When Pfizer announced its intention just more than a week ago to begin marketing its rituximab biosimilar Ruxience® in January 2020, industry watchers wondered when we might hear a response from its sole approved competitor. The wait was over quickly: Teva and Celltrion will begin shipping their own rituximab biosimilar Truxima® on November 11.
Truxima was approved in October 2018 for the cancer indications of Genentech’s reference product Rituxan®. In a joint press release issued by both companies, Brendan O’Grady, Teva’s Executive Vice President and Head of North America Commercial Operations, stated, “We are excited about the first FDA-approved biosimilar to rituximab in the US. Teva’s commitment to biosimilars is focused on the potential to create lower healthcare costs and increased price competition. This focus is consistent with Teva’s mission of making accessible medications to help improve the lives of patients.”
The press release also mentioned a key detail of the partners’ patent settlement with Genentech. Specifically, Celltrion and Teva will be able to market the autoimmune indications (rheumatoid arthritis, granulomatosis, with polyangiitis, and microscopic polyangiitis) in the second quarter of 2020, assuming they receive approval from the Food and Drug Administration for the broader indications. Ruxience is not currently indicated for these same autoimmune disorders.
The partners announced that the wholesale acquisition cost (WAC) for
Truxima will be just 10% below that for Rituxan, which will be subject to
further discounts and rebates negotiated with individual payers. That
works out to a WAC of $845.55 for 100 mg vial (or $4227.75 for 500 mg vial).
Teva will be responsible for marketing Truxima in the US.
Pfizer has not yet announced their intended WAC for Ruxience’s launch in January.
At an earnings call this week, Pfizer’s CEO highlighted the
impending launches of Ruxience®
not long after the previously announced launch of Zirabev®
(bevacizumab) at the end of this year.
The New York–based pharmaceutical manufacturer plans to
begin marketing Ruxience in January 2020, and Trazimera February 15, 2020. This
would make Pfizer first to market with a Rituxan® competitor. Pfizer
follows Amgen to market with Trazimera, as Kanjinti®
launched in July this year.
On the call, Albert Bourla, PhD, indicated that the
company’s infliximab biosimilar (Inflectra®) had grown 8% for the
third quarter of 2019 over the same quarter in 2018 (to $77 million). Inflectra’s
marketshare in the US still remains below 10%, according to IQVIA.
Extrapolation of indications by the Food and Drug
Administration (FDA) has been widely accepted by providers, payers, and most patient
groups. Yet how to address the approval of a narrow indication list (or skinny
label) seems less settled.
The four FDA-approved adalimumab biosimilars received the
agency’s endorsement for a large set of Humira®’s 10 indications. Amjevita®
and its brethren were approved for the treatment of moderate-to-severe
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, moderate-to-severe
Crohn’s disease in adults, plaque psoriasis, moderate-to-severe polyarticular
juvenile idiopathic arthritis, and moderate-to-severe ulcerative colitis. Missing
are indications to treat pediatric Crohn’s disease, hidradenitis suppurativa,
and noninfectious uveitis (regardless of severity). When payers are asked whether
these missing indications (especially involving other autoimmune disorders) are
important for coverage decision making, they will likely agree that it makes
little difference to them.
In perhaps the more important biosimilar example, rituximab,
the indications are split between cancer treatment (e.g., non-Hodgkin’s
lymphoma and chronic lymphocytic leukemia) and autoimmune therapy (e.g., rheumatoid
arthritis, polyangiitis, pemphigus vulgaris). Although the dosing rate (50
mg/hr) is the same, Rituxan is given as part of a cytotoxic chemotherapy regimen
for patients with non-Hodgkin’s cancer versus methotrexate and methylprednisone
for autoimmune treatment. The two rituximab biosimilars (Truxima®
and Ruxience®) approved by the FDA do not have the rheumatoid arthritis
indication, although Ruxience has received approval for polyangiitis.
The reasons their manufacturers sought the skinny labels could
be many, including avoidance of patent infringement, quicker path to FDA
approval, or simply limited resources. However, Pfizer did complete a phase 3
trial in RA for Ruxience. Currently, Amgen/Allergan have completed phase 3
trials for both non-Hodgkin’s
lymphoma and rheumatoid
arthritis for their investigational biosimilar ABP 798. It is possible that
the partners could submit a 351(k) biologic license application at the end of Q4
2019 or Q1 2020.
For payers, the presence of skinny labels for biosimilars versus
approval for the entire set of indications matters little. In several market research
projects we have conducted with managed care medical directors and pharmacy
directors, their answers have been consistent: If the biosimilar is approved by
the FDA and is covered by the health plan or insurer, then the payer will be
far less concerned how the biosimilar is used. The reasons are simple: Payers are
gaining comfort with biosimilar use. If the reference product and biosimilar
have been demonstrated to be sufficiently equivalent to produce equivalent outcomes,
and the biosimilar is less expensive, why overmanage its use?
