Second Etanercept Biosimilar Receives FDA Approval

Samsung Bioepis scored another biosimilar approval in the US, as the Food and Drug Administration gave its nod to etanercept-ykro on April 25, 2019. Formerly known as SB4, Samsung Bioepis dubbed this agent Eticovo™. It is the second
Enbrel® biosimilar to to receive US approval.
 
This approval covered all of the reference product’s autoimmune indications, including ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, and rheumatoid arthritis. Clinical studies were performed in patients with moderate-to-severe rheumatoid arthritis, finding that in combination with methotrexate, Eticovo achieved ACR20 scores that were equivalent to that of Enbrel by week 24 (78.1% vs. 80.3%, respectively). Safety and immunogenicity were also comparable with those of the reference agent.

Eticovo has been approved in the EU and Canada, in addition to other parts of the world, under the brand names Benepali and Brenzys. Samsung Bioepis has not announced a launch date in the US for its biosimilar, and this can be delayed for quite some time. Sandoz’s Erelzi® was approved in 2016, but has not yet reached the market because of patent litigation. Amgen, which manufacturers Enbrel, believes its patents extend effectively into 2028, which would provide for nearly 30 years of product exclusivity.


Both Coherus and Lupin have investigational etanercept biosimilars that are in phase 3 trials. Neither has publicly filed for FDA approval to date.

Does Mass Signing of Adalimumab Licensing Deals Add Up to Biosimilar Access Collusion?

As reported by the Center for Biosimilars, a union has filed a class-action lawsuit against AbbVie and the eight prospective biosimilar adalimumab makers who agreed to delay bringing their agents to market through a royalty arrangement.

Only Boehringer Ingelheim remains as a biosimilar maker who has an approved version of adalimumab but who has not signed on with AbbVie. United Food and Commercial Workers Local 1500 has filed the suit with the other manufacturers and AbbVie, claiming that by their actions, they are trying to “divide the market for adalimumab between Europe and the United States,” according to the Center for Biosimilars report.

This is an interesting question. The individual motivations of the first companies to come to agreement with AbbVie (Amgen, then Samsung Bioepis) included an end to interminable patent legislation in the US. They wanted the ability to immediately plan launches in Europe (starting in October 2018). The motivations of most other subsequent signees almost certainly was to not forfeit marketshare in Europe, which was needed to help sustain biosimilar development efforts for the US market. In fact, many of these prospective US manufacturers already had received approval in the EU.

AbbVie’s principal patents on Humira® expired in Europe in October 2018. The last of the principal patents are supposed to expire around 2023 in the US anyway. Was it necessary to arrange serial US launches as demonstrated in this link? Would patent litigation have continued well past the supposed patent expiration date? Knowing AbbVie, this is likely. Their several patents involving adalimumab use to treat individual diseases would provide AbbVie a basis for forging ahead with lawsuits that would have gained them additional billions of dollars in sales while the suits meandered toward conclusion.

Does this mean that access to Humira is accelerated through the signing of the royalty agreements, rather than delayed through acts of collusion? That is difficult to say. Although should the lone holdout—Boehringer Ingelheim—decide that it makes business sense to launch at risk, it could topple the carefully orchestrated structure of the agreements. Amgen believes that it will launch the first adalimumab biosimilar, and experience a few months of exclusivity in the US. At that point, Amgen (and every subsequent adalimumab biosimilar maker) would have to decide whether (1) to do the same or risk losing its advantage, (2) start working towards marketing plan B, or (3) cede the initial marketshare and its billions in revenue and wait it out. If Boehringer obtains its sought after interchangeability designation, that may well speed up the process.

Personally, I find it hard to believe that these individual acts represent premeditated collusion; although the resulting lack of access to the many biosimilar versions may look to others as an orchestrated maneuver.

Samsung Bioepis Scores FDA Approval of Ontruzant, the Third Biosimilar Trastuzumab

The US Food and Drug Administration (FDA) announced on January 18, 2019 the approval of a new biosimilar version of trastuzumab. Produced by Samsung Bioepis, this agent was dubbed Ontruzant (trastuzumab-dttb).

