did not fall below the pre-specified NI margin (-0.75 g/dL). The INNO2VATE program’s primary safety endpoint, MACE, was independently and blindly assessed by the Brigham and Women’s Hospital’s Clinical Endpoint Center (BWH CEC) in Boston, MA, with a comparison of vadadustat to darbepoetin alfa. MACE is defined as the composite endpoint of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke. To assess MACE, a combined analysis of time to first MACE event from the two INNO2VATE studies was performed. NI was achieved if the upper bound of the 95% confidence interval for the hazard ratio of vadadustat to darbepoetin alfa did not exceed the pre-specified NI margin of 1.25.

Primary and Key Secondary Efficacy Endpoint Results
Vadadustat achieved each of the INNO2VATE studies’ primary efficacy endpoints of mean change in Hb between baseline and the primary evaluation period (mean Hb from weeks 24 to 36) compared to darbepoetin alfa, in adult patients on dialysis, demonstrating non-inferiority to darbepoetin alfa based on using a non-inferiority margin of -0.75 g/dL prospectively agreed to with FDA and EMA.

In INNO2VATE’s Correction/Conversion study of incident dialysis patients (n=369):

  • Primary Efficacy Endpoint Result: Vadadustat was non-inferior to darbepoetin alfa. The least square mean difference in Hb was -0.31 g/dL (95% CI: -0.53, -0.10), achieving the pre-specified non-inferiority criterion of -0.75 g/dL. The mean (SD) Hb level at week 24 to week 36 was 10.36 (1.13) g/dL for vadadustat-treated patients compared to 10.61 (0.94) g/dL for darbepoetin alfa-treated patients.
  • Key Secondary Efficacy Endpoint Result: Vadadustat sustained the target Hb efficacy response at weeks 40 to 52 achieving non-inferiority compared to darbepoetin alfa. The least square mean difference in Hb was -0.07 g/dL (95% CI: -0.34, 0.19). The mean (SD) Hb level at week 40 to week 52 was 10.51 (1.19) g/dL for vadadustat treated-patients compared to 10.55 (1.14) g/dL for darbepoetin alfa-treated patients.

In INNO2VATE’s Conversion study of dialysis patients (n=3,554):

  • Primary Efficacy Endpoint Result: Vadadustat was non-inferior to darbepoetin alfa. The least square mean difference in Hb was -0.17 g/dL (95% CI: -0.23, -0.10), achieving the pre-specified non-inferiority criterion of -0.75 g/dL. The mean (SD) Hb level at week 24 to week 36 was 10.36 (1.01) g/dL for vadadustat-treated patients compared to 10.53 (0.96) g/dL for darbepoetin alfa-treated patients.
  • Key Secondary Efficacy Endpoint Result: Vadadustat sustained efficacy in the Conversion study demonstrating non-inferiority to darbepoetin with a least square mean difference in Hb of -0.18 g/dL (95% CI: -0.25, -0.12). The mean (SD) Hb level at week 40 to week 52 was 10.40 (1.04) g/dL in the vadadustat-treated patients compared to 10.58 (0.98) g/dL for darbepoetin treated patients.

Primary Safety Major Adverse Cardiovascular Events (MACE) Endpoint Result
Vadadustat achieved the INNO2VATE program’s primary safety endpoint of non-inferiority for MACE. In the primary analysis of time to first MACE event, vadadustat demonstrated non-inferiority to darbepoetin alfa using a non-inferiority margin of 1.25 prospectively agreed to by FDA and a non-inferiority margin of 1.3 prospectively agreed to by EMA.

The INNO2VATE program (Correction/Conversion and Conversion studies) of dialysis patients (n=3,902):

  • Vadadustat was non-inferior to darbepoetin alfa. The upper bound of the 95% confidence interval (CI) of the Hazard Ratio (HR) was below the pre-specified non-inferiority margin of 1.25 for primary MACE analysis. (HR 0.96, 95% CI: 0.83, 1.11.) MACE is defined as the composite endpoint of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke.

The incidence of treatment emergent adverse events during the Correction/Conversion study in vadadustat treated patients was 83.8% and 85.5% in darbepoetin alfa treated patients. During the study, the most common treatment emergent adverse events reported in vadadustat/darbepoetin alfa treated patients were hypertension (16.2%/ 12.9%) and diarrhea (10.1%/ 9.7%). Serious treatment emergent adverse events were lower in vadadustat treated patients at 49.7% compared to 56.5% for darbepoetin alfa treated patients. The incidence of treatment emergent adverse events during the Conversion study in the vadadustat treated patients was 88.3%, and 89.3% in darbepoetin alfa treated patients. During the study, the most common treatment emergent adverse events reported in vadadustat/darbepoetin alfa treated patients were diarrhea (13.0%/ 10.1%), pneumonia (11.0%/ 9.7%), hypertension (10.6%/ 13.8%), and hyperkalemia (9.0%/ 10.8%). Serious treatment emergent adverse events were slightly lower for vadadustat treated patients at 55.0% and 58.3% for darbepoetin alfa-treated patients.

“With nearly 4,000 patients participating in INNO2VATE and a total exposure of just over 2,200 patient-years with vadadustat, INNO2VATE has been a tremendous undertaking. We would like to extend our sincere thanks to everyone involved in this study including the patients, physicians, investigators and site coordinators,” said Steven K. Burke, M.D., Senior Vice President, Research & Development and Chief Medical Officer of Akebia. “We believe vadadustat has the potential to play a key role in the treatment of anemia due to CKD, and we are another step closer to realizing that vision. We are very pleased with these clear and consistent findings and are excited to share the full data set, together with the data from our PRO2TECT studies, later this year at a medical conference and in a peer-reviewed journal.”

