Memorandum

FDA releases briefing documents for Advisory Committee meeting for Novo Nordisk’s Xultophy (insulin degludec/liraglutide) – May 20, 2016

Executive Highlights

  • The FDA has posted briefing documents for the May 24th Advisory Committee meeting for Novo Nordisk’s Xultophy (insulin degludec/liraglutide).
  • The FDA briefing document is slightly more negative than we had expected, raising concerns about the lack of dosing flexibility with Xultophy and the interpretability of the clinical trial data. We do expect the panel will advise approval.
  • Novo Nordisk’s briefing document highlights Xultophy’s superior glycemic efficacy and mitigation of side effects vs. its components and portrays the simple titration scheme as an advantage.
  • The FDA’s draft questions ask the panel to consider the benefits of treatment with Xultophy in patients not on basal insulin or a GLP-1 agonist and in patients already treated with one of the components, as well as clinical concerns related to dosing flexibility.  

The FDA has posted briefing documents for the May 24th Advisory Committee meeting for Novo Nordisk’s Xultophy (insulin degludec/liraglutide). Documents for the May 25th meeting for Sanofi’s Lyxumia (lixisenatide) and LixiLan (lixisenatide/insulin glargine) are not yet available and we expect they would be posted on Monday.

The FDA’s briefing document takes a slightly more negative view of Xultophy than we had expected, raising concerns about the lack of dosing flexibility and the interpretability of the clinical trial data. While these concerns may be a reason for some patients and providers to conclude that Xultophy is not the right choice for them, we don’t believe they are on any level sufficient to preclude approval of the drug and we expect it to move forward positively by the end of the day – see below for more thoughts on this. In brief, we note this drug is perceived extremely positively by the patient and HCP communities we know. Novo Nordisk’s briefing document portrays Xultophy as an attractive option that can help meet the unmet need for more effective ways to intensify type 2 diabetes treatment. Based on phase 3 data, the document asserts that Xultophy provides clinically relevant improvements in glycemic control relative to either component and addresses the main treatment barriers of both. We expect the FDA to take issue with two of Novo Nordisk’s claims in particular, which could affect the label – they are: (i) that the pivotal phase 3 data conclusively demonstrates that both components of Xultophy contribute to its effectiveness; and (ii) that the product’s simple dosing/titration scheme is an advantage.

The FDA’s draft discussion questions ask the panel to consider the benefits of treatment with Xultophy in patients not on basal insulin or a GLP-1 agonist and in patients already treated with one of the components. This implies that the ideal target population for this versatile product will be an important part of the discussion and suggests that the discussion on the product may focus on a potential narrower indication, though we see approval for such as unlikely. On the safety side, the panel is asked to discuss clinical concerns related to dosing flexibility and the delivery device. Overall, we expect the verdict to be favorable for Xultophy given the product’s demonstrated significant clinical benefit and lack of any clear safety signals, but these briefing documents suggest that the discussion might be more contentious than we had predicted. Read on below for more details and thoughts on the agenda, along with the list of panelists.

