Inside The FDA: Eli Lilly and Co (LLY) Jardiance Aims at Proving Cardiovascular Benefit in Diabetes, Will FDA Agree?

Introduction

On June 28, 2016, the Endocrinologic and Metabolic Drugs Advisory Committee of the Food and Drug Administration (FDA) met to discuss and vote upon a supplemental New Drug Application (sNDA) for Jardiance, codeveloped by Boehringer Ingelheim Pharmaceuticals and Eli Lilly and Co (NYSE:LLY). The drug is an already approved compound that the FDA gave a green light to back in August 2014 for marketing as an adjunct to diet and exercise to improve glycemic control in adults with type II diabetes mellitus.

Subsequent to the approval, the drug was shown to reduce the likelihood of heart attack, stroke and cardiovascular death. Of these three reductions, the latter was the most dramatic as we will go on to discuss in a little bit more detail shortly. This study now forms the basis of the sNDA, and an approval in this indication could vastly increase the drug’s sales potential heading into 2017 and beyond.

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The FDA is expected to put out a decision at some point in November, but the advisory panel vote was very close, and there is a high degree of uncertainty as to which way the agency will go.

On August 4, the FDA signed off on the meeting minutes from the advisory panel review meeting, and made them available for public inspection. In an attempt to gauge the chances of the agency giving Jardiance a green light for commercialization as a cardiovascular risk- cutting compound, here’s our interpretation of the minutes, and an outline of our expectations for the drug going forward.

Note: The meeting also discussed the potential for approval of one other sNDA submitted by Boehringer Ingelheim regarding the expanded approval of another diabetes drug, Synjardy. Subsequent to the advisory panel review, and in line with the committee’s recommendation, the agency approved Synjardy in its extended indication on July 20, 2016.

Diabetes Type II

A quick review of diabetes is in order for new readers. Type II diabetes of course is characterized by high blood sugar and a lack of insulin. It occurs from a pathophysiological perspective as the result of insufficient insulin production against a background of insulin resistance.

The best way to think about insulin is as a sort of key that opens and closes the cells in the body to glucose. When we eat, certain enzymes break down complex carbohydrates into glucose. In healthy patients, this glucose then transfers into muscle and tissue cells, where it is stored or used as energy. Insulin is what opens up the cells to allow the glucose to get in. In patients with type 2 diabetes, however, a lack of insulin means the cells aren’t open to glucose absorption and the glucose builds up in the blood.

Additionally, in patients with type 2 diabetes, the liver releases too much glucose in the evening and at night. There’s not enough insulin available to deal with the released glucose, and again, it builds up to high levels in the blood.

This buildup can result in a whole host of complications, including tissue damage, circulation issues, kidney damage, sight and hearing issues, cardiovascular issues, stroke and an increased risk of Alzheimer’s disease.

Globally, type 2 diabetes is a massive problem. In the US alone, 30 million people suffer from diabetes, and it is estimated that more than 8 million remain undiagnosed. Of these numbers, between 90-95% fall into the type 2 diabetes category, with the remainder classed as type 1 which is caused by autoimmunity against the pancreas. Nearly 2 million new diagnoses occur in the US every year, and the condition costs the US government an estimated $250 billion annually.

The World Health Organization (WHO) estimates that globally there are more than 387 million individuals living with the condition.

The current across-the-board standard of care is a combination of diet and exercise (the disease is actually preventable through a combination of these two elements, but by the time symptoms show it is generally too late to reverse onset) and regular insulin administration, generally by way of subcutaneous self-injection.

The Drug and the Companies Involved.

What is the drug in question, and which companies have an interest in its application and approval?

As mentioned above, the drug under scrutiny is known commercially as Jardiance. Its scientific name is empagliflozin. It was jointly developed by Boehringer Ingelheim Pharmaceuticals and Eli Lilly and Co (NYSE:LLY), as part of the alliance the two companies formed at the turn of the decade. The alliance was put in place to allow collaboration on a number of high ticket diabetes candidates, and since its inception, has produced a strong portfolio of products in the sector, generating billions in revenues annually.

