American College of Cardiology 2017
Payal H. Marathe, Abigail E. Dove, Helen X. Gao, 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 Marathe, Dove, Gao, and Close review the latest developments relevant to researchers and clinicians.
American College of Cardiology 2017
The 66th Annual Scientific Sessions of the American College of Cardiology gathered thousands of attendees in Washington, DC from 17 to 19 March 2017. The third and final day of the conference included a presentation of CVD-REAL results by Dr Mikhail Kosiborod (University of Missouri, Columbia, MO, USA). This retrospective real-world study compared heart failure and mortality outcomes between 154 523 type 2 diabetes (T2D) patients starting sodium–glucose cotransporter 2 (SGLT-2) inhibitor therapy and 154 523 patients starting treatment with another glucose-lowering medication. There was a 39% risk reduction for heart failure hospitalization associated with SGLT-2 inhibitors versus other diabetes products (P < 0.001). Similarly, SGLT-2 inhibitors reduced risk for all-cause mortality by 51% (P < 0.001) and for the composite endpoint of heart failure hospitalization or death from any cause by 46% (P < 0.001). At baseline, 87% of participants had no prior cardiovascular events or no established cardiovascular disease. Thus, the results hint at primary prevention capabilities for SGLT-2 inhibitors, whereas the randomized controlled trial Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)1 demonstrated secondary prevention capabilities for the SGLT-2 inhibitor Jardiance (empagliflozin; manufactured jointly by Lilly [Indianapolis, IN, USA] and Boehringer Ingelheim [Ingelheim, Germany]) in participants at high risk for cardiovascular complications at baseline. The CVD-REAL results were consistent across countries: investigators used data registries from the US, Norway, Sweden, Denmark, the UK, and Germany. Among the SGLT-2 inhibitors of interest were Invokana (canagliflozin), manufactured by Johnson & Johnson (New Brunswick, NJ, USA), Jardiance (empagliflozin), and Forxiga (dapagliflozin) manufactured by AstraZeneca (London, UK). Of all participants on an SGLT-2 inhibitor, 53% were on Invokana, 42% were on Forxiga, and 5% were on Jardiance. This was skewed by geography, in that 92% of European participants were taking Forxiga, whereas 76% of US-based participants were taking Invokana. Further analysis of the CVD-REAL dataset is ongoing.
Endocrine Society 2017
The 99th Annual Meeting of the Endocrine Society gathered attendees in Orlando (FL, USA) from 1 to 4 April 2017, and included a presentation of 21-year data from the Steno-2 study. This trial randomized 160 individuals with T2D to either intensive, multifactorial intervention involving simultaneous glucose-lowering, blood pressure-lowering, and lipid-lowering efforts, or to standard of care for 8 years with the aim of determining the long-term effect of early, intensive, multifactorial intervention. At 21 years, the hazard ratio for all-cause mortality was 0.55 in favor of intensified treatment (P = 0.005) with a median increase in survival of 7.9 years. Non-cardiovascular death was similar between the two treatment arms. The effect on all-cause mortality was driven by a 65% risk reduction for cardiovascular death (P = 0.003). The hazard ratio for four-point major adverse cardiac events (MACE; non-fatal MI, non-fatal stroke, cardiac revascularization, or cardiovascular death) was 0.36 in favor of intensified treatment (P < 0.001). Fewer than half the participants in the intensive therapy group experienced a cardiovascular event. Risk reduction for mortality and MACE persisted through prespecified subgroup analyses for age and sex. These positive results corroborate earlier findings of improved outcomes for T2D patients on an intensive, multifactorial treatment regimen at 8 and 13 years.2
| Company Updates | |
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| February 23, 2017 | Caladrius Biosciences (Basking Ridge, NJ, USA) recently announced that it received a US$12.2 million grant from the California Institute for Regenerative Medicine (CIRM; Oakland, CA, USA) for the continued development of CLBS03, a regulatory T cell (Treg)-based therapy being studied as a treatment for type 1 diabetes (T1D). The grant will be used to fund the remaining costs of the ongoing Phase 2 Sanford Project T-Rex study (Safety and Efficacy of CLBS03 in Adolescents With Recent Onset Type 1 Diabetes), which Caladrius is pursuing in partnership with Sanford Health (Sioux Falls, SD, USA). The T-Rex study launched in the first quarter of 2016 and will evaluate the effect of two doses (2.5 and 20 million cells/kg) of the Treg therapy on C-peptide preservation after 52 weeks in adolescents (n = 111) with recent onset T1D (i.e. diagnosis of T1D within 100 days of initiation of CLBS03 therapy). Primary completion is expected in March 2019 and full completion in March 2020; an interim analysis of early therapeutic effects will be completed by the end of 2017. |
| March 17, 2017 | Lilly announced the initiation of the EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure) HF clinical trial program to assess the impact of the Boehringer Ingelheim-partnered SGLT-2 inhibitor Jardiance (empagliflozin) on adults with chronic heart failure. The EMPEROR HF program will involve two Phase 3 outcomes studies, EMPEROR HF-Preserved and EMPEROR HF-Reduced, which, respectively, will assess empagliflozin in patients with chronic heart failure with preserved ejection fraction (estimated enrollment = 4100) and reduced ejection fraction (estimated enrollment = 2800). Both studies have a composite primary endpoint of time to either first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure, and both are expected to complete in 2020. Secondary endpoints include estimated glomerular filtration rate (eGFR), time to first occurrence of sustained reduction of eGFR, time to all-cause mortality, time to onset of diabetes, change from baseline in clinical summary score of chronic heart failure, and occurrence of all-cause hospitalization. Although Jardiance is currently indicated as a diabetes drug, the trials will enroll heart failure patients both with and without diabetes, marking the first time that empagliflozin will be evaluated in people without T2D. |
