FDA approves Orexigen/Takeda’s Contrave for chronic weight management - September 16, 2014

Executive Highlights

Following last Wednesday’s FDA approval of Orexigen/Takeda’s Contrave (naltrexone/bupropion) for chronic weight management, Orexigen management held a conference call the following day. As a reminder, Contrave’s label states that the drug is approved for chronic weight management as an adjunct to a reduced-calorie diet and physical activity in adults with a BMI >30 kg/m² or those with a BMI >27 kg/m² and at least one weight-related comorbidity (the same indication as Vivus’ Qsymia and Arena/Eisai’s Belviq). As is the case for Qsymia and Belviq, the label indicates that Contrave should be discontinued after 12 weeks if a patient has not lost at least 5% of baseline body weight. Contrave is the third obesity pharmacotherapy to receive FDA approval in the last two years; the approval announcement came one day ahead of the drug’s extended PDUFA date and on the eve of the FDA Advisory Committee meeting for Novo Nordisk’s Saxenda (liraglutide 3.0 mg for obesity), which ended with a very positive 14-1 vote in favor of approval.

In the conference call, Orexigen did not provide a specific date of Contrave’s launch but noted that Takeda plans to launch the drug this fall (as mentioned in Orexigen’s 2Q14 update).

During the call, management disappointingly announced that the FDA is requiring a new cardiovascular outcomes trial (CVOT) as a post-marketing requirement. This was a surprise, as Orexigen used interim data from the ongoing Contrave CVOT, the Light Study, to support approval. We are very surprised by this and see it as a major blow for the FDA/industry relations; the cost of the study will obviously be very high and will prevent Orexigen from putting funds in other R&D. According to management, the chief reasons for the FDA’s decision were (i) that the Light Study would not be able to show adequate on-drug cardiovascular endpoints and (ii) that the previous disclosure of interim results (to enable approval) could bias the remainder of the trial if the findings are widely disseminated. On the latter point, this obviously has been a risk for some time, and we are surprised and disheartened that the FDA would have allowed this while now changing the goalpost and requiring another study – all without previously informing the company. While management acknowledged that this decision will lead to significant costs (estimated to be $150-200 million), they showed optimism during the call, noting that a new CVOT could be designed to better show potential cardiovascular superiority or other clinical benefits that could fit into the company’s lifecycle development plans. The company plans to complete a final protocol by April 2015 and report study results by January 2022 (approximately five years later than Light’s planned completion date). Indeed, we are very disappointed by the decision that FDA is forcing on Orexigen, as initiating a new trial will require enormous additional investments from patients, investigators, and the companies; the issues arising from interim disclosure of data from CVOTs was discussed extensively at a recent FDA Public Hearing, and we believe this case illustrates why the FDA’s current policy is fraught with challenges. Orexigen will be primarily responsible for funding the new CVOT, but additional incremental costs will be evenly split with Takeda if the trial is eventually expanded to increase the likelihood of detecting superiority. Going forward, of course, we would hope that trials could be designed to show both safety as well as superiority though this is obviously likely very challenging to do.

Notably, the FDA has determined that Contrave does not have abuse liability and will thus not be classified as a DEA scheduled drug – this is a major win for Orexigen and Takeda. Furthermore, the drug does not have a risk evaluation in mitigation strategy or REMS, which hampered initial commercialization of Vivus’ Qsymia. Without the classification of a DEA scheduled drug, Contrave can now be launched on Orexigen/Takeda’s own timeline. This is a major advantage over the 2012 approval of Arena/Eisai’s Belviq, as that launch had to be delayed by four to six months due to DEA scheduling – as well, the classification of drugs with REMS have prompted pause among PCPs. We look forward to hearing more about the launch; management already noted that sampling will be a major part of it, which is great for patients in our view, considering Takeda’s 900 reps outside the US.

• Full Contrave prescribing information can be found at www.contrave.com. Contrave’s prescribing information lists two limitations of its use: (i) effects on cardiovascular morbidity and mortality; and (ii) combination with other weight loss products. These limitations will be evaluated in the post-marketing CVOT and a clinical study evaluating drug-drug interactions. The other post-marketing requirements include two pediatric studies and two other clinical studies evaluating cardiac conduction and hepatic/renal impairment.
  
