Roche Hits Goal For Gazyva Expansion With Follicular Lymphoma Approval

Sales for Roche’s Rituxan follow-on Gazyva grew substantially in 2015 to $128m, but still pale compared to AbbVie/J&J’s Imbruvica, which is approved for three blood cancers and brought in more than $1bn.

Roche hit a goal for the development of its anti-CD20 antibody Gazyva – the follow-on to the firm's major blockbuster Rituxan – with a new indication in relapsed follicular lymphoma.

FDA approved Gazyva (obinutuzumab) in FL, the most common kind of indolent non-Hodgkin lymphoma, on Feb. 26. The indication is for use in combination with bendamustine followed by maintenance treatment with Gazyva monotherapy, in patients who did not respond to or relapsed after a Rituxan (rituximab)-containing regimen.

About one-fifth of NHL cases are indolent, or slow-growing, according to Roche subsidiary Genentech Inc. Follicular lymphoma is the most common kind of iNHL, with an estimated 14,000 new cases diagnosed in 2015.

Gazyva now has two indications – it was initially approved in November 2013 for previously untreated chronic lymphocytic leukemia (Also see "Roche’s Gazyva Clears FDA, But First Breakthrough Approval Breaks No Speed Barriers" - Pink Sheet, 4 Nov, 2013.).

The drug has a tough act to follow. Roche reported about CHF7bn ($7bn) in sales for Rituxan in 2015, up by 5% from the prior year. Initially approved in 1997, Rituxan has five approved indications, including NHL and CLL and rheumatoid arthritis. The drug’s main patents start to expire in the US in 2018, following expiration of some patents in Europe in 2013, and biosimilars are in development.

CLL has become a very competitive market, with two other drugs approved in addition to Gazyva in recent years – AbbVie Inc./Johnson & Johnson’s BTK inhibitor Imbruvica (ibrutinib) and Gilead Sciences Inc.’s PI3 kinase inhibitorZydelig(idelalisib).

More drugs are on the way, notably Roche/AbbVie’s eagerly awaited BCL-2 inhibitor venetoclax, which is under priority review at FDA for relapsed CLL (Also see "Keeping Track: Lilly Files Baricitinib; FDA Approves New Uses For Novartis' Cosentyx" - Pink Sheet, 25 Jan, 2016.). Venetoclax has breakthrough therapy status for three indications: use as a monotherapy in relapsed CLL with 17p deletions; use in combination with Rituxan for relapsed/refractory CLL; and use in combination with hypomethylating agents in patients with untreated acute myeloid leukemia who are ineligible to receive standard induction therapy. Roche is developing Gazyva in combination with venetoclax, with a Phase III study in first-line CLL that started in September 2014.

Infinity Pharmaceuticals Inc. is planning to file its PI3 kinase inhibitor duvelisib in relapsed CLL and relapsed iNHL, including FL, in the fourth quarter (Also see "Infinity Gears Up For Duvelisib Filing, But Differentiation Still A Challenge" - Pink Sheet, 29 Feb, 2016.).

Whereas Imbruvica soared quickly in sales – AbbVie and Pharmacyclics Inc. reported a total of $985m in US sales and partner J&J reported $314m in ex-US sales for 2015. (Updated Imbruvica sales figures.] Zydelig only brought in $132m worldwide and Gazyva/Gazyvaro CHF128m for the year (see table).

Sales of New CLL Drugs
Sponsor/Drug	Initial Approval	Current Indications	2015 Worldwide Sales
Roche’s Gazyva	November 2013: First-line CLL, in combination with chlorambucil	First-line CLL; relapsed FL, after failure with Rituxan-containing regimen, in combination with bendamustine followed by maintenance with Gazyva alone	CHF128m ($128m)
AbbVie/J&J’s Imbruvica	November 2013: MCL after at least one prior therapy.	MCL; CLL after at least one therapy; CLL with 17p deletions; Waldenstrom’s macroglobulinemia; under review for first-line CLL	$1.3bn
Gilead’s Zydelig	July 2014: Relapsed CLL with Rituxan in patients for whom Rituxan monotherapy is not appropriate; FL after failure of two prior therapies	Relapsed CLL with Rituxan in patients for whom Rituxan monotherapy is not appropriate; FL after failure of two prior therapies	$132m
Source: Company statements

Differentiation of Gazyva from Rituxan has been a challenge from the beginning and there have been questions about the comparator used in the first trial supporting the initial approval (Also see "CLL Market Update: Imbruvica Leads Way, Jump-Started By Robust Launch" - Pink Sheet, 23 Feb, 2015.). The pivotal CLL11 study tested Gazyva with chlorambucil, a weak chemotherapy, vs. Rituxan/chlorambucil and chlorambucil alone.

In its Jan. 28 earnings statement, Roche noted “good uptake in the US and other early launch countries” in CLL, despite competitive pressure. The CHF128m reported in 2015 included CHF76m (up by 69%) from the US and reflected an overall increase of 168% from 2014.

“Further growth is expected as additional markets secure reimbursement,” the company said.

Broad Development Program

Roche has had a broad development strategy for Gazyva, with plans to move into a number of new indications.

The FL filing was supported by the Phase III GADOLIN study of 392 iNHL patients, most of whom had FL. The trial tested the combination of Gazyva with bendamustine, a standard treatment for relapsed FL, followed by Gazyva monotherapy as a maintenance therapy.

The Gazyva/bendamustine arm demonstrated a 52% reduction in progression-free survival compared to bendamustine alone. Judged by independent review, median PFS was not reached for the Gazyva/bendamustine combination vs. 13.8 months for bendamustine alone. Investigator review suggested median PFS was 29.2 months for the Gazyva arm compared to 13.8 months for bendamustine, a doubling of benefit.

According to a post hoc analysis, overall survival was also improved by 38% for the Gazyva arm, but the data are immature.

Whereas Gazyva/bendamustine is approved after one type of therapy, Zydelig’s labeling is for a later line FL setting after two prior therapies. It received accelerated approval based on objective response rate data in a single arm study of 72 patients. Gilead is running two Phase III studies in previously treated iNHL, one of which tests the drug in combination with bendamustine and Rituxan, and the other with Rituxan.

In Roche’s GADOLIN study, the most common Grade 3-4 adverse events reported were neutropenia, infusion reactions and thrombocytopenia.

The infection rate was 66% for Gazyva/bendamustine vs. 56% for bendamustine. The rates of Grade 3-4 infection were 16% for the Gazyva arm vs. 14% for bendamustine.

Roche plans to release data from the Phase III GOYA study in front-line aggressive NHL this year and to launch in that indication in 2017. The plan is to follow that up with a release of data from the pivotal GALLIUM study of first-line iNHL in 2017, which could pave the way for launch in that indication in 2018.

Gazyva is also in earlier stages of development for lupus, mantle cell lymphoma, marginal zone lymphoma and end-stage renal disease.