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.


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).

© Copyright M. Loghman-Adham, MD

Posted in M Loghman-Adham, MD | Leave a comment

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

Source:  Business Wire  June 27, 2017


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.


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;

© Copyright M. Loghman-Adham, MD

Posted in M Loghman-Adham, MD | Leave a comment

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


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

© copyright M Loghman-Adham, MD

Posted in M Loghman-Adham, MD | Leave a comment

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;; Business Wire


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).

Posted in M Loghman-Adham, MD | Leave a comment

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].


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.

Posted in M Loghman-Adham, MD | Leave a comment

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.


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.

Posted in M Loghman-Adham, MD | Leave a comment

Overcoming obstacles for successful clinical trials in kidney disease


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.

© Copyright: M. Loghman-Adham, MD

Posted in M Loghman-Adham, MD | Leave a comment

Saxagliptin (Onglyza) fails to reach primary endpoint in a CV outcome study of type 2 diabetic patients

On June 19, 2013 Bristol-Myers Squibb (BMS) announced top-line results of the phase IV study, named SAVOR-TIMI-53. In this study of adult patients with type 2 diabetes with either a history of established cardiovascular disease or multiple risk factors, Onglyza met the primary safety objective of non-inferiority, and did not meet the primary efficacy objective of superiority, for a composite endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal ischemic stroke, when added to a patient’s current standard of care (with or without other anti-diabetic therapies), as compared to placebo.  The full findings will be presented September 2, 2013 at the European Society of Cardiology (ESC) 2013 Congress in Amsterdam. Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor approved in the US, Canada, Europe, and elsewhere as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Non-randomized analyses had suggested that DPP-4 ihbitors might have a CV-protective effect in diabetic patients [see here].

Saxagliptin was the first new diabetes drug to receive FDA approval after the issuance of new agency guidelines in July 2009, requiring companies to perform CV-outcomes studies with new diabetes drugs [see here]. The drug’s clinical development program had been completed before the guidance, but because of the new rule, the company launched SAVOR-TIMI 53. The four-year-long trial had a target enrollment of 16 500 patients [Source: Heartwire].

Commentary.  Prior to approval of saxagliptin, BMS provided an analysis of the phase 2b/3 data, based on  4607 subjects, 3356 of whom had received saxagliptin [see here].  This retrospective analysis, using the newly issued FDA Guidance, showed no increased risk of major adverse cardiac events (MACE) or other CV events.  The upper limit of 95% CI of hazard ratio of point estimates for FDA-defined MACE or acute CV events remained at or below 1.8 for saxagliptin compared to placebo controls [see presentation here].  This information was subsequently published and the authors suggested that saxagliptin may actually lower CV risk in patients with type 2 DM [see Cobble & Frederich].  Other, non-randomized analyses had raised hopes that this class of drugs might provide protective effect on the vasculature of diabetes patients [see here and here] and also published by [Monami et al.] and by [Frederich et al.]. Based on these encouraging data, the sponsors undertook the large phase 4 study named (SAVOR-TIMI-53], a randomized, double-blind, placebo-controlled trial that involved 16,500 patients in 25 countries with type 2 diabetes who had a history of established cardiovascular disease or multiple risk factors, with or without renal impairment [see].  Failure to show superiority compared to standard of care, does not affect Onglyza‘s ability to remain on the market.  However, it removes the possibility of Bristol-Myers and AstraZeneca to update the label to claim an advantage in reducing CV risks in patients with type 2 diabetes. The inability to differentiate Onglyza from competitors could have financial consequences [see here].  As detailed elsewhere on this website, demonstrating cardiovascular benefit in post-approval studies has been an elusive goal for many drugs, which in non-randomized studies or retrospective analyses had shown such benefits.  Recent examples include the TREAT study, the ALTITUDE study, and the EVOLVE  study.