Upon successful completion of the Phase 3 program, which includes the PRO2TECT studies of vadadustat for the treatment of anemia due to CKD in adult patients not on dialysis that the Company expects to read out mid-2020, Akebia plans to submit to FDA an NDA for vadadustat for the treatment of anemia due to CKD in adult dialysis-dependent and non-dialysis dependent patients. In close coordination with its collaborator, Otsuka Pharmaceutical Co. Ltd., the Company also plans to submit a Marketing Authorization Application (MAA) to EMA. Akebia and Otsuka are collaborating on the development and commercialization of vadadustat in the US, Europe, China, Russia, Canada, Australia, the Middle East, and certain other territories. A Japanese New Drug Application (JNDA) for vadadustat was submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) in July 2019 by Mitsubishi Tanabe Pharma Corporation (MTPC), Akebia’s development and commercialization collaboration partner in Japan for vadadustat.

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A proposed clinical trial for COVID-19 pneumonia

This article was originally published on March 23, 2020 on LinkedIn (see link here):

Anecdotal reports suggest that chloroquine (CQ), an old antimalaria drug and its less toxic derivative, hydroxychloroquine (HCQ), may be effective as antiviral treatments against the novel SARS-Cov2, the coronavirus responsible for the now pandemic COVID-19 infection [LinkLinkLinkLinkLink]. The use of these drugs to treat COVID-19 was based on in vitro data suggesting that CQ and HCQ have antiviral       activity against several viruses [LinkLinkLink, Link] including SARS-Cov2 [LinkLink]. There are preliminary reports from China on 100 patients who were treated with CQ or HCQ and showed symptom improvements [Link]. Another recent report from France includes 24 COVID-19 patients who received HCQ with or without azithromycin [Link]. The patients were enrolled consecutively and were not randomized. Forty-two patients completed the trial with data available up to 6 days post-treatment. Hydroxychloroquine was administered at 600 mg a day for 10 days, a dose significantly higher than that recommended for patients with rheumatic and autoimmune diseases [see HCQ PI]. The authors showed that 70% of HCQ-treated patients had viral clearance, versus 12.5% of the controls. An additional 6 patients received HCQ in combination with azithromycin, a macrolide antibiotic.  All 6 patients (100%) in this group had viral clearance at day 6 versus 57% of those treated with HCQ alone [Link]. 

The reasons for the apparent synergistic effects of azithromycin require further study. In addition to its well-known antibiotic activities, azithromycin has both anti-inflammatory and antiviral activities in lower respiratory tract [Link] as well as activity against zika virus [Link]. However, a possible inhibitory activity against SARS-Cov2 has not been studied. The theoretical enhancement of QT prolongation and serious arrhythmias, when combined with HCQ [see HCQ PI] must be weighed against possible benefits. To mitigate this risk, electrocardiograms must be performed at baseline and periodically during treatment. Dosing must also be optimized, since azithromycin could potentially interfere with HCQ metabolism. Based on physiologically-based pharmacokinetic (PBPK) models, a loading dose of 400 mg twice daily of HCQ sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection [Link]

Although encouraging, the human studies of CQ or HCQ so far have been small and non-randomized. Larger randomized controlled trials are needed to definitively establish the efficacy and potential toxicity of these drugs, in combination with azithromycin or other molecules. Several ongoing clinical trials are testing CQ and HCQ for treatment and prophylaxis of COVID-19 in China, Korea and the US and other countries [LinkLinkLink] and many more are on the way.

Zinc appears to be an interesting ion, whose intracellular transport is facilitated by CQ. Zinc inhibits viral replication, including replication of SARS-Cov virus, by inhibiting RNA-dependent RNA polymerase (replicase) [LinkLink]. Unfortunately, zinc, being a positively charged ion does not enter cells. Addition of a zinc ionophore to the cells results in increased intracellular zinc concentration. Interestingly, CQ was found to act as a zinc ionophore [Link] and enhanced inhibition of viral replication. Therefore, CQ appears to exert antiviral activity via multiple interactions with cellular machinery. In addition to increasing endosomal pH and altering ACE2 glycosylation, it also inhibits RNA-dependent RNA polymerase by increasing intracellular zinc concentration. Due to identical mechanisms of action, HCQ is expected to exert similar effects and in fact has been shown to have slightly higher antiviral activity [Link]. Furthermore, based on the early clinical data, the antiviral actions of HCQ can be amplified when azithromycin is added to the therapeutic regimen [Link]. For maximum efficacy, one could envisage using CQ or HCQ in combination with both zinc and azithromycin. Information is already available on the antiviral effects of different zinc salts and the doses required to alter the course of common cold [LinkLink]. Furthermore, low zinc levels in the elderly are associated with higher incidence of pneumonia [Link], and zinc supplementation is associated with shorter duration of severe pneumonia in children [Link]. Considering that the highest mortality in COVID-19 is seen in the elderly and those in nursing homes [LinkLinkLink], the contributing role of zinc deficiency in increased morbidity and mortality among elderly COVID-19 patients must be considered. 

