Theravance’s Persistence On Telavancin Rewarded With Positive Cmte. Vote

FDA’s Anti-Infective Drugs Advisory Committee endorsed Vibativ for limited use in nosocomial pneumonia. The committee was convened at the recommendation of Office of New Drugs Director John Jenkins, who denied the company’s appeal of a second “complete response” letter but urged the NDA be re-evaluated.

Innoviva Inc.’s experience with the nosocomial pneumonia NDA for Vibativ (telavancin) may give other sponsors hope that all is not lost when a review division repeatedly rejects an application.

The company has waged an almost four-year regulatory battle to secure approval of its lipoglycopeptide antibacterial for nosocomial pneumonia. Those years have been marked by an evolution in how FDA views clinical trial designs and endpoints in this indication – a change in thinking that contributed to two “complete response” letters for telavancin, a denied request for dispute resolution and a rejected appeal to the Office of New Drugs.

Theravance’s success with the advisory committee may embolden other sponsors to seek dispute resolution of negative review division decisions.

Yet, that final appeal to OND has opened the door to a re-evaluation of the NDA by the Division of Anti-Infective Products and public discussion of the application by the Anti-Infective Drugs Advisory Committee.

At a Nov. 29 meeting, the committee strongly endorsed approval for limited use in treating nosocomial pneumonia, particularly for those infections caused by methicillin-resistant Staphylococcus aureas. This recommendation came only after the majority concluded the data did not support the safety and efficacy of telavancin across a broader population of nosocomial pneumonia patients (Also see "FDA Panel Breathes New Life Into Telavancin For Nosocomial Pneumonia" - Pink Sheet, 29 Nov, 2012.).

The telavancin NDA remains under review; as is the case with any application brought before an advisory committee, the review division could decide not to follow the panel’s advice and instead stick with a request for new studies prior to approval.

But Theravance’s persistence and its success at the advisory committee may embolden other sponsors to appeal negative review division decisions to a higher level.

Bumpy Regulatory History

Telavancin received FDA approval in September 2009 for treatment of complicated skin and skin structure infections (Also see "Theravance Gets To Market With Vibativ, But HAP Indication Could Be Pushed To 2010" - Pink Sheet, 14 Sep, 2009.). However, the product’s commercialization has been bedeviled by manufacturing troubles at third-party supplier Ben Venue Laboratories Inc. and the termination of a development and commercialization agreement with Astellas Pharma Inc. (Also see "Theravance’s Vibativ To Get FDA Panel Review For Hospital-Acquired Pneumonia" - Pink Sheet, 19 Sep, 2012.). Theravance currently has no commercial sales of the product but is working to secure regulatory approval for the drug’s manufacturing by Hospira Inc.

Advisory Committee Votes

• 9-6 that the totality of the data do not provide substantial evidence of telavancin’s safety and effectiveness for the requested indication of treatment for nosocomial pneumonia, including ventilator-associated pneumonia, caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureas (including methicillin-susceptible and methicillin-resistant isolates) or Streptococcus pneumonia
• 13-2 that the data provide substantial evidence of safety and effectiveness for treatment of nosocomial pneumonia when other alternatives are not suitable

Theravance originally submitted the NDA for nosocomial pneumonia, including ventilator-associated pneumonia, in January 2009. The filing was based upon two identically designed, multinational Phase III trials (0015, 0019) conducted between early 2005 and mid-2007. The studies were non-inferiority in design and used vancomycin as a comparator. In accordance with an FDA guidance document in effect at the time, the primary efficacy analysis was clinical response at the test-of-cure assessment 7-14 days after the last dose of study drug.

Following the telavancin trials’ completion but prior to the NDA filing, FDA initiated public discussions about appropriate trial designs and clinical endpoints for drugs developed to treat nosocomial pneumonia, also referred to as hospital-acquired pneumonia, because the agency believed it was not possible to justify a non-inferiority margin for a clinical response endpoint. Those discussions led to a November 2010 draft guidance that recommended a 28-day all-cause mortality endpoint and a 10% non-inferiority margin (Also see "Hospital-Acquired Pneumonia Is Life Or Death, FDA Says; Recommends Sole Primary Endpoint" - Pink Sheet, 7 Dec, 2010.).

Although the 2010 guidance remains in draft form, FDA has applied the document’s emphasis on mortality to the telavancin review. In November 2009, one year before the guidance was released, FDA issued a “complete response” letter requesting additional mortality data from Theravance.

Theravance resubmitted the NDA in June 2010 with additional mortality data and post-hoc analyses. However, this resulted in a second “complete response” letter issued in December 2010.

“While the pre-specified primary endpoint of clinical response 7-14 days after the last dose of study drug was met in both trials, indicating that telavancin was non-inferior to vancomycin on the basis of clinical response in the treatment of NP due to Gram-positive pathogens, the Agency stated that both trials did not provide sufficient evidence of non-inferiority compared to vancomycin using a 10% margin for a mortality endpoint in the population of patients with nosocomial pneumonia caused by Gram-positive bacteria,” FDA's briefing document for the meeting states (Also see "Mortality Vs. Clinical Cure: Telavancin Review Expected To Renew Debate On Nosocomial Pneumonia Endpoints" - Pink Sheet, 27 Nov, 2012.).

Theravance submitted a formal dispute resolution request to the Office of Antimicrobial Products, which was denied. In a subsequent appeal to OND, the company said Studies 0015 and 0019 demonstrated that telavancin is non-inferior to vancomycin based on the pre-specified endpoint of clinical cure and met the statutory standard for approval. The company also said that since FDA has not finalized its 2010 draft guidance, it would be inappropriate to impose the mortality endpoint when the Phase III trials using the clinical cure endpoint were previously agreed upon by the agency.