© Copyright M. Loghman-Adham, MD

Posted in M Loghman-Adham, MD | Leave a comment

Results of Phase 3 clinical trial of ferric citrate (Zerenex) to be presented at the ISN World Congress of Nephrology (WCN)

According to the WCN program (see here), a poster (#SU401) entitled ” Ferric citrate is a novel efficacious phosphate binder” will be presented on June 2nd by Dr. Julia Lewis from Vanderbilt University Medical Center (view abstract) during the Annual Meeting in Hong Kong.   Top-line results of the phase 3 study were announced by Keryx Biopharmaceuticals on January 28, 2013 (see News release).  The study was a multi-center, randomized, open label trial of ferric citrate, a novel non-calcium containing phosphate binder, in 441 dialysis patients (HD and PD).  The study included a 52 week safety assessment whereby the subjects were randomized 2:1 to receive ferric citrate or an active control (either calcium acetate or sevelamer carbonate).  The safety assessment was followed by a one-month efficacy assessment period during which 192 subjects who remained on ferric citrate were randomized 1:1 to either continue on ferric citrate or switch to placebo.  The ferric citrate doses, given as 1 g capsules with meals were titrated during the study to achieve a serum phosphorus concentration between 3.5 and 5.5 mg/dL.  Oral iron was not permitted and intravenous iron was only permitted if serum ferritin was >1000 ng/ml or TSAT was >30%.  Fairly detailed results are available within the Press Release by Keryx Biopharmaceuticals (see News release) .

The primary efficacy endpoint was the change in mean serum phosphorus from week 52 to week 56.  Mean phosphorus levels were 4.9 ± 1.4 and 7.2 ± 1.5 mg/dL for Zerenex and placebo, respectively (p<0.01).  All the secondary endpoints were also met.  Of interest were the effects of ferric citrate on iron metabolism and on hemoglobin levels. The mean change in ferritin from baseline to week 52 was 302 ng/mL for Zerenex, compared to 9 ng/mL for placebo (p<0.0001). There was also a higher mean Hb concentration in the Zerenex group compared to placebo (11.4 ± 1.5 vs 11.1 ± 1.4 g/dL) at week 52.  Most importantly, Zerenex appeared to be safe and well tolerated. Excluding stool discoloration, which is a known effect of iron salts, the gastrointestinal side effects were similar between Zerenex and active control.  Full analysis of these data will be presented at the WCN and we expect that  they will be also published at about the same time (see News release).

According to Keryx, the NDA (New Drug Application) and European MAA (Marketing Authorization Application) is anticipated in the second quarter of 2013. Generally it takes about one year from the NDA submission until approval.

Commentary:  Phosphate retention and  hyperphosphatemia are common consequences of ESRD and lead to multiple complications, which include not only secondary hyperparathyroidism and renal osteodystrophy, but also vascular calcifications and increased mortality, primarily from coronary artery disease complications (see here).  The use of calcium-free phosphate binders such as sevelamer can result in stabilization and even regression of vascular calcifications (see here).  However, to be effective, all currently available phosphate binders require multiple pills that need to be taken with meals.  The large pill burden often results in gastrointestinal side effects and low patient adherence.   Ferric citrate is no exception.  Zerenex doses  are not given in the available Press Release. In the phase 2 study, patients received three 1 g capsules, which were titrated to obtain the desirable serum phosphorus levels (see Yang et al).  Being an iron compound, it is not entirely surprising to see a beneficial effect of Zerenex on iron metabolism and on Hb concentrations.  The overall effect was a reduction in cumulative intravenous iron doses and a reduction in cumulative ESA doses.  A recently published pharmacoeconomic evaluation assessed the potential cost savings from the use of  ferric citrate compared to other phosphate binders (see Mutell et al.).  The authors concluded that the use of ferric citrate  to treat hyperphosphatemia in ESRD patients may help reduce treatment costs.  The study was sponsored by Keryx Biopharmaceuticals.

Based on what is known in the public domain, the overall data package that will be submitted in support of an NDA appears to be very favorable and could lead to the approval of Zerenex for treatment of hyperphosphatemia in ESRD patients on dialysis.  Additional studies are underway to assess its effectiveness in the management of hyperphosphatemia and anemia in CKD patients not on dialysis (see here).

