Cyltezo

Product Profile:

Adalimumab-adbm (Cyltezo)

Drug Category: anti-TNF inhibitor/autoimmune

Target Indications: Treatment of ankylosing spondylitis, Crohn’s disease in adults, plaque psoriasis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis

Manufactured by Boehringer Ingelheim; will be marketed by Boehringer Ingelheim

Summary: Cyltezo is an FDA-approved biosimilar version of adalimumab (reference product, Humira®, AbbVie).

Originally known as BI 695501, Boehringer Ingelheim submitted a biologic license application for approval via the 351(k) biosimilar pathway in January 18, 2017. The Food and Drug Administration (FDA) approved the biosimilar in August 29, 2017 (without convening its Advisory Committee). The European Medicines Agency approved Cyltezo for use in the EU on November 10, 2017.

Though approved, it is not yet marketed. Like other manufacturers of approved biosimilar versions of adalimumab, Boehringer has signed a licensing agreement with AbbVie that would enable launch in 2023. The company has also signaled its intention to obtain an interchangeable designation for this product, which will enable it to be automatically substituted by pharmacies.

About the Manufacturer

Boehringer Ingelheim was founded established in 1885, and its US headquarters is located in Ridgefield, Connecticut. The company has 50,000 employees globally. Recently, the company has reduced its biosimilar focus to a single product (Cyltezo) in the US market only. The company has well-established therapies in the diabetes, respiratory, oncology, cardiovascular, among other therapeutic areas.

News, Commentary, and Intelligence

Competitor Products and Manufacturer Analysis

Cyltezo was the second adalimumab biosimilar to be approved by the FDA. It, like its competitors, is not yet available on the US market.

ADALIMUMAB BIOSIMILARS APPROVED BY THE FDA: FDA FILING DATES AND ACTIONS

Biosimilar

Manufacturer

Brand Name & Designation

Innovator Product

FDA Filing Date

Status

Adalimumab

Amgen

Amjevita (adalimumab-atto)

Humira

November 25, 2015

Approved September 23, 2016, all indications; not yet marketed; Signed licensing agreement with AbbVie to launch January 2023

Adalimumab

Boehringer Ingelheim

Cyltezo (adalimumab-adbm) 

Humira

January 18, 2017

Approved August 29, 2017; not yet marketed

Adalimumab

Sandoz

Hyrimoz (adalimumab-adaz)

Humira

January 16, 2018

Approved October 31, 2018; Signed licensing agreement with AbbVie to launch Sept 2023

Adalimumab

Samsung Bioepis/Merck

Hadlima (adalimumab-bwwd)

Humira

September 27, 2018

Approved July 2, 2019; Signed licensing agreement with AbbVie to launch June 2023

ADALIMUMAB BIOSIMILARS IN DEVELOPMENT

Company Name, Country

Product Name

Stage of Development

Mylan/Fujifilm Kyowa Kirin Biologics

FKB327

Signed licensing agreement with AbbVie to launch August 2023

Coherus Biosciences

CHS-1420

Completed phase 3 study; FDA submission anticipated Q4 2019

Pfizer

PF-06410293

Completed phase 3 study; Signed licensing agreement with AbbVie to launch November 2023

Momenta

M923

Completed phase 3 study; FDA filing in 2019; signed licensing agreement with AbbVie to launch in Dec 2023; in August 2019, announced halt to plans to commercialize

Fresenius Kabi

MSB11022

Completed phase 3 study

Celltrion

CT-P17

Phase 3 trials to be completed in 2020

See article below on latest updates on licensing agreements with Abbvie.

Momenta Drops Out of Biosimilar Adalimumab Competition

(August 5, 2019) “Today, Momenta announced the Company will cease active development of M923 at this time, due to changes in the market opportunity associated with Humira patent litigation settlements,” according to a company press release.

Boehringer Ingelheim Gives up the Fight, Signs AbbVie Agreement on Adalimumab

(May 15, 2019) This agreement allows Boehringer Ingelheim to enter the marketplace July 1, 2023, getting a slight jump on some other licensees, but it effectively ends the protracted patent litigation that Boehringer hoped to win.

Federal Judge Rules AbbVie Must Give Up Documents to Boehringer

(February 14, 2018) AbbVie, which makes the originator product Humira, must turn over all papers related to the Humira patents, said a federal court judge.This may actually move the court case out of the discovery phase, according to Fierce Healthcare, and potentially closer to an actual, early biosimilar launch.

Update: Who Has Signed Abbvie Licensing Agreements for Adalimumab Biosimilars?

(January 28, 2019) At least 8 biosimilar manufacturers have signed licensing agreements with Abbvie, which allow immediate European launches for approved adalimumab biosimilars and sequentially timed US launches in 2023. This database displays the manufacturer, product name, and date of anticipated launch. Note: not all of these biosimilar adalimumab are approved in the US.

