One of my long term SPA positions is Orexigen (OREX), whose lead candidate Contrave (Naltrexone 4mg, 8mg/Bupropion HCL 90mg extended release tablet, referred to as NB in the excerpts from FDA materials below) is in development for the treatment of obesity and weight management, including weight loss and maintenance of weight loss, in patients with an initial body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more risk factors (e.g. diabetes, dyslipidemia, or hypertension).
I am not going to review the entire clinical development history here, but instead will focus on safety and the LIGHT Study, and my thoughts on likelihood for approval long-term.
In terms of efficacy in achieving weight loss, my personal assessment is that the categorical weight loss achieved with Contrave is slightly better overall than Arena’s Belviq, and slightly inferior overall compared with Vivus’ Qsymia.
The company has been asked to perform a cardiovascular outcomes study to better characterize CV risk prior to approval of this product. This was requested because of a signal detected in review of the original NDA safety database. Readers should refer to the FDA briefing document from the first Advisory Committee meeting for full information.
“Bupropion, as an inhibitor of neuronal reuptake of norepinephrine, has the capacity to increase blood pressure and pulse. In the NB phase 3 clinical trials, subjects treated with NB32 had small but statistically significant mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. The treatment effect was most pronounced during the first eight weeks of treatment. NB32-treated subjects who lost at least 5% of baseline body weight (i.e., responders) had more favorable changes in blood pressure and pulse than NB32 nonresponders, but placebo responders had the most favorable changes overall in blood pressure and pulse. The frequency of hypertension-related adverse events was significantly higher in NB32 compared with placebo subjects.
Given the study subject demographics, and the size and duration of the phase 3 studies, the number of major adverse cardiac events (MACE) was too small to make reliable inferences about NB’s effect on cardiovascular risk. A rigorous assessment of NB’s cardiovascular risk profile would require a dedicated study in an appropriate population of overweight and/or obese individuals. The Division and Orexigen are in the early stages of discussing the design elements of such a study”.
What did the original reviewer find in terms of CV safety?
Here is a recap of the relevant CV findings:
• A greater percentage of subjects experienced blood pressure and pulse TEAEs in the Total NB group compared with the placebo group (5.9% and 4.2%, respectively). This was primarily attributable to the Hypertension (5.3% Total NB and 4.0% placebo). No serious blood pressure and pulse events were reported.
• Blood pressure-related TEAEs (including hypertension and increased blood pressure terms) in both the NB32 and placebo groups were reported mostly by subjects with a history of hypertension or antihypertensive medication use at baseline, occasionally led to treatment discontinuation, and required medication in approximately two-thirds of subjects.
• In Trial NB-304 (individuals with diabetes), 40 (12.0%) subjects in the NB32 group and 11 (6.5%) in the placebo group had a blood pressure-related TEAE during double-blind treatment. Ten percent (4/40) in the NB32 group were severe compared to none (0/11) in the placebo group.
Pulse:
• At both Weeks 4 and 8, the Total NB group had a statistically significant difference from placebo of +2.1 bpm.
• By Week 56, the statistically significant difference from placebo was +1.4 bpm.
• Increases in pulse from baseline (≥5, ≥10, and ≥20 bpm) and pulse increases ≥90 bpm at two consecutive or the final visit were observed at higher incidences in NB-treated subjects.
Systolic Blood Pressure:
• At Week 4 and at Week 8, the Total NB group had a statistically significant difference from placebo of +2.4 mm Hg.
• By Week 56, the statistically significant difference from placebo was +1.5 mm Hg.
• Subjects in the Total NB group were 2.5 x as likely to experience 2 or more SBP readings ≥150 mm Hg and were 2x as likely to experience 2 or more SBP readings ≥160 mm Hg.
Diastolic Blood Pressure:
• At Weeks 4 and 8, the Total NB group had a statistically significant difference from placebo of +1.9 and +2.1 mm Hg, respectively.
• By Week 56, the statistically significant difference from placebo was +1.2 mm Hg.
• Shifts to high potentially clinically significant (PCS) DBP values were 3 to 4 times more frequent in the Total NB group as compared to Placebo in the first 12 weeks. The incidence remained higher in the Total NB group until Week 28 where the incidence of shifts to high PCS between groups was generally similar between placebo and Total NB until trial end.
Cardiovascular Events
• MACE events (CV death, MI, CVA) occurred in 3 NB patients vs 1 Pbo patient.
• Overall Cardiovascular AEs—including atherosclerotic disease, arrhythmias, and congestive heart failure-- were similar between the Total NB and placebo groups.
• Ischemic CV events were too few in number to adequately assess CV risk in this patient population.