  • The prescribing information also includes a boxed warning regarding suicidal thoughts and behaviors, as bupropion is a member of an antidepressant drug class. The label also carries warnings about the risk of seizure and increases in blood pressure and heart rate due to bupropion and a warning for hepatotoxicity due to naltrexone. Contrave is contraindicated in patients with uncontrolled hypertension, seizure disorders, chronic opioid use, and use of MAO inhibitors. All of these safety concerns were largely expected, and they are consistent with the labeling of the two already-approved components.
  • Both Arena/Eisai’s Belviq and Vivus’ Qsymia also have neuropsychiatric safety warnings. Belviq has warnings for Serotonin Syndrome, cognitive impairment, and psychiatric disorders (including euphoria and dissociation). Qsymia has warnings for suicidal behavior and ideation, mood and sleep disorders, and cognitive impairment. Although we do not perceive any unexpected safety concerns compared to the rest of the previously FDA approved obesity pharmacotherapy market, we do believe these safety concerns have presented a major additional barrier to PCPs. We also note, however, that neither Vivus nor Arena had a partner with nearly as much experience as Takeda, and it will be quite interesting to watch the obesity market expand with the marketing and scientific expertise that come with Novo Nordisk’s and Takeda’s entry.

• During Q&A, management expressed continued interest in combining Contrave with Takeda’s diabetes drugs. We were excited to hear this question as we’ve been wondering about this for some time as we see combination therapy very important moving forward in the armamentarium of PCPs and endocrinologists in treatment people with diabetes in particular – management was clear that there was already a plan in place with Takeda and that it was also speaking with other manufacturers. Indeed, management characterized the notion of pursuing a diabetes indication or a fixed-dose combination of Contrave and a diabetes drug “incredibly valuable” and said those ideas will be pursued with Takeda and other potential partners as the lifecycle plan is developed.
• Management noted that the Takeda marketing team is “moving quickly” on the launch, which is currently planned for this fall. The company has planned a national launch meeting and is working on training sales forces, developing marketing materials, packaging the first shipments, and beginning discussions with payers. As we noted in our Orexigen 2Q14 report, the company stands to benefit from Takeda’s significantly larger sales force (900 representatives) compared to Arena/Eisai (600 representatives) and Vivus (150 representatives).

Questions and Answers

Q: I’m wondering what your thoughts are on the label both in terms of breadth and safety considerations in comparison to other drugs? I also wanted to ask you about the messaging of suicidality.

A: I will just remind the audience that most of what’s in the label was expected and predicted many years ago, because a lot of the information on safety is related to what’s in the label for the constituent drugs, bupropion and naltrexone.

Q: I’m wondering whether you see this as a risk to adoption. How will that be addressed in the market?

A: These are elements that are in the bupropion label, and we estimate that bupropion today is still a successful generic antidepressant, used in about 7 million Americans. So for seasonal affective disorder, depression, and smoking cessation, it has been a successful legacy drug. The comfort level that physicians have with bupropion is a plus. There is a lot of comfort and confidence in the drug.

Q: Regarding co-promotion triggers, I know that you said that you’ll be evaluating that, but are there any specific sales milestones or perhaps strategic considerations that you could lay out for us?

A: I think the most important one is a positive ROI. While Takeda reimburses us for a portion of our field force cost, remember that we would be contributing to the total sales and earning back incremental royalties for any sales we can generate. So it’s pretty easy for us to do the math on how much that incremental field force would need to generate before we broke even and for it to contribute to positive ROI.

We’ve discussed that it would be interesting to go where there are opportunities that are untapped by the totality of the Takeda 900 representative force, and obviously those things get a lot easier in terms of ROI if you have more than one product. I think the way we look at this is that you would have plenty of notice as investors and analysts, because of the triggers that we need to notify Takeda of before we do it. This would develop with where we grow the company from here. So, no short-term plans – we’re just highlighting that that option exists and that we will use it as we navigate our future.

Q: I’m interested in your perspective on how significant of an advantage it is for the drug not to be scheduled, like the other products out there. What might the sampling strategy be, if you can comment on that at this point?

A: We see the fact that it is not in schedule as a big point of differentiation, as you can tell by the type of launch we’ve orchestrated with Takeda with 900 sales representatives. We think the way it will be successful is through primary care, though specialists will be important, too. And primary care physicians love samples, so sampling is a part of the tactical plan. I’m not going to get into specifics, but we see it as a big advantage and it has been a big driver in Contrave usage as the drug has launched.

Q: Now that Contrave is approved, are there any views you can share on the potential strategy of combining it with or evaluating the combination with some of Takeda’s diabetes offerings?

A: There is a plan in process. There is lots of evaluation going on for new indications to see how that fits with the new cardiovascular post-marketing trial. So you can imagine that we’re figuring out how to put the pieces together to maximize the value of the total program and how that may improve the total value of the global program. I can’t really say anything other than what we’ve said in the past. It looks incredibly valuable to go pursue a diabetes indication for the products. It also looks incredibly valuable to have fixed-dose combinations of Contrave with diabetes drugs. We’re not engaged in these discussions with Takeda alone, but also with other partners around the globe as we try to determine how to evolve the total development program. [Editor’s note: We assume management means “potential partners”.]

