Cracking Tumor Defiance

Why does immunotherapy achieve dramatic results in some cancer patients but fail in others?

Scientists have elucidated the mechanism behind some tumor’s ability to escape immunotherapy drugs.

Why does immunotherapy achieve dramatic results in some cancer patients but doesn’t help others? It is an urgent and vexing question for many cancer specialists.

Now, two research groups from Harvard Medical School based at Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.

The findings, the researchers say, reveal potential new drug targets and could aid efforts to extend the benefits of immunotherapy treatment to more patients and target additional types of cancer.

The discoveries are detailed in two articles published by the journal Science.

One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, comes from scientists at Dana-Farber and the Broad Institute of MIT and Harvard led by Eliezer Van Allen, HMS assistant professor of medicine at Dana-Farber and an associate member at the Broad, and Toni Choueiri, the HMS Jerome and Nancy Kohlberg Associate Professor of Medicine and director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, HMS professor of neurology and director of Dana-Farber’s Center for Cancer Immunotherapy Research, and X. Shirley Liu of Dana-Farber.

The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.

Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell carcinoma (ccRCC) gain clinical benefit—sometimes durable—from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.

The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive tumor antigens called, neoantigens, which help the patient’s immune system recognize and attack tumors and make the cancer cells’ microenvironment hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.

To search for other characteristics of ccRCC tumors that influence immunotherapy response or resistance, the researchers used whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analyzed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.

When the data were sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumors lacked a functioning PRBM1 gene. About 41 percent of patients with ccRCC kidney cancer have a nonfunctioning PBRM1 gene. That gene encodes a protein called BAF180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodeling complex.

Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, including those in the gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.

The finding does not directly lead to a test for immunotherapy response yet, the scientists caution, but they carry a clear therapeutic promise.

“We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations,” Choueiri said.

In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 tool to sift the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.

The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodeling complex—the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells—as being involved in resistance to immune T cells.

When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors noted, “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack.” Finding ways to alter those target molecules, they added, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”

Research included in the report by Van Allen and Choueiri was supported by Bristol-Myers Squibb, American Association for Cancer Research Kure It Research Grant for Immunotherapy in Kidney Cancer, Kidney SPORE, and Cancer Immunologic Data Commons (National Institutes of Health grant U24CA224316).

A First in Lung Cancer: Immunotherapy Improves Survival

The immune checkpoint inhibitor nivolumab (Opvido, Bristol-Myers Squibb), which was recently approved for use in melanoma, has shown a survival advantage over chemotherapy in a pivotal trial in lung cancer. The trial (known as CheckMate 017) was stopped early due to benefit.

This is the first time that a survival advantage has been demonstrated in lung cancer with an immunomodulator drug, the company notes. It announced the top-line result of a superior overall survival in a press release, and says that clinical data will be presented at a forthcoming meeting.

The trial was conducted in 272 patients with advanced or metastatic squamous cell non-small cell lung cancer, and was open-label, randomizing patients to treatment with either nivolumab 3 mg/kg intravenously every 2 weeks or docetaxel 75 mg/m² intravenously every 3 weeks.

Pharmaceutical analysts reacting to the news speculate that the drug could be approved for use in lung cancer before the end of the year. The company has already filed for this indication in both the United States and Europe, and now says that it will “share” the new data with regulatory authorities.

Another check-point inhibitor is also making progress in lung cancer — pembrolizumab (Keytruda, Merck & Co). The company has announced that it is accelerating its development of the drug for use in lung cancer, and hopes to file for approval of this new indication by mid-year. Pembrolizumab is already marketed for use in melanoma. In fact, it beat nivolumab to the market to be the first program death inhibitor to become available in the United States, to the surprise of many analysts.

Early results with these immunomodulator drugs in lung cancer have been causing excitement at recent meetings, as previously reported by Medscape Medical News, leading one researcher to predict that “immunotherapy is heralding a new era of lung cancer treatment.”

Drugs with dual-hormone action gain attention in diabetes field.

Engineered peptide drugs that simultaneously target two hormone receptors have historically attracted interest among scientists hoping to create new treatments for diabetes. Now, many in the field seem buoyed by new data from a class of diabetes medicines designed to mimic gastrointestinal hormones called incretins, which stimulate insulin release from pancreatic beta cells.

The ‘incretin mimetics’ currently on the market modulate only one receptor. For example, Byetta (exenatide) from California’s Amylin Pharmaceuticals and Victoza (liraglutide) from Denmark’s Novo Nordisk trigger the glucagon-like peptide-1 receptor (GLP-1). To adequately control blood glucose, these drugs are often used at high doses, commonly causing vomiting and nausea. Long-term effects could include increased risk for pancreatitis, pancreatic cancer and thyroid cancer.

The problem is that GLP-1 receptors aren’t confined just to the gut. They’re also found in other tissues, especially the thyroid, pancreas, meninges, kidney and bone. In March, the US Food and Drug Administration began reviewing research linking GLP-1 agonists to increased risk of pancreatitis and precancerous cellular changes associated with pancreatic cancer. And this September, France’s Sanofi withdrew a new drug application in the US for its once-daily injectable GLP-1 agonist lixisenatide owing to concerns over cardiovascular safety.

According to drug developers, drugs that target two receptors simultaneously could provide a solution by more closely approximating the normal physiology lost when type 2 diabetes develops. The hope is to use these drugs at lower doses, decreasing the likelihood for adverse reactions.

Jim Dowdalls / Science Source

Dual fuel: Two-hormone drugs help treat diabetes.

In addition to GLP-1, another endogenous gut hormone is glucose-dependent insulinotropic peptide (GIP), which stimulates postprandial insulin release. Activity of GLP-1 and GIP is thought by some to be impaired in type 2 diabetes. A paper published in late October detailed the effects in humans of a new compound—originally called MAR701 by Indiana’s Marcadia Biotech, which contributed to early development of the compound—that binds and triggers receptors for both GLP-1 and GIP1. It offered data from a phase 2 trial done in collaboration with Roche, the Swiss drug giant, that included 53 patients with inadequately controlled type 2 diabetes.

