Actavis Hypertension Combo Prompts Discussion Of “Me-Too” Drug Standards

FDA’s Cardiovascular and Renal Drugs Advisory Committee used much of its review of a nebivolol/valsartan combo pill to discuss how much of an improvement a “me-too” product should offer over predecessors and a minimum clinical benefit threshold for antihypertensives.

The Cardiovascular and Renal Drugs Advisory Committee’s Sept. 9 review of Allergan PLC’s combination of nebivolol and valsartan highlighted the agency’s efforts to uphold strict standards for so-called “me-too” drugs and gave FDA the chance to get input on its practice of setting a minimal efficacy threshold for combination products in the crowded antihypertensive space.

The panel met to review Actavis’ fixed-dose combination comprising the beta blocker Bystolic (nebivolol) and valsartan (Novartis AG’s now-generic Diovan), an angiotensin receptor blocker. Ultimately, the committee voted 6-4 against recommending approval of the FDC, and even the “yes” votes were conditional and unenthusiastic (Also see "Actavis May Need To Rethink Nebivolol/Valsartan Claim After Negative Panel Vote" - Pink Sheet, 9 Sep, 2014.).

Advisory Committee Votes

Actavis is seeking approval of five dosage strengths (5 mg nebivolol/80 mg valsartan, 5 mg/160 mg, 10 mg/160 mg, 10 mg/320 mg and 20 mg/320 mg) as first-line antihypertension therapy in previously untreated patients, replacement therapy for patients already taking a free combination of nebivolol and valsartan for blood pressure control, and add-on therapy for patients who don’t meet their blood pressure goals with nebivolol or valsartan monotherapy.

• The panel voted 6-4 that the combination should not be approved to treat hypertension.
• The committee agreed it is reasonable to set a minimum blood pressure-effect threshold for a new antihypertensive, but was divided upon whether Actavis’ candidate would meet such a standard. It also agreed that improved tolerability over monotherapy is a valid basis for approval of a combination product, but said Actavis did not demonstrate such a benefit.

Part of the panel’s reluctance was due to the inherent endorsement that an FDA approval carries – with the marketing magic of big pharma, a new brand would be greeted as an important therapeutic advance even if it just has minimal efficacy. “Once a drug is approved, all you hear about in the ads and on TV is how spectacular these drugs are for everyone with this underlying problem,” committee member Stuart Rich, University of Chicago Hospitals, cautioned.

“If this drug is approved, [clinicians] may reach for this combination when there are multiple other combinations that are more efficacious,” James de Lemos, University of Texas Southwestern Medical Center, said. “Given how long it takes people to get to [their blood pressure] goal, I think the idea of approving combination products that are only minimally effective is a problem. If people want to use [the individual components], they can anyway.”

While the nebivolol/valsartan combo met the endpoints in its pivotal trial, in his introductory remarks, Cardiovascular and Renal Drug Products Division Director Norman Stockbridge deemed the value of the effect “questionable,” and other FDA reviewers reached even more negative conclusions.

“Treatment with the FDC does not provide a clinically meaningful reduction in diastolic blood pressure compared with the highest approved dosages of one of its components, that is nebivolol in this case,” Cross-discipline Team Leader Rajanikanth Madabushi told the panel. Neither would the profile support approval based on improved safety, he concluded: “Treatment with the fixed-dose combination does not provide an opportunity to improve the tolerability [of the two drugs] while retaining similar effectiveness.”

Madabushi pointed out that the nebivolol/valsartan FDC presented the smallest blood pressure effect compared to the four most recently approved antihypertension FDCs, despite being tested in the largest pivotal trials conducted for the five products. The four predecessors to the Actavis FDC are: Takeda Pharmaceutical Co. Ltd.’s Edarbyclor (azilsartan medoximil/chlorthalidone); Novartis’ Valturna (aliskiren/valsartan), which was removed from the market in 2012 because of the renal toxicity risk posed to diabetic patients by aliskiren (Tekturna); Novartis’ Tekamlo, (aliskiren/amlodipine); and Boehringer Ingelheim GMBH’s Twynsta (telmisartan/amlodipine) (Also see "With Its Hypertension Franchise in Crisis, Novartis Restructures" - Pink Sheet, 13 Jan, 2012.).

FDA does take the state of the armamentarium into account in evaluating new products. Stockbridge noted that 46 two-drug combos and five three-drug combos already have been approved to reduce blood pressure, and explained the standards the agency has been using for clearing such products (see sidebar).

