- The FDA has approved esketamine nasal spray, Spravato (Janssen Pharmaceuticals), for treatment-resistant depression.
Why this matters
- Approval fills a gap for this patient population, the FDA said in a statement.
- Indication is for adults with depression for whom ≥2 other antidepressant medications have failed.
- It is to be taken with an oral antidepressant.
- A black box warning accompanies approval because of serious adverse event risk, including for sedation, abuse, and suicidal thoughts and behaviors.
- The spray is also subject to restricted distribution under a Risk Evaluation and Mitigation Strategy (REMS):
- REMS requirements include patient commitment not to drive or use heavy machinery on the day of administration.
- Health care providers are to monitor patients for 2 hours after self-administration of the spray, which cannot be taken home.
- Supporting evidence:
- Short-term placebo-controlled trial: effect was detected within 2 days in some cases.
- Results of 2 other short-term trials did not meet threshold for statistical effect.
- Long-term trial suggested stable remission or response, latency to relapse with treatment.
- Side-effects include dissociation, dizziness, increased BP, feeling inebriated.
- Spray is contraindicated in pregnancy and with breastfeeding and may increase risk for vascular events in patients with existing disease.
- The FDA has approved a subcutaneous formulation of trastuzumab that strikingly reduces administration time in human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
- Subcutaneous trastuzumab consists of trastuzumab plus hyaluronidase, an enzyme used to hasten absorption. Administration takes 2-5 minutes, according to an FDA news release, instead of 30-90 minutes with intravenous (IV) trastuzumab, according to a Genentech news release.
Why this matters
- Subcutaneous trastuzumab is a new, more efficient treatment option.
- Prescribing information is here.
- Subcutaneous trastuzumab carries the same indications as the IV formulation for adjuvant treatment of HER2+ breast cancer and metastatic breast cancer, but is not indicated for metastatic gastric cancer.
- The recommended dose is 600 mg trastuzumab and 10,000 units hyaluronidase once every 3 weeks.
- Approval of subcutaneous trastuzumab was based on 2 trials, HannaH and SafeHER.
- HannaH (N=596) showed noninferior pharmacokinetics and pathologic complete response with subcutaneous vs IV trastuzumab.
- SafeHER (N=1864) was a nonrandomized trial assessing safety of a 600-mg fixed dose of subcutaneous trastuzumab. The most frequent adverse events (in ≥10% of patients) included fatigue, arthralgia, diarrhea, and injection site reaction, according to the FDA news release.
IMPORTANT: Medications containing only amlodipine or hydrochlorothiazide (HCTZ) are not being recalled. Manufacturers are recalling medications containing amlodipine in combination with valsartan or losartan, and medications containing hydrochlorothiazide HCTZ in combination with valsartan or losartan.
Torrent again expands its voluntary recall of losartan; Hetero also voluntarily recalls losartan
Update [3/1/2019] Torrent Pharmaceuticals Limited is further expanding its voluntary recall to include 114 additional lots of losartan potassium and losartan potassium/hydrochlorothiazide combination tablets. This recall is due to unacceptable amounts of N-Methylnitrosobutyric acid (NMBA) in the losartan active pharmaceutical ingredient manufactured by Hetero Labs Limited.
Today, the agency also issued a press release to provide additional information about its ongoing investigation and another voluntary recall by Hetero/Camber Pharmaceuticals, which was announced on February 28, of 87 lots of losartan potassium tablets (25 mg, 50 mg and 100 mg). The recalled losartan potassium and losartan potassium/hydrochlorothiazide tablets are also manufactured by Hetero, which are distributed by Camber, and contain the impurity NMBA.
Torrent and Hetero/Camber are only recalling lots of losartan-containing medication with NMBA above the interim acceptable intake limits of 0.96 parts per million (ppm).
The agency also updated the list of losartan products under recall.
Aurobindo expands its voluntary recall of valsartan and amlodipine/valsartan
Update [3/1/2019] AurobindoPharma USA is expanding its voluntary recall to include 38 additional lots of valsartan and amlodipine/valsartan combination tablets. The recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) found in the medicine.