Here we propose a phase II / III study design concept to test all these compounds in order to obtain data needed to inform clinicians for the most effective treatment regimen for moderate to severe COVID-19 infections. The proposed study would be a randomized placebo-controlled parallel group study to assess the efficacy and safety of one of four regimens in the treatment of patients with moderate to severe COVID-19 pneumonia, requiring hospitalization. Following informed consent, patients with an RT-PCR confirmed diagnosis of COVID-19 will be equally divided into 4 groups: 1) control (supportive care), 2) hydroxychloroquine, 3) hydroxychloroquine + azithromycin, 4) hydroxychloroquine + azithromycin + zinc (e.g. zinc acetate). Precise dosing regimens are not discussed and will have to be determined by the investigators based on the available information (see above). Hydroxychloroquine and azithromycin will be administered for 5 days, while zinc may be continued until viral recovery. Baseline assessments will include Chest X-ray, zinc and coper levels, safety laboratory assessments as well as ECG. Those with prolonged QT interval will be excluded. Assessments, including RT-PCR testing for SARS-Cov2, will be performed daily for the first 6 days, then every 2 days until day 10. Zinc and copper levels will also be measured on day 10 or prior to discharge. The primary endpoint will be proportion of patients with viral clearance by day 10. Secondary endpoints could include time to viral clearance, oxygen requirements, need for mechanical ventilation, time to hospital discharge and mortality. Safety assessments will include AEs, SAEs, hepatic, GI, and renal function tests as well as ECG changes. We hope that this high-level study concept will provide the basis for a multi-center collaborative study to quickly determine the most effective and the safest treatment for SARS-Cov2-associated pneumonia.

Mahmoud Loghman-Adham, MD on behalf of Innopiphany, LLC

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Dapagliflozin–saxagliptin ‘attractive’ options for patients with type 2 diabetes with chronic kidney disease

MedwireNews (April 16, 2019): Dapagliflozin, with or without saxagliptin, reduces albuminuria in people with type 2 diabetes and moderate-to-severe chronic kidney disease when used in combination with antihypertensive treatments, DELIGHT study data show. Furthermore, using the sodium-glucose co-transporter (SGLT)2 inhibitor and dipeptidyl peptidase-4 inhibitor together achieved “the dual objectives of effective lowering of blood glucose and reduction of urinary albumin excretion,” Hiddo Heerspink (University of Groningen, the Netherlands) and co-authors write in The Lancet Diabetes & Endocrinology.

They add: “This beneficial profile makes the combination of these drugs a potentially attractive option to slow the progression of kidney and cardiovascular disease in these patients.”

The phase III DELIGHT study included 448 patients with type 2 diabetes and moderate-to-severe chronic kidney disease who were randomly assigned to 24 weeks of once-daily treatment with dapagliflozin 10 mg (n=145), dapagliflozin 10 mg plus saxagliptin 2.5 mg (n=155), or placebo (n=148).  At baseline, median urine albumin-to-creatinine ratio (UACR) ranged from 218.4 to 270.0 mg/g, mean estimated glomerular filtration rate (eGFR) was 47.7–50.2 mL/min per 1.73 m2, and mean glycated hemoglobin (HbA1c) was 8.2–8.6% (66.0–70.0 mmol/mol).  By week 24, UACR was a significant 21% lower in the dapagliflozin group than in the placebo group, and it was  a significant 38% lower  in the dapagliflozin–saxagliptin group. The researchers note that the reductions were “largely independent” of simultaneous changes in HbA1c, systolic blood pressure, eGFR, and uric acid.

Heerspink and team also found that HbA1c was a signficant 0.58% lower in the dapagliflozin–saxagliptin group than in the placebo group at week 24, and was a non-significant 0.16% lower in the dapagliflozin-only group.

They say: “The reduction in HbA1c when saxagliptin is added to dapagliflozin is clinically relevant in patients with kidney impairment because the glycaemic effects of SGLT2 inhibitors are attenuated when kidney function declines.” Both drugs were well tolerated by patients with no new safety signals observed.

In accompanying commentary, Katherine Tuttle (University of Washington, Spokane, USA) stresses the importance of the finding “that dapagliflozin and saxagliptin can be used together safely for glycaemic control in patients with type 2 diabetes and moderate- to severe chronic kidney disease.”

She writes: “Because there are few drugs available to treat hyperglycaemia without increasing risk of hypoglycaemia (and other adverse events) for this population, the current data provide reassurance about combining SGLT2 inhibition with an incretin mimetic.”

Heerspink et al conclude that the DELIGHT data “support the importance of SGLT2 inhibitors in reducing albuminuria in patients with type 2 diabetes and chronic kidney disease when used in addition to guideline­recommended treatment.”  However, they add: “Whether or not this effect translates into improved kidney outcomes remains uncertain and requires dedicated outcome trials with longer follow-up.”

Written by Laura Cowen and reproduced from MedwireNews

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

References:

Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30086-5
Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30116-0

Additional information on diabetic nephropathy can be found here.

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Proton pump inhibitors linked to increased risk of renal toxicity

February 19, 2019 | By Heather Buschman, PhD

Source:  UC San Diego News Center

Proton pump inhibitors (PPIs), which include well-known brand names Prilosec, Nexium and Prevacid, are among the most commonly prescribed medications in the world. Approximately 10 percent of adults in the United States take these drugs for frequent heartburn, acid reflux and gastroesophageal reflux disease. Given their prevalence, researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego mined the FDA Adverse Effect Reporting System (FAERS) database for unexpected consequences of PPI consumption.

In the study, published February 19, 2019 by Scientific Reports, the team found that patients who took PPIs were more likely to experience kidney disease than people who took histamine-2 receptor antagonists, another form of antacid that treats the same conditions and includes the brands Pepcid and Zantac.