The trial found a dose-dependent decrease in hemoglobin A1C (HbA1c) in the experimental group, ranging from a decrease of 0.53% to as much as a 1.11% drop; by comparison, the placebo group had an average drop of 0.16%. No participants experienced vomiting, a common side effect of incretin mimetics on the market, and few had nausea. The study also reported that this type of dual agonist lowers blood glucose levels and weight more effectively than single agonists in animal models.

Incredible incretin?

According to study author Matthias Tschöp, scientific director of the Helmholtz Diabetes Center in Munich, the pace of research on engineered peptides for dual-agonist incretin-based therapy has picked up in recent years. Tschöp and his collaborator Richard DiMarchi, a chemist at the University of Indiana in Bloomington, have worked previously on a GLP-1 and glucagon receptor co-agonist, in collaboration with New Jersey–based Merck, and a GLP-1 and estrogen receptor co-agonist, the latter of which showed potential for reversing the metabolic syndrome in rodents2.

Other researchers are in hot pursuit of similar drugs. Scientists at Amylin Pharmaceuticals, which was acquired last year by New York’s Bristol-Myers Squibb, are working on peptide hybrids made of an analog of Byetta linked to davalintide, which mimics amylin, a hormone released from pancreatic beta cells that helps regulate blood glucose levels after a meal3. “The exendin-amylin mimetic peptide hybrids . . . improve glucose tolerance and reduce HbA1c levels in diabetic rodents, coupled with body weight loss that is greater than that achieved by the parent peptides,” says Soumitra Ghosh, senior director of research programs and collaborations at Amylin.

Researchers at the University of Copenhagen and the University of Alberta, in Canada, in collaboration with Denmark’s Zealand Pharma and Germany’s Boehringer Ingelheim, are working on a single molecule that mimics the gut hormone oxyntmodulin, an endogenous peptide hormone with dual GLP-1 and glucagon receptor agonist activity4. The team is in competition with Merck, which has explored oxyntmodulin mimetics, including one called DualAg5.

Some teams are even looking into triple-receptor agonists. Nigel Irwin, a pharmacologist at the Diabetes Research Group at the University of Ulster in Ireland, works with a group focused on preclinical drug discovery of novel peptides for treating metabolic disease and obesity. Irwin’s team published results in late October showing that a hybrid triple agonist, combining the effects of GLP-1, GIP and glucagon, decreased body weight and significantly improved glucose tolerance and insulin sensitivity in mice fed high-fat diets, as compared to conventional antidiabetic agents6. “We also believe that concurrent activation of three receptors will minimize any potential side effects that can occur through over stimulation of a single regulatory peptide receptor,” Irwin explains.


Noninjectable Insulin Developers Make Progress

Diabetes sufferers may soon be able to avoid the needle.

Noninjectable Insulin Developers Make ProgressLessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. [AndrzejTokarski/Fotolia]

Whether famous like Tom Hanks or not, millions of people with diabetes for generations have had to take insulin by injection, just as a 14-year-old diabetic named Leonard Thompson did when he became the first patient successfully treated with the peptide hormone in 1922.

Nearly a century later, drug developers remain unable to market a noninjectable therapeutic. But of late, lessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. The companies see a growing market: An estimated 552 million people are expected to develop diabetes by 2030, up from 371 million in 2012, according to the International Diabetes Federation.

No Needles Required

MannKind earlier this month resubmitted to FDA its new drug application for Afrezza® (insulin human [rDNA origin]) Inhalation Powder for adults with type 1 or type 2 diabetes)—two years after the agency required two additional clinical studies comparing its current inhaler to its first-generation MedTone inhaler.

In August, MannKind released promising results from two Phase III trials. One study in type 1 patients compared Afrezza to insulin aspart; the other measured inhalable insulin in type 2 patients with inadequate diabetes control following metformin treatment, with or without a second or third oral medication. The type 2 study showed a drop in mean A1c levels of 0.82% in patients using Afrezza, compared to a 0.42% decrease in the comparator group. The type 1 study met its primary endpoint of noninferiority to insulin aspart.

Afrezza combines an inhalation powder with an inhaler called Dreamboat™ designed for use by diabetics at the start of meals. The powder dissolves immediately when inhaled to the deep lung and delivers insulin quickly to the bloodstream. According to MannKind, peak insulin levels occur within 12 to 15 minutes of administration, compared with 45 to 90 minutes for injected rapid acting insulin analogs, and 90–150 minutes for injected regular human insulin.

Joseph Kocinsky, MannKind’s svp, pharmaceutical technology development, told GEN Afrezza’s Technosphere® pulmonary drug delivery platform offers competitive advantages. In addition to ultra-fast delivery, insulin administered via Technosphere formulation avoids the hepatic first-pass metabolism that reduces drug bioavailability.

“The Technosphere technology is applicable to a wide variety of drugs (small molecules, peptides, proteins, monoclonal antibodies) and a wide variety of clinical indications like diabetes, pain, osteoporosis, and respiratory disease,” Kocinsky said.

Perhaps Afrezza’s best advantage is the same one offered by the oral insulin products—it doesn’t require a needle. Injection remains no small hurdle to insulin use among people with diabetes, despite improvements over the past generation such as shorter and sharper disposable needles, notes Robert E. Ratner, M.D., FACP, FACE, chief scientific and medical officer for the American Diabetes Association.

Dr. Ratner’s previously work as an investigator included studying Novo Nordisk’s insulin degludec, a long-acting injectable insulin analog. He said injection has one important advantage: Doses can be titrated and adjusted.

“When you’re giving oral or inhaled insulin, that level of precision in terms of dosing is probably going to be considerably harder,” Dr. Ratner told GEN. “We don’t yet know all of the details about the pharmacokinetics of these [noninjectable] agents—how quickly they’ll get absorbed, what percentage will get absorbed, are we going to be able to change the doses to meet the biologic needs of the individual? Those all remain unknowns. Those are the hurdles the companies need to overcome before we have a viable product.”