Aurobindo is only recalling lots of valsartan-containing medication where NDEA has been detected above the interim acceptable intake limit of 0.083 parts per million. FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin II receptor blockers (ARBs).
The agency also updated the valsartan products under recall.
FDA updates table of interim limits for nitrosamine impurities in ARBs
Update [2/28/2019] FDA is posting the updated table of interim acceptable intake limits for nitrosamine impurities to reflect N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) limits, which are the same as those for NDMA.
The agency will use the interim limits below to recommend manufacturers conduct a voluntary recall if laboratory testing confirms the presence of nitrosamine impurities in finished drug product. FDA is working with industry and international regulators to ensure products entering the market do not contain these impurities, but we are tolerating the impurities below the level established in the table for a short period of time to avoid a possible shortage of ARBs.
Not all ARB products contain NDMA, NDEA or NMBA impurities, so pharmacists may be able to provide an alternative medication not affected by the recalls, or health care professionals may prescribe a different medication that treats the same condition.
|Drug||Maximum Daily Dose (mg/day)||Acceptable Intake NDMA (ng/day)*||Acceptable Intake NDMA (ppm)**||Acceptable Intake NDEA (ng/day)*||Acceptable Intake NDEA (ppm)**||Acceptable Intake NMBA (ng/day)*||Acceptable Intake NMBA (ppm)**|
* The acceptable intake is a daily exposure to a compound such as NDMA, NDEA, or NMBA that approximates a 1:100,000 cancer risk after 70 years exposure
** These values are based on a drug’s maximum daily dose as reflected in the drug label
Losartan distributed by Macleods Pharmaceuticals voluntarily recalled
Update [2/25/2019] FDA is alerting patients and health care professionals to a voluntary recall of one lot of losartan potassium/hydrochlorothiazide (HCTZ) 100mg/25mg combination tablets manufactured by Macleods Pharmaceuticals. The recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) found in the medicine made with active pharmaceutical ingredient manufactured by Hetero Labs Limited.
Macleods is only recalling lots of losartan-containing medication where NDEA has been detected above the interim acceptable intake limit of 0.27 parts per million. FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin II receptor blockers (ARBs).
The agency also updated the list of losartan products under recall.
Torrent further expands its voluntary recall of losartan
Update [1/23/2019] Torrent Pharmaceuticals is further expanding its voluntary recall to include six additional lots of losartan potassium and hydrochlorothiazide combination tablets, for a total of 16 lots of losartan-containing medicines. This recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient manufactured by Hetero Labs Limited.
Torrent is only recalling lots of losartan-containing medication containing NDEA above the interim acceptable intake limits of 0.27 parts per million (ppm).
The agency also updated the list of losartan medications under recall.
Irbesartan distributed by Solco Healthcare voluntarily recalled
Update [1/18/2019] FDA is alerting patients and health care professionals to a voluntary recall of one lot of irbesartan and seven lots of irbesartan and hydrochlorothiazide (HCTZ) combination tablets distributed by Solco Healthcare LLC, a Prinston Pharmaceutical Inc. subsidiary. The recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) in the irbesartan active pharmaceutical ingredient manufactured by Zhejiang Huahai Pharmaceuticals (ZHP).
Solco is only recalling lots of irbesartan-containing medication where NDEA has been detected above the interim limit of 0.088 parts per million. FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin receptor II blockers (ARBs).
The agency also updated the list of irbesartan products under recall.
Torrent expands its voluntary recall of losartan
Update [1/3/2019] Torrent Pharmaceuticals is expanding its voluntary recall to include eight additional lots of losartan potassium tablets, for a total of 10 lots. This recall is due to trace amounts of N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited.
Torrent is only recalling lots of losartan medication containing NDEA above the interim acceptable intake level of 0.27 parts per million.
The agency also updated the list of losartan medications under recall.
FDA alerts patients and health care professionals to Aurobindo’s recall of valsartan medication due to NDEA
Update [1/2/2019] FDA is alerting patients and health care professionals to Aurobindo Pharma USA’s voluntary recall of two lots of valsartan tablets, 26 lots of amlodipine and valsartan combination tablets, and 52 lots of valsartan and hydrochlorothiazide (HCTZ) combination tablets due to the amount of N-Nitrosodiethylamine (NDEA) in the valsartan active pharmaceutical ingredient. Aurobindo is recalling amlodipine and HCTZ only in combination medications containing valsartan. Neither amlodipine nor HCTZ is currently under recall by itself.
