Pfizer Launches Ruxience, Announces Pricing for Upcoming Trazimera

Activity on Pfizer’s biosimilar front has been electric over the past couple of months, as it executes its launch plan for three biosimilar monoclonal antibodies to treat cancer.

Pfizer biosimilar launches

In December, the company launched its bevacizumab biosimilar Zirabev®, and on January 23, Pfizer announced the availability of its rituximab biosimilar Ruxience®. Ruxience is the second launched biosimilar to the reference product Rituxan®; Teva and Celltrion began marketing their rituximab biosimilar in November 2019.

In its latest announcement, Pfizer demonstrates a consistent policy in terms of pricing of these cancer treatments. The wholesale acquisition cost (WAC) for Zirabev was set at $61.34 per 10 mg vial (a 23% WAC discount to Roche’s reference product Avastin®). Ruxience will be sold at a 24% discount to Rituxan, and for its February 15 launch of the trastuzumab biosimilar Trazimera®, it will be offered at a 22% discount to the innovator product Herceptin®. The average sales price (ASP) for Zirabev was 12% below that for Avastin, but it is not the least expensive biosimilar bevacizumab—Amgen’s Mvasi® is 12% below this.

For Ruxience, Pfizer’s pricing ($71.68 per 10 mg vial) represents a significant 16% discount off of Teva’s WAC for Truxima. The latter’s initial WAC discount from Rituxan was only 10% (still 11% lower than Rituxan’s ASP). Pfizer’s Ruxience is presently 24% below the ASP of Roche’s reference biologic. Additional competition for this category is not expected from Amgen until late in the fourth quarter of this year.

Pfizer enters a more crowded marketplace with the upcoming launch of Trazimera. Both Kanjinti® and Ogivri® have been launched, the latter being made available in December 2019 at a 13% ASP discount to Herceptin. Pfizer’s pricing of $80.74 per 10 mg vial would place it at a 24% ASP discount to Herceptin (it should be noted that Roche’s Herceptin Hylecta is priced below this ($79.18 per 10 mg vial).

Two other trastuzumab biosimilars are expected to become available this year, further reducing the cost of these agents.

Bevacizumab ASP Pricing now Dropping With Biosimilar Entries

With the announcement that Pfizer has formally launched its bevacizumab biosimilar Zirabev®, the next logical question is how the price compares with the competition—Roche’s brand Avastin® and Amgen’s biosimilar Mvasi® that are already available.

At Pfizer’s stated pricing of $61.34 for a 10-mg vial, this represents a 23% discount to the reference product’s wholesale acquisition cost. It also represents a 12% discount to Avastin’s average sales price ([ASP] defined as the price after discounts and rebates).

Amgen launched Mvasi in the summer of 2019 at a 15% discount to the WAC price of Avastin (and a 12% discount to the ASP of the reference product at that time). This month is the first where Mvasi’s ASP has been published, which at $69.77 means a 12% lower cost for Pfizer’s Zirabev.

In January 2017, the ASP price for Avastin was $73.73, which rose 10% to $81.18 in January 2019. Between January 2019 and For January 2020, the ASP for the reference product dropped 0.7%. The ASP is what Medicare will reimburse for the drug, and because it does reflect net costs after discounts and rebates, it is a pretty good measure of pricing trends in the commercial market as well. The signs point to a halt in Avastin price rises, and a likely significant drop through the end of 2020.

bevacizumab prices dropping
Net Pricing of Bevacizumab Agents Dropping With New Competition

By that time, the next competitive entry into this category, Samsung Bioepis’ SB8, may launch. Samsung Bioepis is awaiting a fourth quarter decision by the Food and Drug Administration.

These prices may sound reasonable. Keep in mind, however, that a usual dose for bevacizumab in several cancer treatments is 10 mg/kg every 2 weeks—in other words, 70 10-mg vials are needed for a patient weighing 154 pounds (or $5,644 per treatment at Avastin’s current ASP).

Who Are the Key Lucentis Biosimilar Players to Watch?

