Advanced Technologies and Treatments for Diabetes 2018
Abstract
Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians.
More than 2000 attendees gathered in Vienna, Austria, in mid-February for the 11th annual Advanced Technologies and Treatments for Diabetes (ATTD) meeting. There, Dr David Klonoff presented results from Novo Nordisk's (Copenhagen, Denmark) Onset 5 study of Fiasp (faster-acting insulin aspart) versus NovoLog (insulin aspart) in pump users. In adults with type 1 diabetes mellitus (T1DM) on a pump (n = 472), HbA1c lowering was non-inferior for Fiasp compared with NovoLog, dropping from a baseline 7.5% to 7.44% with Fiasp and from the same baseline to 7.35% with NovoLog (P < 0.001 for non-inferiority); NovoLog resulted in a 0.09% greater drop in HbA1c (95% confidence interval [CI] 0.01%–0.17%, P = 0.022). However, Fiasp did demonstrate significant benefit over NovoLog on a 1-h post-meal test, with an estimated treatment difference of 0.91 mmol/L for postprandial increment at Week 16 (95% CI approximately −1.4, −0.4 mmol/L; P = 0.001). The improvement in postprandial glucose with Fiasp versus NovoLog at 1-h after the meal was supported by significantly lower post-meal plasma glucose levels at 30 and 120 min, and by 0–1 and 0–2 h interstitial fluid glucose increments as measured by continuous glucose monitoring (CGM) and by postprandial self-monitoring of blood glucose (SMBG). Hypoglycemia data, including severe hypoglycemia events and blood glucose-confirmed symptomatic events, were neutral across groups, with an estimated treatment ratio of 1.00 (95% CI 0.85–1.16). Looking only at severe glucose-confirmed events, hypoglycemia appeared to be more frequent with Fiasp than NovoLog (21 vs 7 episodes), but excluding three participants who all experienced severe hypoglycemia during the run-in (and who all happened to be randomized to the faster-acting aspart arm), these values fell to 11 versus 7 episodes. Dr Klonoff concluded that Fiasp is safe and effective for pump users.
In addition, results from Sanofi's (Paris, France) real-world LIGHTNING study were presented on a poster and during a symposium at ATTD. The company's next-generation basal insulin Toujeo (insulin glargine U300) reduced severe hypoglycemia risk by more than 60% compared with both Lantus (P = 0.009), which is Sanofi's insulin glargine U100, and Levemir (P = 0.002), which is Novo Nordisk's insulin detemir. Severe hypoglycemia rates were similar with Toujeo compared with Novo Nordisk's next-generation Tresiba (P = 0.370), a formulation of insulin degludec. LIGHTNING analyzed electronic medical records of 10 458 patients with type 2 diabetes mellitus (T2DM) who switched from one basal insulin to another. After propensity score matching, the mean estimated event rates of severe hypoglycemia per 100 patient-years were 3.6 for Toujeo compared with 9.7 for Lantus (P = 0.009), 3.6 for Toujeo compared with 15.1 for Levemir (P = 0.002), and 3.4 for Toujeo compared with 5.3 for Tresiba (P = 0.370). The decrease in HbA1c was similar across all three comparisons, ranging from −0.50% to −0.89% (baseline 9.1%–9.2%), indicating that reductions in hypoglycemia did not occur at the expense of greater hyperglycemia.
During Sanofi's accompanying symposium on basal insulin, Dr Jeremy Pettus (University of California San Diego, CA, USA) commented that real-world studies add confidence to the scientific vigor of randomized trials, demonstrating that clinically meaningful outcomes are maintained outside the structure of a controlled study setting; he expects to be seeing more of these studies in diabetes. To this end, Sanofi has launched an entire real-world evidence campaign around Toujeo. Sanofi's BRIGHT study is a head-to-head comparison of Toujeo and Tresiba in a randomized controlled setting, and thus far has shown a similar proportion of patients (~50%) reaching an HbA1c goal <7% after 24 weeks (baseline HbA1c 8.6%–8.7%). The hypoglycemia findings from BRIGHT are not yet available. As with any real-world study, there were some limitations to LIGHTNING, including that previous basal dose and reasons for switching were not available from the Humedica database. Data were gathered on patients between 1 April 2015 and 31 December 2016 from more than 50 healthcare systems.