Q: I’m trying to understand what the issue is with the Light Study. Is the concern that too many of the events will occur after patients discontinue off the drug or is it because too many of the events were expected to be in the placebo arm?

A: There are two concerns that drove the decision to have a new cardiovascular outcomes trial for the post-marketing requirement. As you may recall, the design of the Light trial essentially kicked patients off blinded study drugs if they didn’t achieve enough weight loss by week 16. It was designed as a real world task, in which we expect those kinds of discontinuations. I think that was a great design for generalizing the overall safety experience for what we would see in the marketplace.

For further evaluation though, if you wanted to look at the effects of Contrave for cardiovascular outcomes, you would want to increase the number of events that occurred on the drug. The future of the Light trial will occur off-drug by virtue of the design. So, that was one factor driving the decision, and it was essential because we could have easily then just added more patients into the Light trial to satisfy that on-and off-treatment dynamic.

The other was data confidentiality, and as people who have been following this in the last year or two, regulators and sponsors encounter challenges when using interim data from ongoing blinded trials for regulatory submissions; both regulators and sponsors have pressures, policies, and legal standards that typically drive public disclosure of all information important to our products. And this competes with the pressures for data confidentiality to maintain the blinded ongoing trials. So even with confidential disclosure for regulatory submission, FDA was concerned that that could eventually lead to broader public dissemination of the information. So those data confidentiality issues were also key, and there have only been two cases now where drugs have been approved using interim analyses from ongoing blinded trials that we’re aware of. And in both of those cases, the final result was projected to be made public very soon after the regulatory approval.

Each case is specific. In our case, the choice was made for a new study to satisfy the post-marketing requirement, and we’re confident we can execute the study well and that value can be generated from this new trial, depending on how we fit it in with our overall lifecycle program. I know that’s a long answer, but I’m sure many people are going to have the same question, so I wanted to give a broad overview.

Q: Does that mean a new cardiovascular study would not have interim analysis?

A: That would be the case. I mean, these test studies always have DMCs to follow in their planned interim analysis. But this would not be comparable to Light, where you need to do an interim analysis for a regulatory purpose such as an approval.

Interim analysis in most trials follows a more or less academic model. A very small number of people –often only the DMC and no one from the sponsor – look at the information. That’s the model you would expect for the post-marketing study.

Q: Is there any potential for the Light Study to generate a superiority result?

A: As with all of these cardiovascular outcomes studies, Light was primarily designed as a non-inferiority study in terms of the first analysis. There is always an opportunity to also test for superiority should the circumstances warrant it. Obviously I do not want to go into many detailed conversations about the interim results, but just as a general concept, all cardiovascular outcome studies have the opportunity to test for superiority should the data support it.

Q: Does Takeda plan to use something like WeightMate, the web-based program that you implemented as part of Light? And are there any estimates as to what fraction of patients would experience 5% weight loss at 12 weeks?

A: In our experience, when you can do behavior change with the pharmacotherapy – and we’ve now done three randomized trials using behavior change programs as an adjunct to Contrave – the results are much better than taking the therapy alone or doing behavior change alone.

It ties into what we mentioned before about how we are impressed with some of the unique tactics Takeda is going to roll out. I don’t want to spill the beans on it, but we are very intrigued by the behavior modification program that they will be using in conjunction with educating physicians on Contrave. That’s how the label is written and that’s how the drug will be promoted; we’ll be focusing on computer data from our COR-BMOD study, and in that trial, combining Contrave with behavioral medication resulted in double-digit weight loss. You’re looking at an average of ~11.5% weight loss sustained over a year; that’s why it’s very important, because all of our market research shows that physicians are most interested in the weight loss they can expect from patients who are both ready to change and willing to stay on medication.

Q: With the Light Study, now that you’ve essentially taken the risk of disclosure off the table with the FDA, how do you think about potentially disclosing data from that trial, whether you continue it through to completion or not?

A: Some of the details of the utility of the ongoing Light trial and the operational plans, including disclosure, are under discussion. But right now, our plan is to let that trial continue to 50% interim. The events accruing towards that 50% interim are due very soon, we expect the analysis to be ready for early next year, and there are some pre-specified analyses that are going to take place that I think could be important. We’ll have to wait and see how that plays out. We’re also going to have to wait and see how disclosure plans play out with regulators where we’ve submitted the information. Because as I said, regulators have requirements for data disclosure for important information on products, and that competes with the desire for maintaining blind ongoing trials.

-- by Melissa An, Adam Brown, Varun Iyengar, Emily Regier, and Kelly Close