Otsuka Announces Phase 3 Results for Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

November 04, 2017 12:03 PM Eastern Daylight Time

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced detailed results from the Phase 3 REPRISE trial of tolvaptan, which is under investigation in the United States in patients with autosomal dominant polycystic kidney disease (ADPKD).

According to trial results, tolvaptan showed greater reduction on the primary endpoint, the rate of change in estimated glomerular filtration rate (eGFR) compared to placebo. Estimated GFR, the primary endpoint of the trial, is a key measure of kidney function. Change in estimated eGFR from pre-treatment baseline to post-treatment follow-up, adjusted by the duration of the trial for each patient and expressed per year was -2.34 mL/min/1.73 m2-year with tolvaptan versus -3.61 mL/min/1.73 m2-year with placebo, representing a 35% reduction of 1.27 mL/min/1.73 m2-year (95% CI 0.86 to 1.68; P<0.001). These data were presented today as a late breaking oral abstract at the American Society of Nephrology (ASN) 2017 Kidney Week in New Orleans,2 and were simultaneously published online in the New England Journal of Medicine.

Polycystic kidney disease (PKD) is a progressive genetic disorder affecting the kidneys, in which fluid-filled cysts develop in the kidneys over time, enlarging these organs and inhibiting their ability to function normally, leading to kidney failure in most patients (see here). Autosomal dominant PKD, known as ADPKD, is the most common type, and is the fourth leading cause of kidney failure.4 By age 57, more than half of people with ADPKD will need dialysis or a kidney transplant (see here and here)

Vicente Torres, MD, PhD, Director of the Mayo Clinic Translational Polycystic Kidney Disease Center, and lead investigator on the REPRISE trial, commented, “Tolvaptan slowed the rate of kidney function decline in this trial. These data represent a significant milestone in the investigation of this condition, for which there are currently no approved treatments in the U.S.”

“It is gratifying to see the significance of findings from the REPRISE trial, which further support the utility of tolvaptan in patients with ADPKD,” said Robert McQuade, Ph.D., Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “These robust findings provide evidence that tolvaptan, if approved in the U.S., may be an important new treatment option with the potential to help patients with this debilitating disease, and we look forward to discussing these data with regulatory agencies.”

Along with results from previous pivotal studies, findings from the REPRISE trial have formed the basis of a response to the Complete Response Letter (CRL) that FDA issued in August 2013, which Otsuka has submitted to the U.S. Food and Drug Administration (FDA) for tolvaptan as a treatment for patients with ADPKD.

About the Phase 3 REPRISE Trial

REPRISE was a Phase 3, multi-center, randomized withdrawal, placebo-controlled, double-blind trial in adult patients with late-stage 2 to early-stage 4 chronic kidney disease due to ADPKD. After an 8-week pre-randomization period including sequential placebo and tolvaptan treatments, 1,370 ADPKD patients were randomized 1:1 to tolvaptan (90 or 120 mg per day) or placebo and treated for 12 months. The primary endpoint measured change in estimated GFR from pre-treatment baseline to post-treatment follow-up adjusted by the duration of the trial for each patient. The key secondary endpoint was the estimated GFR slope derived from the individual slopes in each patient adjusted for the duration of the observations and expressed per year. This analysis used all serum creatinine values from placebo run-in, tolvaptan run-in (not including tolvaptan titration), 12-month double-blind treatment, and posttreatment follow-up measurements. In the trial, tolvaptan patients had a significantly smaller decline, of 3.16mL/min/1.73m2/year compared with 4.17 mL/min/1.73m2/year for placebo treated patients (p<0.0001).

Key safety findings (collected monthly) were generally consistent with previous pivotal data with the majority of events across the study. Following randomization, patients who received tolvaptan experienced more frequent polyuria, nocturia, thirst, polydipsia, dry mouth, fatigue and diarrhea, whereas those who received placebo experienced more frequent peripheral edema, renal pain, and urinary tract infection; most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. In the double-blind treatment period, 5.6 percent of patients taking tolvaptan had significantly abnormal liver blood tests (greater than 3 times the upper limit of normal), compared with 1.2 percent of those taking placebo. Transaminase elevations were reversible after stopping tolvaptan and no patients showed concomitant bilirubin elevations greater than 2 times the upper limit of normal. In the study, risk minimization measures consisting of monthly monitoring of liver parameters helped minimize the risk of serious liver toxicity.

Otsuka collaborated on the development of the protocol for this clinical trial with the FDA through the special protocol assessment process in order to address a CRL issued by the agency for a New Drug Application (NDA) for tolvaptan in ADPKD in 2013. In the coming weeks the FDA will acknowledge whether the company’s response is complete and whether their regulatory review can proceed.

 

Commentary and opinion

As discussed in this forum in November 2012 (see here), following the publication of the data for TEMPO 3:4 trial (see here), the investigators of this study (sponsored by Otsuka Pharmaceuticals) showed moderate slowing in the rate of increase in total kidney volume (TKV) and reduced kidney pain, but this was negated by higher discontinuation rate (23% for Tolvaptan versus 14% in the placebo group), as well as by hepatic adverse events.

Due to the increased risk of hepatic toxicity, the FDA issued a Drug Safety Communication for tolvaptan (Samsca®) and convened an Advisory Committee to review the data from TEMPO 3:4 trial.  The Advisory Committee voted 9 to 6 against approval of Tolvaptan for the treatment of ADPKD (see here).  The panel cited excessive dropouts and limited efficacy in slowing progression of renal disease, despite reductions in kidney volume and pain.  The overall risk was assessed to be higher than the benefit observed, despite a high unmet medical need in this patient population.  The FDA issued a Complete Response Letter, requiring submission of additional data before considering evaluating tolvaptan for this indication. Now, armed with the data from REPRISE trial, the Sponsor is seeking approval of tolvaptan for the treatment of ADPKD.  Since FDA provided advice through Special Protocol Assessment, and since the Sponsors are bound to follow this advice, it is likely that the new data, supported by TEMPO 4:4 extension trial, will provide sufficient evidence of efficacy and a manageable safety profile, to grant approval of tolvaptan for the new indication of treatment of ADPKD if certain severity criteria are met.  This would represent a deviation from the FDA standards that require demonstration of a significant difference in time to doubling of serum Cr or time to 50% decline in eGFR.  However, given that the results of TEMPO 3:4 and REPRISE trials complement each other and both show slowing of the slope of decline in renal function (measured either by reciprocal of serum Cr or by eGFR), and given a high unmet medical need, it is likely that a full approval or a conditional approval will be granted.  In case of conditional approval, there will be a post-approval requirement to continue to follow the subjects to ascertain that the beneficial effects on GFR and other clinically relevant parameters are sustained as well as a REMS requirement, given the hepatotoxicity seen in TEMPO 3:4 trial.