Roche’s reference product Lucentis® (ranibizumab) seems to be the next likely target for biosimilar competition. Sales of the drug in the US were last reported to be $1.5 billion in 2017, but Roche’s revenues from Lucentis are expected to slip, owing to competition from Eylea® (aflibercept) primarily and some newer agents. And new Lucentis biosimilars will hasten that decline.

ranibizumab biosimilars

Ranibizumab is approved for use for several ophthalmologic indications, including wet age-related macular degeneration, diabetic retinopathy and diabetic macular edema, myopic choroidal neovascularization, and macular edema following retinal vein occlusion.

According to reporting by the UK-based Generics and Biosimilar Initiative (GaBI), the patents on Lucentis will expire in the US in June 2020 and in Europe in 2022. GaBI had found some 10 organizations or partnerships working on investigational ranibizumab biosimilars, but little updated information (some were reported as early as 2015).

Today, our research into the Lucentis biosimilar space revealed just a couple of active players, but with rapidly advancing plans. Here are the three initiatives reported publicly:

1. Coherus-Bioeq

This one is a little complex—stick with it, as it could be the first to obtain FDA approval, as early as later this year.

Formycon AG, a German manufacturer, gave Bioeq IP AG exclusive global commercialization rights to FYB201, Formycon’s ranibizumab biosimilar. In November 2019, with Formycon’s assent, Bioeq signed an agreement with Coherus Biosciences to commercialize the biosimilar in the US.

At the recent JP Morgan investor conference, Coherus President Denny Lanfear disclosed that Bioeq filed for FDA approval in December 2019. Coherus is expecting FDA acceptance of the application shortly, and a fourth quarter 2020 decision. This could set up a product launch, according to Coherus, in 2021.

Interestingly, Coherus originally had a different biosimilar ranibizumab in its own pipeline. This agent, CHS-3351, fell by the wayside a couple of years ago. The deal with Bioeq seems to have created a new ranibizumab opportunity for Coherus.

2. Xbrane-Stada Arzneimittel

Sweden-based Xbrane signed an agreement with the German generics manufacturer Stada Arzneimittel to co-develop Xbrane’s Lucentis biosimilar. This agent, currently dubbed Xlucane™, is being tested in a phase 3 trial involving 580 patients with age-related macular degeneration, which is slated for completion in February 2021 (interim results available in May 2020).

3. Biogen-Samsung Bioepis

Samsung Bioepis completed its phase 3 trial of SB11 in December 2019 (primary completion date of May 2019). This trial comprised 705 patients with neovascular age-related macular degeneration. SB11 seems poised to be submitted for approval via the 351(k) biosimilar pathway, and Samsung’s deal with Biogen (already a part owner of the joint venture with Samsung Biologics) for commercialization. Therefore, Biogen will take the marketing reins once an FDA decision has been given. If Samsung submits its filing in Q2 2020, a launch could be possible in Q2 2021, assuming a positive decision.

Are There Any Other Active Players Out There?

The development of PF582 by Pfenex has been on hold since 2018, after the company was handed back the full rights to the agent by former partner Hospira. Pfenex no longer lists this product (or any other biosimilar for that matter) on its pipeline. The drug had progressed through phase 1/2 studies, but has not advanced.

None of the other significant players in the biosimilar industry (including Pfizer, Sandoz, Mylan, Amgen, Celltrion, or Biocon) have publicly announced a ranibizumab biosimilar program at present.

A US–China Partnership: Coherus Biosciences Will Market Chinese Biosimilar Maker’s Avastin Biosimilar in North America

Innovent Biologics (Suzhou) Co., Ltd., based in China, signed an agreement on January 13, 2020 that allows Coherus Biosciences to commercialize its bevacizumab biosimilar when approved by Canadian and American regulators. The investigational agent is known as IB1305 at present.

Coherus

Recently completing a phase 3 trial with Chinese patients, Innovent will need to gather the necessarily analytic comparison data for US approval. In its press release, Coherus believes that an FDA submission could be possible in late 2020 or early 2021, based on the Chinese data.