Posted in M Loghman-Adham, MD | Leave a comment

Abbvie announces initiation of the phase 3 registration trial of atrasentan on renal outcomes in patients with diabetic nephropathy

Atrasentan is a selective endothelin A receptor antagonist,  which was found to have cytostatic properties in prostate cancer (reviewed here) .  Due to promising early results, atresantan was initially developed for the treatment of hormone-refractory prostate cancer (see here).  However, a phase 3 trial of atrasentan in non-metastatic HRPC, showed no statistically significant difference in time to progression between atrasentan and placebo (see ASCO abstract and Cancer 2008).  Furthermore, the incidence of peripheral edema, nasal congestion, headache, dyspnea, and heart failure was greater with atrasentan than with placebo (Cancer 2008).  However, the dose used in oncology trials was 10 mg/day compared to 0.75 mg/day for the planned phase 3 study in diabetic nephropathy (see below).  In September 2005, the Oncology Drug Advisory Committee (ODAC) of the FDA recommended against approval of atrasentan (assigned the brand name Xinlay at the time) (see here).  Another study of atrasentan added to standard chemotherapy in advanced prostate cancer also failed to show any benefit and was terminated by the DSMB for futility (see here and here).  Due to these unfavorable results, Abbott changed its focus to the use of atrasentan in the treatment of diabetic nephropathy.

In a recently completed dose ranging phase 2 study in 89 subjects with diabetic nephropathy (eGFR >20 mL/min/1.73 m2; UACR 100 to 3000 mg/g),  atresantan at doses of 0.75 or 1.75 mg/day resulted in significant reduction in UACR (see JASN article).   Following the positive outcome of the phase 2 trial (see here), Abbvie has initiated a pivotal phase 3 trial of atrasentan in patients with diabetic nephropathy (see News release from Abbvie).  If successful in reaching  the pre-defined endpoints, this study will form the basis of a New Drug Application (NDA) submission to the FDA.  The phase 3 clinical trial, called  SONAR (Study Of Diabetic Nephropathy with Atrasentan)  is a large, multinational, double-blind, placebo-controlled clinical study that is expected to enroll more than 4,000 patients with diabetic nephropathy.   The inclusion criteria include estimated GFR (eGFR) of 25 to 75 mL/min/1.73 m2 (CKD stage 2 to 4), UACR >300 and <5,000 mg/g, and systolic blood pressure within 110 and 160 mgHg (see Abbvie News release).  Based on the phase 2 study, the dose for this trial will be 0.75 mg per day.

The primary endpoint will evaluate the effect of atrasentan on time to doubling of serum creatinine or the onset of ESRD, as defined by need for chronic dialysis, transplant or death due to renal failure. Secondary endpoints will assess the effects of atrasentan on urine albumin excretion, eGFR and cardiovascular events including cardiovascular death, heart attack and stroke.  Quality of life evaluations also will be conducted.  More detailed information about the trial is available at (Abbvie News release).

Commentary:  Very few drugs have been successful in slowing the progression of renal disease.  Currently, only ACE inhibitors and ARBs are approved for this indication.  Bardoxolone methyl, co-developed by Reata Pharmaceuticals and Abbott (now Abbvie) had shown promise in a phase 2 trial in patients with diabetic nephropathy, but its phase 3 trial had to be halted due to excess mortality in the bardoxolone arm (see KDDD posting and Reata news release).  studies aimed at slowing progression of kidney disease in patients with diabetic nephropathy or other types of chronic kidney disease are expensive, requiring large numbers of patients and long treatment durations.  Unfortunately, no surrogate endpoints exist to predict the clinically relevant outcomes (need for dialysis or death), so currently only composite hard endpoints, including doubling of serum Cr or a significant (usually >25%) decrease in eGFR, combined with time to dialysis or death are used in clinical trials.  Changes in proteinuria or albuminuria are not acceptable as endpoints for registration purposes but are often included either as part of the composite endpoint or as secondary endpoints.

Another issue in performing  phase 3 trials in CKD is the need to include patients who show a decline in eGFR,  ascertained either from historical values or during a run-in period.  Inclusion of patients with early stages of CKD (e.g. stage 2) in a trial aimed at slowing the rate of CKD progression will require very long (4 or 5 years) treatment and observation and large numbers of patients, in order to see a statistically significant change in eGFR.  Patients at more advanced stage of CKD (e.g. stage 4) will progress more rapidly and require a shorter treatment and observation period, but in late stages, glomerulosclerosis, interstitial fibrosis, and other “irreversible” changes have already occurred, making it unlikely that the treatment will be effective.  So, selecting patients for such trials is a very difficult task indeed.  Some of these issues  and proposed solutions have been discussed in a recent review by Formentini et al. that was published in NDT.

Until a validated surrogate endpoint, able to predict long-term outcomes in CKD patients has been identified, clinical trials aimed at assessing progression to ESRD will require long observation periods and thousands of patients to have a chance to be successful.

Posted in M Loghman-Adham, MD | Leave a comment