The study design of REPRISE and the overall clinical program for the development of tolvaptan will now set a precedence to guide the development of other drugs for the treatment of ADPKD as well as for other types of slowly progressive chronic kidney disease (CKD).

Tolvaptan is currently approved for the treatment of adult patients with ADPKD in Japan, the EU, Canada, South Korea, Switzerland, Hong Kong and Australia (see EPAR).  However, it has multiple side effects, including aquaresis accompanied by thirst, nocturia and polyuria. It also can result in hepatotoxicity, which can be managed with monthly monitoring of liver function tests.  As a condition of approval, the European Medicines Agency (EMA) has required a non-interventional post-authorization safety study (PASS) to investigate the risks of hepatotoxicity, basal cell carcinoma and glaucoma associated with the use of tolvaptan (marketed under the brand names Smsca and Jinrac)

While we do not know what label restrictions will be imposed by the FDA, due to the above safety issues, tolvaptan may only be suitable for ADPKD patients who have shown rapid progression or who are likely to progress rapidly.  This subset of ADPKD patients are most likely to benefit from long-term therapy with tolvaptan. It is hoped that another V2 receptor antagonist could be developed that would be devoid of organ toxicity. However, the aquaretic effect is an integral part of the mechanism of action of all V2 antagonists and will have to be managed by increased fluid intake and administration of the second dose in the afternoon instead of in the evening (Ron Perrone, MD personal communication).  Drugs targeting other pathways in the pathogenesis of ADPKD are currently in early stage development [see here and here], but it remains to be seen if they will be successful in clinical trials and whether their safety profile will be better than tolvaptan.

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U.S. FDA APPROVES AURYXIA® (FERRIC CITRATE) TABLETS AS A TREATMENT FOR PEOPLE WITH IRON DEFICIENCY ANEMIA AND CHRONIC KIDNEY DISEASE, NOT ON DIALYSIS

BOSTON, Nov. 07, 2017 (GLOBE NEWSWIRE) — Keryx Biopharmaceuticals, Inc. (Nasdaq:KERX), a company focused on bringing innovative medicines to people with kidney disease, today announced that the U.S. Food and Drug Administration (FDA) has approved Auryxia for an additional indication. The approval is for the treatment of iron deficiency anemia in adults with chronic kidney disease (CKD), not on dialysis. Auryxia was originally approved in September 2014 for the control of serum phosphorus levels in people with chronic kidney disease who require dialysis.

With the new indication, millions of people living with chronic kidney disease have the potential to benefit from treatment with Auryxia. This medication is available today in pharmacies and covered broadly by Medicare Part D and commercial insurance providers in the United States.

“More than half of the approximate 30 million people in the United States living with chronic kidney disease are iron deficient, and yet, this is the only tablet that has been developed and approved specifically to address iron deficiency anemia in these patients, who are not on dialysis,” said Steven Fishbane, M.D., chief, division of kidney diseases and hypertension, department of medicine, Northwell Health in Great Neck, New York. “Starting today, physicians can prescribe an oral iron medicine to help people living with this condition, the majority of whom are not being optimally treated.”

“We are pleased with the broad indication permitted by the FDA, as a first-line treatment option for adults with iron deficiency anemia and chronic kidney disease, not on dialysis,” said John Neylan, M.D., senior vice president and chief medical officer of Keryx Biopharmaceuticals. “Physicians and their patients now have a new treatment option to help manage a serious complication of this complex disease.”

Auryxia’s supplemental new drug application (sNDA) approval was based on results from a 24-week placebo controlled Phase 3 clinical trial in 234 adults with stage 3-5 non-dialysis dependent chronic kidney disease. Patients enrolled in the trial had hemoglobin levels between 9.0 g/dL and 11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements. The starting dose in the study was three tablets per day taken with meals; the mean dose was five tablets per day. Importantly, during the study, patients were not allowed to receive any intravenous (IV) or oral iron, or erythropoiesis-stimulating agents (ESAs). In the study, treatment with Auryxia demonstrated significant increases in hemoglobin levels of >1 g/dL at any point during the 16-week efficacy period for the majority of patients (52.1 percent, n=61/117 compared to 19.1 percent, n=22/115 in the placebo group), a clinically meaningful result. In the trial, ferric citrate was generally well tolerated and adverse events were consistent with its known safety profile. The most commonly reported adverse events in the Phase 3 study were diarrhea (21%), constipation (19%), discolored feces (15%), nausea (11%), abdominal pain (6%) and hyperkalemia (7%). Results were published January 2017 in the online issue of the Journal of the American Society of Nephrology (JASN).

Commentary:

Patients with chronic kidney disease (CKD) suffer from multiple metabolic abnormalities, chief among them are disorders of mineral metabolism, including hyperphosphatemia, and disorders of iron metabolism, which can lead to both iron deficiency anemia and iron refractory anemia.  The latter is in part, due to the inflammatory nature of CKD and dialysis and in part, due to erythropoietin deficiency, leading to chronic renal anemia.  While erythropoiesis stimulating agents (ESA) can replace the deficiency of erythropoietin, optimal ESA response requires the concomitant administration of intravenous iron [see here].  Orally administered iron supplements are not effective in restoring iron stores in ESRD patients and are associated with gastrointestinal symptoms.

Ferric citrate [Auryxia®], initially developed as a phosphate binder, was found to also improve iron deficiency anemia in CKD patients, due to the absorption of iron from the GI tract.  Previously marketed phosphate binders have included aluminum hydroxide, which was shown to result in aluminum deposition in bone and in brain in ESRD.  The former can lead to osteomalacia, while the latter is associated with encephalopathy.  For these reasons, the use of aluminum hydroxide as a phosphate binder has been abandoned.  Calcium carbonate, although an effective phosphate binder, was shown to result in hypercalcemia, over-suppression of parathyroid hormone and adynamic bone disease as well as coronary artery and cardiac calcifications [see here]. These side effects led to the development of aluminum-free and calcium-free phosphate binders such as Sevelamer (Renagel®, Renvela®) and lanthanum carbonate (Fosrenol®].  Lanthanum carbonate does not result in any significant lanthanum absorption and has not been shown to have any untoward consequences [see here].  Sevelamer is a non-absorbable resin, so its action is limited to binding phosphate and bile acids in the gut.

The development of ferric citrate as a phosphate binder was a departure from the previous strategies of developing non-absorbable phosphate binding compounds.  This new approach has paid off in that, iron deficiency, a common problem in pre-dialysis CKD patients, was shown to improve with ferric citrate, while it was primarily prescribed as a phosphate binder [Block 20015; Fishbane 2017].  The approval of the supplemental application for the use of ferric citrate [Auryxia®] to treat iron-deficiency anemia in pre-dialysis CKD patients, should now allow patients to obtain re-imbursement for this indication.  Of course, ferric citrate will continue to be used for its primary indication as a phosphate binder in ESRD patients on dialysis.  In this indication, the additional benefit of ferric citrate is the reduced need for intravenous iron and to also the reduction in the ESA dose [see here]and [here].  Considering the high costs of these treatments, reduced doses is likely to reduce the overall cost of anemia treatment, which is currently bundled under the CMS rules [see here].