Aurobindo is recalling lots of valsartan-containing medication that tested positive for NDEA above the interim acceptable daily intake level of 0.083 parts per million.
The agency continues to investigate and test all angiotensin II receptor blockers (ARBs) for the presence of NDEA and N-Nitrosodimethylamine (NDMA) and is taking swift action when it identifies these impurities that are above interim acceptable daily intake levels.
FDA reminds patients taking any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition. Some ARBs contain no NDMA or NDEA.
FDA alerts patients and health care professionals to Torrent’s recall of losartan medication due to NDEA
Update [12/20/2018] FDA is alerting patients and health care professionals to Torrent Pharmaceuticals’
voluntary recall of two lots of losartan potassium 100 mg tablets due to N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited.
Not all Torrent losartan-containing medications distributed in the U.S. are being recalled. Torrent is recalling only those lots of losartan medication that tested positive for NDEA above the acceptable daily intake of 0.27 ppm.
The agency continues to investigate and test all angiotensin II receptor blockers (ARBs) for the presence of NDEA and N-Nitrosodimethylamine (NDMA) and is taking swift action when it identifies these impurities that are above acceptable daily intake levels.
FDA posted a list of losartan medications under recall. Additionally, FDA reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDMA or NDEA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.
FDA presents interim limits of nitrosamines in currently marketed ARBs
Update [12/19/2018] FDA is publishing interim acceptable intake levels of nitrosamine impurities in angiotensin II receptor blockers (ARBs) for manufacturers to use to ensure their finished drug products are safe for patients.
The agency evaluated safety data for N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) to determine an interim acceptable intake level for these impurities in the ARB class. NDMA and NDEA are probable human carcinogens and should not be present in drug products. We are currently aware of NDMA and NDEA in certain valsartan, irbesartan and losartan-containing products, and those products and some active pharmaceutical ingredients (API) used to manufacture them have been recalled from the U.S. market. See the list of valsartan products under recall and the list of irbesartan products under recall.
Drug products that contain NDMA or NDEA above the limits in the table below pose an unacceptable risk to patients. The agency will use the interim limits to recommend manufacturers conduct a voluntary recall if laboratory testing confirms the presence of nitrosamine impurities in finished drug product. FDA is working with industry and international regulators to ensure products entering the market do not contain these impurities, but we are tolerating the impurities below the level established in the table for a short period of time to avoid a possible shortage of ARBs.
The agency reminds manufacturers they are responsible for developing and using suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects a new impurity or higher level of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients. To aid industry and regulatory agencies, FDA has developed and published methods to detect NDMA and NDEA impurities – the gas chromatography/mass spectrometry (GC/MS) headspace method, the combined GC/MS headspace method, and the combined GC/MS direct injection method. These methods can be used for drug substances and products, and users should validate them as part of good manufacturing practices and where data are used to support a regulatory submission or required quality assessment of the API or drug product.
Not all ARB products contain NDMA or NDEA impurities, so pharmacists may be able to provide an alternative medication not affected by the recalls, or health care professionals may prescribe a different medication that treats the same condition.
|Drug||Maximum Daily Dose (mg/day)||Acceptable Intake NDMA (ng/day)*||Acceptable Intake NDMA (ppm)**||Acceptable Intake NDEA (ng/day)*||Acceptable Intake NDEA (ppm)**|
* The acceptable intake is a daily exposure to a compound such as NDMA or NDEA that results in a 1:100,000 cancer
risk after 70 years exposure
** These values are based on a drug’s maximum daily dose as reflected in the drug label
The U.S. Food and Drug Administration is updating the public on the agency’s ongoing investigation surrounding the recent voluntary recalls of multiple generic angiotensin II receptor blocker (ARB) drug products used to treat high blood pressure and heart failure. Hetero Labs Ltd. in India has announced a recall of 87 lots of losartan potassium tablets (25 mg, 50 mg and 100 mg). The recalled losartan potassium tablets made by Hetero Labs and distributed by Camber Pharmaceuticals contain the impurity, N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). The impurity is a known animal and potential human carcinogen. This is the first ARB recall resulting from the presence of NMBA, which is the third type of nitrosamine impurity detected in ARB medicines.
