Sandoz Files 351(k) Application for Adalimumab Biosimilar

Sandoz announced that it has thrown its hat in the ring for another Humira biosimilar. Sandoz filed an European application for approval for GP2017 last year, in the expectation that it will be able to launch soon after the European patent expires in October 2018.

This will be the third application for an adalimumab biosimilar. Versions by Amgen (Amjevita) and Boehringer Ingelheim (Cyltezo) have been approved by the Food and Drug Administration (FDA); however, patent litigation has held up marketing. Amgen had signed an agreement with Humira’s manufacturer Abbvie to postpone marketing until 2023. Boehringer Ingelheim has not signed a similar agreement, but no indication is yet given regarding the US launch of this product.

It is assumed that European revenues will sustain the biosimilar manufacturers until US marketing begins. This is Sandoz’s fifth FDA biosimilar application. It has received approval for Zarxio (filgrastim) and Erelzi (etanercept); its application for rituximab is under review, and it received a rejection for its version of pegfilgrastim.

Are We Now Thinking “Authorized Biosimilars”?

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 Herceptin on the biosimilar for Humira^® seems to be right out of this playbook.

In summary, authorized generics work like this:

A brand manufacturer has a product that is nearing patent expiration
Rather than ceding its marketshare altogether in the face of multisource products, the manufacturer will come to an agreement with a generic drug maker to produce the first generic of its product, which allows the branded company to earn licensing fees and royalties on the drug
The additional royalty or licensing fee means that the price of the authorized generic will likely be higher than if there was no agreement
The maker of the authorized generic will get to market sooner (perhaps even prior to patent expiration)
Competing generic manufacturers will have to edge their way into the market against not only the authorized generic maker but perhaps the branded manufacturer that is benefiting from the agreement

On September 28, Amgen and Abbvie announced an end to the patent litigation between the companies. The agreement will allow Amgen to market its biosimilar (Amjevita™) in the US (in 2023) and in the EU (in 2019). The dates reflect differences in principal patent expirations for the two major markets. The all-important composition-of-matter patent expired in December 2016, which is why potential biosimilar manufacturers had hopes of marketing their products as early as 2017 in the US. The other patents don’t expire until 2023.

Under the agreement, Amgen acknowledges the validity of Abbvie’s myriad non–composition of matter patents on Humira and gives up the litigation fight to market its version of adalimumab. Amgen will pay Abbvie a licensing fee to market the product, similar to the type of deal for an authorized generic.

Presumably, Amgen entered into the agreement and did not launch at risk, because it feared that Abbvie would be able to successfully defend its patent maze in court. The agreement would allow Amgen to launch in the European market, which would sustain it during the wait to launch in the US.

However, Amgen is not the only potential maker of an adalimumab biosimilar. Boehringer Ingelheim has an approved product (Cyltezo™), which was approved in January 2017. Several other players are in later-stage trials, including (at least) Coherus Biosciences, Momenta Pharmaceuticals, Pfizer, Samsung Bioepis, and Sandoz. It is too early to tell what this agreement might mean for them. Might Abbvie be willing to make separate agreements with them as well, thereby ensuring itself of a cut of these profits for years to come?

In the biosimilar space, there is no exclusivity for the first biosimilar to market, and if a drug maker sought to launch at risk, the rewards can actually outweigh the potential penalties if they found themselves on the wrong end of ongoing patent litigation. Pfizer took the gamble with its Inflectra^®biosimilar of infliximab.

If they have to wait until 2023 for this biosimilar, payers may decide to take action. One way would be to encourage the use of other anti-TNF inhibitors or even other effective biologic classes over Humira, if their pricing made sense. However, Humira is often preferred and significant rebates would be at stake.

Legislators did not account for the possibility of authorized biosimilars. It could be a further obstacle to making biologics more accessible to the people who may most benefit from their use.

FDA Approves New Humira Biosimilar, Bypasses Advisory Board Route

Boehringer Ingelheim Pharmaceuticals, Inc. announced August 29 that it had received approval from the Food and Drug Administration (FDA) for its first biosimilar. Named Cyltezo™ (adalimumab-adbm), a biosimilar to Humira^®, it is approved for several autoimmune disorders, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease in adults, plaque psoriasis, and ulcerative colitis.

The FDA approval bypassed the need for an Arthritis Advisory Committee review and recommendation, which the agency suggested may be increasingly common with future biosimilar approvals. One suspects that this is more likely with the licensing of the first biosimilar for a particular originator product, with the assumption of a comprehensive data package on submission.

Like Amgen’s Amjevita^®, Boehringer’s biosimilar will likely enter a holding pattern until patent litigation is settled (or the patents expire) on AbbVie’s Humira. In the meantime, Boehringer indicated that it will seek approval for an autoinjector, to stand alongside its newly approved subcutaneous formulation.