“Post-marketing data collected by the FDA and deposited in the FAERS database allows us to look for potential adverse effects beyond what was found in a clinical trial, which may not have lasted as long or included as much diversity as the FAERS does,” said senior author Ruben Abagyan, PhD, professor of pharmacy.

Abagyan led the study with pharmacy students Tigran Makunts and Isaac Cohen, and Linda Awdishu, PharmD, associate clinical professor and chair of the Division of Clinical Pharmacy, all at Skaggs School of Pharmacy.

The FAERS database contains more than 10 million patient records — all voluntary reports of adverse effects while taking a medication. The research team focused on patients who took PPIs and no other medications, narrowing their study population down to approximately 43,000 patients. They applied a mathematical algorithm to look for statistically significant differences in reported kidney-related complications between patients who took PPIs and the control group, approximately 8,000 patients who took histamine-2 receptor blockers, such as Zantac or Pepcid, and no other medications.

Here’s what they found: Patients who took only PPIs reported a kidney-related adverse reaction at a frequency of 5.6 percent, compared to 0.7 percent for patients who took only histamine-2 receptor antagonists.

Drilling down, the team found that, compared to the control group, patients who took only PPIs were 28.4 times more likely to report chronic kidney disease, as well as acute kidney injury (4.2 times more likely), end-stage renal disease (35.5 times more likely) and unspecified kidney impairment (8 times more likely). Patients who took PPIs were also more likely to experience electrolyte abnormalities, but this varied more by individual PPI, while the kidney-specific effects held true for all five PPIs examined.

Abagyan cautioned that this study does not reveal the absolute frequency of these kidney-related complaints for all people taking PPIs, since reporting in the FAERS is voluntary. He also says it’s possible, though unlikely, the effect could be due to unidentified confounding factors. A large, randomized, controlled clinical trial would be needed to definitively show causality between PPI usage and absolute risk of kidney disease in humans.

As the World Health Organization notes, PPIs are essential medicines for many people, helping them to control symptoms that are often painful and disruptive to daily life. But Abagyan hopes this initial data will prompt health care providers to provide the appropriate warnings, education and monitoring for patients who require PPIs, particularly if they are already at elevated risk for kidney disease and electrolyte abnormalities. Researchers made similar recommendations following a 2017 UC San Diego School of Medicine study that found evidence in mice and humans that PPIs promote chronic liver disease.

PPIs are relatively inexpensive medications, retailing for approximately $7 for a recommended two-week course of generic, over-the-counter Prilosec (omeprazole). But the frequency of use adds up — one study estimated Americans spend $11 billion on PPIs each year. There are inexpensive and readily available alternatives to PPIs. However, non-PPI-based antacids (e.g., Pepto-Bismol, Tums, histamine-2 receptor antagonists) may not be as effective.

This research was funded, in part, by the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.

Commentary:

The three phases of clinical trials generate important safety information for new drugs, but they can miss adverse effects that are very infrequent and those that only occur after prolonged use.  Post-authorization studies and post-marketing safety surveillance allow for the detection of these rare events, which cumulatively can affect many patients, if a drug is prescribed for a common medical problem such as acid reflux or as an analgesic.

The study by Makunts et al. as well as the earlier study by Llorente et al. shed light on the potential kidney and liver and toxicity of proton pump inhibitors (PPIs) as a class, when used on a chronic basis.  The implications of these findings, as the authors suggest, are the increased awareness of the safety issues of PPIs and the consequent need for close monitoring of patients during long-term treatment courses.

M. Loghman-Adham, MD

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Disappointing Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

FOSTER CITY, Calif.–(BUSINESS WIRE)–Feb. 11, 2019– Gilead Sciences, Inc. (Nasdaq: GILD) today announced that STELLAR-4, a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib, an investigational, once-daily, oral inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in patients with compensated cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH), did not meet the pre-specified week 48 primary endpoint of a ≥ 1-stage histologic improvement in fibrosis without worsening of NASH.

In the study of 877 enrolled patients who received study drug, 14.4 percent of patients treated with selonsertib 18 mg (p=0.56 vs. placebo) and 12.5 percent of patients treated with selonsertib 6 mg (p=1.00) achieved a ≥ 1-stage improvement in fibrosis according to the NASH Clinical Research Network (CRN) classification without worsening of NASH after 48 weeks of treatment, compared with 12.8 percent of patients who received placebo. Selonsertib was generally well-tolerated and safety results were consistent with prior studies.

“While we are disappointed that the STELLAR-4 study did not achieve its primary endpoint, we remain committed to advancing therapies for patients with advanced fibrosis due to NASH, where there is a significant unmet need for effective and well-tolerated treatments. Gilead has a long-term commitment and proven track record of addressing significant challenges in the field of liver diseases. Data from this large study of patients with compensated cirrhosis due to NASH, including the extensive set of biomarkers collected, will further advance our understanding of the disease and inform our broader NASH development programs,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead. “We are grateful to the patients and investigators who participated in the STELLAR-4 study, and we now await the upcoming results from the Phase 3 STELLAR-3 trial of selonsertib in patients with bridging fibrosis (F3) due to NASH and the Phase 2 ATLAS combination trial of selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976) in patients with advanced fibrosis due to NASH later this year.”

Further in-depth analysis of the findings is ongoing and the data will be submitted to an upcoming scientific conference. Gilead will work with the Data Monitoring Committee and investigators to conclude the STELLAR-4 study in a manner consistent with the best interests of each patient.