Further support for this view was published this month in BioDrugs.
These South Korean authors evaluated 11 head-to-head randomized, control trials
of rituximab biosimilars for use either non-Hodgkins lymphoma or RA. A total of
3,163 patients were included in the meta-analysis. Response rates in the trials
for lymphoma and RA were consistently equivalent, and no significant
differences were revealed in the formation of antidrug antibodies.
Perhaps the best opportunity for managed care organizations to restrict
the use of a biosimilar (or biologic) outside of step therapy is the ubiquitous
prior authorization (PA). Today, there is little, if no, reason for PA criteria
to be different for a reference biologic or its biosimilar(s), other than price
preference. In that case, the skinny label has little effect on a payer’s coverage.
In a busy beginning of the week, the US Food and Drug
Administration approved new biosimilars for Humira®and Rituxan®. Samsung Bioepis gained approval for Hadlima™
(adalimumab-bwwd), and Pfizer scored with Ruxience™
The approval for Hadlima covers the following indications:
Juvenile idiopathic arthritis
Crohn’s disease in adults
Formerly known as SB5, Samsung Bioepis secured Hadlima’s approval
on the basis of phase 1 and phase 3 studies in rheumatoid arthritis.
The phase 3 investigation included over 500 patients, finding ACR20
responses to be equivalent to that of Humira (at 72%). Immunogenicity profiles
for the two agents were also similar through 52 weeks of a switching study.
According to its licensing agreement with Abbvie, manufacturer of Humira, Samsung will not be able to market this agent until end of June 2023. This agent joins Samsung’s two other approved anti-TNF biosimilars, Renflexis (infliximab) and Eticovo (etanercept). Only Renflexis is currently marketed in the US.
Pfizer’s newest biosimilar entry, Ruxience, has been
approved for a subset of indications of reference product Rituxan, including:
Treatment of adult patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma who are CD20-positive and have failed prior treatments
Patients who have nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin’s lymphoma and who are stable after receiving a prior chemotherapy regimen containing cyclophosphamide, vincristine and prednisone
Patients with CD20-positive follicular lymphoma who are therapy naïve in combination with chemotherapy or who had responded to previous rituximab therapy
Patients with CD20-positive chronic lymphocytic leukemia in combination with fludarabine and cyclophosphamide
Granulomatosis with polyangiitis in adult patients in combination with glucocorticoids
The biosimilar does not include Rituxan’s labeled indication for rheumatoid arthritis, similar to the other approved rituximab biosimilar.
The application for Ruxience included the results of the
phase 3 clinical trial (REFLECTIONS), which included
394 patients with follicular lymphoma. Compared with the EU-licensed version of
rituximab (MabThera®), Ruxience was found to provide equivalent
clinical and safety outcomes.
Originally designated PF-05280586, Pfizer has not disclosed when Ruxience will be available. Pfizer signed a settlement with Roche (Genentech) over litigation for a key Rituxan patent, but terms of this agreement were not disclosed. The other FDA-approved biosimilar competitor in this space, Celltrion’s Truxima®, is similarly awaiting launch.
Apotex has recently made news in Canada, introducing biosimilars and obtaining marketshare there. However, the story of Apotex and its Apobiologix biosimilar subsidiary in the US is less positive.
As we’ve listed in our updated table, Apotex had originally
filed for approval for its pegfilgrastim biosimilar with the FDA in late 2014
and its filgrastim biosimilar in early 2015. In 2019, no announcement has been
made with regard to the filing status of either biosimilar.
In April 2018, we spoke with Apobiologix executives, who told us that the company “were still in discussions with the FDA” about the path forward for its G-CSF biosimilars. Unfortunately, this statement has not changed at all on its website. If there were discussions, they didn’t go far. And so the mystery continues.
There is some support for the view that the parent company is
seeking to shed the Apobiologix subsidiary, and has been actively seeking a
buyer for some time. This would make sense to a degree, as any of its newly approved
biosimilars would be facing a difficult crawl to US marketshare, being the
third or fourth filgrastim or pegfilgrastim biosimilar to launch. Realizing that its marketshare potential would
be substantially limited, why spend the additional developmental dollars?
In April 2018, Canada had granted the company approval to market its pegfilgrastim biosimilar (Lapelga™), and in Canada’s provincial systems, it has become a dominant player. Filgrastim was approved in Canada in 2016 (and in the EU in 2014).