Empagliflozin is an SGLT-2 inhibitor, a type of drug covered in an earlier Market Exclusive diabetes research report. The SGLT-2 here stands for sodium glucose co-transporter-2. Another term for SGLT-2 inhibitors is gliflozin. They essentially block the reabsorption of glucose in the kidney, and promote its removal by way of urination. This prevention means less glucose is retained in the blood, and by proxy, lowers the blood sugar levels in patients with diabetes.

The drug first picked up an approval in August 2014, when the FDA gave it the green light for commercialization in type II diabetes patients as an adjunct to diet and exercise. Boehringer Ingelheim and Eli Lilly split the revenues derived from the drug, which as of first quarter 2016, came in at a little over $38 million.

As an addendum to the FDA’s approving the drug, Eli Lilly was requested to undertake an extension study investigating the impact on cardiovascular risk in diabetes patients that underwent a regimen of Jardiance treatment, versus a placebo. It is this extension on which the sNDA is based.

The Trial and the Data

The trial in question was called the EMPA-REG OUTCOME trial. The primary endpoint (3-point MACE) was the time to first occurrence of CV death (including fatal myocardial infarction and fatal stroke), non-fatal MI, or non-fatal stroke. The key secondary endpoint (4-point MACE) was the time to first occurrence of any component in the 3-point MACE plus hospitalization for heart failure. The MACE endpoint is one that is hotly debated in biotech. It’s the standard efficacy measurement in most of these sorts of cardiovascular trials, but it doesn’t have a standard definition. This makes it difficult to compare like for like trials.

Anyway, looking at this trial specifically, the 3-point MACE outcome occurred in 490 of 4,687 patients (10.5%) in the empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group. For the secondary endpoint, the 4-point MACE which includes hospitalization for heart failure occurred in 599 of 4687 patients (12.8%) in the empagliflozin group and in 333 of 2333 patients (14.3%) in the placebo group.

There are two important takeaways from the data, and it’s on one of these two takeaways that Eli Lilly and Boehringer decided to go for the extended approval.

The first, and the most relevant, is that CV death occurred in 172 of 4687 patients (3.7%) in the empagliflozin group and in 137 of 2333 patients (5.9%) in theplacebo group. To put this another way, the drug reduced CV death by 38%. That’s big, and highly significant.

The second is that all-cause mortality occurred in 269 of 4687 patients (5.7%) in the empagliflozin group and in 194 of 2333 patients (8.3%) in the placebo group. This is a reduction of 32%. Again, highly significant.

Safety issues, tolerability concerns and adverse events across the entire trial were comparable between placebo and active arms, suggesting this shouldn’t be an issue when the FDA comes to making a decision.

The Panel Review

Now let’s get to the primary documents here and here. How did the panel view the application?

The committee reviewed all the material, and then asked a number of questions rooted in the trial and its outcome. The committee then summarized the individual answers to these questions and published summaries as part of the review document. It is these summaries that we will be working from.

The first question related to how the study was conducted, and addressed the exclusion of some data from the final endpoint calculation. Specifically, the removal of certain data relating to silent myocardial infarction, and how this might impact the reliability of the data that pointed towards an endpoint hit.

The response to this one was mixed, but looks weighted towards the opinion that these changes don’t really impact the reliability of the data. The fact that the changes occurred before an interim unblinding fell in favor of the endpoint hit, and the robustness of the data on which the extension is resting (i.e. the CV death data), as well as this data’s chances of being affected by the exclusion of silent MI (i.e. very slim) supported this opinion.

Interpretation – generally positive and favors approval.

The second question again referred to the changes discussed in the first question, and sought to identify the committee’s confidence in the data supporting the primary analysis – i.e. the 3-point MACE reduction.

Again, the panel served up a mixed response to this one, but this time it looks as though the response was slightly weighted against approval. Specifically, a large number of CV deaths were excluded from the trial and classed as not evaluable as part of the final analysis. The uncertainty surrounding the justifiability of these non-inclusions looks to have translated to some loss of confidence in the bottom line numbers, and in turn, the drug’s justifiability as an extended indication. Additional concerns surrounding the exact mechanism of action (MOA) were also raised. To quote:

“Some committee members stated that the trial results do not clearly point to a readily identifiable mechanism to explain the CV mortality results.”