This is the third trastuzumab biosimilar approved by the FDA, following those by Mylan and Biocon in December 2017 (Ogivri®) and Teva and Celltrion last month (Herzuma®). As with biosimilars other than Herzuma and the reference biologic Herceptin®, this agent is approved for use in the treatment of HER2-overexpressing breast cancer and the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Herzuma is not approved for the latter indication.

As with Renflexis®, Samsung Bioepis’ first FDA-approved biosimilar, Merck will market the product in the US when launched. No launch date has yet been revealed.

Mylan and Biocon had signed a licensing agreement with Roche, the manufacturer of Herceptin, which ended their patent fight, but which delayed launch. Teva and Celltrion have not yet disclosed whether a similar deal has been reached with Roche. Pfizer has an investigational trastuzumab biosimilar, and they too have signed a licensing agreement with Roche.

Will the Government Shutdown Slow Biosimilar Approvals?

The partial federal government shutdown is having specific effects in various important areas of government, but it may not be particularly troubling for FDA user-fee funded activities.

Scott Gottlieb, MD, Commissioner of the FDA, has been especially busy on Twitter, trying to inform the public how the government shut down is affecting FDA operations. He made it clear that the agency is prioritizing its efforts on ensuring consumer safety.

During an extended tweet storm (the past 7 days), he has not directly addressed the effect of the shutdown on current drug approvals. However, since the pharmaceutical companies have paid into the drug approval activities of the Center for Drug Evaluation and Review, there may be sufficient funds and resources for ongoing approval activities. In a tweet last week, Dr. Gottlieb mentioned that FDA was bringing onto staff several new user-fee funded staffers. Yet, in a January 7 tweet, he promised additional information on how the shutdown would affect biosimilars; this has not yet been addressed.

In terms of biosimilars, two trastuzumab drug makers are expecting FDA decisions this quarter (Pfizer and Samsung Bioepis). However, Pfizer’s biosimilar launch is subject to a licensing agreement with Genentech (Roche), the maker of the reference product Herceptin®. Therefore, if there was a short delay in FDA approval, it will not likely have a material effect on availability for prescription. We anticipate that Pfizer will also be hearing from the FDA on its rituximab biosimilar in the second quarter.

This could raise a secondary problem with the shutdown: Will the current furlough cause a chain reaction of delays in the evaluation of existing biologic licensing applications? How long might it take the full FDA staff to catch up, if that is the case?

In a January 13 tweet, Dr. Gottlieb said, “The lapse in funding represents one of the most significant operational challenges in FDA’s recent history. But as an agency, we’re committed to fulfilling our consumer protection mandate, to the best of our abilities, under our current configuration.”

In other biosimilar news… A January 10 story in The Pink Sheet reported that Leah Christl, PhD, Associate Director of Therapeutic Biologics at FDA intends to depart the agency in the near future (a specific date was not given).

An Update on Potential Biosimilars for Bevacizumab

Embroiled in patent litigation, the partnership of Amgen and Allergan have waited for the opportunity to launch Mvasi® since September 2017. During this time, the competition has not been stagnant, with Pfizer moving towards an FDA decision. The next 6 months may prove critical, but when will providers, patients, and payers have access to Avastin® biosimilars? That may be based more on guesstimates than on fact.

Avastin patent litigation

WHAT DO WE KNOW?

(1) Amgen and Allergan received its FDA approval for Mvasi (bevacizumab-awwb) September 17, 2017. The approval covered all of the reference product’s indications. The drug was approved for use by the European Medicines Agency in January 2018.

(2) In court documents filed during its patent battle with Genentech, Amgen had originally stated that it planned to begin marketing Mvasi once the last 8 patents it considered valid expired on December 18, 2018.

(3) Amgen then revised this potential launch date, according to the court filing, saying that it could launch several months earlier, on April 5, 2018.