Selonsertib, cilofexor and firsocostat, alone or in combination, are investigational compounds and are not approved by the U.S. Food & Drug Administration (FDA) or any other regulatory authority. Safety and efficacy have not been established for these agents.

About Selonsertib and the STELLAR-4 Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

The STELLAR-4 study is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib in patients with compensated cirrhosis (F4) due to NASH. Eligible adults ages 18 to 70 years were randomized and received selonsertib 18 mg (n=354), selonsertib 6 mg (n=351) or placebo (n=172) for up to 240 weeks. Either selonsertib or placebo is being administered orally once daily. The primary endpoints of the study are a composite of the proportion of patients who achieve a ≥ 1-stage improvement in fibrosis according to the NASH CRN classification without worsening of NASH at week 48 and event-free survival at week 240 as assessed by time to the first clinical event. Further information about the clinical study can be found at www.clinicaltrials.gov.

Commentary:

Non-alcoholic steatohepatitis (NASH) is a progressive disease that affects about 3% of adults. It can progress to fibrosis, cirrhosis and hepatocellular carcinoma.  Many patients have features of metabolic syndrome and insulin resistance.  There are no drugs approved specifically for NASH but, many pharmaceutical companies are developing drugs for this indication.  Selonsertib had shown promise in phase 2 studies, but as is often the case with new therapies, positive results cannot always be replicated in larger Phase 3 studies with more heterogeneous populations.  Last year, Intercept pharmaceuticals announced the start of the phase 3 study of obeticholic acid (Oaliva), a farsenoid X receptor agonist in patients with NASH.  Ocaliva is already approved for the treatment of primary biliary c h o l a n g i t i s (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA (see Prescribing Information).  Ocaliva remains the forerunner in the race for NASH treatment and analysts have high expectations that it could succeed. It remains to be seen which pharma company will win the race to develop an effective treatment for NASH.

Update (29-February-2019). Today, Inercept Pharmaceuticals announced positive topline results from their Ph3 REGENERATE study of Obeticholic acid in the treatment of patients with liver fibrosis due to NASH (see here). The data from this trial will form the basis of FDA submission for approval.

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Alexion Announces Positive Top-Line Results From Phase 3 Study Of ULTOMIRIS™ (Ravulizumab-Cwvz) In Complement Inhibitor-Naïve Patients With Atypical Hemolytic Uremic Syndrome (AHUS)

Monday, January 28, 2019 6:30 am EST

BOSTON–(BUSINESS WIRE)–Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) today announced that the Phase 3 study of ULTOMIRIS™ (ravulizumab-cwvz), the company’s long-acting C5 complement inhibitor, met its primary objective in complement inhibitor-naïve patients with atypical hemolytic uremic syndrome (aHUS). In the initial 26 week treatment period, 53.6 percent of patients (95% CI [39.6%, 67.5%]) demonstrated complete thrombotic microangiopathy (TMA) response. ULTOMIRIS provided immediate and complete inhibition of the complement C5 protein that was sustained over the entire eight-week dosing interval.

The primary endpoint of complete TMA response was defined by hematologic normalization and improved kidney function. Treatment with ULTOMIRIS resulted in:

  • reduced thrombocytopenia, as measured by normalization in platelet count, in 83.9 percent of patients (95% CI [73.4%, 94.4%]),
  • reduced hemolysis (the destruction of red blood cells), as measured by normalization in lactate dehydrogenase (LDH) level, in 76.8 percent of patients (95% CI [64.8%, 88.7%]) and
  • improved kidney function, as measured by ≥ 25 percent improvement in serum creatinine level from baseline, in 58.9 percent of patients (95% CI [45.2%, 72.7%]). For patients on dialysis at enrollment, baseline was established after they had come off dialysis.

To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days.

The safety profile was consistent with that observed in two large Phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH).1,2

“We are very pleased with these data, which demonstrate that ULTOMIRIS can provide clinically meaningful benefits to patients with aHUS,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function, and provide confidence that ULTOMIRIS has the potential to become the new standard of care for patients with aHUS. We are preparing regulatory submissions for ULTOMIRIS in aHUS in the U.S., European Union and Japan as quickly as possible.”

Atypical HUS is a severe and chronic ultra-rare disease that can cause progressive damage to vital organs, predominantly the kidneys, leading to kidney failure and premature death. The disease is characterized by TMA (inflammation and blood clotting in small blood vessels throughout the body) that is mediated by chronic, uncontrolled activation of the complement system.3,4,5,6,7

“If left untreated, many patients progress to end-stage renal disease or die during the first clinical manifestations of aHUS or in the first year following these manifestations despite supportive care,” said Spero Cataland, M.D., hematologist at Ohio State University Wexner Medical Center and an investigator in the study. “I am very excited about these data and the potential for an effective new treatment option that can provide hematologic normalization and improved kidney function, including the potential to stop dialysis, when administered every eight weeks.”

The most frequently observed adverse events in this study were headache, diarrhea and vomiting. The most frequently observed serious adverse events were pneumonia and hypertension. In these critically ill patients, there were four patient deaths, none of which were considered related to treatment with ULTOMIRIS. No case of meningococcal infection was observed. Meningococcal infections are a known risk with terminal complement inhibition. To minimize the risk for patients, specific risk-mitigation plans have been established for ULTOMIRIS, based on plans that have been in place for more than 11 years for SOLIRIS® (eculizumab).

Detailed results from this Phase 3 study will be presented at a future medical congress. A Phase 3 study of ULTOMIRIS in children and adolescents with aHUS is currently ongoing.