Copyright © M. Loghman-Adham, MD

 

References:

Besarab, Anatole, et al. “Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients.” Journal of the American Society of Nephrology 11.3 (2000): 530-538.

Fishbane S1, Block GA, Loram L, Neylan J, Pergola PE, Uhlig K, Chertow GM. Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia.  J Am Soc Nephrol. 2017 Jun;28(6):1851-1858. doi: 10.1681/ASN.2016101053. Epub 2017 Jan 12. (see here)

Block, Geoffrey A., et al. “A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD stages 3-5.” American Journal of Kidney Diseases 65.5 (2015): 728-736.

Umanath K, Jalal DI, Greco BA, Umeukeje EM, Reisin E, Manley J, Zeig S, Negoi DG, Hiremath AN, Blumenthal SS, Sika M, Niecestro R, Koury MJ, Ma KN, Greene T, Lewis JB, Dwyer JP; Collaborative Study Group. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD. J Am Soc Nephrol. 2015 Oct;26(10):2578-87

Lewis JB, Sika M, Koury MJ, Chuang P, Schulman G, Smith MT, Whittier FC, Linfert DR, Galphin CM, Athreya BP, Nossuli AK, Chang IJ, Blumenthal SS, Manley J, Zeig S, Kant KS, Olivero JJ, Greene T, Dwyer JP; Collaborative Study Group. Ferric citrate controls phosphorus and delivers iron in patients on dialysis. J Am Soc Nephrol. 2015 Feb;26(2):493-503

How ‘Bundling’ Changed Dialysis Care.  Renal & Urology News March 02, 2017  (see here)

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Pharmalink AB announces the publication in Lancet of Phase 2b trial of Nefecon in primary IgA nephropathy. The data were also presented at the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) conference (Madrid, Spain)

 

Stockholm, Sweden – June 4, 2017 (see press release). The Phase 2b trial (known as the NEFIGAN trial), was presented in a special session co-hosted by The Lancet by lead author Bengt Fellström, MD, PhD, Professor of Nephrology at Uppsala University Hospital and Principal Investigator of the NEFIGAN Trial.

Nefecon® is an investigational treatment for patients with primary IgAN at risk of developing ESRD. Nefecon®  has successfully completed a randomized, placebo-controlled Phase 2b study in 149 primary IgAN patients (full analysis set) at risk of developing ESRD, under standardized rigorous blood pressure control with an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB).  Nefecon®  is an oral, targeted-release and locally acting formulation of the potent corticosteroid, budesonide, that down-regulates the disease process in the kidney through suppression of the gastrointestinal immune system thus exploiting the pivotal role the gastrointestinal tract plays in the overall immune response. These promising results indicate that treatment with Nefecon® may provide clinical benefits to primary IgAN patients at risk of progressing to ESRD, and provide an alternative to dialysis and transplantation. Nefecon® has received orphan drug designation in primary IgAN by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

The NEFIGAN trial was randomized, double-blinded, and placebo-controlled in male and female patients (aged >18 years) with primary IgAN and overt proteinuria considered at risk of progressing to end-stage renal disease (ESRD)1. The trial was conducted at 62 sites across 10 European countries between November 2012 and June 2015. Data from 149 patients constituted the final analysis set, from a total of 249 patients screened.  Following a 6-month run-in phase (to optimize RAS blockade treatment), patients underwent a 9-month treatment phase in which they were randomized in a 1:1:1 ratio to receive Nefecon at 16 mg/day, 8 mg/day or placebo.  The primary outcome of the Phase 2b clinical trial was assessed on the full analysis set (n=149), defined as all randomized patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement (modified intention-to-treat analysis). At nine months, mean urine protein to creatinine ratio (UPCR) decreased by -26.4% with Nefecon [p=0.0066] (-29.3% with 16 mg/day [p=0.009; p=NS], -23.7% with 8 mg/day [p=0.029]), vs. placebo. The effect was sustained throughout the follow-up; mean UPCR decreased by -32% from baseline at 12 months for 16 mg/day vs. a 0.5% increase for placebo. Over nine months, eGFR was stable with Nefecon but decreased 9.8% with placebo (Nefecon vs. placebo: p=0.001). Nefecon was well tolerated and the total incidence of treatment-emergent adverse events was similar across all treatment groups.

Commentary:

Immunoglobulin A (IgA) nephropathy (IgAN) is a chronic glomerular disease characterized histologically by the presence of mesangial deposits of IgA, which are often accompanied by IgG or IgM deposits and often by complement deposits. It is a slowly progressive disease, leading to end-stage renal disease (ESRD) in 20% to 40% of patients over 20 years.  IgA nephropathy IgA Nephropathy is the most common primary glomerulonephritis worldwide2,3.

The presence of hypertension and low GFR at the onset are associated with more rapid progression and worse outcomes.2,3  Multiple studies have shown that proteinuria is a risk factor for progression of renal disease in patients with IgAN and other glomerular diseases. Furthermore, higher levels of proteinuria are associated with a more rapid decline in renal function and reduction in proteinuria with treatment, may lead to slowing of the rate of progression of kidney dysfunction.4

Several studies have shown the benefit of treatment with corticosteroids, given either as 6 monthly pulses of methylprednisolone or orally for 8 weeks. Inhibition of the renin-angiotensin system (RAS) pathway is also recommended 5,6.  In addition to lowering blood pressure, it reduces proteinuria.  Treatment recommendations for IgAN have recently been summarized in the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines.6 Treatment of hypertension targeting a blood pressure (BP) <130/80 mmHg should slow the rate of progression of disease. Additionally, the guidelines recommend treatment using RAS blockade (as tolerated, with either an ACE inhibitor or an angiotensin receptor blocker [ARB]) to achieve a maximal reduction in proteinuria, when proteinuria is >1 g/24 h.6 Other supportive therapy, such as fish oil and statins, should be considered and have been associated with clinical benefits.

The novelty of the targeted release budesonide (Nefecon)® is the ability to target the distal ileum and block the immune mechanisms responsible for the development of circulating immune complexes, while reducing the adverse effects seen with systemic steroid treatment.  The reduction in proteinuria is an acceptable endpoint for Phase 2 proof-of-concept studies in IgAN and other forms of GN.  However, for Phase 3 registration studies, both the FDA and the EMA require assessment of time to doubling of serum creatinine or 50% reduction in eGFR or time to ESRD.  To reach these endpoints, long treatment and follow-up times (24-36 months) are needed7.  Recent studies suggest that reductions in eGFR less than 50% may be acceptable, but agreement of the agency is required before finalizing the design of the clinical trial.