(4) In either case, the launch has not occurred. According to the Purple Book, Avastin was first approved by the FDA February 26, 2004. That is approximately 15 years, and counting.

(5) The US District Court handling the litigation is expressing impatience with the back and forth between the two parties (read the Judge’s concluding remarks). A trial court date was set for June 2020.

(6) Pfizer completed its phase 3 trial for PF-06439535 in nonsquamous non–small cell lung cancer and filed for FDA approval in August 2018. An FDA decision is expected in the second quarter of this year.

(7) In November 2018, Boehringer Ingelheim completed its phase 3 trial in lung cancer for BI 695502.

(8) Samsung Bioepis completed its phase 3 trial in lung cancer in October 2018 (compared with EU-licensed Avastin).

(9) In addition, Centus Biotherapeutics is scheduled to complete its phase 3 trial in June 2019 as well.

WHAT WE DON’T REALLY KNOW

So much for what we know. Here are some things we know less well.

At a drug pipeline update at the Academy of Managed Care Pharmacy in October 2018, Express Scripts’ Aimee Tharaldson, PharmD, Senior Clinical Consultant—Emerging Therapeutics, offered a projected launch date of July 2019. In an E-mail communication with Biosimilars Review & Report, Dr. Tharaldson clarified that this estimate was based on the anticipated expiration of a key patent on Avastin that month.

Bevacizumab Biosimilars
Aimee Tharaldson, PharmD

When we contacted a senior Amgen executive, he stated that the company declined to discuss potential launch dates.

Goodwin’s Big Molecule Watch, which keeps a close eye on biosimilar-related patent litigation, does not list any ongoing suits between Genentech and Pfizer or Boehringer Ingelheim regarding Avastin (which may be surprising in itself).

We would anticipate that Pfizer will launch as soon as feasible, if they receive an FDA approval by June. Pfizer has an established record of moving their biosimilars quickly to market (e.g., Inflectra® [with Celltrion], Retacrit®, and Nivestym®).

Samsung Bioepis has not yet revealed their plans around an FDA filing for their investigational biosimilar of bevacizumab.

Boehringer had not yet filed a 351(k) application for approval of BI 695502. Comments by Molly Burich, Director, Public Policy: Biosimilars and Pipeline, in our interview last Fall, made it clear that the company is laser focused on bringing its adalimumab biosimilar (Cytelzo®) to market. In fact, this bevacizumab biosimilar was no longer posted on their pipeline at that time.

WHAT WE FOUND OUT

Today, Susan Holz, Director, Communications, Specialty Care, confirmed that the company decided that this agent was not in its strategic plans and it simply allowed the study to be completed. She said, “Boehringer Ingelheim made the decision to terminate all activities related to the BI 695502 program, a biosimilar candidate to Avastin. It is important to note that this decision was not based on any safety or efficacy findings with the investigational medicinal product BI 695502. Boehringer Ingelheim continuously evaluates our business portfolio and assesses potential strategic partnerships to help enhance our pipeline and development capabilities.”

Perhaps several of these unknowns will be resolved by the end of July, and the clouds will lift a bit. I suspect at that time, we’ll be much closer to biosimilar access for this biologic, which racked up $7 billion worldwide in sales in 2017.

Pfizer Signs Licensing Agreement With Roche on Trastuzumab Biosimilar

With Pfizer expecting to hear back on its 351(k) resubmission on a trastuzumab biosimilar in early 2019, Genentech and its parent, Roche, may have been getting nervous about their competitor’s intentions. After all, Pfizer was willing to launch at risk with its marketing of Inflectra®, the infliximab biosimilar manufactured by partner Celltrion. In fact, it is the only biosimilar manufacturer that has gambled on an at-risk biosimilar launch.

According to a report in the Pink Sheet, a district court filing on December 4 noted that the two parties signed a settlement that will put an end to their patent litigation, and presumably allow Pfizer to market its biosimilar trastuzumab in the US at a future date. As in previous agreements signed by Roche, the terms are confidential, and launch dates and licensing fees are unknown.

trastuzumab biosimilar

A similar confidential agreement was completed between Mylan and Roche, for Mylan and partner Biocon’s Ogivri®, the first trastuzumab biosimilar approved by the Food and Drug Administration (FDA) in April 2017.