More Adalimumab News: Abbvie Signs a Licensing Deal With Coherus, Coherus Sues Amgen for Patent Infringement

(January 28, 2019) Coherus becomes the eighth biosimilar maker to sign a licensing agreement with Abbvie, and it also becomes the first biosimilar maker to sue another (Amgen) for patent infringement.

Pfizer Pulls One Biosimilar Adalimumab Application From the EMA

(December 17, 2018) Earlier this month, Pfizer notified the European Medicines Agency (EMA) that it was withdrawing one of its two applications for approval of its biosimilar adalimumab.

Boehringer Ingelheim Decides to Market Cyltezo® in the US Only

(November 28, 2018)  Boehringer has now announced its intention to discontinue all efforts to market and develop any biosimilars outside of the US market.

Pfizer Signs Licensing Deal With Abbvie on Adalimumab Biosimilar Candidate

(November 27, 2018)  According to the announcement, Pfizer will market this agent (PF-06410293), if approved by the Food and Drug Administration, in November 2023.

A Third Biosimilar Adalimumab Approval in the US

(November 1, 2018)  The Food and Drug Administration (FDA) announced yesterday the approval of adalimumab-adaz from Sandoz. The new agent, dubbed Hyrimoz™, will not be launched in the US until 2023.

Word From the Adalimumab Front: A Conversation With Molly Burich, MS, Boehringer Ingelheim: Part 2

(October 24, 2018) In part two and the conclusion of this interview, Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, speaks to Boehringer Ingelheim’s progress in Cytelzo interchangeability studies, its plans for the product in Europe in the face of several adalimumab biosimilars launches in the EU, and also the complexity inherent in CMS’s plans to move biologic agents from part B to part D coverage.

Word From the Adalimumab Front: A Conversation With Molly Burich, MS, Boehringer Ingelheim: Part 1

(October 23, 2018)  In the first portion of a two-part interview with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim, we cover the challenges of driving biosimilar uptake, as well as the unique situation that has focused this manufacturer’s attention on biosimilars and interchangeability.

Part B to Part D and Other Questions: How CMS’s Plans Could Affect Biosimilars

(August 10, 2018)  Some of these tactics are a bit late to the party, as commercial insurers and health plans have been employing them for years. To the extent that an injectable treatment can be managed through the pharmacy benefit rather than the medical benefit, the drug can be easily subjected to prior authorization, step therapy, quantity limits, and other tools routinely used.

Up to 5 Biosimilar Horses in the Race for Adalimumab in Europe: Heading for the Starting Gate

(August 3, 2018) A long-sought dream in the United States will be a welcome reality in Europe this October: a stampede for Abbvie’s marketshare with adalimumab biosimilars and the savings that go with it.

An FDA Filing for Momenta’s Adalimumab Biosimilar Coming Soon?

(June 22, 2018) In its recent investor conference, the company disclosed that it is ready to send M923, its adalimumab biosimilar, to the agency for approval.

With the Samsung Bioepis Deal, Abbvie Tightening Its Grip on the US Adalimumab Market

(April 6, 2018) Samsung Bioepis and Biogen has reached a deal with Abbvie that would enable it to market its biosimilar adalimumab (should it be granted approval) in June 2023.

What Will Cost Savings on 2023 Adalimumab Biosimilars Really Be Worth?

(February 5, 2018) AbbVie executives are sticking to their pledge to restrict annual price increases on Humira® below 10%, but even payer price protections won’t mitigate the increasing expenditures before adalimumab biosimilars hit the market.

Sandoz Files 351(k) Application for Adalimumab Biosimilar

(January 16, 2019) Sandoz announced that it has thrown its hat in the ring for another Humira biosimilar.

Are We Now Thinking “Authorized Biosimilars”?

(October 3, 2017) Authorized generics have been around for a couple of decades. They can be a challenge to payers, health systems, and patients who are seeking the price-reduction benefits borne out of normal competition. The Amgen-Abbvie agreement for the former’s adalimumab biosimilar is right out of this playbook.

FDA Approves New Humira Biosimilar, Bypasses Advisory Board Route

(August 29, 2017) Boehringer Ingelheim Pharmaceuticals, Inc. announced August 29 that it had received approval from the Food and Drug Administration (FDA) for its first biosimilar.

Boehringer May Seek Interchangeable Designation for Adalimumab Biosimilar

(July 28, 2017)  One biosimilar developer announced on July 27 that it is embarking on a study specifically to prove interchangeability of its biosimilar version of adalimumab.

Impressions on the Adalimumab Biosimilar Arthritis Advisory Committee Meeting

(July 12, 2017) FDA Advisory Committee members considered the data package provided by Amgen to be comprehensive, but the 26-0 vote was not without some interesting points and drama.