References:

  1. Fellström BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sørensen SS, Tsars V, Del Vecchio L; NEFIGAN Trial Investigators. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomized, placebo-controlled phase 2b trial.  2017 May 27;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0. Epub 2017 Mar 28.(link)
  2. Canetta PA, Kiryluk K, Appel GB. Glomerular diseases: emerging tests and therapies for IgA nephropathy. Clin J Am Soc Nephrol 2014; 9: 617-25 (link).
  3. Rodrigues JC1, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017 Apr 3;12(4):677-686. doi: 10.2215/CJN.07420716. Epub 2017 Feb 3 (link).
  4. Reich HN, Troyanov S, Scholey JW, Cattran DC, for the Toronto Glomerulonephritis Registry. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol 2007; 18:3177-83 (link). doi:10.1681/ASN.2007050526.
  5. Lv J, Zhang H, Chen Y, et al. Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis 2009; 53:26-32 (link).
  6. KDIGO Clinical Practice Guideline for Glomerulonephritis. June 2012; 2(2). http://www.kidney-international.org (link).
  7. Formentini I, Bobadilla M, Haefliger C, Hartmann G, Loghman-Adham M, Mizrahi J, Pomposiello S, Prunotto M, Meier M. Current drug development challenges in chronic kidney disease (CKD)—identification of individualized determinants of renal progression and premature cardiovascular disease (CVD). Nephrol Dial Transplant; 27 (suppl 3), 2012, iii81–iii88, https://doi.org/10.1093/ndt/gfs270 (link)

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Amgen and AbbVie reach a settlement on Humira biosimilar patent litigation

From  Reuters (September 28, 2017)

Amgen Inc has reached a settlement with AbbVie Inc that will delay the U.S. launch of Amgen’s cheaper biosimilar version of AbbVie’s cash cow, the blockbuster rheumatoid arthritis drug Humira, until Jan. 31, 2023, the companies said on Thursday (see also  AbbVie news release and Amgen/PR Newswire)

Humira, known chemically as adalimumab, is by far the world’s top-selling prescription medicine with second-quarter global sales of $4.7 billion, putting it on track for annual sales exceeding $18 billion.  The settlement, which removes a major overhang for AbbVie given its dependence on Humira, sent its shares to an all-time high of $90.95 before settling back to $89.87, up 6 percent.  Under terms of the settlement, which ends all pending patent litigation between the companies, AbbVie said it will be entitled to unspecified royalties on sales of Amgen’s biosimilar of Humira.

The Humira settlement “adds unexpected royalties during the biosimilar years and indicates that AbbVie’s patents … are defensible,” BMO Capital Markets analyst Alex Arfaei said in a research note.  The settlement also allows Amgen to begin selling its biosimilar of Humira in Europe on Oct. 16, 2018.

”This agreement will allow us to secure a strong foothold in the $4 billion European adalimumab market,” Scott Foraker, head of biosimilars for Amgen, said in a statement.

Amgen was the first company to win U.S. approval for a Humira biosimilar, but delayed selling it until the patent situation was resolved. Other companies that also intend to market their own biosimilar versions of Humira are still challenging its patents.

Commentary:

Adalimumab, marketed as Humira, is a fully human monoclonal antibody against tumor necrosis factor.  It has been approved for multiple indications (see Prescribing Information) and, as a result, has attained blockbuster status for several years.  It is therefore, not surprising that several companies are vying for a share of the Humira market by developing adalimumab biosimilars.  Unlike small molecule generics, which only require bioequivalence studies for approval, biosimilars must demonstrate clinical efficacy, in addition to rigorous CMC and molecular characterization, including immunogenicity studies.  Although several biosimilars are currently approved and marketed in the European Union, only 5 have been approved in the US (see here).  The recent approval of adalimumab biosimilar from Amgen, has ushered in a flood of other biosimilar monoclonal antibodies as the patents on the innovator molecules begin to expire (see here).

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Merck Provides Update on REVEAL Outcomes Study of Anacetrapib

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced that the REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid modification) outcomes study of anacetrapib met its primary endpoint, significantly reducing major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization) compared to placebo in patients at risk for cardiac events who are already receiving an effective LDL-C lowering regimen. The safety profile of anacetrapib in the early analysis was generally consistent with that demonstrated in previous studies of the drug, including accumulation of anacetrapib in adipose tissue, as has been previously reported. Merck plans to review the results of the trial with external experts, and will consider whether to file new drug applications with the U.S. Food and Drug Administration (FDA) and other regulatory agencies. The results of the REVEAL study will be presented at the European Society of Cardiology meeting on Aug. 29, 2017.

Anacetrapib is Merck’s investigational cholesteryl ester transfer protein (CETP) inhibitor. The REVEAL study is a randomized, double-blind placebo-controlled clinical trial to assess the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for a median duration of at least 4 years among approximately 30,000 patients at high risk of cardiovascular events. REVEAL was designed and independently conducted by investigators at the Clinical Trial Service Unit (CTSU) at the University of Oxford, the trial’s regulatory sponsor, in collaboration with the TIMI Study Group based at Brigham and Women’s Hospital in Boston and Merck. Merck provided funding for REVEAL. Details on the REVEAL study design are available at clinicaltrials.gov: https://clinicaltrials.gov/show/NCT01252953.

Source:  Business Wire  June 27, 2017

 Commentary:

Although low concentrations of high-density lipoprotein cholesterol HDL-C (<40 mg/dL) have been recognized as a risk factor for coronary heart disease [Troth 2004], it is not clear whether increased HDL-C levels confer additional risk reduction, independent of lowering LDL-C levels [Sing 2007].  Raising HDL-C with diet and lifestyle modifications has proven challenging [Troth 2004].  Niacin and fibrates were shown to raise HDL-C but outcome studies did not show long-term benefits in terms of reduced CV mortality [Keene 2014].  More recently, small molecule inhibitors of CETP have been discovered that are able to raise HDL-C levels with or without a reduction of LDL-C. Their development was predicated on the inverse relationship between HDL-C levels and risk of atherosclerosis and the theoretical possibility that higher HDL-C levels may protect against cardiovascular disease and its complications in humans. Unfortunately, this once promising class of drugs has not produced the anticipated results.  The development of torcetrapib was discontinued due to higher incidence of hypertension and increased mortality observed in the torcetrapib-treated subjects compared to the placebo group [Barter 2007].  This was found to be an off-target effect specific to torcetrapib and not observed with dalcetrapib or anacetrapib [Joy & Hegele 2009].  Despite an adequate safety profile, the development of dalcetrapib was also discontinued in phase 3 due to lack of beneficial effects on cardiovascular outcomes [Schwartz 2012]. The latest CTEP inhibitor to fail in phase 3 due to lack of benefit on cardiovascular outcomes is evacetrapib [see here and here]. The failure of dalcetrapib and evacetrapib raise the question whether plasma HDL-C is a good biomarker of HDL-C functionality or whether other biomarkers of anti-atherogenic properties of HDL-C particles may need to be developed [Kontush 2006; Joy & Hegele 2009, Mohammadpour 2013].  HDL-C may protect against atherosclerosis by promoting reverse cholesterol transport (RCT), and potentially through anti-inflammatory, antioxidative and anti-thrombotic effects [Duffy 2009; Khera 2011]. Therefore, determination of cholesterol efflux capacity may be a better measure of HDL function than plasma HDL-C levels [Khera 2011].  Unless future trials of drugs aimed at raising HDL-C address these issues, the likelihood of reaching the required hard efficacy endpoints will remain elusive. One could also question whether CTEP inhibitors confer any measurable benefits over and above those obtained with statins, and whether the costs of conducting very large clinical trials with this class of drugs can be justified [see commentary in FB].

