The American Diabetes Association (ADA) 76th Scientific Sessions was held in New Orleans, LA from June 10-14, 2016. Details from Victoza's (NVO) LEADER CV outcomes trial (CVOT) were undoubtedly the highlight of the ADA conference, along with comparisons to those from Jardiance's EMPA-REG trial, which had an update at the meeting, as well. Other clinical data presentations involved more established themes. There were first Phase III data or at least first Phase III conference presentations from a number of drugs or studies, including ertugliflozin (MRK, PFE), semaglutide's SUSTAIN 2 and 3 (NVO), ITCA 650's FREEDOM-2 (Intarcia, Servier), the biosimilar insulins MK-1293 (MRK) and SAR342434 (SNY), and faster-acting aspart (NVO). While their results were not too surprising, details helped to confirm expectations or, in some cases, raised issues, and helped to give a better picture of product profiles. There was also a great deal of interest in Tresiba's (NVO) SWITCH studies, which were designed to show a hypoglycemia benefit over Lantus (SNY). For earlier stage drugs, there were no clear novel breakthrough mechanisms, but some interesting concepts presented, including RPC8844 (Receptos/Celgene), a small molecule GLP-1 receptor allosteric modulator and MEDI4166 (AZN), a fusion molecule of a GLP-1 analog and PCSK9 antibody. On the device front, Dexcom had initial data from the Type 1 cohort in the DIaMonD study of continuous glucose monitoring (CGM) without insulin pump use. For added perspective, the report also has information from Pharmaprojects® on the diabetes pipeline and from Trialtrove® on CVOTs in diabetes and industry-sponsored trials initiated since the last ADA meeting. Below we summarize the highlights from these presentations: GLP-1 Agonists versus SGLT2 Inhibitors, CVOTs and Renal Effects

• While it was impressive that Victoza even showed a CV benefit in LEADER, the overall reduction in the MACE primary endpoint was only moderate. Nevertheless, most speakers and attendees we queried felt even a modest benefit would be meaningful. Moreover, the benefit on CV death was larger, and importantly drove a benefit on overall death.
  • Of course, how much of an impact the results have will depend on whether Victoza can gain an indication for a CV benefit or at least have the superiority data shown on its label. This may be more challenging in the US than in Europe. Shortly after the meeting, an advisory committee vote on the CV benefit of SGLT2 inhibitor Jardiance was split, and it is unclear what the FDA will decide to do. Like LEADER, Jardiance's EMPA-REG was conducted to satisfy FDA safety requirements.
    • Victoza had a somewhat smaller p-value and may not face certain issues that arose for Jardiance, but it may have some of its own.
  • At the LEADER presentation – and interestingly at an update session on Jardiance's EMPA-REG, as well – speakers talked about the different patterns in the outcomes and how Victoza likely impacted atherosclerosis whereas Jardiance likely involves other mechanisms benefiting cardiac dysfunction. While others could have more questions in the future on the mechanism for Victoza, NVO will no doubt seek to press these points in its marketing to differentiate the two, particularly since Victoza is an injectable and so faces more resistance from patients.
    • Physicians were still grappling with how to choose patients for Victoza versus Jardiance, with some simply saying Victoza for atherosclerosis and Jardiance for patients with heart failure type pathology, though a LEADER investigator acknowledged a number of other practical issues will also likely come into play.
    • While the reduction in CV death for Jardiance was larger than for Victoza, the problem Jardiance faces is that the mechanism for its benefit and which patients are likely to benefit most are unclear. Interestingly, both a prominent Jardiance investigator and a speaker at a session on EMPA-REG suggested Jardiance and Victoza could be used together. It will be interesting to see if that is a message that gets repeated more often.
    • Cardiologists may have an important role to play in driving adoption, yet may only want to recommend usage if patients have another primary diabetes provider.
• The mechanism for Jardiance's benefit in EMPA-REG was another prominent issue at the conference, though nothing definitive was presented.
  • Hypotheses were presented on how an SGLT2 inhibitor mediated increase in ketone bodies could serve as a more efficient fuel for the heart, as well as for the kidney, where there was also a suggestion of a benefit in EMPA-REG. More research will be done to investigate this pathway.
  • A mediation analysis of EMPA-REG found the only initial covariate that had an impact on CV death was hematocrit, which the investigators used as a surrogate for a plasma volume/diuretic effect. However, one of the presenters of the ketone body hypothesis also felt an increase in hematocrit itself could contribute to the benefit due to greater oxygen delivery. Interestingly, in the mediation analysis, other risk factors such as blood pressure and weight did not appear to have an impact, though it was only a univariate analysis.
• Renal data from both Victoza in LEADER and more details from Jardiance in EMPA-REG were also of interest.
  • While Victoza did show renal benefits, this was driven by a reduction in macroalbuminuria, rather than other more clinically relevant endpoints. The latter were still numerically favorable, albeit only to a modest extent.
  • Jardiance did have an impact on more clinically relevant endpoints, but the FDA advisory committee meeting soon after the conference raised issues about the robustness of the data. Hence, it appears unlikely the information will make it on to Jardiance's label without data from its own additional studies.
    • Still, the data are suggestive, with positive implications for Invokana's ongoing, dedicated diabetic nephropathy trial. Invokana had more details at the conference on slowing renal function decline from a trial against glimepiride, which was suggestive, though some of the data were mixed.