Recent testing of these recalled lots of losartan potassium tablets showed NMBA levels higher than the FDA’s interim acceptable intake limits. The FDA’s evaluation suggests that the nitrosamines found in ARBs may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s API, and may also result from the reuse of materials, such as solvents.
“We are deeply concerned about the presence of a third nitrosamine impurity in certain ARB medications, but it’s important to underscore that, based on the FDA’s initial evaluation, the increased risk of cancer to patients with NMBA exposure appears to be the same for NDMA exposure but less than the risk from NDEA exposure. That said, any presence of such impurities in drug products is not acceptable. Over the past few months, the FDA has conducted a major investigation and has worked with drug companies to address the presence of impurities in these products,” said FDA Commissioner Scott Gottlieb, M.D. “Our ongoing effort has determined that the impurities may be generated by specific chemical reactions in the manufacturing process of the drug’s active pharmaceutical ingredients. FDA scientists have developed novel and sophisticated testing methods specifically designed to detect and measure N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) impurities in ARB medicines. Because of the potential for discovering other nitrosamine impurities, we are conducting an extensive organic chemistry analysis to develop novel testing methods to detect additional nitrosamine impurities, including NMBA. We’re continuing to share these testing methods with international regulators, industry and the public to help manufacturers and other regulators evaluate these products for any potential nitrosamine impurity. We are making important strides at understanding how these impurities form and we are continuing to examine if nitrosamine impurities may also arise during the manufacture of other ARB drug products. The FDA is committed to implementing measures to prevent the formation of these impurities during drug manufacturing processes in the future.”
Hetero Labs identified NMBA in lots of losartan potassium during recent testing. NMBA has not been found in previously recalled ARB products; however, the FDA is continuing its investigation. Previously, two other nitrosamine impurities, NDMA and NDEA, were found in drug products containing the active pharmaceutical ingredients valsartan, losartan and irbesartan and those products containing nitrosamines above the interim acceptable limits were recalled.
Recent FDA analyses of NDMA and NDEA in recalled valsartan found that overall, the risk to individual patients is very low, although this doesn’t diminish the significance of this issue or the FDA’s concerns. The agency continues to evaluate the risks nitrosamines pose to patients. The FDA and drug manufacturers continue to test all ARBs for nitrosamine impurities. If NDEA, NDMA, NMBA, or other nitrosamine impurities are found in products at levels above the interim acceptable intake limits, the FDA will work with companies to swiftly remove affected products from the market.
The FDA will continue to update the list of products included in the recall as more information becomes available from ongoing testing. If patients take an ARB drug product, they should check the list periodically, as information may change.
The FDA reminds patients taking an ARB medication from a recalled lot to continue taking their medicine until their doctor or pharmacist provides a replacement or a different treatment option. Any patient taking an ARB from a recalled lot who has not yet spoken to their pharmacist or doctor should do so promptly. Not all ARBs contain nitrosamine impurities.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
Among abiraterone-treated patients, increased mortality ranged from 21.4% for those with ischemic heart disease to 25.6% for those with acute myocardial infarction (MI), compared with 15.8% for those without a heart condition, reported Grace Lu-Yao, PhD, MPH, of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.
“Our data show that patients with existing cardiovascular conditions experience significantly higher 6-month mortality than those without CVD,” Lu-Yao said during a media briefing ahead of the American Association for Cancer Research (AACR) meeting, to be held here March 29-April 3.
Of the 2,845 patients in the study, 67.6% had a pre-existing heart condition (n=1,924). Patients with atrial fibrillation, congestive heart failure, and stroke had increased mortality risks of 24.4%, 23.4%, and 22.1%, respectively, within these first 6 months.
