FDA Accentuates Venclexta Superiority To Imbruvica

FDA denied breakthrough therapy request until AbbVie and Roche demonstrated substantial improvement over available treatment in 17p deletion chronic lymphocytic leukemia, review documents show.

Comparative efficacy played a major role in FDA’s approval of AbbVie Inc. and Roche’s Venclexta (venetoclax), agency review documents show. The drug’s superiority to Johnson & Johnson/AbbVie's Imbruvica (ibrutinib) was critical both to Venclexta’s breakthrough therapy designation and accelerated approval for relapsed or refractory chronic lymphocytic leukemia (CLL) patients with a deletion in chromosome 17p.

While FDA statutes do not require that new drugs show superiority over existing therapy for approval, access to the expedited review programs is reserved for drugs that demonstrate the potential for a meaningful advantage or substantial improvement over available therapy.

“Because the applicant is seeking accelerated approval, venetoclax must be better than ibrutinib for the treatment of patients with CLL who harbor the del(17p) mutation,” review team leader Virginia Kwitkowski noted. Despite a fast pace of new drug approvals in the CLL space – eight since 2007 -- Imbruvica is the only other drug to receive a claim specifically for CLL patients with a 17p deletion, which is associated with poor prognosis.

Given the rapid pace of development in CLL, which could move the goalposts for accelerated approval, FDA urged AbbVie and Roche to “make every possible argument as to why ABT-199 [venetoclax] provides an improvement over available therapy in their NDA submission,” according to minutes of the July 2, 2014 end-of-Phase II meeting (see sidebar for a chronology of Venclexta development). The drugs have not been compared head-to-head.

Imbruvica received approval in the 17p deletion population in July 2014 with an overall response rate of 48% and no complete responses. Venclexta, approved less than two years later on April 11, 2016, showed an overall response rate of 80% and a complete response rate of 7.5%. Both drugs are designated breakthrough therapies for the indication.

Venclexta, the first protein B-cell lymphoma 2 (BCL-2) inhibitor, is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as determined by an FDA approved test, who have received at least one prior therapy (Also see "Venclexta Out Of The Starting Gate With Approval In High-Risk CLL Subset" - Pink Sheet, 11 Apr, 2016.).

Battling For Breakthrough Status

FDA turned down AbbVie’s first attempt to get a breakthrough therapy designation for Venclexta because the preliminary evidence submitted did "not indicate that the drug may demonstrate substantial improvement over existing treatment on one or more clinically significant endpoints,” Division of Hematology Products Director Ann Farrell explained in a July 24, 2013 letter.

The initial breakthrough request, submitted June 3, 2013, relied on preliminary data from 17 patients in an ongoing Phase I dose-escalation trial, M12-175. The 16 patients who were evaluable for efficacy showed an overall response rate of 81% and a median duration of response of 13 months, but FDA deemed the number of patients too few to demonstrate a benefit over existing therapy.

The sponsors returned to FDA on Feb. 27, 2015 with a second request for breakthrough status that incorporated data from the ongoing pivotal Phase II trial M13-982. The dataset included 33 17p patients in total (25 from the Phase II trial and 8 from Phase I). This time, FDA found the evidence for substantial improvement over existing treatment to be sufficient for a breakthrough designation.

Importantly, the second breakthrough request included data from patients treated with the dose regimen and prophylaxis measures developed to reduce the risk of tumor lysis syndrome (TLS). The Phase I study set the stage for the final dosing, but did not treat patients with that regimen, FDA noted.

Confirmatory Trial Sets Stage For Label Expansion

Those two trials went on to form the clinical basis of the NDA. The application submitted on Oct. 29, 2015 established efficacy with the single-arm Phase II M13-982 trial, which enrolled 107 patients; 106 of them had the 17p deletion. The Phase I dose-escalation trial, M12-175, was included to show safety and provide the rationale for the Phase II dose.

The primary efficacy endpoint was overall response rate (ORR), an accepted surrogate for survival in CLL under accelerated approval regulations.

For traditional approval, FDA prefers progression-free survival (PFS). CLL is an indolent disease, making the gold standard overall survival endpoint infeasible. The confirmatory trial required by Venclexta’s accelerated approval, the ongoing 392-patient Phase III MURANO study, is assessing PFS; patients on the venetoclax arm will receive treatment until disease progression or two years after treatment start, with an estimated time on study of five years.

The MURANO trial could expand Venclexta labeling in addition to converting the accelerated approval to full approval.

The accelerated approval indication for Venclexta is for monotherapy and is limited to relapsed or refractory CLL patients with 17p deletion as determined by an FDA-approved test. (The test, Abbott Molecular Inc.’s Vysis CLL FISH probe kit to detect the 17p deletion, was approved alongside Venclexta as a companion diagnostic by the Center for Devices and Radiological Health.)