Road to Success Paved with Failure

Drug developers have long struggled to develop noninjectable diabetes treatments. In 2007, Pfizer stopped marketing Exubera® after 13 months following disappointing sales, took $2.8 billion in pre-tax charges, and returned product rights to partner Nektar Therapeutics.

One key factor in Exubera’s failure was its delivery system: Its inhaler was about a foot long, more conspicuous and clumsier than even the needle. Afrezza can be inhaled through a smaller inhaler requiring no maintenance because it is discarded and replaced every 15 days. Also unlike Exubera, Afrezza is dosed in traditional insulin units that are linear; two three-unit cartridges equal a six-unit cartridge.

Within months of Exubera’s exit, both Novo Nordisk and Eli Lilly ended programs to develop new inhalable insulin products that had advanced to Phase III trials, insisting they had not acted from safety concerns. Lilly brought insulin to market in 1923, and 60 years later launched the first insulin analogs.

Today, Novo Nordisk and another drug developer, Oramed, are well into clinical studies of oral insulin products, with years to go: “We won’t be looking at oral insulin for the next five to six years at the very least.”

Future Possibilities

Also working on noninjectable insulin is Biocon, which last year landed Bristol-Myers Squibb (BMS) as its partner to partially fund Phase II trials of its IN-105 outside India for two years. After that, BMS has the option to assume full responsibility for IN-105, including all development and commercialization activities outside India—in return for BMS paying Biocon a license fee, milestone payments, and royalties on IN-105 sales outside India.

Oramed in July enrolled its first patient in a Phase IIa trial assessing the safety of ORMD-0801, an orally ingestible insulin capsule on patients with type 2 diabetes. A total 30 patients will be enrolled.

“Results of the trial are anticipated by the end of the calendar year,” Aviva Sherman, an Oramed spokeswoman, told GEN.

ORMD-0801 is also under study in a clinical trial in Israel in August that began recruiting patients with type 1 diabetes, for which -0801 is envisioned as a complement to injections, allowing fewer daily injections.

In September, Oramed submitted a pre-IND package to FDA for its ORMD-0901 (oral exenatide), a GLP-1 analog for type 2 diabetes. “By acting on multiple fronts, i.e., stimulation of insulin release and suppression of glucagon release, as well as other actions, GLP-1 addresses diabetes-related glycemia issues on a broader level than does exogenously administered insulin,” Sherman said.

Oramed said its oral insulin mimics insulin’s natural location and gradients in the body by traveling through the gastrointestinal tract encapsulated, then releasing the insulin in the small intestine, from which it is ferried to the liver via the portal vein. The first-pass metabolism significantly reduces the risk of hypoglycemia, the most common side effect of injected insulins.

Novo Nordisk’s candidate OI362GT or NN1954, an oral basal insulin analog intended as a tablet treatment, generated successful results from a single-dose Phase I trial earlier this year. Peter Kurtzhals, svp in diabetes research at Novo Nordisk, told GEN NN1954 is delivered through enteric coated tablets targeting the duodenum, facilitated by the rise in pH that occurs when a substance passes from the acidic milieu in the stomach into the intestine.

“The delivery in duodenum is not more porous, but contents of the gall fluid secreted here may play a role in facilitating absorption of some substances from this part of the gut,” Kurtzhals said.

NN1954 absorption is enabled via partner Merrion Pharmaceuticals’ GIPET® technology. GIPET uses specifically designed oral formulations of patented absorption enhancers designed to activate micelle formation, facilitating transport of drug and increasing absorption.

The drug and enhancer are not bound to each other chemically, but are both ingredients of the tablet, with no interaction between active pharmaceutical ingredient and absorption enhancer. Co-release of the drug and absorption enhancer occurs following dissolution of the coating and a general disintegration of the tablet.

“The oral insulin project is currently in Phase I clinical development. Contingent on successful outcome of these trials, Phase II will be initiated within 1–2 years,” Kurtzhals said.

By the time Novo Nordisk and Oramed complete their required additional trials, followed by formal regulatory reviews, MannKind may have already delivered the first noninjectable insulin to grateful diabetics. Or not. FDA can be expected to show particular caution with noninjectable insulin candidates, given the problems inhalables have had in recent years. To win approvals, companies will have to show not only the usual safety and efficacy, but that their products are better than past noninjectable candidates—drugs young Leonard Thompson could only dream about when he took insulin by needle and made history nearly a century ago.

SAVOR-TIMI 53 raises bar for CV outcome trials in diabetes.

When added to standard care in patients with type 2 diabetes at high CV risk, saxagliptin neither reduced nor increased risk for ischemic events, according to results from the SAVOR-TIMI 53 trial.

Saxagliptin (Onglyza, AstraZeneca and Bristol-Myers Squibb) was also shown to improve glycemic control, but was associated with a small increase in the rate of hospitalization for HF.

The multicenter, randomized, double blind, placebo-controlled, phase 4 trial was designed to determine whether saxagliptin was noninferior to placebo when added to background therapy, for the composite endpoint of CV death, nonfatal MI or nonfatal ischemic stroke, Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School and Chief Medical Editor of Cardiology Today’s Intervention, said at an ESC Congress 2013 press conference.

During a mean follow-up of 2.1 years, the primary endpointoccurred in 7.3% of patients assigned saxagliptin compared with 7.2% assigned placebo (HR=1.00; 95% CI, 0.89-1.12;P=.99 for superiority; P<.001 for noninferiority). An on-treatment analysis yielded similar results (HR=1.03; 95% CI, 0.91-1.17).

The major secondary endpoint, a composite of CV death, MI, stroke and hospitalization for unstable angina, coronary revascularization or HF, occurred in 12.8% of patients assigned saxagliptin compared with 12.4% assigned placebo (HR=1.02; 95% CI, 0.94-1.11). Of note, the saxagliptin group had more hospitalizations for HF (3.5% vs. 2.8%; HR=1.27; 95% CI, 1.07-1.51). In addition, a prespecified secondary endpoint of all-cause mortality occurred in 4.9% of patients assigned saxagliptin compared with 4.2% assigned placebo (HR=1.11; 95% CI, 0.96-1.27).