“Typically clinical trials do exclude people who have significant medical problems,” said AACR President Elizabeth Jaffee, MD, of Johns Hopkins Medicine in Baltimore. “I think this has been rationalized as a safety measure by both investigators and sponsors.”
In her presentation, Lu-Yao highlighted that roughly 40% of prostate cancer patients have uncontrolled hypertension. These patients, plus those with a history of major heart conditions, are usually excluded from clinical trials. In the STAMPEDE study, for instance, exclusion criteria included those with a history of severe angina or heart failure, and those with a recent MI.
Jaffe noted that testing new agents in the healthiest patients does not provide the real-world data physicians need.
The researchers used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data to look at prostate cancer patients treated with abiraterone from 2011 to 2014.
The study also found an increased risk of hospitalizations by examining hospital use in the 6 months before and after starting abiraterone treatment. Risk of hospitalization was increased for patients without a history of CVD for incidence rate ratios (IRR) 1.43 (95% CI 1.30-1.57), as well as for those with pre-existing CVD:
- Acute MI: IRR 1.44 (95% CI 1.12-1.86)
- Congestive heart failure: IRR 1.35 (95% CI 1.21-1.51)
- Stroke: IRR 1.30 (95% CI 1.07-1.57)
- Atrial fibrillation: IRR 1.27 (95% CI 1.09-1.48)
- Ischemic heart disease: IRR 1.22 (95% CI 1.01-1.48)
The study captured the period from when abiraterone was first approved by the FDA in 2011 for use in late-stage castration-resistant prostate cancer after prior treatment with docetaxel, and when it was then expanded in 2012 to also include use before chemotherapy. In the study, roughly 20% of the patients had received prior chemotherapy (n=586), with the rest being chemotherapy naive. Lu-Yao said that regardless of prior chemotherapy use, the patterns for both early mortality and hospitalization were “quite similar.”
Jaffee noted that while the study is retrospective, it still provides important data, similar to that of a phase IV study.
“Once a drug’s approved, all physicians can administer these drugs, and we don’t really have a handle on who may have worse side effects from these drugs,” she said. “We know that all therapies have side effects, and we need to be able to predict early, screen early, so we can at least monitor for these side effects and intervene at an early stage before patients have severe consequences from these drugs.”
Study limitations included the possibility of misclassification of patients’ CVD, the fact that treatment efficacy could not be assessed, and that there was no control group to look at expected survival for this patient population. A lack of clinical data also meant that the researchers could not compare the study population against the pivotal trials of abiraterone acetate.
If you aren’t taking statins, there is a good chance you know several people who do. After all, a quarter of the American population over the age of 45 takes one daily. Given their widespread use, you would think they are incredibly effective and safe, but nothing could be further from the truth – and some doctors are speaking out about the dangers.
When a respected heart surgeon like Dr. Dwight Lundell, who is the retired Chief of Surgery and Chief of Staff at Arizona’s Banner Heart Hospital, voices his concerns about statins, everyone should take notice. With 25 years of experience and more than 5,000 open heart surgeries under his belt, the doctor recently confessed that he, like many other physicians, has been getting it wrong when it comes to statins.
Dr. Lundell said that statins are no longer working, and the recommendations to take such medications and severely restrict fat intake are “no longer scientifically or morally defensible.”
As you might expect, his comments were not welcomed by the medical industry. Statins are huge money-makers in a population that is rife with obesity, poor eating habits and heart health concerns. Costing anywhere from $53 to $600 per month, drugs like Lipitor have racked up lifetime sales of $125 billion, while Crestor, 2013’s top-selling statin, generated $5.2 billion of revenue that year alone. With more people taking these drugs than ever, why are heart disease-related deaths still rising?
Lundell says that it’s time for a paradigm shift in how heart disease is treated now that we know its true cause is arterial wall inflammation. He said that foods full of sugars and simple carbohydrates, along with processed foods with omega-6 oils, “have slowly been poisoning everyone” and our bodies react to such “foreign invaders” with inflammation in the walls of arteries. If this inflammation is the cause of heart disease rather than high cholesterol, of course, there is no need for cholesterol-lowering statins. The inflammation, he says, causes the cholesterol to accumulate in blood vessel walls, so it’s the inflammation that we need to target.
