Celltrion’s Rituximab Biosimilar Heads To Panel Review With US FDA Backing, Thanks To Additional Clinical Trial

Non-inferiority study in advanced follicular lymphoma patients created uncertainty as to whether there were any clinically meaningful differences between CT-P10 and Genentech’s Rituxan, but a newly submitted, equivalence study appears to have put those concerns to rest for agency reviewers.

Celltrion Inc.’s resubmitted biosimilar application for CT-P10 appears to have addressed the US FDA’s first-cycle review concerns as to whether there are any clinically meaningful differences between the proposed biosimilar and its reference product, Genentech Inc.’s Rituxan (rituximab).

In briefing documents released ahead of an Oct. 10 Oncologic Drugs Advisory Committee meeting, FDA reviewers conclude the analytical data show that CT-P10 is highly similar to Rituxan notwithstanding minor differences in clinically inactive components, and that comparative efficacy, safety and immunogenicity support the conclusion that there are no clinically meaningful differences between the two products.

 

Data from a second lymphoma study included in the resubmission provided reassurance that there were no clinically meaningful differences in efficacy or safety between the proposed biosimilar and the reference product, FDA said.

 

The agency reaches this conclusion despite initial concerns that efficacy and safety results from a clinical, non-inferiority study, CT-P10 3.3, in patients with advanced follicular lymphoma “may not have provided support of a demonstration of no clinically meaningful differences between CT-P10 and the reference product, US-licensed Rituxan, for the targeted oncology population,” the briefing document states.

Because of its design and small size, Study 3.3 failed to rule out the potential that CT-P10 was superior to Rituxan in overall response rate. There also was a numerical imbalance in serious adverse events with the proposed biosimilar product compared to Rituxan.

However, FDA concluded that data from an equivalence study, CT-P10 3.4, which was included in the BLA resubmission, provided reassurance that there were no clinically meaningful differences in efficacy or safety between the proposed biosimilar and the reference product.

Whether advisory committee members will be similarly reassured by the Study 3.4 results remains to be seen. In draft questions released Oct. 5, FDA asks the committee to discuss three points:

• Whether the evidence supports a demonstration that CT-P10 is highly similar to US-licensed Rituxan notwithstanding minor differences in clinically active components;

• Whether the evidence supports a demonstration that there are no clinically meaningful differences between CT-P10 and Rituxan; and

• Whether there is adequate justification to support licensure for the proposed indications sought by the applicant.

The agency poses one voting question on whether the totality of evidence supports licensure as a biosimilar product for the indications requested by Celltrion.

More Than Just GMP Deficiencies

Celltrion is seeking approval of CT-P10, which is partnered with Teva Pharmaceutical Industries Ltd., for three of Rituxan’s non-Hodgkin’s lymphoma (NHL) indications. (See box.)

Celltrion’s Requested Indications For CT-P10

• Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent

• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to CT-P10 in combination with chemotherapy, as single-agent maintenance therapy

• Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine and prednisone chemotherapy

However, approval is not sought for Rituxan’s fourth NHL indication or four other indications, including rheumatoid arthritis (RA), on the reference product’s labeling. Only one of the excluded indications – pemphigus vulgaris – currently is protected by orphan drug exclusivity. (Also see "Celltrion’s Biosimilar Rituximab Brings Indication Carve Outs To US FDA Panel Review" - Pink Sheet, 12 Sep, 2018.)

Celltrion carved five Rituxan indications out of its proposed biosimilar labeling “due to the current intellectual property and exclusivity landscape,” the company’s briefing document states.

This makes Celltrion the first biosimilar sponsor to reach the advisory committee stage with a proposed label that excludes indications for reasons other than orphan product exclusivity, and it could raise some questions and confusion in the minds of the agency’s external experts.

The initial 351(k) BLA submission in April 2017 resulted in a February 2018 complete response letter. Celltrion previously has said that the CRL “was directly related” to a January 2018 warning letter that cited numerous good manufacturing practice (GMP) deficiencies at one of its facilities in Incheon, South Korea. (Also see "The New 180 Days? Humira Biosimilar Deals Give Amgen 150-Day Jump On Samsung" - Pink Sheet, 5 Apr, 2018.)

 

A first-cycle, complete response letter was issued in February 2018 “for clinical, product quality and facility deficiencies,” FDA said.

 

However, FDA’s briefing document suggests there was more to the regulatory setback than just the GMP issues, saying the CRL was issued “for clinical, product quality and facility deficiencies.”

From a Division of Hematology Products clinical and statistical perspective, “there were concerns that the safety and efficacy results of clinical study CT-P10 3.3 may not have provided support of a demonstration of no clinically meaningful differences between CT-P10 and the reference product … for the targeted oncology population,” FDA’s briefing document states.

The application was resubmitted May 28 with additional long-term efficacy and safety data from Study 3.3 that was generated since the initial submission, as well as new clinical data from Study 3.4, Celltrion’s briefing document states.