FDA Briefing Document

  • At first look, the FDA’s briefing document is a bit more negative than we had expected, raising concerns about the lack of dosing flexibility with Xultophy and the interpretability of the clinical trial data. The document states that fixed-combination products can be approved when each component has been demonstrated to contribute to the claimed effects (improvement in glycemic control in this case) and the proposed dosage is safe and effective for a significant population. It states that in general, a new combination product should offer doses for all possible combinations that would be available by combining the individual products. The absence of any such dose combination must be justified “based on solid grounds,” such as evidence that the specific combination would be used by only a small minority of patients. The FDA also argues that it is difficult to interpret claims of a safety/tolerability advantage for a combination product over its components because what might appear to be an advantage for one risk (e.g., less hypoglycemia) could be counterbalanced by a disadvantage for another risk (e.g., more nausea).
  • The FDA outlines several specific concerns related to Xultophy:
    • It combines a fixed-dose product with a titratable product dosed on a continuous scale.
    • The proposed dosage for the liraglutide component of the combination is different from the approved dosage of standalone liraglutide. The proposed dose range includes low doses that have been demonstrated to be ineffective on their own, meaning patients could be exposed to a component that provides no benefit and causes adverse events.
    • Insulin dosing was artificially constrained in the clinical trials for Xultophy, limiting the clinical applicability of the results. In trials investigating Xultophy against an insulin comparator, the starting dose, dose adjustments, and maximum allowable dose of the insulin were all fixed, whereas providers have much more dosing flexibility in real-world practice.
    • Inadequate insulin dosing may have biased efficacy results in favor of Xultophy in clinical trials. The FDA notes that the majority of participants in the clinical trial program never reached their fasting glucose targets, suggesting that insulin dosing may have been inadequate. Therefore, it believes that Novo Nordisk’s claims of clinical superiority for Xultophy vs. insulin are difficult to interpret.  
    • Patients already on a GLP-1 agonist or basal insulin would need to reduce the dose of their current treatment when switching to the combination. This could translate to poorer glycemic control compared to adding the second component independently.
    • Patients not on either component would be exposed to the adverse effects of two products rather than one. Some of those patients might have been able to achieve good glycemic control with a single agent, running a lower risk of adverse events. 
    • The complexity of the proposed combination (such as the fact that the two components have different dosing measurements) may lead to clinical errors. The high number of clinical errors today with insulin alone is a sobering concern, of course, although it was not discussed in the briefing materials.
  • While some of these concerns may be relevant for some patients, we see them as manageable, and do not believe they would ultimately preclude approval of the drug. There is significant positivity about the drug in patient and provider communities and we can imagine significant opposition if the FDA moved toward non-approval. While some patients may prefer the greater dosing flexibility that comes with titrating the two components independently, the simplicity and convenience of the dosing regimen for Xultophy will likely be a major advantage for others, to say nothing of HCPs. We believe this critique overlooks the fact that many patients and providers (particularly in the primary care setting) are reluctant to initiate or intensify insulin therapy and find complex titration schemes overwhelming. We are also skeptical of the claim that the performance of the insulin comparators in the DUAL trials was worse than it would have been in the real world. For example, in DUAL V, patients already on Lantus were able to achieve an average additional A1c reduction of 1.1% simply by intensifying therapy – we find it hard to believe that those patients would have achieved better results under usual care. Finally, we do not think it is fair to treat the side effect profiles of the two components as equivalent, as the dangers of hypoglycemia and the stigma associated with weight gain are likely more meaningful for many patients than the risk of transient nausea. Overall, we believe it comes down to choice – these concerns are legitimate reasons for some providers and patients to decide Xultophy is not right for them, but we do not believe they are sufficient to deny others access to a drug that could be very beneficial for them, particularly in this environment in which so many patients – and HCPs – are struggling with poor glucose management.

Novo Nordisk Briefing Document

  • Novo Nordisk’s briefing document portrays Xultophy as an attractive option that can help meet the unmet need for more effective ways to intensify type 2 diabetes treatment. The company notes that most people with type 2 diabetes currently do not achieve tight control, partly due to barriers to treatment intensification, and that the ability to intensify treatment without adding injections is a huge advantage for patients. Novo Nordisk also argues that because the pathophysiology of type 2 diabetes is so complex, optimal control requires a multifaceted approach. The complementary mechanisms of basal insulin (primarily targeting fasting glucose) and GLP-1 agonists (primarily targeting postprandial glucose) make these combinations particularly attractive in the company’s view.
  • Based on phase 3 data, the document asserts that Xultophy provides clinically relevant improvements in glycemic control relative to either component and addresses the main treatment barriers of both. Relative to basal insulin, the combination offers superior glycemic control with no additional injections while mitigating the main side effects of insulin (hypoglycemia and weight gain). These benefits are balanced against the risk of GI side effects with liraglutide. Novo Nordisk argues that the combination can also be a good alternative to GLP-1 agonists for some patients due to improved glycemic efficacy and fewer GI events, though avoiding hypoglycemia is an important consideration. All of this is consistent with commentary we have heard from a number of speakers on the diabetes conference circuit over the past few years.
  • Based on its briefing document, we expect the FDA could take issue with two of Novo Nordisk’s claims in particular: (i) the pivotal phase 3 data conclusively demonstrates that both components of Xultophy contribute to its effectiveness; and (ii) the product’s simple dosing/titration scheme is an advantage. Novo Nordisk’s document states that the DUAL I trial confirmed the contribution of the insulin degludec component to the combination’s efficacy and that the DUAL II trial confirmed the contribution of the liraglutide component, even at doses lower than those that are approved – the FDA’s briefing document suggests that the Agency believes these conclusions are not so clear-cut. Novo Nordisk also claims that Xultophy’s delivery device and simple titration scheme will allow patients and providers to achieve appropriate dosages and remove much of the uncertainty that would otherwise surround basal insulin/GLP-1 agonist combination therapy. Based on its briefing document, the FDA seems to believe this scheme might give providers too little flexibility to effectively titrate doses.