“The high risk of hospitalization for HF was unexpected, but it was a predefined adjudicated endpoint. Therefore, it does merit further evaluation given the history of other diabetic agents and HF,” Bhatt said. “Additional analyses are ongoing and preliminary data suggest that the risk is highest in those with elevated baseline clinical risk for HF, such as a history of prior HF and/or elevated BNP levels at baseline.”

Fewer patients assigned saxagliptin required the addition or increase of any new antidiabetic medications (23.7% vs. 29.3%; HR=0.77; 95% CI, 0.73-0.82) or the initiation of insulin therapy for more than 3 months (5.5% vs. 7.8%; HR=0.7; 95% CI, 0.62-0.79). Reductions in blood glucose were also greater with saxagliptin, with mean reductions in HbA1c of 0.5% at 2 years in the saxagliptin group compared with 0.2% in the placebo group (P<.001). More patients assigned saxagliptin achieved or maintained goal HbA1c <7% (40% vs. 30.3%; P<.001). About 15% of patients in the saxagliptin group reported at least one hypoglycemic event compared with 13.4% of patients in the placebo group (P<.001). Hospitalization for hypoglycemia was infrequent and similar between groups (0.6% vs. 0.5%; P=.33).

Additionally, saxagliptin was associated with reduced development and progession of microalbuminuria.

“It is very encouraging that within such a short time, 2 years of follow-up, that saxagliptin has demonstrated a beneficial effect on the kidney,” researcherItamar Raz, MD, head of the diabetes unit, department of medicine, Haddassah University Medical Center, Jerusalem, told Cardiology Today.

Rates of pancreatitis were similar with saxagliptin and placebo (0.3% for both; P=.77). Five cases of pancreatic cancer were reported in the saxagliptin group compared with 12 in the placebo group. The incidence of other prespecified safety endpoints were balanced, Bhatt said.

Premature discontinuation of the study drug occurred more in the placebo group (20.8% vs. 18.4%; P<.001).

“There is still a great need to bring patients to HbA1c target and we know today that we only have 50% to 60% of diabetes patients at target. [Saxagliptin] is a safe drug that was not shown to do CV harm, as was shown in the primary and secondary endpoint results,” Raz said.

In The New England Journal of Medicine study, the researchers acknowledged “there remains a strong clinical need to identify antihyperglycemic agents that are, at a minimum, safe and that can potentially reduce cardiovascular complications.”

Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. – by Katie Kalvaitis

Source: Endocrine Today.



Oral Apixaban for the Treatment of Acute Venous Thromboembolism.


Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.


In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.


The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.



A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM





AMPLIFY: Apixaban in Acute VTE as Effective But Safer Than Standard Anticoagulation.

The oral factor Xa inhibitorapixaban (Eliquis, Pfizer/Bristol-Myers Squibb) was as effective as standard enoxaparin plus warfarin in treating acute venous thromboembolism (VTE) in a large randomized trial, one in which treatment with apixaban also led to a 69% drop in risk of major bleeding complications[1].

“The efficacy of apixaban in the patients with pulmonary embolism was similar to that in patients with deep vein thrombosis [DVT], and the relative effect was maintained in the approximately 40% of patients who presented with extensive disease,” write Dr Giancarlo Agnelli (University of Perugia, Italy) and associates, in the New England Journal of Medicine.

Their report on the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, conducted at 358 centers in 28 countries, was slated for publication July 1, 2013 in conjunction with the study’s scheduled presentation here at the 2013 Congress of the International Society on Thrombosis and Haemostasis. The New England Journal of Medicine lifted its embargo on AMPLIFY coverage on June 30, following, it said, an embargo break by Reuters

“After 60 years of warfarin, it is an exciting time in thrombosis care,” writes Dr Mary Cushman(University of Vermont, Burlington) in an accompanying editorial [2]. However, “shifting with care to new treatments is essential to safe and effective practice.” She cautions that “new anticoagulants are not for every patient” and notes developments that have helped make warfarin management less burdensome, including the advent of prothrombin-time self-testing, anticoagulation clinics, and reduced monitoring frequency for some patients.

Also, she notes, a lot remains to be learned about the new oral agents, apixaban along with dabigatran(Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson), including reversal strategies, monitoring (eg, in the presence of interacting drugs, extremes of patient weight, or bleeding or thrombosis complications), [and] approaches to treatment failure.”

The trial randomized 5395 patients with acute, symptomatic proximal VTE and/or pulmonary embolism (PE) to receive, with double blinding, either apixaban (n=2691) or subcutaneous enoxaparin followed by warfarin (n=2704). The factor Xa inhibitor was given as 10 mg twice daily for seven days followed by 5 mg twice daily for six months; enoxaparin was given for at least five days (median 6.5 days), with warfarin continued for six months.

The primary efficacy outcome was seen in 2.3% of patients taking apixaban and 2.7% of those on conventional therapy, which handily met the prespecified criteria for apixaban noninferiority (p<0.001). The results were nearly identical in each of the two VTE subgroups: those who entered with DVT and those who had PE.

Major bleeding occurred in 0.6% of the apixaban and 1.8% of the conventional-therapy groups, for a 69% drop in relative risk with the factor Xa inhibitor (p<0.001 for superiority). The composite of major bleeding or clinically relevant nonmajor bleeding fell by 56% (p<0.001 for superiority). VTE recurred within 30 days in 0.2% and 0.3%, respectively.