Three other trastuzumab biosimilars are also trying to reach the market. Amgen and Allergan received a complete response letter in June 2018, and have not yet announced when it might resubmit its 351(k) application. Samsung Bioepis is awaiting its initial decision on its trastuzumab biosimilar, filed in January 2018. Teva and Celltrion seem to be on the cusp of an FDA decision, after receiving their initial rejection in July 2017.

Roche has it covered, though. It filed patient litigation against Samsung Bioepis in September 2018 and partners Celltrion and Teva as well.

This is the very situation that the federal government, payers, and patients want to try to avoid, however. Licensing fees paid to the reference manufacturers may work to significantly inflate the drug’s price to the health system. The lack of transparency characterizing these agreements and the associated delays in launch are being decried by those patients and entities who can benefit from access to biosimilar competition. Herceptin was first approved in 1998. No one envisioned Genentech having 20+ years of marketing exclusivity.

In other biosimilarnews… MomentaPharmaceuticals, which signed an Abbvie licensing agreement for its biosimilar adalimumab, said in a statement that it will delay FDA filing M923 beyond 2019, which will help reduce its corporate expenditures. This delay should not impact the expected commercial launch date of November 20, 2023, according to the company.

Celltrion announced that it has filed an application for European Medicines Agency approval for its subcutaneous form of its infliximab biosimilar Remsima (US brand name, Inflectra®). This would provide the first subcutaneous injection formulation of infliximab.

Momenta Signs Licensing Deal With Abbvie. Did It Have a Choice?

We previously reported that Momenta Pharmaceuticals reevaluated its biopharmaceutical strategy going forward, deciding to move forward only with its investigational adalimumab and aflibercept biosimilars. Yesterday, Momenta announced that it has joined the long queue of pharmaceutical manufacturers signing a biosimilar licensing deal with Abbvie, which will allow commercialization of M923, its biosimilar to Humira, should it obtain regulatory approval. Momenta’s licensing deal is the fifth one signed by prospective biosimilar marketers in the US.

This agreement was pretty much a no-brainer for Momenta. The company did not have the stomach for attempting either an extended patent fight or an at-risk launch. However, the biosimilar licensing agreement only allows Momenta to market its adalimumab biosimilar in the US after December 2023, which will make it the fifth Humira biosimilar that will launch under the licensing agreements (Table). The main patents for Humira have expired in Europe, and these agreements have generally allowed the European launches to occur as of October 16 of this year.

Of the manufacturers signing biosimilar licensing deals with Abbvie , only Amgen and Sandoz have earned FDA approval for Amjevita® and Hyrimoz®, respectively. And Boehringer Ingelheim is still duking out patent litigation with Abbvie in the courts over its approved biosimilar agent Cytelzo®, for which it hopes to receive an interchangeability designation. The second through fifth agents entering the fight will be likely pounding away at subsequently smaller slices of revenue.

Perhaps the most frustrating part is that Abbvie is running a lucrative game; it will collect royalties from all of these manufacturers in 2023 and beyond, which will help offset declining marketshare from its biggest revenue contributor.

 

In Abbvie’s Web: Who Has Signed Licensing Agreements for Biosimilar Adalimumab?

Company/Partner

Drug Name

Launch Date

Amgen

Amjevita*

January 2023

Samsung Bioepis/Merck

SB5

June 2023

Mylan/Fujifilm Kyowa Kirin Biologics

Hulio

August 2023

Sandoz

Hyrimoz*

September 2023

Momenta

M923

December 2023

*Received FDA Approval.

Note: This post was revised and corrected, November 8, 2018.

Tidal Wave of Pegfilgrastim Biosimilars About to Hit Europe

We had mentioned the upcoming deluge of adalimumab biosimilars aiming to hit the European market in mid-October, but another biosimilar tidal wave may actually precede this.