Underpowered Study Raises Uncertainty

While FDA’s briefing document shines some light on agency concerns about the adequacy of the clinical data to support a finding of no clinically meaningful differences, it also suggests these concerns have been put to rest as far as the clinical review team is concerned.

Celltrion submitted two clinical studies that compared CT-P10 to US-licensed Rituxan in the oncology setting: Study 3.3 in advanced follicular lymphoma patients, and Study CT-P10 3.4 in low tumor burden follicular lymphoma (LTBFL) patients.

In Study 3.3, patients were randomized to receive either CT-P10 or US-licensed Rituxan, in combination with CVP (cyclophosphamide, vincristine and prednisone) chemotherapy. The primary endpoints were pharmacokinetic similarity (Part 1) and non-inferiority in efficacy as determined by overall response rate (ORR) during the core study period, which consisted of eight cycles (Part 2). For the latter endpoint, Celltrion proposed a non-inferiority margin of 7%.

“Sample size was based on the primary endpoint ORR (Part 2),” FDA said. “A sample size of 134 patients (67 patients in each treatment group) was planned to obtain 116 evaluable patients (58 patients in each treatment group) assuming 13% drop out rate. The study was under-powered to demonstrate equivalence with respect to the primary endpoint.”

On the primary endpoint, 95.7% of patients in the CT-P10 arm experienced an overall response, compared to 90% in the Rituxan arm, for an ORR difference of 5.7% (90% CI: -1.7%, 14.7%).

Since the lower bound of the 90% confidence interval was greater than the proposed non-inferiority margin of -7%, the primary objective was met for non-inferiority of ORR, FDA said. “However, the upper bound of the difference does not rule out superiority, which may be due to the fact that the study was underpowered.”

“Based on the details of Celltrion’s development program, FDA would recommend an equivalence design, rather than NI, in the comparative clinical study in an oncology population to support a demonstration of no clinically meaningful differences for the sought indications,” the agency said. The non-inferiority design of Study 3.3 “raised uncertainty regarding this demonstration.”

Equivalence Study Comes To The Rescue

However, Study 3.4 was designed as an equivalence study, with the primary objective to evaluate whether CT-P10 is similar to Rituxan in ORR at seven months in patients with LTBFL, with an equivalence margin of 17%.

In the CT-P10 arm, 83.1% of patients met the overall response primary endpoint, compared to 81.3% in the Rituxan arm. “The 90% confidence interval for the difference in ORR between CT-P10 and US-Rituxan was within the +17% margins,” FDA said. “This finding supports the assertion that there are no clinically meaningful differences between the two products.”

Study 3.4 also aided the agency’s interpretation of safety findings from Study 3.3, particularly with regard to serious adverse events, neutropenia, and death.

In Study 3.3, more subjects in the CT-P10 group experienced neutropenia. “However, this was likely confounded by the number of subjects with bone marrow involvement of disease at baseline,” FDA said. The results “may also have been confounded by the concomitant use of CVP chemotherapy. There were no differences in the incidence of neutropenia in study CT-P10 3.4.”

In Study 3.3, more subjects who received the proposed biosimilar experienced at least one serious adverse event and discontinued treatment due to an AE. “There were also more deaths in the CT-P10 treatment group than in the US-Rituxan treatment group,” FDA said. “However, the number of patients enrolled on Study CT-P10 3.3 was relatively small and there were slight differences in baseline characteristics, which limited the interpretation of the safety results.”

In Study 3.4, the overall number of subjects who experienced AEs and the distribution of AEs were similar in both treatment groups, FDA said. “The safety results of Study CT-P10 3.4 support the demonstration that there are unlikely to be clinically meaningful differences between CT-P10 and US-Rituxan,” FDA said.

FDA Comfortable With Analytical, Nonclinical Package

Celltrion’s analytical similarity data package consisted of three pair-wise comparisons: CT-P10 to US-Rituxan, CT-P10 to Genentech’s European Union-approved rituximab (known as MabThera), and EU-approved MabThera to US-Rituxan. Fifteen lots of each product were used in the analytical similarity assessment.

“Size variants, change variants, and some post-translational modifications including high mannose glycans were found to be slightly different between CT-P10 and US-licensed Rituxan lots,” FDA said. “However, based on the supportive analytical studies and justifications provided by the applicant, these differences were adequately addressed.”

“In considering the comparative analytical studies in their entirety, the FDA concludes the data submitted supports a demonstration that CT-P10 is highly similar to US-licensed Rituxan, notwithstanding minor differences in clinically inactive components.”

FDA said data from two animal studies also support the demonstration of biosimilarity. In addition, immunogenicity data from a clinical trial conducted in RA patients indicate no increased immunogenicity risk for CT-P10 as compared to US-Rituxan, and no increased safety risk with a single transition between Rituxan and CT-P10, FDA said.