Dispute Resolution Can Clarify Path Forward

Although the use of dispute resolution by sponsors appears to be on the rise, this appellate avenue comes with its own concerns for industry.

Speaking at Elsevier Business Intelligence’s FDA/CMS Summit in December 2011, OND Director Jenkins said he has seen an increase in dispute resolution requests, particularly from smaller companies. He suggested this was because it is cheaper to appeal a decision than to conduct a new study requested by a review division (Also see "Emerging Sponsors And FDA: Will Better Communication Under PDUFA V Ease Inherent Tensions?" - Pink Sheet, 2 Jan, 2012.). Although most dispute resolution requests are rejected because the underlying decisions are sound, sponsors sometimes receive clarity on the path forward, he said.

However, the decision to seek dispute resolution is not one companies take lightly. At the recent Mid-Atlantic BIO meeting, Hogan Lovells partner Lynn Whipkey Mehler, a former FDA staff attorney, said sponsors worry that appealing a review division’s decision will ruin their reputation with the agency (Also see "Maximizing PDUFA V Meeting Opportunities Requires Work By Sponsors" - Pink Sheet, 22 Oct, 2012.).

For Theravance, its decision to appeal to OND gave it new hope for a route to approval. Although Jenkins denied the company’s appeal, he recommended Theravance resubmit the application for further agency review and presentation to the advisory committee.

“The clinical development program for telavancin in NP has generated a large amount of data, which I believe must be carefully re-evaluated to support a decision on whether the new indication should be approved,” Jenkins said in a Feb. 17, 2012 letter to Theravance, which was included in FDA’s briefing document. “These data may also help the Agency inform its thinking on the appropriate design, endpoints, and analysis for trials to support approval of antibacterial drugs in NP.”

The letter acknowledged Theravance’s concerns that the presentations and questions to the committee would be a “stacked deck.”

“As I interpret your concerns, you want to ensure that the data will be presented to the committee in a fair manner,” the letter states. “In particular, you were concerned that the Agency briefing documents and presentations not state that the only acceptable endpoint for approval is all-cause mortality with a NI margin of 10%, as recommended in the draft HABP/VABP guidance.”

Jenkins said the agency’s background material and presentation would make clear that the draft guidance is not final, the panel’s advice is sought based upon the totality of the data from the telavancin application, and the drug’s clinical development program was completed before the guidance’s release. “I believe we can have a ‘fair hearing’ before the AIDAC, and I will work with the staff in [Office of Antimicrobial Products] and [Office of Biostatistics] to ensure that goal.”

Carving Out A Niche For Limited Use

The committee meeting, which Jenkins attended, gave Theravance an opportunity to make the case for telavancin’s safety and efficacy before a panel of infectious disease clinicians. Perhaps more importantly, however, it provided a forum for discussion about the serious nature of nosocomial pneumonia and the dearth of therapeutic options for those infections resistant to current antibiotics, thereby suggesting a void that telavancin might fill.

The panel majority was reluctant to endorse a broad indication for various reasons. These included lingering questions about the meaningfulness of clinical cure rates with the drug, failure to demonstrate non-inferiority to vancomycin on mortality in two separate trials pursuant to FDA’s analyses, and signals of an increased risk of death in renally impaired patients. Some panel members also objected to approving the drug for use in infections caused by Streptococcus pneumonia, which they said is more commonly associated with community-acquired pneumonia and for which effective treatments currently exist.

Drugs such as telavancin “need to be available in the armamentarium of physicians who are caring for patients in the ICU, who are critically ill, for which perhaps no other option is available,” committee chairman Moore said.

“The issue really for me was a blanket statement of safety,” committee chairman Thomas Moore, University of Kansas, said in explaining his negative vote on the question of safety and efficacy for a broad indication. “The drug appears to be safe except in the individuals who have lower creatinine clearance, and that seems substantial enough to me to warrant a ‘no’ vote.”

Nevertheless, drugs such as telavancin, “despite their blemishes, need to be available in the armamentarium of physicians who are caring for patients in the ICU, who are critically ill, for which perhaps no other option is available,” Moore said. “I do think ultimately the drug ought to be approved and at least available for use in special situations.”

Many panel members said they believed telavancin should be reserved for the most difficult-to-treat infections, such as those caused by methicillin-resistant strains of Staphylococcus aureus, although some also supported use for treating methicillin-susceptible strains. Use should also be limited, or strongly cautioned against, in patients whose creatinine clearance levels fall below a certain threshold, although panel members were unsure what that cut point should be.

Temporary voting member William Calhoun, University of Texas, was among the members who voted against a broad indication but favored a narrower claim. “The difference in this question for me, as a clinician, is context,” he said. “If other alternatives – vancomycin or linezolid – aren’t available, then we don’t have anything else, and so in that context I’m willing to look at the test-of-cure data with a little more liberal eye, a little more open mind.”

The idea of a limited indication targeted to a specific, high-need population is consistent with the Infectious Diseases Society of America’s proposal for a Limited Population Antibacterial Drug approval pathway (Also see "Antibiotic Incentives: FDA’s Woodcock Says LPAD Could Be Better Than Exclusivity, But Questions Remain" - Pink Sheet, 18 Apr, 2012.). LPAD did not make it into the FDA Safety and Innovation Act of 2012, but IDSA confirms that it intends to seek a legislative vehicle in the coming year.