MURANO, on the other hand, is testing the combination of Venclexta and Roche’s hematology mainstay Rituxan (rituximab) in relapsed or refractory CLL patients regardless of 17p status. The comparator arm treats patients with a combination of rituximab and Teva's Treanda (bendamustine).

Under terms of the accelerated approval, FDA calls for Roche and AbbVie to submit the final data report from MURANO in 2019. AbbVie, however, indicated that the companies could act sooner: AbbVie intends to submit for approval of the venetoclax/rituximab combination in relapsed/refractory CLL in 2017.

AbbVie and Roche have a broad program of venetoclax trials supporting further label expansion. A Phase III study of venetoclax plus Roche's Gazyva (obinutuzumab) vs. Gazyva plus chlorambucil is under way in previously untreated CLL, and another first-line CLL Phase III trial is slated to start in the second half of 2016 to evaluate Venclexta with Gazyva and Imbruvica. The companies also have multiple trials of Venclexta ongoing in other hematologic malignancies, including non-Hodgkin lymphoma, multiple myeloma and acute myeloid leukemia.

AbbVie presented data from two Phase Ib studies in elderly AML patients ineligible to receive first-line standard high-intensity induction chemotherapy at the American Society of Clinical Oncology's June 3-7 annual meeting in Chicago (Also see "Ten Programs To Watch Out For At ASCO" - Pink Sheet, 20 May, 2016.).

First, Focus On 17p Deletion

The Venclexta NDA was submitted for a broader indication than FDA approved. The sponsors sought an indication for “treatment of patients with relapsed or refractory chronic lymphocytic leukemia who have received at least one prior therapy, including those with 17p deletion,” Kwitkowski observed.

The agency limited the claim to the 17p subset only and included the companion diagnostic in the indication statement.

While discussion of a broader claim is redacted in the review documents, the context suggests that FDA focused the indication on the population where efficacy was substantially improved over available therapy – the 17p deletion subset, where the only other approved product is Imbruvica.

Indeed, a month after Imbruvica received its 17p deletion claim, FDA told the sponsors that they should increase the sample size for venetoclax’s accelerated approval application “given the recent regular approval of ibrutinib in this indication,” clinical reviewer Lori Ehrlich reported. “The ABT-199 NDA submission will be stronger by waiting.” The sponsors followed FDA’s advice, and submitted the Venclexta NDA with data on 107 patients instead of the 70 patients that had been envisioned before Imbruvica.

How Venclexta Stacks Up Against Other Therapies

While the comparison of Venclexta and Imbruvica was central to FDA’s consideration of available therapy, the agency’s review took in the broader CLL landscape as well. Other therapies have been used to treat 17p deletion patients even if they do not have an indication specifying such patients – FDA-approved therapies for a general relapsed or refractory CLL indication include rituximab in combination with fludarabine and cyclosphosphamide; Imbruvica; Gilead Sciences Inc.'s Zydelig (idelalisib) in combination with rituximab; Novartis AG's Arzerra (ofatumumab) in combination with chlorambucil; Gazyva/chlorambucil; and Teva Pharmaceutical Industries Ltd.'s Treanda (bendamustine).

Gilead’s idelalisib is approved in Europe as first line treatment for patients with 17p deletion or TP53 mutations unsuitable for chemo-immunotherapy, FDA noted.

Venetoclax provides a higher overall response rate than these therapies and provides a complete response while the others do not, the review team observed (see chart below). The common standard therapies of fludarabine+cyclophosphamide+rituximab or bendamustin+rituximab have historically low response rates of 35% and 7%, respectively, reviewers pointed out.

Comparison of Venclexta To Available Therapies in 17p deletion CLL
	Venetoclax	Ibrutinib	Idelalisib + Rituximab	Ofatumumab	Fludarabine/ Cyclosphosphamide/ Rituximab
CR/CRi rate	15%	0	0	---	0
ORR	82%	48%	78%	14%	35%
Source: FDA

Comparative Safety

FDA also examined the safety profile of Venclexta in the context of other CLL therapies, noting that safety concerns with other therapies are not evident with Venclexta. Imbruvica, for example, is associated with atrial fibrillation (6-9%) and bleeding events (6% ≥grade 3) and Zydelig is associated with hepatitis (14%), colitis (14%), pneumonitis (3.6%) and severe cutaneous reactions.

The most common adverse reactions with Venclexta (≥20%) were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue.