| March 22, 2017 | Semma Therapeutics (Cambridge, MA, USA) and the Juvenile Diabetes Research Foundation (JDRF; New York, NY, USA) announced a new investment from the JDRF T1D Fund, with an aim to push forward Semma's stem cell-derived insulin-producing β-cells into clinical development. The product is based on the work of Harvard University's (Cambridge, MA, USA) Dr Doug Melton, who devised an approach to create large quantities of insulin-secreting cells from human stem cells.3 In December, Semma partnered with Defymed (Strasbourg, France), a biotech company with a preclinical MAILPAN “bioartificial pancreas” macroencapsulation system featuring a semipermeable membrane pouch. This collaboration hopes to advance a joint product, namely Semma's insulin-producing cells inside Defymed's MAILPAN system, into clinical studies. |
| March 24, 2017 | Novo Nordisk (Bagsværd, Denmark) announced that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending a label update for Tresiba (insulin degludec) to include data from the Trial Comparing the Safety and Efficacy of Insulin Degludec and Insulin Glargine, Both With Insulin Aspart as Mealtime Insulin in Subjects With Type 1 Diabetes (SWITCH 1) and the Trial Comparing the Safety and Efficacy of Insulin Degludec and Insulin Glargine, With or Without OADs in Subjects With Type 2 Diabetes (SWITCH 2). The two trials demonstrated significant reductions in hypoglycemia with Tresiba therapy compared with standard-of-care Lantus (insulin glargine) manufactured by Sanofi (Paris, France). This bodes well for a final approval decision on the label update from the EMA, expected in the second quarter of 2017 following the November 2016 filing for inclusion of these data. The company filed a similar application with the US Food and Drug Administration (FDA) last year, and a decision for this is expected by September 2017. |
| March 29, 2017 | Novo Nordisk announced that faster-acting insulin aspart has been resubmitted to the FDA. A US regulatory decision for the product is now expected in the fourth quarter of 2017. This is the second time Novo Nordisk has submitted a New Drug Application (NDA) for the next-generation prandial insulin; the first was met with a Complete Response Letter (CRL) in October 2016 due to concerns with the immunogenicity and pharmacology assay for the faster-acting insulin. Faster-acting insulin aspart would be the first-to-market next-generation meal-time insulin therapy in the US. The product launched in Canada on 27 March 2017 under the brand name Fiasp and received marketing authorization from the EMA in January 2017. The product was also recently approved in Norway and Iceland and is under review in Switzerland, Australia, Brazil, South Africa, Argentina, and Israel. |
| March 29, 2017 | Daiichi Sankyo (Tokyo, Japan) and Mitsubishi Tanabe Pharma (Tokyo, Japan) announced plans to jointly commercialize MT-2412, an SGLT-2 inhibitor/dipeptidyl peptidase-4 (DPP-4) inhibitor fixed-dose combination tablet for T2D (canagliflozin/teneligliptin) in Japan as part of an expanded strategic alliance in the diabetes field. An NDA for MT-2412 has already been filed with Japanese regulatory authorities on the basis of Phase 3 trials completed in August 2016; based on a standard review, a decision would be expected in the second quarter of 2018. As per the recent agreement, Daiichi Sankyo will take the lead on marketing after manufacturing and marketing approval from Mitsubishi Pharma, whereas both companies will promote the product together. |
| March 29, 2017 | ViaCyte (San Diego, CA, USA) announced that it has partnered with materials science company W.L. Gore & Associates (Newark, DE, USA) to develop a novel implantable encapsulation device for ViaCyte's stem cell-derived β-cell precursors. The collaboration hopes to create an encapsulation device that can protect these insulin-producing, β-like cells from immune attack, eliminating the need for chronic immunosuppressant therapy associated with donor islet transplantation and ViaCyte's preclinical PEC-Direct microencapsulation/direct vascularization product. ViaCyte already has a macroencapsulation β-cell replacement therapy intended to eliminate the need for immunosuppressants (PEC-Encap) in a Phase 1/2 clinical trial, but the candidate has demonstrated variable efficacy due to differences in foreign body response from patient to patient. As a result, the company has been de-emphasizing the more advanced and ambitious PEC-Encap in favor of PEC-Direct. Presumably, Gore's expertise in materials for life sciences applications can help develop a product to avoid these issues with the foreign body response. |
| April 7, 2017 | Merck (Kenilworth, NJ, USA) announced that the FDA has issued a CRL for the inclusion of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) data on the labels of three drugs in the DPP-4 inhibitor sitagliptin franchise: Januvia (sitagliptin), Janumet (sitagliptin/metformin), and Janumet XR (sitagliptin/metformin extended release). Results from the TECOS cardiovascular outcomes trial (CVOT), presented first at ADA 2015,4 were resoundingly neutral: sitagliptin demonstrated non-inferiority for the primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, or cardiovascular death) plus hospitalization for unstable angina with a hazard ratio of 0.98 (95% confidence interval [CI] 0.89–1.08), and also showed non-inferiority for the secondary endpoint of three-point MACE with a hazard ratio of 0.99 (95% CI 0.89–1.10). Merck is reviewing the CRL and plans to discuss next steps with the FDA. |