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Those whose livelihoods depend on statin profits won’t be too thrilled with his advice: “By eliminating inflammatory foods and adding essential nutrients from fresh unprocessed food, you will reverse years of damage in your arteries and throughout your body from consuming the typical American diet.”
They’d much rather have people continuing to bark up the wrong tree, avoiding beneficial fats in favor of the very processed foods that create high cholesterol in the first place so they can convince you that you need their medications to bring it back down – medications that cause a slew of other health problems that will only drive you to need even more pills as the profits pile up.
For example, statins have been shown in studies to double your chances of developing diabetes and raise your risk of suffering serious diabetic complications, and they’ve also been linked to obesity.
Try a natural approach to heart health
So what should you do if you want to enhance your heart health? Increasing your physical activity, regardless of your current level, can make an impact, whether you’re completely sedentary and decide to start taking an evening stroll a few times a week or you already lift weights and choose to increase your reps.
Avoiding the foods Dr. Lundell identified as dangerous for heart health is another step that can make a big difference, so say goodbye to simple sugars and carbohydrates like refined sugar, white bread, and cookies, along with processed food.
While statins aren’t nearly as effective or safe as those who sell them would like you to believe, there are some very simple and affordable ways to keep your heart healthy without any negative side effects.
Astonishing results from a small, well-designed study may have far-reaching implications.
Though ondansetron is viewed by many as the first-line agent for nausea in the emergency department (ED), there is evidence it doesn’t work in noncancer patients (NEJM JW Emerg Med Aug 2014 and Ann Emerg Med 2014; 64:526). An alternative agent, inhaled isopropyl alcohol, has shown promise (NEJM JW Emerg Med Feb 2016 and Ann Emerg Med 2016; 68:1).
In the current trial, 120 adult ED patients with nausea or vomiting who did not require intravenous access were randomized to inhaled isopropyl alcohol plus 4 mg oral ondansetron; inhaled isopropyl alcohol plus oral placebo; or inhaled saline plus 4 mg oral ondansetron. Isopropyl alcohol was provided in the form of a standard alcohol swab. Patients received a single dose of the oral intervention but could sniff alcohol or saline swabs repeatedly. Nausea was measured on a 100-mm visual analog scale at baseline and 30 minutes.
Mean nausea scores decreased by 30 mm in the alcohol/ondansetron group, 32 mm in the alcohol/placebo group, and 9 mm in the saline/ondansetron group. Rescue antiemetic therapy was given to 28%, 25%, and 45% of each group, respectively. Differences between alcohol and saline groups were statistically significant. Patients in the inhaled alcohol groups also had better nausea control at the time of discharge and reported higher satisfaction with nausea treatment. No adverse events occurred. The mechanism of action is currently unknown.
It is uncommon for us to assign a rating of “Practice Changing” to a small, single-center study, but these results are truly remarkable and are consistent with prior research. For patients not obviously requiring IV therapy, we should treat nausea with repeated inhalations from an isopropyl alcohol swab instead of administering any other drug. And, although this study provides no direct evidence of benefit to patients who do require IV therapy, there would seem to be little downside to trying this simple and safe intervention in that group, too.
Although numerous drugs for nonalcoholic steatohepatitis (NASH) have shown positive results in phase 2 clinical trials, the cure might lie in combinations of drugs with different mechanisms, experts say.
In fact, curing NASH might turn out to be as challenging as curing type 2 diabetes, said Sidney Barritt IV, MD, from the University of North Carolina at Chapel Hill.
Unlike hepatitis C, which can be treated with the blockbuster antiviral drugs that have recently proven so effective, NASH is more complicated because there are no effective drugs to treat it.
With the obesity epidemic, NASH is increasingly common, and results from phase 2 trials attracted throngs of conference-goers with questions here at The Liver Meeting 2018.
Some of the results look encouraging, Barritt told Medscape Medical News. “I think they’re clinically significant.”
Phase 2 results have been positive for MGL-3196 (Madrigal Pharmaceuticals), GS-9674 (Gilead Sciences), NGM282 (NGM Bio), arachidyl amido cholanoic acid (Aramchol, Galmed Pharmaceuticals), tropifexor (Novartis), and VK2809 (Viking Therapeutics).