About the ULTOMIRIS aHUS-311 Study 
This global, multicenter, single arm, Phase 3 study evaluated the safety and efficacy of ULTOMIRIS administered by intravenous infusion in 56 adults (≥ 18 years of age) who hadn’t been treated with a complement inhibitor before. The study consists of an up to seven-day screening period, a 26-week initial evaluation period and an extension period of up to two years, which is still ongoing. Patients received a weight-based loading dose (≥ 40 to < 60 kg = 2,400 mg; ≥ 60 to < 100 kg = 2,700 mg; ≥ 100 kg = 3,000 mg) on Day 1, followed by weight-based maintenance doses (≥ 40 to < 60 kg = 3,000 mg; ≥ 60 to < 100 kg = 3,300 mg; ≥ 100 kg = 3,600 mg) on Day 15 and once every eight weeks thereafter. The primary endpoint was defined as complete TMA response during the 26-week initial evaluation period, as evidenced by normalization of platelet count and lactate dehydrogenase (LDH) level and an improvement in serum creatinine of ≥ 25 percent from baseline. For patients on dialysis at enrollment, baseline was established after they had come off dialysis. To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days. Complete C5 inhibition was defined as free C5 levels of <0.5 µg/mL.

About atypical Hemolytic Uremic Syndrome (aHUS) 
Atypical hemolytic uremic syndrome (aHUS) is a chronic, progressive and debilitating ultra-rare disease that affects both children and adults and can lead to potentially irreversible damage to kidneys and other vital organs, sudden or progressive kidney failure (requiring dialysis or transplant) and premature death.3,4,7,8 aHUS is characterized by inflammation and the formation of blood clots in small blood vessels throughout the body (thrombotic microangiopathy [TMA]) mediated by chronic, uncontrolled activation of the complement system, which is part of the body’s immune system.3,4,5,6,7 TMA consists of reduced platelet count (thrombocytopenia), hemolytic anemia (as a result of hemolysis [destruction of red blood cells]) and acute kidney injury (AKI).5,7,9,10 If left untreated, significant proportions of adults (46 percent) and children (16 percent) can progress to end-stage renal disease (ESRD) or die during first clinical manifestations of aHUS despite supportive care, including plasma exchange or plasma infusion (PE/PI). One year following clinical manifestations, 56 percent of adults and 29 percent of children can progress to ESRD or die, if left untreated.11 Early and careful diagnosis of aHUS is critical as many coexisting diseases and events are known or suspected to activate the complement cascade, and as patients may not necessarily present with the classic TMA triad of thrombocytopenia, hemolytic anemia and renal impairment12 or may have less severe renal involvement.13 Available tests can help distinguish aHUS from other hemolytic diseases with similar symptoms such as HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS) and thrombotic thrombocytopenic purpura (TTP).7

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Tricida Announces Positive Pivotal Phase 3 Clinical Trial Results for TRC101 in CKD Patients With Metabolic Acidosis

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Tricida, Inc., a late-stage pharmaceutical company, announced results from its pivotal Phase 3 double-blind, randomized, placebo-controlled, multi-center Phase 3 clinical trial, TRCA-301, in 217 chronic kidney disease (CKD) patients with metabolic acidosis. TRC101 represents a first-in-class candidate for the treatment of metabolic acidosis, a common complication of CKD that can accelerate progression of kidney disease, increase the risk of muscle wasting and cause the loss of bone density.

Based on the initial topline analyses, the TRCA-301 trial met both its primary and secondary endpoints in a highly statistically significant manner (p < 0.0001 for all primary and secondary endpoints). TRC101 was well tolerated in the TRCA-301 trial. Both active (124 subjects) and placebo groups (93 subjects) had low discontinuation rates and low rates of treatment-related adverse events.

For the primary endpoint, after 12 weeks of treatment, 59.2% of subjects in the TRC101 treatment group exhibited an increase in blood bicarbonate level of at least 4 milliequivalents per liter (mEq/L) or achieved a blood bicarbonate level in the normal range of 22 to 29 mEq/L, compared with 22.5% of subjects in the placebo group (p< 0.0001). For the secondary endpoint, the mean change in blood bicarbonate from baseline to week 12, subjects in the TRC101 treatment group exhibited a mean increase in blood bicarbonate of 4.49 mEq/L, compared with 1.66 mEq/L in the placebo group (p<0.0001).

In addition, two pre-specified exploratory endpoints of the pivotal Phase 3 TRCA-301 trial assessed patient quality of life and improvement in muscle function. The first exploratory endpoint examined the effect of treatment with TRC101 on self-reported responses to the physical functioning subpart of the Kidney Disease and Quality of Life Short Form survey (KDQOL-SF survey). The second exploratory endpoint objectively measured physical function, assessed using a repeated chair stand test, involving a timed measurement of five repetitions of moving from a seated to standing position. Initial topline analyses of the results of the physical functioning KDQOL-SF survey showed a statistically significant positive difference in the TRC101-treated subjects compared with the placebo group after 12 weeks of treatment (p=0.0122) and the repeated chair stand test showed a trend toward significance in the positive difference in the TRC101-treated subjects compared with the placebo group (p=0.0630).