The main reason for the nebivolol/valsartan advisory committee meeting, he asserted, was to discuss the evolving basis for approval of combo products in that therapeutic area.

The committee unanimously agreed that it would be appropriate to set an efficacy benefit threshold for FDC hypertension products, and there was general consensus that systolic blood pressure is a better measure for determining benefit than diastolic blood pressure.

Panel Agrees On Minimum Benefit Threshold, But Was It Met?

“I would argue that if the agency is looking for a direction to establish a minimum effect size for an anti-hypertensive, it should choose a systolic blood pressure delta that the epidemiology studies support to reduce morbidity,” Rich said.

“Absent other advantages, it is reasonable that there be a minimum [standard],” Chair Michael Lincoff, Cleveland Clinic, said in summarizing the discussion. “It seems like most believe that that should be based on systolic blood pressure, rather than diastolic, because that’s the current state-of-the-art, and although there are variations, one approach it seems most feel is [that] an epidemiologic basis would be more fair from a standpoint of [making a therapeutic] plan and also as the scientific basis of predicting outcomes in terms of mortality and morbidity.”

He added that the panel reached no consensus on a threshold, but that many members thought a mean systolic reduction of 3-4 mmHg works in terms of a standard that is worthwhile for producing a minimum optimal effect.

Having agreed that a newly approved FDC should yield a minimum treatment effect, the panel could not agree on whether Actavis’ candidate would meet such a threshold. Rich said a mixed response was the best he could muster on the question.

“I think when compared to monotherapy valsartan, the answer is clear that the combination was better,” he explained. “I think the conundrum that we face is [the use of] single-dose nebivolol at 40 mg [as a control], and the problem is that there is no 40 mg [in practice]. At least, if you want to prescribe 40 mg in this country, you prescribe 20 mg twice, so your monotherapy becomes two pills, and apparently it’s not done in this country with any frequency at all.”

“So now we’re asked to make a judgment on a combination therapy versus a monotherapy that’s not available and that’s really difficult to do because my sense is the drug works, [it] works better than valsartan alone, it probably works better than nebivolol at lower doses, but we don’t have the 20 mg dose to compare [the FDC] with in the study, so we’re going to be left for the rest of this discussion with a hypothetical,” Rich continued. “That’s really what the problem is, because if we had clear-cut data against 20 mg all the way through, we could probably make an easier decision here, so I don’t know how else to say it. Against valsartan, for sure. Against nebivolol, maybe.”

More certain was de Lemos, who noted that Robert Temple, CDER’s deputy director for clinical science, had questioned earlier in the discussion whether a combination of an ARB and a beta blocker made much sense as a hypertension therapy.

“Against each individual component, the answer is no,” de Lemos asserted. “It’s not an obvious combination from a mechanistic standpoint and that’s borne out by a remarkably weak effect. … It was not a direct comparison against [nebivolol] 20 mg; it doesn’t seem to meet the standard for comparison with 40 mg,” he said. “I think it’s a weak effect.”

Speaking for the sponsor, however, Michael Weber, State University of New York, argued that “small reductions in blood pressure during treatment can multiply into useful cardiovascular benefits.” He noted that Takeda’s azilsartan obtained a superiority claim based on a 2-3 mmHg comparative benefit in systolic blood pressure reduction. Reductions of that size “were associated with major differences between treatment groups in cardiovascular outcomes, stroke in particular, but also other outcomes such as heart failure as well,” he told the panel.

David Bharucha, clinical program lead and senior director of clinical development at Forest Laboratories Inc., followed by stating that all five doses of the FDC produced greater reductions “of clinically meaningful magnitude” in both systolic and diastolic pressure than control arms of monotherapy. These data included individual responses showing reductions of 20/10 mmHg or greater, an agreed clinically meaningful difference, he added. Later in the discussion, several members of the advisory committee suggested that labeling including a responder analysis of the pivotal trial would be very helpful guidance for prescribers (see related story, (Also see "Hypertension Drug Labeling Would Benefit From Responder Analysis" - Pink Sheet, 15 Sep, 2014.)).

Use Of Bystolic Control Dose Questioned

The committee expressed significant concern that the pivotal trial used nebivolol 40 mg as a monotherapy control, even though Actavis/Forest do not manufacture or market a 40 mg pill in the U.S. and usage data show less than 1% of Bystolic patients receive that daily dose. Members said data demonstrating the FDC’s efficacy compared to nebivolol 20 mg would have been more helpful for their considerations.