Relative Risk (95% CI) for Outcomes Apixaban vs Conventional Therapy

End points RR (95% CI)
First recurrent VTE or VTE-related death* 0.84 (0.60–1.18)
Major bleeding 0.31 (0.17–0.55)
Major or clinically relevant nonmajor bleeding 0.44 (0.36–0.55)
Death during treatment period 0.79 (0.53–1.19)
VTE or CV death 0.80 (0.57–1.11)
VTE, VTE-related death, or major bleeding 0.62 (0.47–0.83)

*Primary efficacy outcome

“The efficacy and safety of apixaban were consistent across a broad range of subgroups, including those based on clinically important features such as an age of more than 75 years, a body weight of more than 100 kg, use of parenteral anticoagulant treatment before randomization, and the duration of such treatment,” suggesting that the findings are likely generalizable across a broad spectrum of patients, according to the group. The findings at participating centers where warfarin-treated patients were more often maintained in a therapeutic INR range were also consistent with trial’s overall results, they write.

“On the basis of the results of this trial, together with those of the [AMPLIFY-EXT] trial, apixaban provided a simple, effective, and safe regimen for the initial and long-term treatment of venous thromboembolism.”

In AMPLIFY-EXT, as heartwire reported late last year, the risk of recurrent VTE or death was significantly reduced among patients who completed a full six-month course of anticoagulation for VTE and then stayed on apixaban another six to 12 months, so-called extended therapy for VTE, compared with anticoagulated patients who were then given placebo.

The trial was funded by Pfizer and Bristol-Myers Squibb. Agnelli discloses receiving personal fees from Pfizer in relation to the conduct of the trial, and other personal fees from Boehringer Ingelheim, Sanofi, Daiichi-Sankyo, and Bayer Healthcare. Disclosures for the coauthors are listed on the journal’s website. Cushman had no disclosures.


ti�ue�&� �t� effects. If you’re taking a supplement, it’s a good idea to check the FDA website periodically for updates.


Source: Mayo clinic



white�pn�t� X1� font-size:9.0pt;font-family:”Arial”,”sans-serif”;color:#666666′>And, I’ll tell you right now, after this last year, leaving Waiheke Island, going to Hawaii (as detailed in Going Out On A Limb), well… I feel freer, happier, more peaceful and more my true self than I ever have in 35 years and I categorically COULD NOT have done it if I had not reached out for support.


So, I implore you, if you are someone who is afraid to reach out for support, please… for the love of all things… swallow your fears, your negative self-talk, your pride or whatever is keeping you stuck and please, please put your freaking hand up! The Universe will deliver what you need if you will only step up to help yourself. People will materialise to support you. Information will find its way to you when you move forward to open your arms to receive it. You will find help in the most unlikely of places if you are willing to step outside your comfort zone. Do not judge how things may have gone before… perhaps once before you reached out and you didn’t get the response and support you needed. The past is gone and it has no bearing now. Life is short, don’t waste one second of it when the support you need lies all around you, beckoning you to call upon it.


Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?.

Incretin mimetics have been called “the darlings of diabetes treatment” and they may soon also be licensed for treating obesity. But a BMJ investigation has found growing safety concerns linked to the drugs’ mechanism of action. Deborah Cohen asks why patients and doctors have not been told.

They’ve been touted as the “new darlings of diabetes treatment”—the biggest breakthrough since the discovery of insulin nearly a hundred years before. The so called incretin therapies—glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors—looked as if they might change the face of type 2 diabetes. Their dual action of switching on insulin and suppressing glucagon to help control blood glucose was the ultimate in diabetes care.

The promise of a Nobel prize for the investigators loomed large. Scientists had discovered a treatment that could potentially modify disease progression. Studies in experimental animals showed that GLP-1 caused a proliferation in new insulin producing β cells. The hope was that these new cells might be able to replace those that died off in the course of human diabetes.

Nor did the promise end there. GLP-1 acts on the brain to makes people feel less hungry and the more powerful drugs aid weight loss—rather than weight gain like many antidiabetic drugs before them.

It’s an effect companies are seeking to market in its own right. Spurred on by the US Food and Drug Administration’s willingness to license new obesity treatment, Novo Nordisk’s chief science officer Mads Krogsgaard Thomsen said last year that the “political establishment in the US now knows that behaviour change alone is not enough.”1

His company’s drug, liraglutide, is in the process of late stage clinical tests, which Thomsen says show promising results.

But an investigation by the BMJ suggests Thomsen’s confidence might be optimistic. Concerns held by some specialists about the potential side effects of GLP-1 drugs have emerged into the mainstream after both the FDA and the European Medicines Agency announced in March that they would launch a review into whether the drugs may cause or contribute to the development of pancreatic cancer.

As yet neither agency has reached any conclusions, but they are meeting to discuss the matter later this month. And, as this investigation has found, for the regulators it is not a new concern. Over the years, drug assessors have become increasingly concerned that the incretin drugs have the potential for unwanted proliferative effects.

Expert concerns

Concerns long held by some experts about the potential side effects of incretin mimetics have gathered momentum with three publications this year. An independent analysis of health insurance data published in February found that people taking exenatide and sitagliptin were at twice the risk of hospital admission for acute pancreatitis compared with people taking other antidiabetic drugs2—the absolute risk 0.6%. And in April an analysis of data from the US Food and Drug Administration’s adverse event reporting system showed an increase in reports for pancreatitis and pancreatic cancer in people taking incretin mimetics compared with those taking other antidiabetic drugs.3

The FDA and EMA have both confirmed to the BMJ that their own analyses also show increased reporting or signals of pancreatic cancer with incretin mimetics. But they emphasise that this does not mean the relation is causal.

Both agencies announced in March that they will review data from a study just published showing pre-cancerous and dysplastic changes to the pancreas in organ donors exposed to incretin mimetics.4

The evidence is fiercely contested, with manufacturers stoutly defending the safety of their products. Merck, for example, told the BMJ that independent observational studies and a meta-analysis of clinical trials involving 33 881 patients found no association between DPP-4 inhibitors and pancreatic cancer. Bristol-Myers Squibb says that “post-marketing data does not confirm a causal relationship between saxagliptin or exenatide and pancreatitis and/or pancreatic cancer” (see for full questions and answers with manufacturers).