According to its website, Apobiologix had been developing
the following products for the US market:
Epoetin alfa (reference drug, Epogen®),
in Phase 3
Darbepoetin alfa (Aranesp®), in preclinical
Bevacizumab (Avastin®), in Phase 1
Rituximab (Rituxan®), in Phase 1
Trastuzumab (Herceptin®), in preclinical
Although the pipeline lists the epoetin, bevacizumab, and
rituximab biosimilars in clinical trials, no mention of any of these specific
investigations can be found on www.clinicaltrials.gov, under
Apotex or Apobiologix as a sponsor. A request for comment from Apobiologix was
not answered by the time of this publication.
If this is the case, it is less the FDA than the parent drug maker who has lost faith in their biosimilars’ potential in the US. We can ill afford fewer active players in this market.
On November 28, 2018, the Food and Drug Administration (FDA) announced the approval of rituximab-abbs (Truxima™), produced by Celltrion and marketed by Teva.
Approval for this rituximab biosimilar was overwhelmingly recommended by the FDA’s Oncology Drug Advisory Committee by a vote of 16-0 in October. It is the first biosimilar agent approved for the treatment of relapsed or refractory, low grade, or follicular non-Hodgkin’s lymphoma—specifically in adult patients with the CD20+ B-cell variety. The drug makers did not seek approval for the Rituxan’s autoimmune indications, and the FDA did not grant extrapolated approval for them.
According to the FDA’s announcement, the most common side effects of Truxima are infusion reactions, fever, abnormally low level of lymphocytes in the blood (lymphopenia), chills, infection and weakness (asthenia). Health care providers are advised to monitor patients for tumor lysis syndrome (a complication of treatment where tumor cells are killed off at the same time and released into the bloodstream), cardiac adverse reactions, damage to kidneys (renal toxicity), and bowel obstruction and perforation.
This leaves a wide open marketing window for Celltrion and Teva, as Sandoz announced in late October that it was halting its effort to bring its own rituximab biosimilar to the market. There is no word as of this writing regarding the launch and pricing of Truxima in the US. This also represents the second FDA approval for Celltrion; its infliximab biosimilar, Inflectra, was approved in 2016.
In Other Biosimilar News… As BR&R reported in our October discussion with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim had decided to forego marketing its adalimumab biosimilar Cyltezo® in the EU. This is likely owing to the highly competitive environment and the huge pricing discounts being signed by European countries. However, Boehringer has now announced its intention to discontinue all efforts to market and develop any biosimilars outside of the US market. This may come as little surprise, as the Boehringer biosimilar pipeline was not aggressively stocked. Instead, it has been focused on seeking interchangeability status for Cyltezo and to launch this product as soon as possible.
On October 30, Novartis announced that it was culling its investigational drug pipeline and dropping 20% of its development programs. Just three days later, its subsidiary Sandoz announced that it would halt its efforts to obtain approval for its biosimilar version of rituximab from the US Food and Drug Administration (FDA). The decision by Sandoz to halt its rituximab biosimilar filing efforts seems to have culminated from Novartis’ announcement and FDA actions.
Sandoz had received a complete response letter on May 2, 2018 in its attempt to obtain approval for use for Rituxan®’s oncologic (but not autoimmune) indications. According to Sandoz’s press release, the FDA had asked them for additional information before providing a new decision. Sandoz did not specify the type of data sought in the request, although the company’s Global Head of Biopharmaceuticals, Stefan Hedriks, hinted that additional studies were involved. He stated, “We appreciate the important conversations with the FDA, which have provided specific requirements for our potential US biosimilar rituximab, but believe the patient and marketplace needs in the US will be satisfied before we can generate the data required.” Generally, that means more than a re-analysis of existing data. This seems to be the principal reason for its decision to development and the rituximab biosimilar filing.
However, Rituxan is already available in several major markets, including Australia and New Zealand, the European Union, Japan, and Switzerland. Sandoz received US approval for three biosimilars, but only Zarxio® is currently marketed. Next up for Sandoz will be a refiling for FDA approval of its pegfilgrastim biosimilar. The company announced the original FDA rejection of this product in July 2016.
A German manufacturer is considering its options after the successful completion of two clinical studies involving a pegfilgrastim biosimilar (MSB11455).
Fresenius Kabi, which completed its purchase of the biosimilar business from Merck KGaA in September 2017, announced its investigational biosimilar agent had proved sufficiently similar to the reference product Neulasta® in these phase 1 investigations (conducted in healthy participants). These may serve as pivotal investigations for the manufacturer, which said in its release, “Both studies are designed to enable the application for marketing authorization in the EU and US.” This may be the first indication that Fresenius Kabi seeks to be a player in the US.