Currently, anacetrapib remains the only small molecule CETP inhibitor in late phase development.  Judging by the recent news release from Merck, it appears that anacetrapib is well-tolerated and, if further analysis confirms the top down information given by Merck, it is likely that anacetrapib may become the first CETP inhibitor to be approved.  However, longer term observations will be needed to definitively assess the benefits of increasing HDL-C via CETP inhibition on cardiovascular outcomes in the Real-World setting. The medical community is anxiously awaiting the results of REVEAL trial in late August of this year.

Update

The results of the REVEAL study were presented at the  European Society of Cardiology Congress on August 29, 2017 (see Merck press release) and simultaneously published online in the New England Journal of Medicine (see here).  This is the first phase 3 trial of a CETP inhibitor, which has reached its primary endpoint, but the effect size was relatively small and it is still not clear whether the difference can be attributed solely to the rise in HLD-C or to some other effect of anacetrapib that may differentiate it from other CETP inhibitors (see also commentary).  It remains to be seen whether Merck will proceed with submission of the dossier for FDA approval and if approved, the pricing would justify the small additional benefit of anacetrapib on top of intensive statin therapy.

Keywords: atherosclerosis; Cholesteryl ester transfer protein; reverse cholesterol transport;

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New drugs to treat anemia of chronic kidney disease

Anemia is a major complication in patients with CKD, starting in pre-dialysis stages and worsening with worsening renal function and as dialysis is initiated.  It can result in significant morbidity and impact quality of life.  Current treatments include erythropoiesis stimulating agents (ESAs) which were first approved in 1989 with Amgen’s Epogen, which is usually given three times a week iv or sc.  Longer acting versions such as darbepoetin alpha (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera) can be injected once every week to once every 4 weeks [Egrie JC 2003; Locatelli F 2007].  Although very effective in treating anemia, ESAs are not as effective in overcoming anemia associated with inflammation, resulting in EPO hypo-responsiveness in a significant number of patients.  This can lead to the requirements for higher doses to maintain Hb within the current guidelines [see KDOQI and KDIGO], which in turn can increase adverse effects such as hypertension and the risk of thromboembolic events [Adamson JW 2009; Pfeffer MA 2003; Krapf R 2009].

The discovery and characterization of the principal cellular oxygen sensor, hypoxia-inducible factor (HIF) by Gregg Semenza [Wang GL 1995] led to the understanding of how oxygen tension regulates EPO production and a host of other cellular events [ke Q 2006; Haas VH 2013].  Further discovery of the regulation of HIF by prolyl and asparaginyl hydroxylases (PHD and FIH) [Bruick RK 2001; Masson N 2003] led to the development of PHD inhibitors that are poised to become major contenders in the treatment of anemia of CKD and cancer.  This article summarizes the mechanisms by which PHD inhibition and HIF stabilization improves anemia and the development status of the several PHD inhibitors vying for Health Authority approvals in the near future.

Hypoxia-Inducible Factor (HIF) and its Regulation:

Under hypoxic conditions, prolyl hydroxylases (PHDs) are inactive, so HIF is released and binds to hypoxia response elements (HRE) on the effector gene such as EPO and increases transcription and synthesis of EPO, which in turn stimulates red cell production.  Under normoxic conditions, PHD adds hydoxl groups on two proline residues of HIF-1α, which allows it to bind von Hipple Lindau (VHL) tumor suppressor and prime it for ubiquitination, followed by proteasomal degradation.   Inhibition of PHD stabilizes HIF and prevents its degradation, therefore leading to stimulation of erythropoietin gene transcription and EPO synthesis, followed by increased red cell production by the bone marrow.

HIF molecule is composed of α and ß subunits.  HIF-2α is the HIF isoform responsible for regulation of EPO in the kidney (Bernhardt WM 2010). HIF-2α is also the dominant isoform responsible for regulation of iron metabolism genes and also stimulates EPO production (see above).  HIF-1α responds to tissue ischemia and hypoxia to increase angiogenic factors (Muchnik E 2011).  HIF-1α and HIF-1ß isoforms have different specificities to different prolyl hydroxylases (PHDs), enzymes that are responsible for degradation of HIF.  In addition to its role in EPO production, HIF increases intestinal iron absorption via upregulation of duodenal divalent metal transporter 1 (DMT-1), the major iron transporter.  It also downregulates hepcidin expression.  Hepcidin, a peptide hormone that sequesters iron and prevents its absorption and/or release into the circulation, also downregulates DMT-1, so its reduction can further increase intestinal iron transport and absorption [Gupta N 2017].  These effects further complement the effect of PHD inhibition on EPO production.  Accordingly, PHD inhibitor treatment results in the suppression of hepcidin levels and increased iron absorption and availability, so intravenous iron is not needed. When EPO is administered, it is necessary to administer intravenous iron to maintain adequate iron levels and maintain effectiveness. A major cause of EPO unresponsiveness or EPO resistance is “functional iron deficiency”, which is due to unavailability of iron despite adequate iron stores. This appears to be due to high levels of hepcidin, an iron regulatory peptide that can sequester iron and make it unavailable for use in erythropoiesis [Bernhardt WM 2010; Maxwell PH 2016; Gupta N 2017].  Other potential indications for PHD inhibitors:  preclinical studies suggest roles in cytoprotective and neuroprotective actions of PHD inhibitors [Reischl S 2014].

HIF stabilizers as novel therapies for anemia and other conditions:

Several new molecular entities belonging to a novel class of drugs called hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors are currently in Phase 2 to late-stage development by several pharmaceutical and biotech companies.   They include roxadustat, being developed by Fibrogen in collaboration with AstraZeneca, vadadustat, being jointly developed by Akebia, Otsuka and Mitsubishi Tanabe, daprodustat, being developed by GlaxoSmithKline (GSK), and molidustat being developed by Bayer Healthcare.  All four compounds are taken orally but differ slightly in their pharmacokinetic properties.