Other GLP-1 Agonist Highlights

• Much of the data for semaglutide (NVO) from SUSTAIN 2 and 3 were expected from the top-line releases, with a fairly sizeable efficacy advantage on A1C and weight loss over Bydureon, albeit at a cost of almost double the nausea (the latter was similar to Victoza). A sizable imbalance in malignancies in SUSTAIN 3 will need to be followed up with data from other trials, but a company spokesperson said the imbalance tends to disappear across the program.
  • It will be quite interesting to see positive CV outcomes results from SUSTAIN 6 at the upcoming EASD meeting, though superiority was not prespecified, and given the size of the study, there may not be sufficient events to be considered robust.
• In FREEDOM-2, ITCA 650's (Intarcia, Servier) advantage on A1C and weight over DPP-IV inhibitor Januvia was as expected and comparable with data from some other GLP-1 agonists. The rate of nausea was also comparable, but vomiting appeared high, as it had in FREEDOM-1. We comment on likely uptake.
  • A novel placement tool should reduce the risk of fibrosis with the implantable mini-pump device.
• Results from weekly Trulicity's (LLY) AWARD-9 add-on to insulin study were pretty much expected, but interesting in light of the fact that the combination will have to compete with new fixed-dose combinations (Xultophy and LixiLan) likely to enter the US market soon. At Xultophy's recent FDA recent advisory committee meeting, one of the panelists raised the issue of alternatively using a weekly GLP-1 agonist with daily basal insulin.
  • Xultophy would have an advantage on side effects during the titration period and in patients who may forget to take a weekly dose, but Trulicity would be an option if physicians prefer to dose the individual components separately.
  • After the conference, LLY announced a novel performance-based contract with Harvard Pilgrim Health Care for Trulicity, and is talking to other payers about similar contracts.
• LixiLan (SNY, Zealand), a fixed dose combination (FDC) of the GLP-1 agonist Lyxumia and basal insulin Lantus, had first conference presentations from its pivotal trials, but much of the details had already been released at the FDA advisory committee meeting. The FDC is handicapped by Lyxumia's modest efficacy when given once-daily, though when asked about this by audience physicians, KOLs at a symposium suggested the FDC may have a role in patients with high post-prandial glucose.

Other SGLT2 Inhibitor Highlights

• First Phase III trial data for ertugliflozin (MRK, PFE) were consistent with other SGLT2 inhibitors, but the drug's value lies in its combination with sitagliptin, for which there were also Phase III data at the conference. This combination is likely to gain strong traction due to Januvia’s widespread use in the market.
• A combination of Invokana (JNJ) and phentermine appeared to show synergistic effects in non-diabetic obese and overweight patients. Weight loss from Invokana alone, however, was fairly modest.
  • The company has not said yet whether it will pursue development of the combination. Of course with phentermine's sympathetic stimulant effects, physicians may not be comfortable with the combination without a definitive CVOT showing safety. Obesity drugs have also struggled a great deal in the market, and it is not clear why this combination should do better, since the weight loss may still turn out to be modest.
  • In contrast, data from a combination study of Farxiga and Bydureon (AZN) in non-diabetic obese patients were fairly modest.
• Data in Type 1 patients regarding Invokana and also Farxiga added to Victoza highlighted the risks of diabetic ketoacidosis in this segment, though that could be mitigated by maintaining a certain insulin dose.
• An FDA warning on amputations with certain SGLT2 inhibitors, which came the month before the meeting, was not much of a topic, and physicians did not appear too concerned.