The European Medicines Agency (EMA) has had an extremely busy week in the pegfilgrastim biosimilars arena. In addition to granting marketing authorization to Coherus Biosciences for its pegfilgrastim biosimilar, it has also approved the marketing of Pelgraz®, a pegfilgrastim produced by Accord Healthcare. In addition, the EMA’s Committee for Medicinal Products for Human Use has also recommended approval for three pegfilgrastim biosimilars—from Sandoz, Cinfa, and Mylan.

Mylan is the only drug maker with a marketed biosimilar version of pegfilgrastim in the United States. Its product Fulphila® hit the US market in early July. Coherus’ product, Udenyca™, is awaiting a November 2 decision from the Food and Drug Administration. Coherus is reportedly looking for a partner to market its pegfilgrastim biosimilar overseas, while it intends to market the product internally in the US. This means that Accord may have the first pegfilgrastim biosimilar to reach patients in the EU, though this advantage will be short lived should Mylan in particular gain approval.

In other biosimilar news…Boehringer Ingelheim announced positive results in its clinical study of Cylteza® versus Humira® in patients with moderate-to-severe plaque psoriasis. The study results were announced at the European Society of Dermatology and Venereology.

Samsung Bioepis Co., Ltd. announced that the FDA has accepted its 351(k) application for SB5, a biosimilar to adalimumab. Samsung is the fourth manufacturer seeking to enter the biosimilar market for Humira. Two have been approved (Amjevita® by Amgen and Cyltezo® by Boehringer Ingelheim) but are not yet marketed. A decision on Sandoz’s application is expected later this year.

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

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.

Four or possibly five manufacturers will be lined up in the starting gate. Fujifilm Kyowa Kirin Biologics and its marketing partner Mylan have not yet received approval from the European Medicines Agency (EMA), but they do have a positive opinion from the Committee on Human Medicinal Products. They expect to hear a final decision from the EMA by October and hope to market it that same month, joining the other adalimumab biosimilar drugmakers.

Those who already have approval to race include:

Manufacturer/Marketing  Partner

Molecule Designation

Brand Name

Samsung Bioepis/Merck
SB5
Imraldi
Boehringer Ingelheim
BI 695501
Cyltezo
Amgen
ABP 501
Amgevita
Sandoz
GP2017
Hyrimoz
Adapted from: http://www.gabionline.net/Biosimilars/General/Biosimilars-of-adalimumab.

Several other manufacturers are also in the running, but will be late entries. They have completed phase III studies but their biosimilar adalimumab applications are not yet filed: Coherus, Pfizer, Fresenius, and Momenta.

adalimumab biosimilarsOn October 16, Abbvie’s Humira® patent expires and the starting gate should open. We’ve not seen anything similar in the US biosimilar market. Even when Abbvie’s patents expire in 2022 and agreements go into effect, this will be more of a staggered start, with Amgen having first crack at the market in January 2023 followed by Samsung Bioepis in June of that year. That is, unless another biosimilar manufacturer refuses to sign a licensing agreement with Abbvie and launches at risk earlier.

In any case, the savings seen in the EU should be immediate and if competition is not hindered, adalimumab biosimilar prices will be slashed. It will be interesting to see how this situation plays out, with one of the world’s biologic sales leaders.

It will certainly leave American payers dreaming about what could be, but will not be, for several years at least.

Let’s not Knock Innovation, but Biosimilars Exist for the Sake of Competition

A recent Twitter conversation between a blogging colleague of mine and a German advocate of precision medicine propelled this post: What is the real benefit of biosimilars? Does biosimilar development detract from efforts to produce innovative medicines? Is the main societal benefit biosimilar cost savings?

biosimilar cost savings

Biosimilar Development Is Separate From Innovation Development

The main reason that the Biologics and Biosimilars Price Competition and Innovation Act (BPCIA) was signed into legislation was related to cost containment. For biologics, there was no pathway for the evaluation and approval for lower-cost copies in the US health system, akin to the generic-brand name dynamic for conventional drugs. Adding competition has been the first and only point. The specialty drug trend had been rising rapidly, and the long-term estimates were frightening: Costs associated with specialty drugs like biologics threaten to eat 48% of the total drug spending pie in the United States by 2020.