HIF-PHD inhibitors are attractive molecules for the treatment of anemia of CKD as well as anemia due to other chronic diseases such as cancer and inflammation.  They have the advantage of oral administration and the data published or communicated as news releases show that these drugs can correct anemia relatively rapidly without an increase in blood pressure.  Interestingly, vadadustat was effective not only in anemic patients with ND-CKD, but it also resulted in increased Hb in dialysis patients, including nephric and anephric subjects (Bernhardt WM 2010).  This suggests that the kidney’s ability to produce EPO is suppressed but not destroyed by CKD, and extrarenal erythropoiesis (e.g. in the liver) could be activated.  The increase in Hb after HIF-PHD inhibition is associated with a much lower rise in serum EPO levels, within the range observed in normal individuals, whereas exogenous EPO administration causes a marked increase in serum EPO levels, which may be a contributing factor to some of the adverse events observed when high EPO doses have been administered in an attempt to increase Hb levels toward normal [Levin A 2007; 4 Pfeffer MA 2009].

An additional therapeutic area for PHD inhibitors and one that has become very limited for other ESAs (exogenous EPOs) is anemia of cancer (chemotherapy-induced anemia) and anemia of chronic disease [Nagel S 2010].  The mechanism of action of PHD inhibitors is such that they can overcome the resistance or unresponsiveness to EPO due to the inability of iron to be mobilized from stores.  This class of drugs increases intestinal iron absorption and improves iron mobilization through reduction in hepcidin.  The overall effect is to bypass the functional iron deficiency seen in anemia of chronic disease.  The exogenous EPO levels needed to overcome “EPO unresponsiveness” are in the 100,000 IU range, and have been associated with significant adverse events, including cardiovascular events and mortality, leading to strict label restrictions on their use in chemotherapy-induced anemia in cancer patients [Szczech LA 2008; Rizzo JD 2010].

Based on available data, HIF-PHD inhibitors are generally well-tolerated with adverse events primarily related to the GI tract, including nausea and diarrhea in approximately 4% of treated subjects compared to 2% in placebo [Pergola PE 2016].  Because of theoretical enhancement of tumor growth and promotion of angiogenesis with HIF 1α and 2α overexpression, increased vigilance and continuous monitoring of off-target effects is warranted [Muchnick E 2011].  However, based on the data available to date, increased VEGF levels have not been reported in studies of HIF-PHD inhibitors under development [Gupta N 2017].

Key words: Anemia;  erythropoietin; hypoxia-inducible factor; prolyl hydroxylase; HIF stabilizer; hepcidin

References:

Adamson, John W. “Hyporesponsiveness to erythropoiesis stimulating agents in chronic kidney disease: the many faces of inflammation.” Advances in chronic kidney disease 16.2 (2009): 76-82.

Bernhardt, Wanja M., et al. “Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.” Journal of the American Society of Nephrology 21.12 (2010): 2151-2156.

Bruick, Richard K., and Steven L. McKnight. “A conserved family of prolyl-4-hydroxylases that modify HIF.” Science 294.5545 (2001): 1337-1340.

Egrie, Joan C., et al. “Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin.” Experimental hematology 31.4 (2003): 290-299.

Gupta, Nupur, and Jay B. Wish. “Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD.” American Journal of Kidney Diseases (2017).

Haase, Volker H. “Regulation of erythropoiesis by hypoxia-inducible factors.” Blood reviews 27.1 (2013): 41-53.

Ke, Qingdong, and Max Costa. “Hypoxia-inducible factor-1 (HIF-1).” Molecular pharmacology 70.5 (2006): 1469-1480.

Krapf, Reto, and Henry N. Hulter. “Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA).” Clinical Journal of the American Society of Nephrology 4.2 (2009): 470-480.

Levin, Adeera. “Understanding recent haemoglobin trials in CKD: methods and lesson learned from CREATE and CHOIR.” Nephrology dialysis transplantation 22.2 (2007): 309-312.

Locatelli, Francesco, et al. “Effect of a continuous erythropoietin receptor activator (CERA) on stable haemoglobin in patients with CKD on dialysis: once monthly administration.” Current medical research and opinion 23.5 (2007): 969-979.

Masson, Norma, and Peter J. Ratcliffe. “HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O 2 levels.” Journal of cell science 116.15 (2003): 3041-3049.

Maxwell, Patrick H., and Kai-Uwe Eckardt. “HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond.” Nature Reviews Nephrology 12.3 (2016): 157-168.

Muchnik, Eugene, and Joshua Kaplan. “HIF prolyl hydroxylase inhibitors for anemia.” Expert opinion on investigational drugs 20.5 (2011): 645-656.

Nagel, Simon, et al. “Therapeutic manipulation of the HIF hydroxylases.” Antioxidants & redox signaling 12.4 (2010): 481-501.

Pergola, Pablo E., et al. “Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.” Kidney international 90.5 (2016): 1115-1122.

Pfeffer, Marc A., et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” New England Journal of Medicine 361.21 (2009): 2019-2032.

Reischl, Stefan, et al. “Inhibition of HIF prolyl-4-hydroxylases by FG-4497 reduces brain tissue injury and edema formation during ischemic stroke.” PLoS One 9.1 (2014): e84767.

Rizzo, J. Douglas, et al. “American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.” Journal of Clinical Oncology 28.33 (2010): 4996-5010.

Szczech, Lynda A., et al. “Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes.” Kidney international 74.6 (2008): 791-798.

Wang, Guang L., et al. “Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.” Proceedings of the national academy of sciences 92.12 (1995): 5510-5514

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FDA Endocrinologic and Metabolic Drugs Advisory Committee recommends approval of dapagliflozin for the treatment of type 2 diabetes in adults

Today, the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 10-4 in favor of the updated cardiovascular risk profile of the investigational sodium-glucose co-transporter 2 inhibitor, dapagliflozin. The committee also voted 13-1 in favor of the agent as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (see here).

“We found no evidence of increased CV risk in the pre-specified meta-analysis,” Eugenio Andraca-Carrera, PhD, a mathematical statistician at FDA, said during the meeting.

Dapagliflozin (Bristol-Myers Squibb/AstraZeneca) was denied approval by the FDA in the United States in January 2012. Six months prior, the advisory committee recommended against the approval of the drug at a July 2011 meeting by a 9-6 vote due to concerns of potential breast or bladder cancer risks found in the 11 phase-3 clinical trials (see here).

Recent studies and additional long-term cardiovascular data compared with previously submitted studies were included in the resubmission, according to briefing documents.

Diabetes remains an epidemic with significant morbidity and mortality. Improvements in metabolic parameters are associated with improved outcomes. Numerous treatment options are available but each has its limitations; a need remains for new therapeutic options,” Harold E. Bays, MD, FTOS, FACE, FNLA, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center Inc., said during the meeting.

Dapagliflozin is currently approved for the treatment of type 2 diabetes in the European Union, Australia, Brazil, Mexico and New Zealand.