Basically, we don’t really know why this drug reduces risk of CV death, even if the data suggests it does. For some panel members, and as many of these sorts of meetings have shown historically, this isn’t a big issue. For some, however, it can be. It seems there may have been more of the latter group on this panel than the former.

Interpretation – again mixed, but somewhat weighted against approval.

The third question was a sort of combination of the first two, seeking to address the persuasiveness of the findings when looked at in favor of approval.

The answer to this one was clear, but again, mixed in its inference. The panel pretty much agreed across the board that the data suggested Jardiance has a positive impact on CV deaths in diabetes patients, and based this agreement on the low P Value for the data. In other words, statistically, the drug looks to work well. However, based on the lack of understanding of a clear MOA, the panel (again, pretty much unanimously) agreed that the robustness of the results is questionable.

Interpretation – mixed, weighted towards no approval based on a lack of scientific understanding.

The fourth question addressed a specific point of the study relating to heart failure. Essentially they were asked to discuss whether the drug is effective in reducing heart failure, based on the available data.

The answer to this one is clear and simple – no, the data is not sufficient to say with any confidence that the drug is effective in reducing the rate of heart failure. Further, the data is not only insufficient to make this assumption, it suggests that the drug is NOT effective to this end.

Interpretation – negative, but not overly relevant. The labelling expansion is targeting reduced risk of cardiovascular risk, yes, but heart failure is going to make up only a small part of this labelling.

The fifth and final question looked at the so called renal findings. By way of a brief introduction here, the trial threw up some data that suggested an improved profile over placebo in renal risk, and in some of the numbers, even suggested that the drug might have a renal benefit on patients in this indication. The question posed here relates to this benefit, with regards to whether the data is reliable enough to justify any sort of labeling, or further investigation into the renal side of the equation.

Again here the interpretation was profoundly negative. The panel noted that the data was intriguing, but far from usable for either of the above-mentioned goals, and that a lack of proper adjudication pretty much renders it irrelevant to the trial and – in turn – the outcome of this application.

Interpretation – again, negative to some extent, but judged to be totally irrelevant, so it shouldn’t impact the panel’s, or the FDA’s final decision.

After the fifth question, the panel was asked to vote on two points.

The first:

“Based on data in the briefing materials and presentations at today’s meeting, do you believe the EMPA-REG OUTCOME study results have fulfilled the recommendations laid out in the 2008 Guidance for Industry by demonstrating that use of empagliflozin to improve glycemic control would not result in an unacceptable increase in cardiovascular risk?”

Result:

– Yes – 23

– No – 0

– Abstain – 0

Interpretation – this is a given. The initial endpoint looked at non superiority (as opposed to creating a discernible benefit) and with the numbers produced in the trial, there is a clear non inferiority of Jardiance to the current SOC.

This is the important one though:

The second:

“Based on data in the briefing materials and presentations at today’s meeting, do you believe the EMPA-REG OUTCOME study results provide substantial evidence to establish that empagliflozin reduces cardiovascular mortality in the population studied?”

Result:

– Yes – 12

– No – 11

– Abstain – 0

Interpretation – the panel voted slightly in favor of the drug’s ability to reduce cardiovascular risk, but noted a few key points in support of the null hypothesis. Specifically, that they do not understand the MOA sufficiently to make such a call. We keep coming back to this, and it’s probably going to play a big part in the FDA’s ultimate decision. Additionally, the members who voted no suggested that the standard procedure for this sort of thing is that the FDA requires two Phase III studies before it can address an application. The first generally establishes efficacy. The second reinforces efficacy, and addresses any shortcomings of the first. The panel’s view on this is that without the second trial, it’s difficult to vote in favor of the hypothesis.

Conclusion – FDA Will Ask For Another Trial

So, this is what it all comes down to. What will the agency say about the application, and will it approve the drug in this expanded indication?

Our answer – no, it probably won’t. The FDA has been dragging its feet lately even on diabetes drugs with much more obvious supportive data like IDegLira from Novo Nordisk A/S (NYSE:NVO) and IGlarLixi from Sanofi SA (NYSE:SNY).

We see the two most commonly raised issues as real stumbling blocks – the lack of understanding of the MOA and the inability to address inefficiencies without a second Phase III trial.

We believe the FDA will issue a CRL and request a second Phase III trial.