The overall safety profile of TRC101 observed in the trial was consistent with that expected for the general population of patients with Stage 3 to 5 CKD and with similar non-absorbed polymer drugs with a site of action in the gastrointestinal tract. The incidence of serious adverse events was low and balanced in the two treatment groups and none were assessed to be related to TRC101 by the clinical investigator, Medical Monitor or Drug Safety and Pharmacovigilance Team. There were two deaths in the study and both occurred in the placebo group. Overall treatment-related adverse events occurred in 9.7% of subjects in the placebo group and 13.7% of the TRC101-treated subjects. Treatment-related gastrointestinal adverse events that occurred in more than one subject include diarrhea, flatulence, nausea and constipation. Over 95% of the subjects in each group completed the trial.

TRCA-301 Clinical Trial Design

The TRCA-301 double-blind, randomized, placebo-controlled Phase 3 trial was conducted at 47 sites in the United States and Europe and enrolled 217 Stage 3b or 4 CKD patients with baseline blood bicarbonate levels between 12 mEq/L and 20 mEq/L. Subjects were randomized in a 4:3 ratio to receive TRC101 or placebo. The study drug dosing (TRC101 or placebo) continued for 12 weeks once daily. The primary outcome measure was change from baseline in blood bicarbonate (Time Frame: Week 12) and included comparison of TRC101 and placebo with regard to the proportions of subjects with change from baseline in blood bicarbonate ≥ 4 mEq/L or with blood bicarbonate in the normal range (22 to 29 mEq/L). Eligible subjects that completed the TRCA-301 trial were invited to participate in a 40-week safety extension trial, TRCA-301E. Of the 208 subjects who completed the TRCA-301 trial, 196 were enrolled in the TRCA-301E safety extension trial.

The principal investigator for the trial was Dr. Donald E. Wesson, MD, MBA, Professor of Medicine at Texas A&M Health Sciences Center College of Medicine in Dallas, Texas, President of the Baylor Scott & White Health and Wellness Center (BSW HWC), Senior Vice President of Baylor Scott & White Weight Management Services and a board-certified internist and nephrologist.

About TRC101

TRC101 represents a first-in-class candidate for the treatment of metabolic acidosis, a common complication of CKD that can result in accelerated progression of kidney disease. It is a novel, non-absorbed polymer drug that is designed to bind hydrochloric acid in the gastrointestinal tract, removing it from the body with high capacity and specificity, with the objective to treat chronic metabolic acidosis associated with CKD as measured by an increase in blood bicarbonate levels.

Additional information:

Tricida presentation at the 37th annual JP Morgan Healthcare Conference Jan 9, 2019

Published Phase 2 results of TRC101

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AstraZeneca Reports Full Results from DECLARE-TIMI 58 Cardiovascular Outcomes Trial for FARXIGA (dapagliflozin)

November 12, 2018;  Reproduced from StreetInsider

AstraZeneca today announced positive full results from the DECLARE-TIMI 58 cardiovascular (CV) outcomes trial (CVOT) for FARXIGA (dapagliflozin). The data were presented as a late-breaking abstract (#19485) at the American Heart Association (AHA) Scientific Sessions 2018 in Chicago, IL, and simultaneously published in the New England Journal of Medicine (NEJM).

Results from DECLARE-TIMI 58, the largest SGLT-2 inhibitor (SGLT-2i) CVOT conducted to date, including more than 17,000 patients across 33 countries, showed that FARXIGA significantly reduced the risk of hospitalization for heart failure (hHF) or CV death composite vs. placebo by 17% (4.9% vs. 5.8%; HR 0.83 [95% CI 0.73-0.95], p=0.005), one of the two primary efficacy endpoints. The reduction in hHF or CV death was consistent across the entire patient population, which included those with CV risk factors and those with established CV disease.1 FARXIGA is not indicated to reduce the risk of CV events or hHF.

Additionally, there were fewer major adverse cardiovascular events (MACE) observed with FARXIGA for the other primary efficacy endpoint, however this did not reach statistical significance (8.8% for FARXIGA vs. 9.4% for placebo; HR 0.93 [95% CI 0.84-1.03], p=0.17).1

DECLARE-TIMI 58 also confirmed the well-established safety profile for FARXIGA, which met the primary safety endpoint of non-inferiority vs. placebo, demonstrating no increase in the composite of MACE, defined as CV death, heart attack (myocardial infarction), or stroke.

Further, on other relevant safety measures, the trial showed no imbalance with FARXIGA vs. placebo in amputations (1.4% vs. 1.3%), fractures (5.3% vs. 5.1%), bladder cancer (0.3% vs. 0.5%) or Fournier’s gangrene (1 case vs. 5 cases). The respective incidences of diabetic ketoacidosis (0.3% vs. 0.1%) and genital infections (0.9% vs. 0.1%) were rare.1

Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and Metabolism, Global Medicines Development, said: “These positive results are clinically relevant to the 425 million people worldwide living with diabetes, of whom those with type 2 diabetes have a two-to-five times greater risk of heart failure along with an increased risk of a heart attack or stroke. Heart failure survival rates are only 50% after five years from diagnosis, which is why these new findings are so important in broadening our understanding of how to go beyond blood glucose, so we may better address this serious and often overlooked cardiovascular complication.”2-6

Although secondary endpoints were only nominally significant, the renal composite endpoint showed that FARXIGA reduced the rate of new or worsening nephropathy by 24% vs. placebo across the broad patient population studied (4.3% vs. 5.6%; HR 0.76 [95% CI 0.67-0.87]), and there were fewer all-cause mortality events with FARXIGA vs. placebo (6.2% vs. 6.6%; HR 0.93 [95% CI 0.82-1.04]).1 FARXIGA is not indicated to reduce the risk of HF, other CV outcomes, nephropathy or all-cause mortality.