Sources: Healio Endocrinology; Drugs.com; Business Wire

Commentary:

The renal sodium- glucose cotransporter or SGLT-2 is an interesting target for treatment of diabetes.  Inhibition of this transporter blocks glucose reabsorption and increases urinary glucose excretion.  This leads to lowering of blood glucose levels with a lower risk of hypoglycemia than sulfonylureas (see here).   The loss of glucose is also associated with weight loss, which by itself may improve insulin sensitivity.  The clinical experience to date shows that dapagliflozin is well-tolerated.  There is an increased risk of genital  infections and urinary tract infections (see here).  The previous experience with other antidiabetic drugs, mainly those belonging to thiazolidinedione (TZD) class, has led to a very cautious approach by regulatory agencies and to a recent FDA Guidance FDA Guidance that mandates large cardiovascular outcome studies for new anti-diabetic drugs.  Furthermore, as stated above, the possible increased risk of  bladder and  breast cancer during dapagliflozin trials had led the FDA panel to recommend against approval of this agent in January 2012.  Additional data provided by the sponsors has now convinced the Advisory Committee to recommend for approval of dapagliflozin.  If approved, which is likely, dapagliflozin will be the second SGLT-2 inhibitor to be approved by the US FDA for the treatment of type 2 diabetes.  The first agent from this class, canagliflozin (Invokana, Janssen Pharmaceuticals), was approved by the FDA on March 29, 2013 (see here and here).

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Combined ACE inhibition and angiotensin receptor blockade shows no advantage over single agent RAS inhibition in patients with diabetic nephropathy: VA-Nephron D study

The results of the recently completed VA-Nephron D study were presented at a Late Breaking Abstract Session at the ASN-Kidney Week and simultaneously published in the New England Journal of Medicine.  The study randomized 1448 type 2 diabetic patients half of whom were randomly assigned to losartan (an angiotensin receptor blocker) plus placebo and the other half to receive losartan plus lisinopril (an angiotensin converting enzyme inhibitor).   The mean eGFR was 53.7 ± 16.2 ml/min/1.73 m2 for the ARB + placebo group and 53.6 ± 15.5 ml/min/1.73 m2 for the combined ARB + ACE inhibitor group.   The median urinary albumin to Cr ratio was approximately 500 mg/g for both groups.   At the start of the trial, 2/3rd of the patients were on ACE inhibitor monotherapy, 16-20% on ARB monotherapy, around 6% on combination therapy and 8% on neither ACE nor ARB therapy.   The primary endpoint was the first occurrence of a change in the eGFR, end-stage renal disease, or death.   The study was an event-driven study, and the sample size was expected to be adequate for an expected 5-year cumulative rate of 758 primary end-point events during a minimum of 2 years follow up on treatment [see CJASN design paper].  The safety of the enrolled subjects was monitored every 6 months by a Data and Safety Monitoring Committee (DMC).

In October 2012, the DMC recommended that the treatment be stopped due to safety concerns, namely increased rates of serious adverse events (hyperkalemia and acute kidney injury) in the combination therapy  arm [see NEJM].  There were 152 primary endpoint events in the monotherapy group and 132 in the combination group [HR 0.88, p=0.30].  Further, there was no change in mortality [HR 1.04, p=0.75] or cardiovascular events with combination therapy, while there was an increased risk of hyperkalemia [p<0.001] and AKI [p<0.001] with combination therapy. The authors concluded that [combination therapy with an ACE inhibitor and an ARB is associated with an increased risk of adverse events among patients with diabetic nephropathy].

Commentary:

There is general agreement that both ACE inhibitors and ARBs reduce proteinuria over and above their anti-hypertensive effects, particularly in patients with diabetic nephropathy [see Maschio et al.,  Lewis et al., and Lewis et al; Brenner et al].  It also appears that the anti-proteinuric and renoprotective effects of these drugs are similar [see here and here] and the selection of a particular agent is primarily based on the adverse events profile and convenience.  Similarly, the addition of aliskiren, a direct renin inhibitor to maximal doses of losartan was found to further reduce proteinuria in a study of patients with type 2 diabetes and nephropathy [see here].   In contrast with diabetic patients with macroalbuminuria, a renoprotective effect of RAS blockade in subjects without macroalbuminuria is not certain [see here].  A meta-analysis of 49 studies conducted by Regina Kuntz and colleagues, also suggested that combination of ACEI and ARBs is more effective [see here] than either agent alone.  However, as the authors commented, proteinuria is a surrogate marker and may not be predictive of progression of CKD or end-stage renal disease.  In addition to anti-proteinuric and reno-protective effects, RAS blockade also provides cardio-protection in patients without heart failure and multiple trials have been conducted that confirm this [summarized here].

The encouraging results of these trials led to a large outcome trial of ramipril, an ACE inhibitor, and telmisartan, an ARB called ONTARGET Study, which included 25,620 patients 55 years or older with established atherosclerotic vascular disease or with diabetes and end-organ damage, randomly assigned to ramipril, telmisartan or a combination of both drugs.  Surprisingly, the combination treatment led to worse renal outcomes than monotherapy.   Another trial, (ALITITUDE Trial), used aliskiren, a renin inhibitor, in combination with an ACE inhibitor or an ARB in type 2 diabetic patients with CKD, CVD or both.  As  reported previously in KDDD, this trial was terminated due to increased adverse events.  Now, the VA Nephron D trial has reached a similar outcome, which also includes increased risk of hyperkalemia and acute kidney injury.  HALT-PKD is another trial of combination ACE inhibitors and ARBs in patients with autosomal dominant polycystic kidney disease (ADPKD) that aims to determine whether this regimen will slow the progression of renal disease.  There is in vitro and in vivo animal evidence of overactivity of the intrarenal RAS in ADPKD (see here and here), which may drive the early development of hypertension and also independently contribute to the progression of kidney damage.  The results of HALT-PKD trial are anxiously awaited.

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FDA Advisory Committee recommends against approval of Tolvaptan for polycystic kidney disease

As noted in a previous posting, Tolvaptan, a vasopression type-2 receptor antagonist, currently approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, is also being developed for the treatment of autosomal dominant polycystic kidney disease (ADPKD).  Otsuka pharmaceuticals had sponsored a development program,  including a phase 2 and a recently completed phase 3 (TEMPO 3:4) study in 1445 patients, the results of which were published in New England Journal of Medicine  and summarized in this forum (see here).

On April 12, 2013, the FDA granted priority review for Tolvaptan’s New Drug Application (NDA) (see press release).  On April 30, 2013, following the review of the data from the Tolvaptan TEMPO study in ADPKD, the FDA issued a Drug Safety Communication on possible liver injury with Tolvaptan. The specific warning is as follows: [Samsca treatment should be stopped if the patient develops signs of liver disease. Treatment duration should be limited to 30 days or less, and use should be avoided in patients with underlying liver disease, including cirrhosis. Patients should be aware that Samsca may cause liver problems, including life-threatening liver failure, and should contact their health care professional to discuss any questions or concerns about Samsca].  The company updated the Samsca label to indicate that the drug should be limited to 30 days and that it is no longer indicated in patients with cirrhosis (see here).  As a result of these new findings, which had not been seen in patients treated with Tolvaptan for hyponatremia, the FDA sought the advice of an advisory committee prior to a final decision on possible approval.