FDA Discussion Questions

1) Discussion: Discuss the benefit(s) of starting the fixed-combination drug product containing liraglutide and insulin degludec in patients with type 2 diabetes mellitus not treated with either a basal insulin or a GLP-1 agonist (i.e., starting two new drugs at once). In your discussion, identify the patient population in whom this use would be useful and address why you would select the fixed-combination product over use of an available GLP-1 agonist or basal insulin in these patients. Explain your rationale using data from the briefing materials and presentations, or from your own clinical experience. On a broad level, we appreciate the acknowledgement/discussion of personalized therapy and acknowledgement that “one size doesn’t fit all”.

2) Discussion: Discuss the benefit(s) of using the combination product containing liraglutide and degludec in patients with type 2 diabetes previously treated with either a basal insulin or a GLP-1 agonist (i.e., adding a single new drug to an existing regimen). In your answer, identify the patient population in whom use of the combination product in this manner would be useful. Explain your rationale using data from the briefing materials and presentations, or from your own clinical experience.

3) Discussion: Discuss clinical concerns related to the use of the fixed-combination product which combines a drug that, when used alone, has a wide effective dose range and is titrated to effect on a continuous scale (i.e., insulin degludec) with a drug that, when used alone, has one or two recommended effective dose(s) (i.e., liraglutide).

Specifically discuss:

A. Issues related to loss of dosing flexibility including but not limited to: Use of potentially ineffective doses of one agent in population with low insulin requirements, inability to dose the two drugs independently with the device presentation proposed, inability to increase the insulin dose beyond 50 units.

B. Issues related specifically to product presentation/device including but not limited to: use errors that may occur in the care setting related to a lack of clarity on the amount of each product delivered with each given dose, insufficient understanding that, unlike insulin products, the maximum dose for the combination is capped.

4) Vote: Based on data in the briefing materials and presentations at today’s meeting, do you recommend approval of the liraglutide/degludec fixed-combination drug, delivered using the proposed device, for the treatment of adult patients with type 2 diabetes mellitus?

A. If you voted yes, explain your rationale and discuss whether use of the combination should be approved for patients who have never been treated with a basal insulin product or a GLP-1 product, for patients who are inadequately controlled on either a basal insulin product or a GLP-1 product or for both populations. Recommend additional post-approval studies if you think these are needed.

B. If you voted no, explain your rationale and recommend additional pre-approval studies if you think these are needed.

Panelists

  • Robert Smith, MD (Chairperson, Brown University, Providence, RI)
  • LaToya Bonner, PharmD (Non-voting Designated Federal Officer, FDA, Silver Spring, MD)
  • Daniel Budnitz, MD, MPH (CDC, Atlanta, GA)
  • David Cooke, MD (Johns Hopkins University, Baltimore, MD)
  • Brendan Everett, MD, MPH (Brigham and Women’s Hospital, Boston, MA)
  • Diana Hallare, MPH (Consumer Representative, Visalia, CA)
  • Reshma Kewalramani, MD (Non-voting Industry Representative, Amgen, Thousand Oaks, CA)
  • James Neaton, PhD (University of Minnesota, Minneapolis, MN)
  • Charles Stanley, MD (University of Pennsylvania, Philadelphia, PA)
  • Peter Wilson, MD (Emory University, Atlanta, GA)
  • Susan Yanovski, MD (NIDDK, Bethesda, MD)
  • Barbara Berney (Patient Representative, Rockford, IL)
  • Kenneth Burman, MD (MedStar Georgetown University Hospital, Washington, DC)
  • Marie Gelato, MD, PhD (Stony Brook University, Stony Brook, NY)
  • Timothy Lesar, PharmD (Albany Medical Center, Albany, NY)
  • Steven Meisel, PharmD (Fairview Health Services, Minneapolis, MN)
  • Martha Nason, PhD (NIH, Bethesda, MD)
  • Michael Reed, PharmD (Rainbow Babies and Children's Hospital, Cleveland, OH)

 

-- by Emily Regier, Ava Runge, and Kelly Close