| Company Updates | |
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| January 4, 2018: | Arecor (Cambridge, UK) announced that preclinical studies of its ultra-concentrated (U1000) rapid-acting insulin have been completed. This preclinical program received JDRF funding of up to US$900000 over 12 months in July 2016, and the candidate is now scheduled to enter in-human trials in people with T1DM 2018. According to Arecor, onset time with this candidate is similar to currently marketed rapid-acting insulin analogs. Although no specific timeline was provided for Phase 1 clinical development, Arecor stands to become the first company to advance a U1000 mealtime insulin into human trials. This candidate has been positioned for patients with insulin requirements >200 units daily. Lilly's Humulin U500 (human insulin) is the highest-concentration rapid-acting insulin on the market today. |
| January 9, 2018: | Health Canada approved Novo Nordisk's glucagon-like peptide-1 (GLP-1) agonist Ozempic (semaglutide once-weekly) for the treatment of T2DM, following Ozempic's December 2017 US Food and Drug Administration (FDA) approval and Committee for Medicinal Products for Human Use (CHMP) endorsement for European Medicines Agency (EMA) approval. No details were shared on launch timing or pricing in Canada, but Novo Nordisk has said that, in the US, Ozempic would be priced similarly to other once-weekly GLP-1 agonists. Ozempic has shown superior glucose lowering and weight loss in head-to-head trials against other available diabetes drugs, including Lilly's once-weekly GLP-1 agonist Trulicity.1 Final marketing authorization for Ozempic in Europe is anticipated in the first quarter of 2018. |
| January 17, 2018: | A new post hoc analysis of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) for Merck's (Kenilworth, NJ, USA) dipeptidyl peptidase 4 inhibitor Januvia was published in the January edition of Diabetes Care.2 The authors found that severe hypoglycemia was associated with an increased risk for a subsequent primary endpoint event (non-fatal myocardial infarction [MI], non-fatal stroke, hospitalization for unstable angina, or cardiovascular death), with a hazard ratio (HR) of 1.55 (95% CI 1.06–2.28; P = 0.025). Severe hypoglycemia also increased the risk for all-cause death (HR 1.83, 95% CI 1.22–2.75; P = 0.004) and for cardiovascular death (HR 1.72, 95% CI 1.02–2.87; P = 0.040). Flipping the time course, non-fatal MI (HR 3.02, 95% CI 1.83–4.96; P < 0.001), non-fatal stroke (HR 2.77, 95% CI 1.36–5.63; P = 0.005), and hospitalization for heart failure (HR 3.68, 95% CI 2.13–6.36; P < 0.001) were associated with a greater risk for subsequent severe hypoglycemia. Fully adjusted models did not show an association between severe hypoglycemia and later atherosclerotic cardiovascular or heart failure events, but the association between cardiovascular events and subsequent severe hypoglycemia remained. |
| January 25, 2018: | The CHMP recommended Merck and Pfizer's (New York, NY, USA) sodium–glucose cotransporter 2 (SGLT-2) inhibitor Steglatro (ertugliflozin) for EMA approval. This positive opinion also applies to fixed-dose combinations Segluromet (ertugliflozin/metformin) and Steglujan (ertugliflozin/sitagliptin). Final marketing authorization for Europe is expected in the first half of 2018. All three ertugliflozin products were approved by the FDA in December 2017. The FDA approved label for Steglatro notes the imbalance of lower limb amputations, especially toe amputations, seen across seven Phase 3 trials of ertugliflozin (11 patients on the active drug vs 1 patient on placebo), but also acknowledges that this was not statistically significant, stating that no causal association has been definitively established between Steglatro and lower limb amputations. |
| January 29, 2018: | Mylan (Canonsburg, PA, USA) announced that its Biocon (Bangalore, India)-partnered biosimilar insulin glargine has been recommended by CHMP for EMA approval. The hopeful European Union (EU) brand name for the product is Semglee, and a final EMA decision is expected in April 2018. If approved, Semglee would likely become the second-to-market biosimilar basal insulin in Europe, after Lilly and Boehringer Ingelheim's (Ingelheim am Rhein, Germany) Abasaglar, also a biosimilar formulation of glargine, commercially known as Sanofi's Lantus. Mylan also filed a New Drug Application for biosimilar insulin glargine in September 2017, meaning an FDA decision is expected between July and September 2018. This filing prompted a patent infringement lawsuit from Sanofi in the US, which could push back full FDA approval and launch until mid-2020. |
| February 1, 2018: | Novo Nordisk announced that the company will initiate a post-market cardiovascular outcomes trial of the GLP-1 agonist semaglutide (branded Ozempic) in T2DM. Called “SOUL”, the study will enroll approximately 13 000 people with T2DM at high cardiovascular risk and is scheduled to begin by mid-2018, with results expected in 2023. Novo Nordisk also noted that the Phase 3 STEP program of semaglutide in obesity is on track to launch in 2018, with expected completion of the four trials in 2020. The SELECT cardiovascular outcomes trial of semaglutide in obesity is also set to begin in 2018, enrolling an estimated 17 500 patients. |