On August 5, 2013, the FDA Cardiovascular and Renal Advisory Committee evaluated the data submitted by the sponsor in patients with ADPKD.  The materials submitted (briefing package, FDA summary) are available at the FDA website.  Following review, the Advisory Committee voted 9 to 6 against approval of Tolvaptan for the treatment of ADPKD.  The panel cited excessive dropouts and limited efficacy in slowing progression of renal disease, despite reductions in kidney volume and pain.  The overall risk was assessed to be higher than the benefit observed, despite a high unmet medical need in this patient population.  Additional information can be found here and at Medpage Today.  See also Otsuka press release.

Commentary:

There have been very few drugs approved for the treatment of kidney diseases (see here). Many drugs that appeared to show promise in animal models, have failed to show efficacy in human kidney diseases.  The traditional outcomes such as doubling of serum Cr or time to dialysis require many years in a disease with relatively slow progression such as ADPKD.  The decision to move tolvaptan forward for the treatment of ADPKD was in part due to prior efforts by the renal community with support from NIDDK and the PKD Foundation.  The formation of the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP Consortium), led to longitudinal studies aiming to establish changes in kidney volume as a surrogate endpoint for the clinical studies of ADPKD. Therefore, we must congratulate the sponsor and the investigators for undertaking such a risky clinical development program.  Whatever the final FDA decision, the PKD community has benefited from the acceptance of renal volume as an endpoint in studying progression in ADPKD.  Another important effort in this direction is the recent formation of the PKD Outcomes Consortium Project (PKDOC), which is an ongoing project supported by the PKD Foundation, academic nephrologists, pharmaceutical representatives and the FDA.  I had the privilege of being involved in this effort.

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Overcoming obstacles for successful clinical trials in kidney disease

Introduction

The incidence and prevalence of chronic kidney disease (CKD) has been increasing, led by diabetes (DM) and hypertension (HTN) that are consequences of poor lifestyle and dietary habits (see USRDS 2012). Although effective treatments are available for both DM and HTN, recent observations from two large observational studies, namely Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) have shown that HTN is poorly controlled in CKD patients with only 20-40% of patients meeting the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) criteria for BP control.  The same reports show that, in diabetic patients with CKD, renin-angiotensin system (RAS) blockade with the use of ACE inhibitors and ARBs is vastly under-utilized, with only about 40% of diabetic CKD patients receiving such treatments [Vassalotti et al.], despite evidence that it can slow progression.

Very few drugs have been developed specifically to treat kidney disease.  Below is a list of drugs approved between 2003 and 2013 for CKD or kidney-related diseases or conditions (Reference):

Procysbi (cysteamine bitartrate) for the management of nephropathic cystinosis

Omontys (peginesatide) for anemia in dialysis patients

Soliris (eculizumab) for atypical HUS

Afinitor (everalimus) for kidney transplant rejection

Mircera (methoxy polyethylene glycol epoetin beta) for anemia associated with CKD

Renvela (sevelamer carbonate) for hyperphosphatemia

Fosrenol (lanthanum carbonate) for hyperphosphatemia

Sensipar (cinacalcet) for secondary hyperparathyroidism

Fabrazyme for Fabry’s disease

Most of the approved drugs listed above are for supportive care of CKD patients or for rare orphan diseases involving the kidneys.  Treatments are mainly focused on comorbidities such as diabetes,  hypertension, anemia, hyperlipidemia and disorders of mineral metabolism.  Despite a significant increase in R&D budgets in the past dacade, no new pharmaceutical agent has been approved specifically for the treatment of the underlying causes of AKI or CKD or for different types of glomerulonephritis.  Dialysis and  transplantation, although lifesaving procedures, are not ideal treatments.  They are associated with significant costs and the need for multiple treatments, including immunosuppressive drugs for transplantation.

What are the major gaps that need to be filled?

The current unmet needs in nephrology include: (1) Prevention and treatment of acute kidney injury; (2) Prevention and treatment of renal fibrosis and vasculitis, (3) diabetic nephropathy; (4) Lupus nephritis; (5) IgA nephropathy; (6) Steroid-resistant nephrotic syndrome, particularly focal segmental glomerulosclerosis; (7) MPGN and other types of glomerulonephritis; (8) Chronic transplant nephropathy; (9) Polycystic kidney disease.  Some relevant publications can be found here and here.

Why have so few drugs been developed to specifically target renal diseases?

The are many reasons but the main ones are as follows: (1) Kidney diseases are heterogeneous, comprising genetic/hereditary, metabolic, infectious, immunological and inflammatory diseases; (2) Multiple mechanisms underlie kidney disease progression, so drugs acting on a single target may not be effective; (3) Successful results in animal models of AKI and CKD do not always translate into clinical successes; (4) FDA does not accept surrogate endpoints such as reduction in proteinuria for approval, but is evaluating options. Currently only hard outcomes are acceptable, which requires 2-4 year studies and large numbers of subjects; (5) Nephrologists traditionally have not been organized to conduct large scale clinical trials, but the situation is changing through formation of consortia.

What should be done to accelerate the development and approval of novel drugs for kidney diseases?

A few ideas are presented here but new and fresh ideas are sorely needed:  (1) Better education of academic nephrologists in drug discovery, clinical trials and regulatory issues; (2) Development of a one-year pharmaceutical and clinical trials fellowship track, with certification.  This could be combined with existing trainings in this area from other sub-specialties; (3) Development of courses and symposia organized  by ASN, ISN and NKF on renal drug discovery and clinical trials.  4) Identification of new targets and new pathways of kidney injury and progression; (5) Development and validation of diagnostic and prognostic biomarkers to identify injury early and to be used as surrogate markers for registration trials.  Some of these ideas are already being evaluated.  NIH, in conjunction with the FDA,  academic and pharmaceutical scientists, has organized workshops for evaluation of drug targets and endpoints in both CKD and AKI (see here and here and here).  Next year, there will be an ISN Nexus 2014 symposium entitled “Efficient drug discovery and clinical trials in kidney disease”.  ISN Nexus 2014. Finally, FDA, in collaboration with NIH, academia and pharmaceutical companies, has initiated the Critical Path initiative, tasked at identifying such biomarkers.  C-Path is also working on developing Patient- Reported Outcomes (PROs) measurement instruments for drug development in CKD (see PROs in CKD).  A review of C-Path initiatives and completed projects is available at the C-Path website and in a 2008 review by Drs Janet Woodcock and Raymond Woosley.

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