But a “Dear Doctor” letter from Bristol-Myers Squibb and AstraZeneca on the UK Medicine and Healthcare Products Regulatory Agency’s website says: “A review of reports of pancreatitis from post-marketing experience revealed that signs of pancreatitis occurred after the start of saxaglitpin treatment and resolved after discontinuation, which is suggestive of a causal relationship. Moreover, pancreatitis has been recognized as an adverse event for other DPP-4 inhibitors.”5 A spokeswoman for Boehringer Ingelheim told the BMJ: “Pancreatitis has been reported in clinical trials and spontaneous post marketing sources. Guidelines for the use of linagliptin in patients with suspected pancreatitis are included in the prescribing information of the treatment.”

The increasingly fractious debate among scientists and doctors was played out last month in the specialty journal Diabetes Care.

Experienced GLP-1 investigator, Professor Michael Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany, and a consultant to many of the manufacturers, argued that the published evidence against the drugs is weak. “The potential harms and risks typically refer to rare events and are discussed in a controversial manner,” he wrote.6 But a team of four academics from the US and UK (one an expert witness in litigation against one of the manufacturers) suggested that neither the safety nor the effectiveness of the class can be assumed. “The story is familiar. A new class of antidiabetic agents is rushed to market and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates, but is vigorously discounted,” they wrote in their response. 7

In the course of this investigation, the BMJ has reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to unwanted proliferative or inflammatory pancreatic effects.

The BMJ has also found that, despite published reports that indicated safety concerns, companies have not done critical safety studies; nor have regulators requested them. And access to raw data that would have helped resolve doubts about the safety of these drugs has been denied.

On their own, the individual pieces of unpublished evidence may seem inconclusive — increases in size and abnormal changes in animal pancreases, raised pancreatic enzyme concentrations in humans, reports of thyroid neoplasms, and pancreatitis in early clinical trials.

But when considered alongside other emerging and long standing evidence—such as concerns about the effect of GLP-1agonists on α cells first published in 19998; the presence of the GLP-1 receptor on cells other than the target pancreatic β cell; and increasing signals from regulatory databases2 9—a more coherent and worrying picture emerges, posing serious questions about the safety of this class of drug.

What’s going on in the pancreas?

In a world where the prevalence of type 2 diabetes is increasing rapidly, finding new targets for therapy is a high priority for drug companies. The discovery by scientists in the 1970s and the then publication in 1993 by Michael Nauck of the double action of GLP-1 (glucagon-like peptide-1) provided just such a target.

GLP-1 is a hormone-like peptide released by the intestine in response to a meal; its functions include regulating insulin and blood glucose and slowing gastric emptying. In his study, Nauck found that GLP-1 both increased the insulin made in the pancreas and, by inhibiting the secretion of glucagon, reduced the glucose released by the liver. Excessive glucose release by the liver underpins the high circulating glucose that defines type 2 diabetes. Following secretion, GLP-1 is quickly inactivated by an enzyme, dipeptidyl peptidase-4 (DPP-4). The GLP-1 drugs are either analogues that are not inactivated by DPP-4, taken by injection (exenatide, liraglutide) or oral drugs that inhibit DPP-4 (sitagliptin, saxagliptin, and linagliptin).

The saliva of the desert dwelling Gila monster was the source for the first GLP-1 analogue on the market, exenatide. A heavy slow moving lizard, it eats once or twice a year, and uses the secretion of its salivary hormone exendin-4—which displays similar properties to GLP-1—to induce proliferation of its pancreas and gut to assimilate a meal. Some say this should have provided a valuable clue to the unwanted effects of raised circulating levels of a hormone that usually lasts for only minutes before it is broken down.

But now that most of the other treatments for type 2 diabetes are off patent, these are valuable drugs. Merck’s market leading drug sitagliptin generated about $4.1bn (£2.6bn; €3bn) in sales in 2012 with liraglutide’s 2012 sales of $1.7bn coming in behind. The profit margins mean there is much at stake for the companies and the organisations and doctors who depend on their support.

However, serious doubts about the wisdom of basing treatments on GLP-1 agonists have existed since the beginning. And the companies and regulators have, on reflection, had in their hands ample warning signs—and chance to resolve some of the emerging controversies.

In 2005, the New England Journal of Medicine published a study that showed pancreatic changes in patients who had a type of gastric bypass surgery called Roux-en-Y. The authors noted hypertrophy and hyperplasia of the islet cells, also affecting the cells in the pancreatic ducts. They thought this might be due to raised levels of the hormone GLP-1, which were known to occur after this type of procedure.21 (A later study on this type of surgery also showed a “pronounced” increase in α cell mass22).

Senior executives from Amylin and Lilly wrote to the New England Journal to distance their drug from the paper and to stress the lack of evidence of a pathological effect on the islets in animal studies. “A study of nine months’ duration in healthy cynomolgus monkeys at doses of more than 400 times those used in humans showed minimal-to-mild islet hypercellularity with no increase in islet size (data on file, Amylin Pharmaceuticals),” they said.

The suppression of glucagon by incretin mimetics was highlighted by companies in their drug licensing applications and was noted by regulators. Billions of dollars of sales later, after concerns have been raised about the safety of glucagon suppression and its effect on glucagon producing α cells, the extent to which they do this is being contested.

Butler and colleagues’ finding of α cell hyperplasia in humans taking GLP1 based drugs4 was not the first. In 1999 GLP-1 researcher Joel Habener and a team at Harvard found that exendin-4 (exenatide) induced an increase in α cells in rats.8

But evidence of α cell hyperplasia has come from multiple models and sources—including the companies themselves. Whether this is applicable to GLP-1 based treatments is subject to fierce debate.

Only last October, Professor Dan Drucker, a long standing consultant to many of the companies, gave a keynote lecture at European Association for the Study of Diabetes conference. “The therapeutic window for reduction of glucagon action to manifest beneficial effects for glucose control while avoiding enhancement of hepatic lipid storage, dyslipidemia, hepatocyte injury, and α-cell proliferation in diabetic subjects is unclear,” the official conference journal reported.23

Others in industry have previously highlighted the important role of glucagon suppression in the control of diabetes. In 2005 at a session entitled “GLP-1s: the new darlings of diabetes treatment” Jens Holst, scientific director of the Novo Nordisk Foundation for Metabolic Research at Copenhagen University and a long standing consultant to the company, told the American Diabetes Association annual conference that GLP-1 agonists were a powerful inhibitor of glucagon secretion, adding that he thought this would be “a very important action to diabetes patients.”