It is important to note that CV events were not centrally adjudicated and were very small in number for the total database; N=4
Key Points:
Table 34 in the briefing document is very helpful. It shows that at baseline, the average systolic BP is 119 mmHg in the Contrave group, this increases to 120.5 mmHg by week 56 for patients on therapy. In my opinion a systolic BP of 121 mm Hg would most likely be considered normal and not associated with any increased CV risk. Similarly Table 37 looks at changes in diastolic blood pressure. The diastolic BP was 77 mm Hg at baseline and was reduced to 76 mm Hg by week 56 (+0.51 mm Hg placebo adjusted change). Again, to me the absolute magnitude of this change does not suggest any increased risk of CV events.
Table 40 looks at absolute changes in pulse rate, another concern flagged by the reviewer. At baseline, the mean bpm was 72, at week 56 it was 72.3. Again, this to me is not really a red flag in terms of incremental CV risk.
Ultimately the company reached agreement with FDA to conduct a cardiovascular outcomes study prior to approval for which the protocol received a SPA. The details are here:
This trial is set to recruit N=9880 obese patients at high risk for CV events (assuming a background event rate of ~1.5%). An important factor is that patients not achieving pre-defined weight loss goals at 16 weeks of therapy must discontinue treatment, thus reducing the risk of unnecessary drug exposure (something that did not happen in the SCOUT trial for Meridia). Contrave CV risk will be deemed acceptable if OREX can exclude a doubling of CV risk (i.e., the upper bound of 95% CI not crossing 2.0) in the interim analysis, or if it can exclude 1.4 x risk in the final analysis. The interim analysis can be conducted after 87 events (expected to occur in 2013). OREX believes that if 50 or less of the 87 CV events occur in the Contrave arm, it will be able to reach approvable safety in the interim analysis. The important point here is that if the interim safety analysis fails to exclude a doubling of risk, it does not mean the trial has failed overall, but will continue with further safety analyses prior to study end.
What has impressed me most about this trial has been the rapidity with which enrollment has occurred. The trial opened on 6/6/2012 and was ~50% enrolled by 8/31/2012. Enrolling nearly 5,000 patients in 3 months is pretty impressive in my opinion. The company expects to close enrollment by the end of Q4 12 and to have accrued sufficient CV events for the interim analysis sometime in 2013.
What are my concerns with the trial?
This trial is enriched with obese patients at higher risk for CV disease than the patients who were enrolled in the original phase 3 studies. The inclusion criteria for greater CV risk are below:
- At increased risk of adverse cardiovascular outcomes:
· Cardiovascular disease (confirmed diagnosis or at high likelihood of cardiovascular disease) with at least one of the following:
· History of documented myocardial infarction >3 months prior to screening
· History of coronary revascularization
· History of carotid or peripheral revascularization
· Angina with ischemic changes (resting ECG), ECG changes on a graded exercise test (GXT), or positive cardiac imaging study
· Ankle brachial index <0.9 (by simple palpation) within prior 2 years
· ≥50% stenosis of a coronary, carotid, or lower extremity artery within prior 2 years
AND/OR
· Type 2 diabetes mellitus with at least 2 of the following:
· Hypertension (controlled with or without pharmacotherapy at <145/95 mm Hg)
· Dyslipidemia requiring pharmacotherapy
· Documented low HDL cholesterol (<50 mg/dL in women or <40 mg/dL in men) within prior 12 months
· Current tobacco smoker
There is a chance that Contrave and exacerbate risk and lead to significantly worse outcomes in this group. Per the review of the original NDA, blood pressure related adverse events occurred more often in patients with pre-existing hypertension, in some cases leading to patients coming off the study. However, a couple of factors are reassuring; Firstly, patients who are non-responders will discontinue therapy mitigating long term inappropriate drug exposure risk. Secondly, from the FDA’s responder analysis (see figures 7, 9 & 11) for individual CV parameters, you can see that Contrave non-responders experienced increases in blood pressure and heart rate, whereas Contrave responders experienced reductions in the same parameters. By eliminating the non-responders from the trial, we should in theory mitigate any potential risk posed by the small observed increases in blood pressure and heart rate.
The other concern is around costs of the study and the company’s state of funding. While the cost of the trial is estimated to be ~$100MM, Orexigen does not have sufficient funds today to finance through approval. In a best case scenario, if sufficient events accrue for a positive interim analysis by Q4 13, one would anticipate a filing of a response to the CRL by mid-2014, and approval late 2014. The study still needs to run to completion until 2017. The company's guidance is that current cash, cash equivalents and marketable securities will last through the anticipated timing of the resubmission of the Contrave NDA alone, so they will definitely have to raise cash at some point, I would guess before the interim safety analysis. I will be watching to add more to my position at that point.
Overall, I think the pro’s outweigh the cons for holding this position long term, especially given the significant potential near term catalysts.
This article is not meant as trading advice. Please conduct your own due diligence and trade securities at your own risk.
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