The Benefits of Biosimilars

The Promise of Biosimilars

Clinical Trials of Cyltezo

Cyltezo has been the subject of an extensive clinical trial program, including not only the standard phase 1 pharmacokinetic studies, but also phase 2 studies testing the efficacy of the autoinjector and phase 3 investigations testing seeking comparative clinical results that incorporated switching components.

Rheumatoid Arthritis

Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study.

In this double-blind investigation, 645 patients (mean age, 54 yr) with active rheumatoid arthritis (RA) were randomized to receive either BI 695501 (Cyltezo) or US-licensed Humira in equivalent doses along while continuing their methotrexate therapy. After 24 weeks, the remaining 593 patients were randomly reassigned to continue on their original regimen or to switch to the biosimilar from the reference product. The primary endpoints were the percentage of patients judged to have a 20% improvement in the American College of Rheumatology response criteria (ACR20) after 12 and 24 weeks of therapy. The researchers evaluated immunogenicity, adverse reactions, and ACR50 and ACR70 responses through 58 weeks of treatment.

There were no significant differences in demographics or baseline measures between the two groups of patients. In both groups, previous use of another biologic agent was just over one-quarter.

Roughly 70% of patients attained ACR20 by 24 weeks, and this percentage remained the same for patients remaining on their individual therapies or switched by week 48. Approximately 36% of all populations attained ACR50 and 14% of the biosimilar and 18% of the Humira subgroups reached ACR70 by week 48. There were no significant differences in switched patients or in biosimilar vs. reference product populations. This was also true for DAS28 scores. In the group continuously receiving Cyltezo, 5.6% experienced serious side effects versus 9.8% in those receiving Humira during the same period. Antidrug antibodies were seen in 11 of those taking the biosimilar compared with 21 of those receiving the reference agent.

According to the multinational group of investigators, weeks 12 and 24 results indicated that Cyltezo was noninferior to the reference agent. There was no difference in reasons for discontinuation at the time of rerandomization.

The investigators conducted an open-label extension trial to help determine the long-term safety and efficacy of Cyltezo in patients with rheumatoid arthritis through 48 weeks. The clinical outcomes of ACR20 and EULAR-rated response were not significantly different. Safety data indicated that serious adverse effects were exhibited by 6.2% of those receiving Cyltezo throughout, 7.8% receiving Humira through week 48, and only 3.9% for those switched from Humira to Cyltezo. The results of this extension trial supported the findings of the randomized, controlled trial.

Psoriasis

Efficacy, Safety and Immunogenicity of BI 695501 Versus Humira® in Patients With Moderate to Severe Chronic Plaque Psoriasis

Although the full results of this phase 3 study have not yet been published, a report from the Congress of the European Dermatology and Venerology Association 2018 and a press release from Boehringer hint at its success.

In this investigation, Cyltezo was compared with the reference drug Humira in 308 patients with moderate-to-severe plaque psoriasis symptoms. The study lasted 16 weeks, and the primary outcome was the percentage of patients attaining PASI75 scores during that period. Patients were given the same doses of either medication: day 1: 80 mg; day 7: 40 mg; every week for 16 weeks: 40 mg.

The researchers found that Cyltezo was as effective as the originator drug in terms of this endpoint (70% of the patients in each group attained PASI75). They concluded that the two therapies result in equivalent clinical outcomes, safety profile, and in immunogenicity.

Patients who achieved at least a PASI50 after 16 weeks were invited to continue in a study extension (to 34 wk of dosing). All others were tracked to detect any safety issues. These results have not yet been made available.

Phase 1 Studies

Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE®-PK) in healthy subjects.

Similar Pharmacokinetics of the Adalimumab (Humira®) Biosimilar BI 695501 Whether Administered via Subcutaneous Autoinjector or Prefilled Syringe (VOLTAIRE®-AI and VOLTAIRE®-TAI): Phase 1, Randomized, Open-Label, Parallel-Group Trials

Ongoing Studies

BI 695501 Versus Humira in Patients With Active Crohn’s Disease: a Trial Comparing Efficacy, Endoscopic Improvement, Safety, and Immunogenicity

VOLTAIRE-X: Pharmacokinetics, Safety, Immunogenicity and Efficacy of BI 695501 Versus Humira® in Patients With Moderate to Severe Chronic Plaque Psoriasis: a Randomized, Double-blind, Parallel-arm, Multiple-dose, Active Comparator Trial

This 240-patient multiple-switch trial will be completed later in 2019. The investigation focuses on patient with plaque psoriasis.

Efficacy, Safety and Immunogenicity of BI 695501 Versus Humira® in Patients With Moderate to Severe Chronic Plaque Psoriasis (VOLAIRE-X)

Another study involving plaque psoriasis is scheduled to be complete in 2020. This investigation will comprise 350 patients with active disease.

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