A spokesperson for Novo Nordisk acknowledged an effect on α cells but only from full not partial glucagon suppression. She told the BMJ: “Complete removal or blocking of the glucagon receptor, or important signalling components, have caused α cell hyperplasia. This is separate from the relatively modest lowering of glucagon secretion induced by GLP-1.”

The BMJ asked Drucker about this. In response he sent a copy of an article he had written in Cell Metabolism, but this did not describe α cell effects.24 Yet the BMJhas found that the companies were aware of the unwanted effects of the full and partial suppression of glucagon before the incretin mimetics came onto the market.

At the turn of the century, Holst, working with scientists from Novo Nordisk, reported that glucagon suppression in mice resulted in massive enlargement of the pancreas and the proliferation of α cells (α cell hyperplasia).25 They concluded that α cells appear not just in the islets but in the pancreatic ductal epithelium—something that Butler and colleagues found. Importantly, this effect did not require complete blocking of glucagon receptors or the stopping of glucagon production. Even a partial reduction in the hormone signalling resulted in α cell hyperplasia, as shown by Eli Lilly in 2004.26 The Lilly team acknowledged that they hadn’t seen any neoplasia; the studies up until that point had been short—only four months long. They suggested that both glucagon and its receptor must be functional in order to maintain a feedback loop that restrains α cell growth “but the exact nature of this feedback loop is unclear.”26

Over the years, evidence of the effects of modifying glucagon signalling has mounted. In 2009 Run Yu, codirector of the carcinoid and neuroendocrine tumour programme at Cedars Sinai Hospital in Los Angeles, published a report in patients with a rare condition causing deficiencies in glucagon signalling.27 He found α cell hyperplasia and neuroendocrine tumours.

“In type 2 diabetes glucagon plays a role but there is a price to pay with reducing it,” he told the BMJ.

Yu said that he had shared his view with certain companies after the study came out. Because of agreements with the companies, he was unable to say which they were.

He then did a study in mice with decreased glucagon signalling that was far longer than any conducted by the companies. He found that neuroendocrine tumours invariably developed after formation of α cell hyperplasia and eventually led to death. Yu concluded that glucagon suppression was not a safe way to treat diabetes.28But whether this applies to GLP-1based therapies is still uncertain.

In the course of this investigation, the BMJ has looked at thousands of pages of regulatory documents from both the FDA and the EMA. There seems to be little discussion about the potential adverse effects of interfering with glucagon signalling on the α cell, even though the manufacturers spelt out —and the regulators noted—that glucagon suppression was one of the effects of the drugs. Michael Elashoff, a former FDA reviewer who has analysed the safety of the drugs, believes the regulators should have been more cautious in approving them.

“If some of the side effects can be anticipated in advance, then it seems incumbent upon the FDA to really force the companies to do real significant investigation of these potential side effects before the drug goes on the market and not leave it to experiment with actual patients taking the drug,” he said.

The FDA maintains that: “Long-term studies of incretin mimetics in rodents, dogs, and monkeys failed to demonstrate adverse pancreatic pathology or other toxicology reflective of a glucagon deficit that could be interpreted as a clear risk to human subjects.”

The BMJ asked the five companies who market incretin mimetics if they have ever studied the effects of glucagon suppression on the proliferation of α cells. Only Novo Nordisk responded to the question. It stressed that it had never seen α cell hyperplasia in any of its studies.29 30 31 “Alpha-cell hyperplasia is not mediated by the GLP-1 receptor,” a spokeswoman said. Behind the scenes, concerns also started to emerge about the potential inflammatory effects on the pancreas. Effects on pancreatic enzymes: Internal industry documents show that in 2005, one industry key opinion leader reported “extremely high” lipase levels in a patient taking exenatide. He was concerned that the company had missed signs of potential inflammation in its clinical trials.

Dennis Kim, then executive director at Amylin, wrote in an email that the doctor’s report was a “bit concerning” and confirmed that pancreatic amylase and lipase were not measured systematically in the company’s clinical trials.

The BMJ has found that companies have measured these enzymes for “safety issues,” but in many cases the data have not been reported in the published studies.

For example, in one Lilly funded trial comparing weekly exenatide with sitagliptin and two other diabetes treatments—insulin and pioglitazone—enzyme levels increased in a higher percentage of people taking incretin mimetics after 26 weeks of treatment.

Regulatory documents show the mean (SD) lipase concentration in the exenatide group increased from 42.0 (23.77) U/L on day 1 to 60.8 (38.39) U/L at week 26. Sitagliptin also increased lipase from 40.3 (21.3) U/L to 48.7 (30.7) U/L. The levels in the pioglitazone control dropped. However, when the trial was published in theLancet, these data did not make the final cut.32 The company did not say why when the BMJ put it to them. Neither did lead author, Richard Bergenstahl, answer theBMJ’s queries.

Earlier this year, the Lancet published another study funded by Eli Lilly and Amylin in which enzyme levels were measured but not reported.33 “Routinely measured concentrations of pancreatic lipase and total amylase varied in both groups and were not predictive of gastrointestinal symptoms,” the paper said.

The FDA says that the clinical value of routine amylase and lipase monitoring in asymptomatic patients is not clear. But pancreatologists, have told the BMJ that reporting enzyme levels is important because they may reflect a subclinical effect of the drug.

“Many large phase III trials report findings of significant biochemical abnormalities, even though the clinical significance may be uncertain at the time, and in this case where the drug is known to exert effects on the pancreas, I would find such information of value,” Thor Halfdanarson, a pancreatic surgeon, at the Mayo Clinic in Arizona said.

