Memorandum

Vivus announces topline two-year data from SEQUEL study; 11% weight loss and 76% reduction in new-onset diabetes – September 21, 2010

Executive Highlights

  • Patients on full-dose Qnexa for two years lost an average of 11.4% (26 lbs) of baseline body weight and those on mid-dose Qnexa lost an average of 10.4% (23 lbs), compared to 2.5% (6 lbs) in placebo.
  • The incidence of new-onset type 2 diabetes among those without diabetes at baseline was reduced by 54% and 76% in patients on mid- and high-dose Qnexa, respectively, compared to placebo.

Early this morning, Vivus released two-year data from the SEQUEL study (OB-305), a 52-week extension study of the phase 3 CONQUER trial. This study was a double blind, placebo-controlled study with three arms: full-dose Qnexa (n=295), mid-dose Qnexa (n=153), and placebo (n=227). Patients continued receiving the same treatment they had been receiving from the CONQUER study in a blinded fashion (mean BMI of all SEQUEL participants was 36.1 kg/m2). The co-primary endpoints were the difference between treatments in weight loss and the percent weight loss over a two-year period from the beginning of CONQUER to the end of treatment (108 weeks, if the SEQUEL study was completed). Patients were advised to continue a hypocaloric diet (500 kcal/day deficit) and a lifestyle modification program. Patients on full-dose Qnexa for two years lost an average of 11.4% (26 lbs) of baseline body weight and those on mid-dose Qnexa lost an average of 10.4% (23 lbs), compared to 2.5% (6 lbs) in placebo (intent to treat, last observation carried forward analysis). In addition, Vivus shared striking data on the progression to diabetes within SEQUEL – the incidence of new-onset type 2 diabetes among those without diabetes at baseline was reduced by 54% and 76% in patients on mid- and high-dose Qnexa, respectively, compared to placebo.

On the safety front, there were no cases of suicidal attempts or suicidal behavior, and the depression measure PHQ-9 improved in both treatment arms. In addition, Vivus noted that the effect of Qnexa on heart rate was “small” in SEQUEL and there were no clinically relevant decreases of serum bicarbonate. Of major note, Vivus reported outcomes data across the entire Qnexa development program, involving 4,323 patients and including SEQUEL. Serious cardiovascular and neurovascular adverse event rates in patients taking Qnexa were “similar” to placebo with a relative risk of 0.59 (95% CI: 0.33-1.06). With the SEQUEL data in hand, Vivus remains on track to file Qnexa in the Europe by the end of the year. As we understand it, Vivus is still planning to file for European approval under the centralized procedure, which will involve the submission of a single Marketing Authorization Application (MAA) to the EMEA and grant approval for marketing in all of the European Union.

  • As a reminder, The CONQUER study (OB-303) was a placebo controlled, double- blind, randomized study in which 2,497 obese patients with two or more co- morbidities were evaluated over 56 weeks and treated with either placebo, medium- dose, or-full dose Qnexa. The mid-dose arm consisted of 498 patients while the full-dose arm consisted of 995 patients; 994 patients were given placebo. The majority of patients, 70%, were women. Patients were titrated for a four-week period and evaluated for an additional 52 weeks of treatment. Patients suffered from obesity-related co-morbidities such as hypertension (69%),diabetes (16%), and dyslipidemia (57%). As we understand it, the majority of patients had prediabetes; however, specifics were not reported. Average baseline BMI was 36.6 kg/m2, baseline weight was 227 lbs, and average patient age was 51 years old. Average A1c was 7.1 to 7.3% for a subgroup of obese diabetics; average A1c for all patients was not reported.
  • After two years, patients taking the mid- and high-dose of Qnexa experienced a mean weight loss 10.4% and 11.4%, respectively, compared to 2.5% in placebo (ITT- LOCF; p <0.0001). We note that these patients were likely stronger responders than the typical patients, given that they successfully completed CONQUER and agreed to enroll into an extension study. Although companies are sometimes criticized for showing “responder” analysis, we point out that the overall obese population is so high that undoubtedly the percentage of people that do respond and benefit from Qnexa is likely large, even if not everyone who took the compound in the original 52-week trial. Notably, the mid-range efficacy is almost as impressive as the high- dose efficacy. The following table provides a summary of the categorical weight loss (* denotes statistical significance of p <0.0001 compared to placebo):

Categorical Weight Loss (ITT-LOCF)