All the drugs reduced liver fat measured with MRI-derived proton density fat fraction (PDFF). The drugs also improved various other measures of the disease, such as NASH Activity Score, fibrosis, and alanine aminotransferase.
These NASH agents add to the four already in phase 3 trials: obeticholic acid (Ocaliva, Intercept Pharmaceuticals), elafibranor (Genfit), selonsertib (Gilead), and cenicriviroc (Tobira Therapeutics).
But no clear winner has emerged from these studies. It’s hard to know how well the biomarkers measured in trials will protect patients from sickness and death, Barritt explained. NASH destroys the liver gradually; most of its victims die from the heart disease or cancer that results from this damage, which takes decades.
“The real test is going to be real-world efficacy,” he said. “Are the drugs going to have the impact that we expect them to have based on the clinical trial data?”
The development of NASH is mostly related to lifestyle factors, such as overeating and lack of exercise, so there is no obvious target for a drug as there is with a virus. As a result, drug makers have focused on various aspects of inflammation, fat accumulation, and scar formation.
Like obeticholic acid, GS-9674 and tropifexor are farnesoid X receptor (FXR) agonists, which help regulate bile acids, carbohydrate and lipid metabolism, and insulin sensitivity. They also play a role in growth and regeneration after liver injury.
MGL-3196 and VK2809 are thyroid hormone-receptor beta agonists designed to mediate the effects of the thyroid hormone on the liver, on low-density-lipoprotein cholesterol, on triglycerides, on fatty liver, and on insulin sensitivity.
Arachidyl amido cholanoic acid inhibits stearoyl CoA desaturase. It has a “dual mode of action on liver fibrosis, downregulation of steatosis, and a direct effect on hepatic stellate cells, the human collagen-producing cells,” according to Galmed Pharmaceuticals.
The potential for all these approaches was evident in the phase 2 results presented. But the most effective treatments might be a combination of drugs that act on different pathways, said Keyur Patel, BM, from Duke University in Durham, North Carolina, who is a GS-9674 investigator.
In a separate phase 2 trial now underway, Gilead is testing the combination of GS-9674 plus selonsertib, a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), plus GS-9676, an acetyl-CoA carboxylase inhibitor, Patel told Medscape Medical News.
A Strong Placebo Effect
Combining the drugs makes sense because the drugs now in phase 3 trials have not shown the potential to cure NASH on their own, according to Jerry Colca, PhD, chief scientific officer of Cirius Therapeutics in Kalamazoo, Michigan. “They have shown minimal effects in phase 2b,” he said.
One of the challenges that researchers have is the strong placebo effect, Colca told Medscape Medical News. Patients in placebo groups typically diet and exercise, which addresses the underlying cause of NASH, and drugs don’t always show much improvement over that.
Cirius is currently conducting a phase 2b study of MSDC-0602K, an insulin sensitizer “designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition,” the company reports.
The effect of MSDC-0602K on NASH might be broader than that of competing drugs because it acts further upstream, Colca noted.
In the phase 2 studies presented, the drugs appear to be well tolerated, although some adverse events, such as pruritus and diarrhea, were reported.
Many of the questions about these drugs might not be addressed until they are already on the market.
“What we don’t know from these trials is what the expected duration of therapy will be,” Barritt said. “Are they drugs for 1 to 3 years to reset the clock while the patient addresses diet and exercise? Or are they going to be lifetime medications?”
A simulation analysis funded by Sandoz Inc is projecting cost savings or more than $40 million if their biosimilar filgrastim, known as filgrastim-sdnz (Zarxio), is used instead of the reference drug (Neupogen, Amgen) for the prevention and treatment of febrile neutropenia in breast cancer patients who are Medicare beneficiaries.
A poster of the new analysis was presented earlier this month during the San Antonio Breast Cancer Symposium (SABCS) 2018.
However, the authors of an unrelated “real-world” simulation study of the use of biosimilars for the same indication say that to date, cost savings have been “modest,” in part because of similar pricing.