Indeed, writing in support of incretin mimetics in Diabetes Care last month, Michael Nauck said that the effect on pancreatic enzymes may be important.6 “Effects of GLP-1 receptor stimulation on pancreatic enzyme synthesis, potential leakage into the circulation rather than direct secretion into pancreatic digestive juice, and a potential induction if a chronic inflammatory response need to be studied,” he said.


Source: BMJ



Metreleptin improved metabolic parameters in children with lipodystrophy .

Positive results from an NIH-supported analysis indicate an investigational recombinant analogue of human leptin has potential as a therapy for pediatric lipodystrophy, according to data presented at the 2013 Pediatric Academic Societies Annual Meeting.

The literature has established that lipodystrophy is known to cause metabolic abnormalities (ie, hypertriglyceridemia, insulin resistance, diabetes andsteatohepatitis), which tend to become severe through childhood and adolescence, and may be resistant to current treatment options.

Rebecca Brown, MD, assistant clinical investigator of the diabetes, endocrinology and obesity branch at the National Institute of Diabetes and Digestive and Kidney Diseases, and colleagues included pediatric patients in an ongoing, open-label study at the NIH (2000 to present).

According to abstract data, patients included in the study (n=39; nine male and 30 female; mean age, 11.9 years) had four subtypes of the disease: congenital generalized lipodystrophy (n=26, 67%), acquired generalized lipodystrophy (n=9, 23%), familial partial lipodystrophy (n=2, 5%), and acquired partial lipodystrophy (n=2, 5%).

On average, the researchers administered metreleptin 4.4 mg (Bristol-Myers Squibb and AstraZeneca) subcutaneously once or twice daily for a mean duration of 3.9 years.

Data indicate that baseline HbA1c (9.8%) decreased significantly to 7.7% after 12 months (–2.3; 95% CI, –3.2 to –1.4) in adolescent patients aged 12 to 18 years.

Triglycerides were notably high in the same group at baseline (1,378 mg/dL), but improved significantly to 385 mg/dL after 12 months (–44; 95% CI, –73 to –15), according to data.

Both age groups displayed significantly elevated mean alanine aminotransferase (ALT; ≤12 years: 193 U/L; adolescents: 105 U/L) and aspartate aminotransferase (AST; ≤12 years: 119 U/L; adolescents: 87 U/L) at baseline. However, ALT (≤12 years: 155 U/L; adolescents: 59 U/L) and AST (≤12 years: 90 U/L; adolescents: 57 U/L) decreased after metreleptin therapy, according to data.

“Metabolic disorders resulting from lipodystrophy can develop in childhood and adolescence and are exacerbated over time,” Brown said in a press release. “This new analysis supports the continued study of investigational metreleptin as a potential treatment option for pediatric patients with lipodystrophy.”

Overall, metreleptin was well tolerated, and the most common adverse events reported were decreased weight (n=3, 7.7%) and hypoglycemia (n=3, 7.7%), followed by fatigue (n=2, 5.1%) and nausea (n=2, 5.1%), the researchers wrote.

According to the press release, metreleptin has acquired orphan designation from the FDA, and the European Medicines Agency is evaluating the agent.

  • o    Source: Endocrine Today


Metreleptin improved metabolic parameters in children with lipodystrophy.

Positive results from an NIH-supported analysis indicate an investigational recombinant analogue of human leptin has potential as a therapy for pediatric lipodystrophy, according to data presented at the 2013 Pediatric Academic Societies Annual Meeting.

The literature has established that lipodystrophy is known to cause metabolic abnormalities (ie, hypertriglyceridemia, insulin resistance, diabetes andsteatohepatitis), which tend to become severe through childhood and adolescence, and may be resistant to current treatment options.

Rebecca Brown, MD, assistant clinical investigator of the diabetes, endocrinology and obesity branch at the National Institute of Diabetes and Digestive and Kidney Diseases, and colleagues included pediatric patients in an ongoing, open-label study at the NIH (2000 to present).

According to abstract data, patients included in the study (n=39; nine male and 30 female; mean age, 11.9 years) had four subtypes of the disease: congenital generalized lipodystrophy (n=26, 67%), acquired generalized lipodystrophy (n=9, 23%), familial partial lipodystrophy (n=2, 5%), and acquired partial lipodystrophy (n=2, 5%).

On average, the researchers administered metreleptin 4.4 mg (Bristol-Myers Squibb and AstraZeneca) subcutaneously once or twice daily for a mean duration of 3.9 years.

Data indicate that baseline HbA1c (9.8%) decreased significantly to 7.7% after 12 months (–2.3; 95% CI, –3.2 to –1.4) in adolescent patients aged 12 to 18 years.

Triglycerides were notably high in the same group at baseline (1,378 mg/dL), but improved significantly to 385 mg/dL after 12 months (–44; 95% CI, –73 to –15), according to data.

Both age groups displayed significantly elevated mean alanine aminotransferase (ALT; ≤12 years: 193 U/L; adolescents: 105 U/L) and aspartate aminotransferase (AST; ≤12 years: 119 U/L; adolescents: 87 U/L) at baseline. However, ALT (≤12 years: 155 U/L; adolescents: 59 U/L) and AST (≤12 years: 90 U/L; adolescents: 57 U/L) decreased after metreleptin therapy, according to data.

“Metabolic disorders resulting from lipodystrophy can develop in childhood and adolescence and are exacerbated over time,” Brown said in a press release. “This new analysis supports the continued study of investigational metreleptin as a potential treatment option for pediatric patients with lipodystrophy.”

Overall, metreleptin was well tolerated, and the most common adverse events reported were decreased weight (n=3, 7.7%) and hypoglycemia (n=3, 7.7%), followed by fatigue (n=2, 5.1%) and nausea (n=2, 5.1%), the researchers wrote.

According to the press release, metreleptin has acquired orphan designation from the FDA, and the European Medicines Agency is evaluating the agent.

For more information:

Brown R. #3490.3. Presented at: Pediatric Academic Societies Annual Meeting; May 4-7, 2013; Washington.

Source: Endocrine today