FDA identified the main safety concerns with Venclexta as the risk of tumor lysis syndrome – estimated to be 6% – and neutropenia. FDA determined that TLS risks are adequately conveyed in the labeling, a Medication Guide, and a guide in a Start Pack. The labeling recommends a ramp-up dosing schedule over five weeks, and warns of the need for blood chemistry monitoring and prophylaxis measures, including hydration, medications to reduce uric acid levels, and hospitalization. FDA reviewers noted that neutropenia is usually manageable with standard of care treatments, including antibiotics and G-CSF.

FDA did not find the TLS or neutropenia risk to rise to the level of a boxed warning, giving Venclexta a labeling advantage over most of the approved therapies, which do feature box warnings in labeling. (Imbruvica, however, like Venclexta, does not carry a box warning.)

Rituxan has a boxed warning of fatal infusion reactions; severe mucocutaneous reactions, some with fatal outcomes; hepatitis B virus reactivation in some cases resulting in fulminant hepatitis, hepatic failure, and death; and progressive multifocal leukoencephalopathy resulting in death. Arzerra and Gazyva have boxed warnings with the same hepatitis B virus and PML warnings. And Zydelig has a boxed warning of fatal and serious toxicities of hepatotoxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation. Zydelig also has a REMS requiring healthcare provider letters, publication of information pieces in several journals and patient safety information cards.

Managing Tumor Lysis Syndrome Risk

The development of a management strategy for TLS was an important factor in keeping Venclexta’s labeling clean. TLS is a group of metabolic and electrolyte abnormalities that can occur when large numbers of neoplastic cells are rapidly killed, leading to the sudden release of intracellular contents into the peripheral blood.

In December 2012, FDA placed the venetoclax IND on partial clinical hold (halting enrollment and dose escalation) due to the death of two CLL patients from TLS, which occurred after the first and lowest dose. One patient did not have the 17p deletion while the other did. There were also seven serious events of TLS requiring patients to be hospitalized.

Prior to the clinical hold, the drug was administered at a starting dose of 50 mg and the dose was increased incrementally using a step-up approach. The study was amended to lengthen the ramp-up dosing period, and to provide enhanced monitoring and prophylaxis measures, including oral and IV hydration, a uric acid reducing agent, and hospitalization for the first doses. The partial clinical hold was lifted five months later (Also see "Roche/AbbVie Move Beyond GDC-0199 Toxicity Issue To Show Results In Tough-To-Treat CLL" - Pink Sheet, 8 Dec, 2013.).

FDA reviewers noted that the TLS signal declined from 20% to 9% following initiation of stepped dosing and prophylaxis. Labeling directs physicians to start Venclexta therapy at 20 mg once daily for seven days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg.

Entering The Market

AbbVie and Roche are introducing Venclexta at a wholesale acquisition price of $109,500 for the first year, during which the dose ramps up; the price will be slightly higher in following years. “In determining the price of our product, we took a number of factors into account including the overall market dynamics, the benefits of the therapy to patients, the cost effectiveness of treatment and the value that the product brings to off-setting short-term and long-term costs,” AbbVie said.

AbbVie also markets Venclexta’s main competition, Imbruvica, but the drugs have “wholly separate sales teams,” the company said. AbbVie and Roche's Genentech Inc. unit are co-marketing Venclexta in the US; AbbVie is marketing the drug outside the US. Imbruvica is co-marketed by AbbVie’s Pharmacyclics Inc. subsidiary and Johnson & Johnson’s Janssen Biotech Inc. in the U.S., while J&J holds rights outside the country.

While Venclexta has an efficacy advantage over Imbruvica in 17p deletion CLL, the (slightly) older drug has built a formidable market presence. Imbruvica first received accelerated approval in mantle cell lymphoma in November 2013, and rapidly expanded to relapsed or refractory CLL (accelerated approval February 2014, converted to full in July 2014), CLL with 17p deletion (full approval July 2014) and frontline CLL (March 2016). Most recently, on May 6, 2016, FDA cleared sNDAs adding data on combination use with bendamustine and rituximab in CLL and small lymphocytic leukemia (Also see "Imbruvica’s New Label Opens Door For Use With Popular Rituxan Combo" - Pink Sheet, 9 May, 2016.).

AbbVie appears inclined to use Venclexta’s data on minimal residual disease (MRD), an exploratory endpoint in the pivotal Phase II trial, as one way to differentiate the new drug. “MRD negativity determined in the peripheral blood is presently being evaluated as a predictor of treatment efficacy in CLL,” review team leader Kwitkowski noted.

“Using readily available lab tests (e.g. flow cytometry), MRD negativity means that less than one CLL cell per 10,000 leukocytes exists in the peripheral blood and bone marrow of a patient at the time of testing,” AbbVie said. “MRD-negativity is a promising endpoint that AbbVie and Genentech are committed to studying with Venetoclax, including in our MURANO trial.” AbbVie highlighted the 3% MRD rate seen in 17p deletion CLL patients during its June 3 R&D Day.