Boehringer has also applied for approval with the European Medicines Agency, which is expected to decide on its approval before the end of this year. Samsung Bioepsis and partner Biogen earned its own European approval for Imraldi™ this week, another adalimumab biosimilar.

Boehringer May Seek Interchangeable Designation for Adalimumab Biosimilar

The US Food and Drug Administration (FDA) announced earlier this year its draft standards for assessing the interchangeability of biosimilars with originator products. One biosimilar developer announced on July 27 that it is embarking on a study specifically to prove interchangeability of its biosimilar version of adalimumab.

Initial recruitment of the “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” was announced by Boehringer Ingelheim to provide evidence that its investigational biosimilar BI 695501 can be substituted for Humira without significant negative clinical or safety effects. The study will incorporate repeated switching between the originator and the biosimilar agent in 240 patients with plaque psoriasis.

Boehringer’s 351(k) application for BI 695501 was sent to FDA in January 2017. A decision is expected in the fourth quarter. The clinical studies supporting BI 695501 were conducted in patients with rheumatoid arthritis; another is underway in patients with active Crohn’s disease. The VOLTAIRE-X interchange study will not be completed until July 2019; therefore, any FDA decision regarding interchangeability on this biosimilar will be made at least 2 years from now.

Biosimilar Rituximab Under FDA Review

Celltrion announced June 30, 2017 that it has submitted its 351(k) application to the Food and Drug Administration for approval of its biosimilar version of rituximab. This represents the first biosimilar application for rituximab, a monoclonal antibody to CD20.

The product, known during investigations as CT-P10, was approved in the European Union in February, and has been launched there as Truxima in late April. Clinical data have been presented on this biosimilar’s efficacy and safety in treating rheumatoid arthritis and advanced follicular lymphoma, a form of non-Hodgkin lymphoma

If approved, Celltrion will market this product with Teva in North America, which signed a partnership agreement with Celltrion in October 2016 for this biosimilar agent to treat cancer and for CT-P6 (trastuzumab). The FDA application for trastuzumab is expected to be filed this summer. It is currently partnered with Pfizer to market its product Inflectra^® (infliximab-dyyb) in the US and Canada.

Also in June, Sandoz received approval from the European Medicines Agency to market its own version of rituximab, called Rixathon™.

In other biosimilar news…Coherus Biosciences, which took hits from the FDA and its investors in the rejection of its pegfilgrastim biosimilar in June, laid off 51 workers (about 30% of its workforce) in an effort to cut costs. Coherus is working towards addressing the issues outlined in FDA’s Complete Response Letter on pegfilgrastim. In its letter, FDA did not require additional clinical studies. In the meantime, Coherus still is seeking to file its biosimilar etanercept for approval in Europe later this year, and its version of adalimumab in the US in early 2018. However, John Carroll reported that Coherus’ clinical development partner on etanercept in Japan, Daiichi Sankyo, has decided to pull out because of concerns that Coherus will not be able to manufacture the product.

Savvy Move or Illegal Anticompetitive Action?

Merck, which markets Remicade^® in Europe, may have stepped over an anticompetitive line when Pfizer’s Inflectra^® biosimilar was first made available, according to the U.K.’s Competition and Markets Authority. In the US, however, this activity would be considered routine. Certainly, nothing prevents this action and it would be fully expected, in terms of net costs.

According the UK’s Competition and Markets Authority, Merck took unfair advantage of “dominant position through a discount scheme for Remicade that was likely to restrict competition” from the biosimilar infliximab when it was launched in 2015. In this scheme, the drugmaker “unfairly” discounted the product to customers who remained loyal to the product.

Is this really different than offering rebates for preferred positioning? Anecdotal reports in the US indicate that Janssen Biotech, which markets the originator agent in North America, has taken similar action with rebates against Inflectra^® (infliximab-dyyb). In fact, Amgen did the same to ward off competition from Zarxio^® (filgrastim-sndz). In their cases, they did not discount the wholesale acquisition cost (WAC) to meet the biosimilars’ but simply increased the rebate to yield an equivalent net cost.

This action may be more attractive because it may have fewer implications for “best pricing” discounts required by Medicaid and other payers. Certainly, the maker of the originator product can cut their WAC costs if they desired; at the biosimilars’ modest 15% discounts, this would simply roll pricing back to 2015 levels.

In other news…A case report has been published from New York City, in which a patient switching from the reference infliximab agent to the biosimilar version experienced papulosquamous lesions a few days after the change in medication. Skin biopsy revealed the existence of a lichenoid eruption. This adverse event has not been cited previously in the literature with the reference agent Inflectra^®. The direct cause of the drug reaction is unknown but further monitoring is warranted, according to the authors.

On June 2, the European Medicines Agency accepted Sandoz’s application for biosimilar infliximab and adalimumab. Sandoz has not filed a 351(k) application with the US Food and Drug Administration for either product.