| February 2, 2018: | Intarcia (Boston, MA, USA) terminated two clinical trials of implantable exenatide mini pump ITCA 650 as part of a recent clinical hold required to allow an investigation to take place at a third-party laboratory conducting routine long-term tests of manufacturing batches. The two terminated studies include a small open-label 30-person trial investigating ITCA 650 in T2DM patients with high baseline HbA1c (between 10% and 12%) and a large head-to-head trial (n = 930) comparing ITCA 650 with SGLT-2 inhibitor Jardiance (Lilly/Boehringer Ingelheim's empagliflozin) and sulfonylurea glimepiride. These were commercial trials that would support marketing and promotion around Intarcia's product after approval. Intarcia received a Complete Response Letter from the FDA on ITCA 650 in September 2017. |
| February 5, 2018: | Novo Nordisk announced the US launch of the GLP-1 agonist Ozempic (semaglutide) and rapid-acting insulin Fiasp (faster-acting insulin aspart). Once-weekly Ozempic offers lower injection burden than Novo Nordisk's once-daily GLP-1 agonist Victoza (liraglutide). Fiasp is the first-ever mealtime insulin injection approved without a premeal dosing recommendation; it can be injected up to 20 min after start of a meal, as per its label. Ozempic will be priced on par with current market-leading, once-weekly GLP-1 agonists, whereas Fiasp will be priced on par with NovoLog (the company's first-generation insulin aspart). |
| February 9, 2018: | Novo Nordisk's once-weekly GLP-1 agonist Ozempic (semaglutide) received full EMA approval, following a positive CHMP opinion in December 2017. The company plans to file a follow-up variation application with the agency: the EMA approved an Ozempic FlexTouch pen with three possible doses (0.25, 0.5, and 1.0 mg), but Novo Nordisk aims to market Ozempic in two separate pens, one with the capability to dose 0.25 mg (for titration) and 0.5 mg, and another with the capability to dose 1.0 mg semaglutide. Launch in the first European countries is slated for the second half of 2018, pending EMA approval of the variation application. As part of EMA approval, Novo Nordisk has agreed to conduct a long-term retinopathy outcomes study with semaglutide. |
| February 22, 2018: | Novo Nordisk released topline data from the PIONEER 1 trial of oral semaglutide, which was the first Phase 3 readout on an oral GLP-1 agonist and the first of 10 PIONEER studies to complete. In PIONEER 1 (n = 703), oral semaglutide met its primary endpoint of significant HbA1c reduction over 26 weeks compared with placebo. Adults with T2DM were randomized to one of four treatment arms: (i) 3 mg oral semaglutide once daily; (ii) 7 mg once daily; (iii) 14 mg once daily; or (iv) placebo. All three doses of the active agent showed superior HbA1c lowering versus placebo at Week 26, but the margin of HbA1c decline with each dose was not disclosed. Baseline HbA1c was 8% across treatment groups. Oral semaglutide at 14 mg daily also demonstrated significantly superior weight loss than placebo (baseline body weight 88 kg). The lower doses showed greater but non-significant weight loss compared with placebo. |
| February 23, 2018: | Merck received tentative FDA approval for a 10-mL vial of Lusduna, a biosimilar formulation of insulin glargine (Sanofi's Lantus). This follows FDA's July 2017 tentative approval of Lusduna Nexvue, biosimilar glargine in a prefilled pen. Both products have satisfied all regulatory requirements for approval but cannot be launched in the US until patent infringement lawsuits from Sanofi are settled. This can happen in one of three ways: (i) Sanofi and Merck reach an agreement; (ii) a court decides in favor of Merck; or (iii) 30 months elapse since Sanofi filed the lawsuits (September 2016 for Lusduna Nexvue and August 2017 for the vial). |
| February 26, 2018: | Lilly announced the publication of AWARD 10 (n = 424), investigating GLP-1 agonist Trulicity (dulaglutide) as an add-on to SGLT-2 inhibitor therapy, in Lancet Diabetes & Endocrinology.3 From a baseline 8%, mean HbA1c reduction among patients randomized to 0.75 mg dulaglutide once weekly (n = 142) was 1.2% after 24 weeks compared with 0.5% among patients on placebo (n = 140; P < 0.0001). In the 1.5-mg dulaglutide arm (n = 142), average HbA1c drop was 1.3% after 24 weeks (P < 0.0001 vs placebo). Further, 60% of the 0.75-mg dulaglutide group and 71% of the 1.5-mg dulaglutide group achieved HbA1c target <7% at the end of the trial, compared with only 32% of the placebo group; 38%, 50%, and 14% of the 0.75-mg, 1.5-mg, and placebo groups, respectively, reached HbA1c < 6.5%. Combination therapy with Trulicity and an SGLT-2 inhibitor was found to be safe and well tolerated. Serious adverse events occurred in 4% of the 1.5-mg group (five patients), 2% of the 0.75-mg group (three patients), and 4% of the placebo group (five patients). Gastrointestinal side effects (nausea, diarrhea, vomiting) were more common among Trulicity-treated participants. |
| March 5, 2018: | AstraZeneca (London, UK) announced that the EMA has accepted an application for the SGLT-2 inhibitor Forxiga (EU tradename; dapagliflozin) in T1DM. Assuming a standard 10- to 12-month review period, a decision is expected in the first quarter of 2019. If the program continues on schedule, the company will file Farxiga (US tradename) for a T1DM indication with the FDA in the second half of 2018. Dapagliflozin could be the first-to-market oral adjunct therapy for T1DM, but Sanofi and Lexicon's (The Woodlands, TX, USA) SGLT-1/2 dual inhibitor sotagliflozin is close behind, with US filing expected by the end of March 2018. |