Two factors were responsible. The first, increasing specialty drug utilization, has been especially difficult to address. The pipeline is congested with biologics. Medical societies are increasingly incorporating biologics into their guidelines and clinical pathways. Prescribers have grown more comfortable with these agents, and payers have limited tools at their disposal to put the brakes on their use.

The second, price increases, are well known and publicized. Without competition, drug companies tend to test what the market will bear, and to this point, they have borne quite a bit. Unlike in Europe, where the tender system of pharmaceutical purchasing has resulted in better cost containment, the US payers have been accustomed to stomaching large price increases through increased use of rebate contracts with price guarantees. But the overall costs continue to rise, as contracts expire and new ones are drawn up. Thus, the list prices for drugs like Enbrel® and Humira® have skyrocketed, with Humira’s more than doubling in a few years.

There is no evidence to say that biosimilar manufacturers would have engaged in the development of innovative new agents had they not devoted resources to this area. Indeed, pure-play biosimilar makers, like Coherus or Adello, were only introduced to produce biosimilars. Other makers, such as Samsung Bioepis, are joint ventures of existing manufacturers to do the same. Biogen recently raised its stake in Samsung Bioepis to nearly 50% of the company’s shares. This could be construed as a case of an originator company pouring $700 million into a biosimilar manufacturer, which could be using that money directly for other purposes. Finally, firms like Apotex, Mylan, Sandoz, and Hospira (now part of Pfizer) are heavily involved in generic drug manufacturing. Biosimilar development was a natural extension for them. Even big pharma players, such as Amgen, Merck, and Pfizer, are more commonly engaged in biosimilar marketing partnerships rather than purely R&D efforts (e.g., Amgen/Allergan, Merck/Samsung Bioepis, Pfizer/Celltrion).

One can also make an argument that pharmaceutical innovation is more evident at the drug discovery level. These days, big pharma seems less interested in pursuing drug discovery than in purchasing it.

The Societal Benefits of Biosimilars

The EMA and FDA biosimilar pathways were created to introduce competition that would lower drug costs. This in turn would make innovative biologic therapy available to more patients. Biosimilar cost savings could drive greater access to important drug technologies.

With the EU’s longer and more extensive experience with biosimilar medications, costs have indeed been saved. Although this has varied by country, it is undeniable.

In the US, with very limited economic experience with biosimilars (filgrastim and infliximab), savings figures are more theoretical than real. Although the infusion of a biosimilar into the new market may reduce wholesale acquisition price of the reference drug a bit, it will have a greater effect on net pricing, after rebates. And, of more immediate importance, the new biosimilar has the potential to halt further price increases for the originator product. This aspect of biosimilars cost savings cannot be overemphasized. Between the first adalimumab biosimilar approval and the initial availability of these products in 2023, the list price of Humira can increase upwards of 40% (or more, if Abbvie veers from its pledge to limit price increases). The initial price of the first adalimumab biosimilar will thus be much higher than if it was launched last year. On the other hand, adalimumab biosimilars will launch in the EU in October of this year, which should effectively lower cost products and limit their EU members’ exposure to future Humira price increases.

Biosimilar cost savings can have real benefits in terms of improved access. Payers’ incentives to use biosimilars (if they are motivated to implement them) can result in lower patient cost sharing. For example, a fourth-tier biologic may be subject to a 20% cost share, whereas a third-tier biosimilar may carry a flat copay of $100. This can make a difference in terms of therapeutic choices available to patients.

In conclusion, the German correspondent is only partly right. Biosimilars are not innovative. They are highly complex, cost-control medications. Do they detract the focus of manufacturers from new innovative products? There’s no evidence of this. However, we are beginning to see limited evidence in the US of the societal benefits, namely cost savings, they can bring.