5% weight loss

10% weight loss

15% weight loss

High-dose

79%*

54%*

32%*

Mid-dose

75%*

50%*

24%*

Placebo

30%

12%

7%

  • Strikingly, the incidence of new-onset type 2 diabetes among those without diabetes at baseline was reduced by 54% and 76% in patients on mid- and high-dose Qnexa, respectively, compared to placebo. We note that in Vivus’ briefing document for the FDA advisory committee meeting, the company noted that the majority of patients in CONQUER had impaired glucose tolerance at baseline and the progression to type 2 diabetes was 14.6%, 10.7%, and 9.2% in those treated with placebo, mid-dose Qenxa, and high-dose Qnexa. According to the briefing document, the number needed to treat to prevent one case of new-onset type 2 diabetes over a one-year period was roughly 11 patients. Even though these data are likely inflated relative to the “real-world” (due to less frequent clinical visits to diagnose diabetes), we believe these results could have significant implications for prediabetes. While no drug has been approved in the US for prediabetes, the FDA has included brief, vague, and ambitious guidance in its draft guidance for diabetes drug development (see Appendix A for this section of the guidance document).
  • Treatment-emergent serious adverse event rates were 2.6%, 4.1%, and 4.0% for mid- dose Qnexa, high-dose Qnexa, and placebo, respectively. While increases in heart rate were characterized as small, Vivus emphasized that changes in heart rate were accompanied by improvements in blood pressure from baseline. Despite presenting this argument along with data on the rate pressure product at the FDA advisory panel, the advisory committee (see July 16, 2010 Closer Look) remained worried about the higher proportion of patients in the Qnexa arm (17%) compared to placebo (10%) that experienced a persistent heart rate elevation (defined as two measurements of a heart rate >100 bpm).
  • The completion rate in SEQUEL was exceptional; roughly 83% for Qnexa-treated patients and 86% for patients in the placebo arm stayed in the trial. This is fairly unheard of for obesity trials. Only 3.9%, 4.1%, and 2.6% of patients taking mid-dose Qnexa, high- dose Qnexa, and placebo discontinued due to adverse events. We note that the sample in the extension trial is likely skewed towards patients who experienced fewer adverse events during CONQUER.
  • With the SEQUEL data in hand, Vivus remains on track to file Qnexa in the Europe by the end of the year. As a reminder, the European regulatory agency requires two-year data for obesity drugs. As we understand it, Vivus is still planning to file for European approval under the centralized procedure, which will involve the submission of a single Marketing Authorization Application (MAA) to the EMEA and grant approval for marketing in all of the European Union. We also suspect Vivus will provide these data to the FDA. Pending a positive agency review of the SEQUEL safety data, these results may offer some assurance with respect to depression; however, we believe the FDA will still recommend strict REMS to monitor the primary safety concerns highlighted at the FDA panel (depression/suicidality and teratogenicity), both of which will require large numbers of patients (presumably in either post-marketing registries/trials and/or a limited launch of the product).

Close Concerns Questions:

How many patients had prediabetes at baseline in the entire Qnexa clinical development program, including SEQUEL?

What were the number of patents with CV and neurovascular events?

What is the typical expected timeline for the European review? Are limited launches allowed in the EU?

--by Sanjay Trehan and Kelly Close

 

Appendix A: FDA’s Guidance for Developing Drugs for the Prevention of Type 2 Diabetes Mellitus

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf

In phase 3 studies for products intended to prevent the development of type 2 diabetes in high-risk individuals (such as individuals with impaired glucose tolerance, impaired fasting glucose, or with a  history of gestational diabetes), potential endpoints supporting approval include delay in type 2 diabetes diagnosis or reduction in the proportion of patients diagnosed with type 2 diabetes by ADA criteria, relative to placebo. These study designs should include a follow-up (washout) period to assess whether the tested agent truly delays progression to diabetes or only masks diabetes during the treatment period. Such studies will likely be of substantial duration (years) and size. The FDA cannot a priori define the magnitude of a clinically meaningful effect size.

For prevention studies of drugs with a pharmacological action of improving glycemic parameters (e.g., approved treatments used in the prevention setting), improvement in clinical parameters beyond those that would be expected from glucose lowering alone should be demonstrated, since the forestalling of a biochemical diagnosis of frank diabetes from the prediabetic state may not itself be a sufficiently tangible benefit against which one can appropriately judge the risks. Such supportive evidence can include a demonstration of a durable delay in the onset of type 2 diabetes after the prevention therapy is stopped, or can show that the delay in progression to type 2 diabetes mellitus is accompanied by other indicators of clinical benefit (e.g., delay or lessening in microvascular or macrovascular complications). That said, the more modest the treatment effect, the higher the standard for safety and the more restricted (e.g., to subjects at highest risk  for near-term conversion to frank type 2 diabetes) the indicated target   population.