This second study, from a private healthcare analytics group, was published online November 3 in JAMA Oncology.
In the first study, lead author Gary Puckrein, PhD, National Minority Quality Forum, Washington, DC, and colleagues carried out a simulation to estimate the potential out-of-pocket cost savings for Medicare patients with breast cancer who undergo treatment with filgrastim-sdnz instead of reference filgrastim.
The researchers also estimated potential savings to Medicare on payments for the administration of the same biosimilar rather than the reference drug for the treatment or prophylaxis of febrile neutropenia in beneficiaries with breast cancer.
The average out-of-pocket cost for patients and any reduction in Medicare payments per claim were then calculated for patients who received filgrastim-sdnz instead of brand-name filgrastim.
This was then extrapolated to simulate 1 million claims from 100,000 Medicare patients at an estimated 10 claims per patient.
The average cost savings per claim for each patient treated with filgrastim-sndz instead of reference filgrastim was $9.51, the researchers report.
Extrapolated to 100,000 beneficiaries — or 1 million claims — the simulation model estimated that Medicare beneficiaries would save approximately $9.6 million if they were treated with filgrastim-sndz. Medicare would see a reduction in payments of $32.9 million if the same strategy were adopted.
“It is important to understand that this is a simulation model, so further analyses of real-world patient cases are needed to more thoroughly understand the appropriate patients who should receive a filgrastim biosimilar, as well as dosing needs,” Carlos Sattler, MD, vice-president of clinical development and medical affairs at Sandoz, North America, told Medscape Medical News in an email.
“But the main message emanating from this study is that Medicare patients who were prescribed biosimilar filgrastim saved about $9.60 per claim relative to those who were prescribed reference filgrastim, and this underscores the potential value of biosimilars in saving money for patients,” he added.
More filgrastim-sndz is prescribed now in the United States than reference filgrastim, according to Sandoz.
In 2012, the total cost for treating hospitalizations for cancer-related neutropenia was $2.3 billion for adults in the United States.
On the other hand, an investigation of the real-world safety and effectiveness of biosimilar filgrastim compared with the brand-name drug suggests that cost savings to commercially insured patients in the United States are modest.
In a retrospective observational study, Abiy Agiro, PhD, HealthCore Inc, Wilmington, Delaware, and colleagues analyzed 11,202 commercially insured adults who underwent chemotherapy and were treated with either reference filgrastim or one of two biosimilar agents — the Sandoz product, and tbo-tiligrastim (Granix, Teva) — over a period of almost 5 years.
“Patients were observed for 21 days postindex to assess filgrastim treatment cost (total and per day of use) and the incidence of FN [febrile neutropenia] and AEs [adverse events],” the researchers write.
Of this large group of patients, 13.7% were prescribed biosimilar filgrastim, they note. (The use of biosimilar filgrastim has risen steadily from 7% of filgrastim users in 2014 to 36% of users in the United States 2016.)
“Incidence rates of strict (neutropenia and fever) and broad (neutropenia or fever) definitions of FN were similar between the 2 groups,” the researchers indicate.
The cost differential between treating patients with either biosimilar compared to reference filgrastim was also not that dramatic; the mean cost of treating a single patient with any one of the three products was very similar.
Table. Treatment Costs for Biosimilar Filgrastim vs Reference Filgrastim
|Biosimilar Filgrastim||Tbo-Filgrastim (Granix, Teva)||Filgrastim-sndz||Reference Filgrastim|
|Mean cost per day of use||$731.00||$765.00||$667.00||$748.00|
|Mean treatment cost per patient||$2522||$2585.00||$2363.00||$2516.00|
“The cost per day of use was 2.3% less for biosimilar filgrastim,” the researchers indicate. “[T]he mean total cost per patient and per day of use were 6.1% and 10.8% less for filgrastim-sndz (P = .07 and P < .001, respectively) and were marginally higher for tbo-filgrastim (2.7% and 2.3%, respectively),” they add.
Agiro and colleagues point out that savings associated with biosimilar versions of filgrastim have been modest because uptake of these agents has been slow and because current pricing for biosimilar drugs closely tracks that of the reference product.