“We’re asked to make a judgment on a combination therapy versus a monotherapy that’s not available and that’s really difficult to do,” Rich said.

“A very deliberate decision was made not to test a combination of, let’s say, 40 mg/320 mg, although both of those are the highest approved doses of either drug,” Bharucha replied. “Factors that went into this decision included the fact that 40 mg of nebivolol is very rarely, if ever, used as a drug for hypertension, so we felt that examining 40/320 would produce interesting data, but not clinically useful data or clinically relevant data.”

He added that protocol discussions with FDA led to a determination that since 40 mg was the highest approved dose of nebivolol, that was the appropriate dose to use as control in the study in order to meet the combination therapy standard.

Temple said that, nonetheless, it would have made sense for the sponsor to include a 20 mg control arm in its study. The trial did compare the FDC to 20 mg nebivolol monotherapy but only out to four weeks of treatment, while the efficacy endpoints were measured on comparisons of treatment effect after eight weeks of therapy.

Sponsor Tries For Tolerability, Compliance

While the company argued for the significance of the demonstrated efficacy, Actavis hedged its bet by arguing that the combo also could offer a tolerance benefit compared to monotherapy – which FDA also allows as the basis for approval, though the reviewers did not think the data supported a safety advantage (Also see "FDA Floats Minimum Efficacy Requirement To Nebivolol/Valsartan Panel" - Pink Sheet, 5 Sep, 2014.). The panel also was largely unconvinced that the company succeeded in making that case.

The sponsor further attempted to build a case for approval out of the convenience benefit of an FDC.

“I can’t emphasize enough how much patients hate taking a whole handful of pills and how much better they psychologically feel if they can take two pills with four drugs rather than four single pills,” William White, University of Connecticut Health Center, said in speaking for the sponsor. “If they’re on five drugs, [with FDC products] it’s two pills or two-and-a-half pills,” he said. “It’s a lot better than taking five pills.”

Rich, who ultimately voted to recommend approval, wondered aloud about how big an advantage a reduction in pill burden might be. He suggested anecdotally that he thought only about 30% of hypertension patients achieve their blood pressure goals, which can be related to poor compliance.

The actual number is closer to 55%, White offered, though some health care systems achieve even higher rates. He cited Kaiser Permanente, which yields about a 75% rate for blood pressure goal achievement through the use of “beautiful algorithms” to determine combination therapy use in stage 2 hypertension patients. Guidance and use of electronic health records also help the firm reach that rate, he said.

But Efficacy Trumps Convenience Factors

Voting against approval, patient representative Susan Leighton, Huntsville, Ala., said the pill-burden rationale could not supersede the question of efficacy benefit.

“Reducing pill burden is certainly important to the patient population, but more important to us is that drugs actually deliver the clinical benefit that we expect them to deliver, and I just didn’t see evidence that this would provide any benefit [of getting] to goal any faster,” she said.

Following the meeting, Actavis Chief Medical Officer Gavin Corcoran said the company’s intent was to continue working with FDA to try to find a pathway to approval for the FDC before the fourth-quarter user fee deadline.

“We need to continue to work with the FDA with regard to what the vote actually means,” he said in an interview. “FDA will take it into consideration and we will continue to work with them – we’re kind of in the middle of the regulatory process and we’ll keep on going.”

He also indicated that Actavis still believes in the rationale for approval based upon a tolerance benefit compared to Bystolic or valsartan monotherapy. “Based on the data, we believe that there is a tolerance difference and so, from our standpoint, again we’d like to go back to work with the FDA to continue on to the review and to show them the information that we have,” Corcoran said.

Unanswered for now is how much additional effort Actavis wants to put into a program that it did not initiate and that its CEO indirectly indicated was not the kind of program it will prioritize going forward.

Bystolic was acquired by Actavis in its merger with Forest; the combo represents a lifecycle-expansion effort for the drug, which is subject to patent expirations in June 2015 and December 2021, but it is not much of a fit with Actavis’ CEO Brent Saunders’ stated goal to focus on higher-innovation products rather than follow-on drugs (Also see "Actavis’ Brent Saunders And Paul Bisaro Talk Innovation Vs. Discovery" - Pink Sheet, 30 Jun, 2014.).