Fresenius Kabi does not yet have an approved biosimilar on the European market. It hopes that MSB11455 may propel its fortunes on both sides of the Atlantic.
In its first study, the company reported that its biosimilar “met all primary pharmacokinetic endpoints, [maximum plasma concentration], and area under the curve, as well as the primary pharmacodynamic endpoints of absolute neutrophil count (ANC).” Fresenius Kabi added that there were no meaningful differences in the frequency of adverse events in these healthy volunteers. The second study focused on the biosimilar’s potential for immunogenicity, and this was also determined to be no different between the reference drug and the biosimilar. In addition, neutralizng antibodies were not found.
If Fresenius Kabi proceeds with an application for approval in either market, it will find a good deal of competition for pegfilgrastim biosimilars. In Europe, up to 5 biosimilars may be approved (2 already are). In the US, Mylan’s product is the only one to be approved, but another (Coherus Biosciences) is expecting a decision from the Food and Drug Administration (FDA) in early November. Two others (Sandoz and Apotex) are seeking US drug approval.
In other biosimilar news…The Food and Drug Administration’s Oncology Drug Advisory Committee voted unanimously (16-0) today to recommend Celltrion’s CT-P10 rituximab biosimilar for approval. If the biosimilar is approved by the FDA, it will be marketed by Teva….Mundipharma purchased European biosimilar maker Cinfa, which has a pegfilgrastim that has received a CHMP recommendation for approval in the EU.
The information package released by reviewers for the Food and Drug Administration (FDA) indicates that a positive recommendation for Celltrion’s rituximab biosimilar is likely at the Advisory Committee meeting on October 10.
The members of the Oncologic Drugs Advisory Committee will review the data and hear public comments before voting to recommend that the FDA ultimately approve or reject CT-P10 for the treatment of non-Hodgkin lymphoma. Celltrion did not perform clinical trials for rituximab’s autoimmune indications. However, if the FDA approves CT-P10, it may extrapolate the approval to other indications as well.
The original 351(k) application by Celltrion in April 2017 resulted in a complete response letter from the FDA. The rejection for this rituximab biosimilar cited multiple deficiencies, including “clinical, product quality, and facility” problems, as well as clinical study issues from the original submission.
According to the FDA reviewers, “In considering the totality of the evidence, the data submitted by [Celltrion] show that CT-P10 is highly similar to US-licensed Rituxan®, notwithstanding minor differences in clinically inactive compounds, and support a demonstration that there are no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of safety, purity, and potency of the product.”
BR&R will cover the Oncology Drug Advisory Committee meeting and provide updates on its decision. If this rituximab biosimilar is eventually approved by the FDA, Teva would market the product in North America, based on a previous partnership agreement.
In other biosimilar news…Merck has inked an exclusive contract to supply its biosimilar infliximab (Renflexis®) with the US Department of Veterans Affairs. According to a report from Pharmaphorum, it will be the only infliximab biosimilar on the VA’s national formulary.
On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight a joint venture between AstraZeneca and Samsung BioLogics, Archigen Biotech Ltd.
Established in 2014, Archigen has focused on the development of a single biosimilar drug, SAIT101, which will compete in the rituximab space against the likes of Rituxan® and MabThera® (and perhaps other approved rituximab biosimilars). According to a 2016 report, Samsung Electronics had initially sought to develop this agent in 2012, but abandoned the effort soon afterward because of lack of capital.
One of the partners, Samsung BioLogics, also has a stake in Samsung Bioepis (with Biogen). Archigen says on its website that it will be relying on “leading global Contract Research Organizations and Contract Manufacturing Organizations to ensure efficient execution of drug development activities.”
Why you may be hearing more about this company: Its phase 1 study of SAIT101 was implemented October 2016, and clinical results should be available soon. This study was conducted with 246 patients with rheumatoid arthritis, testing the drug against both reference drugs, and included a switching arm. This is unusual for both the size and extent of a phase 1 investigation. Additionally, the organization did not conduct a separate drug trial in healthy volunteers, which is often a first step in analyzing the medication’s pharmacokinetics and pharmacodynamics. Instead, Archigen is moving directly to a phase 3 trial in patients with follicular lymphoma. This study started in January 2017, with initial results expected in May 2019. The phase 3 trial will have over 300 patients, and use MabThera as the comparator.
Based on these dates, a 351(k) filing could be achieved as early as the fourth quarter of 2019, with potential approval in the third quarter of 2020.
Archigen Biotech has not posted on its website any information about subsequent drug targets. Indeed, its website is sparse. It is possible that following the clinical development of SAIT101, Archigen will be more focused on new branded agents, leaving Samsung Bioepis to work on its biosimilar portfolio.