References:

Zinman, Bernard, et al. “Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.” New England Journal of Medicine 373.22 (2015): 2117-2128.

Wanner, Christoph, et al. “Empagliflozin and progression of kidney disease in type 2 diabetes.” New England Journal of Medicine 375.4 (2016): 323-334.

Neal, Bruce, et al. “Canagliflozin and cardiovascular and renal events in type 2 diabetes.” New England Journal of Medicine 377.7 (2017): 644-657.

Wiviott SD et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine Nov 12, 2018 DOI: 10.1056/NEJMoa1812389

Commentary:

Dapagliflozin is the third SGLT2 inhibitor that has completed a cardiovascular outcome trial (CVOT), as required for all new drugs approved for treatment of type 2 diabetes (see FDA Guidance).  Previous CVOT studies include EMPA-REG Outcome trial  for empagliflozin and the CANVAS study for canagliflozin.  The results for dapagliflozin are not as compelling since it did not reduce MACE compared to placebo. Another interesting finding with SGLT2 inhibitors is their ability to slow the progression of renal disease in type 2 diabetes and perhaps even in non-diabetic chronic kidney disease. The renal outcome trial of canagliflozin (CREDENCE trial) was recently stopped earlier than planned due to meeting the pre-specified primary composite endpoint.  The empagliflozin renal outcome trial is also ongoing and is based on encouraging secondary reno-protection data from the EMPA-REG Outcome trial (see here). These encouraging results open new therapeutic options to slow the progression of CKD not only in patients with type 2 diabetes and cardiovascular disease but in patients with CKD due to other causes. The result of the CANVAS trial are awaited with great enthusiasm from the renal community.

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Lokelma approved in the US for the treatment of adults with hyperkalemia

On May 18, 2018 AstraZeneca announced the FDA approval of their new drug Lokelma, for the treatment of hyperkalemia.  The full new release is reproduced below:

The US Food and Drug Administration (FDA) has approved Lokelma (sodium zirconium cyclosilicate), formerly ZS-9, for the treatment of adults with hyperkalaemia,1 a serious condition characterized by elevated potassium levels in the blood associated with cardiovascular, renal and metabolic diseases.2

The risk of hyperkalemia increases significantly for patients with chronic kidney disease (CKD) and for those who take common medications for heart failure (HF), such as renin-angiotensin-aldosterone system (RAAS) inhibitors, which can increase potassium in the blood.2,3 To help prevent the recurrence of hyperkalemia, RAAS-inhibitor therapy is often modified or discontinued, which can compromise cardio-renal outcomes and increase the risk of death.3,4

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “We are pleased by today’s FDA approval of Lokelma as it enables us to help address a long-standing clinical need with a new medicine that offers rapid and sustained treatment for adults with hyperkalemia. The consequences of hyperkalemia can be very serious and it’s reassuring for treating physicians that Lokelma has demonstrated lowering of potassium levels in patients with chronic kidney disease, heart failure, diabetes and those taking RAAS inhibitors.”

Lokelma is a highly-selective, oral potassium-removing agent.The FDA approval is supported by data from three double-blind, placebo-controlled trials and two open-label trials, which showed that for patients receiving Lokelma the onset of action was at 1.0 hour and the median time to achieving normal potassium levels in the blood was 2.2 hours, with 92% of patients achieving normal potassium levels within 48 hours from baseline.1,8 The treatment effect was maintained for up to 12 months.1,5,6,7,8

Steven Fishbane, MD, Professor, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, New York, said: “This FDA approval represents an exciting milestone, as it stands to deliver a rapid, effective and generally well-tolerated treatment option to patients suffering from hyperkalemia in the US.”

The European Commission granted marketing authorization for Lokelma in the European Union on 22 March 2018.

About Hyperkalemia

The risk of hyperkalemia increases significantly for patients with CKD and for those who take common medications for HF, such as RAAS inhibitors, which can increase potassium in the blood. Hyperkalemia occurs in 23% to 47% of patients with CKD and/or HF, with an estimated 200 million and 38 million people, respectively, living with each condition worldwide. Hyperkaliemia may lead to cardiac arrest and death, with mortality being up to 30% in patients with severe hyperkalaemia, if not treated rapidly.

About Lokelma

Lokelma is an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension, that acts as a highly-selective potassium-removing agent. It is administered orally, is odorless, tasteless and stable at room temperature. It has been studied in three double-blind, placebo-controlled trials and in two 12-month open label clinical trials in adult patients with hyperkalemia.

About AstraZeneca in Cardiovascular, Renal & Metabolism

Cardiovascular and metabolic diseases are a main therapy area and a key growth platform for AstraZeneca, which is now called Cardiovascular, Renal & Metabolism (CVRM), following the addition of Lokelma to our portfolio of medicines.

By following the science to understand more clearly the underlying links between the heart, kidney and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of these diseases and even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CVRM health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

Commentary: hyperkalemia is a common complication in patients with chronic kidney disease, particularly those who require treatment with renin-angiotensin aldosterone (RAAS) inhibitors. Until recently, the only available oral treatment for hyperkalemia was sodium polystyrene sulfonate (Kayexalate).  In 2015 another drug, patiromer (Valtessa), was approved for this indication and provided a new treatment option. The recent approval of sodium zirconium cyclosilicate (Lokelma) provides an addition treatment choice for hyperkalemia. With the availability of oral therapies, patients should be able to take their RAAS inhibitors without the fear of hyperkalemia and without the need for frequent blood tests. It remains to be seen if these new treatments will have a favorable impact on long-term patient outcomes.

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