Insulins

• Merck’s insulin glargine biosimilar had positive, albeit expected, first Phase III data in both Type 1 and Type 2 diabetes. While timing is unclear, its launch will serve to further intensify pricing pressures within the basal insulin space which has become increasingly cost- conscious in recent years.
• Similarly, SAR342434, Sanofi's biosimilar insulin lispro, demonstrated non-inferiority in Type 1 patients. The biosimilar should provide Sanofi with an opportunity to gain lost ground within the prandial insulin analog market.
• Details for the SWITCH studies of Tresiba, designed to confirm a hypoglycemia benefit over market-leading Lantus in a double-blind fashion, were generally positive and without major surprises relative to the previous top-line release.
  • While the data for Type 2 patients were somewhat stronger than for Type 1, an investigator acknowledged that the patients selected for being at higher risk of hypoglycemia in the study are not ones who would be treated as aggressively in clinical practice.
    • In practice, the investigator tends to use Tresiba more as a niche product, reserving it for Type 1 diabetics, as they have more hypoglycemia, and Type 2 patients who require two doses of Lantus and so could benefit from a longer acting insulin. The investigator and others acknowledged titration was easier with Lantus. Competition of course also depends to a large degree on discounting and formulary placement, which will be impacted by glargine biosimilars, as noted above.
• Data from Phase III trials investigating faster-acting insulin aspart (FIAsp) indicated only marginal benefits over NovoLog.
  • Presenters and physicians seemingly concur that FIAsp and BioChaperone Lispro, which also had data at the conference, are likely to offer the greatest benefit in Type 1 diabetes patients, and particularly in those receiving continuous subcutaneous insulin infusion (CSII). This is likely to severely limit the commercial potential of the new insulin analogs.

Devices (from Meddevicetracker)

• In Dexcom's DIaMonD study, continuous glucose monitoring (CGM) in Type 1 patients not on a pump led to a moderate reduction in A1C with slightly less biochemical hypoglycemia.
  • Patients still used self-monitoring blood glucose (SMBG) checks ("fingersticks") in the trial. However, the company is hoping to reduce the number of those measures needed, with a new generation device that should require only one SMBG for calibration and an advisory committee meeting on July 21 for allowing CGM to be used instead of SMBG when making titration decisions.

Other Mechanisms

• Despite falling out of favor, there were data from glucokinase activators and glucagon antagonists still in development (Hua Medicine's HMS5552, vTv Therapeutics' TTP399, and Pfizer's PF-06293620 and PF-06291874).
  • In more troubling news for the glucagon antagonists, a study of Lilly's suspended LY2409021 that sought to clarify other potential side effects did in fact also find modest increases in blood pressure, LDL-c, and triglycerides.
• Merck's MK-8666 was suspended due to liver toxicity, similar to Takeda's fasiglifam. Nevertheless, Connexios is still pursuing the target, as it does not believe that it is necessarily an on-target effect.

The report includes news or data on a number of other drugs and topics, as well, including: LixiLan (SNY, Zealand), SAR425899 (SNY) and MEDI0382 (AZN) (both are dual GLP-1 and glucagon agonists), RPC8844 (Receptos/Celgene; small molecule GLP-1 receptor allosteric modulator), MEDI4166 (AZN; fusion molecule of GLP-1 analog and PCSK9 antibody), BioChaperone Lispro (LLY, Adocia) and Combo (Adocia), MLR-1023 (Melior, Bukwang; Lyn Kinase Activator), DS-8500a (Daiichi Sankyo; GPR119 agonist), CNX-010-710 (Connexios; 11ß-HSD1 Inhibitor), MTBL0036 (Metabolys; mitochondrial uncoupler). Like our report? Have any questions or feedback? Please let us know at askanalyst@sagientresearch.com.

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