Implications for Eli Lilly, Novo Nordisk, Oramed Pharmaceuticals Inc. (NASDAQ:ORMP)

The importance of this trial is not only for Jardiance and Eli Lilly alone because there are implications for other companies involved in the diabetes space. This Jardiance trial that the sNDA was based on as we noted above was a special case in that it was an extension study to see if the drug had a negative effect on cardiovascular health. The purpose of the trial was to dispel that, which it did. Since the results did seem to additionally show some cardiovascular benefit, Eli Lilly and Boehringer decided to submit an sNDA on that stroke of good fortune. If the FDA approves the sNDA, Jardiance would become the first oral type II diabetes medicine to be able to market itself as reducing the risk of cardiovascular death.

This would vastly expand its use and turn Jardiance into something much bigger than just a $38 million drug. If the FDA says that it does reduce the risk of CV death, then it would likely become a supplemental drug for most diabetics, rather than just another niche supplemental therapy option for some.

This reveals a market vacuum here because there currently is no oral diabetes medication proven to reduce the risk of CV death. The first diabetes company to fill this vacuum would benefit greatly. Assuming Jardiance does not get this designation in the near term, which we feel is the most likely scenario as of now, then the vacuum will likely remain for some time.

The other factor here is that it is not possible to directly test whether subcutaneous insulin therapy reduces the risk of cardiovascular death, because it would have to be tested against a control, and you cannot compare diabetics on insulin with diabetics on placebo for obvious reasons. The doubt as to whether insulin increases or decreases CV death is one of the reasons why insulin therapy is generally delayed until there is no other choice.

However, there are two companies that could conceivably fill the vacuum, assuming Jardiance does not fill it with a second Phase III trial. These are Novo Nordisk A/S (NYSE:NVO) and Oramed Pharmaceuticals Inc. (NASDAQ:ORMP). As we have pointed out in previous diabetes Inside the FDA reports, both companies are developing an oral insulin pill, and both companies have successfully completed Phase II trials with promising results. Novo’s pill seems to so far successfully lower blood sugar on par with subcutaneous insulin, while Oramed’s seems to maintain blood sugar levels over placebo.

While subcutaneous insulin cannot really be trialed against a control to test for cardiovascular benefits, an oral insulin pill can, and this opens both candidates up to the possibility of being the first insulin therapy proven to lower the chances of CV death. Trials could theoretically be designed to test oral insulin versus subcutaneous insulin on the same MACE endpoints as the Jardiance trial. This would seem appropriate in Novo’s case, whose oral therapy is showing evidence of lowering glucose levels. Novo’s pill was trialed against insulin glargine, so the same setup to test for CV risks would be consistent.

As for Oramed, it may decide to go a slightly different route of testing its own oral insulin versus placebo as it has done for its most recent Phase II trial. This would be possible in Oramed’s case because judging by the latest Phase II results, its candidate ORMD-0801 seems more appropriate for early stage or prediabetics since it seems to stabilize nighttime blood sugar rather than substantially lower it. It is conceivable to conduct a placebo-controlled trial in this case because early stage diabetics generally do not go on insulin so quickly anyway, and so a control arm could be tested against ORMD-0801 to test for cardiovascular events.

Overall, the inference here is that there is a major vacuum in the diabetes market. Insulin cannot yet be proven to reduce CV death because of the limits of testing the hypothesis, but oral insulin in theory could be tested in this way. The first company to get an oral insulin to market, whether it is Novo or Oramed, may be asked to conduct post-marketing studies just like Eli Lilly and Co (NYSE:LLY) and Boehringer conducted one for Jardiance. If either company can prove it, not only will it open up a brand new market in oral insulin, it may also be able to claim reduced chances of cardiovascular death, bringing more diabetes and prediabetes patients on insulin earlier on in their disease.

There is reason to suspect from a scientific standpoint that both Novo and Oramed’s formulations might actually do this. Since oral insulin goes directly to the liver through the portal vein, in theory it acts as insulin acts in normal healthy people. This in itself implies that it might reduce CV death, which would make either pill a big hit in diabetes markets.

Yet another reason why oral insulin could change the diabetes landscape.

Note: This article is written by David Rich and originally published at Market Exclusive.