Innovent Biologics

A phase 1 study was listed in ClinicalTrials.gov, which had an estimated completion date of 2017, but there has not been an update to this information. Coherus stated that “The Company anticipates completing a single dose pharmacokinetic clinical study and certain analytical/bioanalytical exercises to support the U.S. filing.” This could mean that a new phase 1 study will be undertaken. Coherus also indicated that it will handle the biologic licensing application process in the US and subsequent marketing in the US and Canada.

Additionally, the press release announced that Innovent’s biosimilar rituximab candidate (IB1301) may also be part of this deal. In June 2019, Innovent filed for approval with the Chinese drug regulatory authorities. According to the terms of the agreement, Coherus has an option to commercialize this agent in North America. IB1301 has been subject to oncology testing in China patients (not to treat autoimmune disorders).

This agreement is significant for Coherus, which is trying to build upon its success in launching the pegfilgrastim biosimilar Udenyca® in the US. Innovent’s biosimilars represent a new oncology pipeline for Coherus in the US and Canada, which already includes two anti-TNF inhibitors (adalimumab and etanercept), and two ophthalmology biosimilars (although aflibercept is still in preclinical development).

And Now for Something Completely Different… Eflapegrastim vs. Pegfilgrastim

On January 2, 2020, Spectrum Pharmaceuticals announced that the FDA had accepted its 351(a) application for a novel granulocyte colony-stimulating factor (G-CSF), eflapegrastim. And no, the name is not misspelled here; the name is a close cousin of pegfilgrastim.

As reported in 2018 by the Center for Biosimilars, this agent showed promise versus pegfilgrastim. As with the pegfilgrastim biosimilars, the road to approval for Spectrum has been bumpy. The manufacturer decided to withdraw its original application for approval in 2019 after FDA required more information on manufacturing of the eflapegrastim.

Not a follow-on agent or a biosimilar, eflapegrastim is intended to be introduced as a new innovative brand. As the early results hinted at somewhat greater potency than Neulasta®, the current application cites clinical data that supports noninferiority of eflapegrastim to Neulasta in terms of preventing febrile neutropenia. The study objective was to demonstrate noninferiority, not superiority. The phase 3 RECOVER investigation also found no significant differences in terms of safety between the agents.

One might ask, what’s the point of this product if it isn’t an improvement over pegfilgrastim? Well, it may be proven to be superior in some future study (though no further comparator investigations are currently listed on ClinicalTrials.gov).

It might possibly be an example of corporate inertia. Pfizer went through with its FDA approval of Ixifi™ (infliximab) even though it knew that it would not be marketing this biosimilar in the US. When Spectrum first submitted its application in December 2018, there were already two approved pegfilgrastim biosimilars, and one, Fulphila®, was being marketed. One wonders why Spectrum may have believed another branded G-CSF could still be an important player at that time.

Or the pharmaceutical company understood the small portion of marketshare that eflapegrastim could obtain, in the face of competition with three biosimilars and two forms of Neulasta in the long-acting G-CSF market. Even a small slice will be a difficult reach for Spectrum, especially since it will have to contend with actively lowering prices for the pegfilgrastim category.

The Food and Drug Administration set a PDUFA date of September 24, 2020 for eflapegrastim.

Will the Supreme Court Fast Forward Health Insurance Reform in 2020?

The year 2020 has gotten off to a flying start—probably a direct consequence of 2019 finishing with a flurry. One of the first eye-catching bits of news was the request by several states for the Supreme Court to intervene now, not later, in the case that threatens the fundamental basis on which the biosimilar pathway is based.

As reported in December, the Fifth District Court affirmed the ruling that the individual mandate was invalid. However, it sent back to Texas District Court Justice Reed O’Connor the decision as to whether the individual mandate is “severable” from the rest of the Affordable Care Act. In other words, if the individual mandate is cut from the ACA, does that mean that all other aspects of this legislation, including the biosimilar pathway created by the BPCIA, must also be declared invalid?

In Judge O’Connor’s original decision, he took the broadest view, stating that if the individual mandate has been withdrawn, then the entire ACA is invalid. One wonders why the Fifth District Court of Appeals thinks that Judge O’Connor will reconsider his logic. If he doesn’t, the case winds up in the Supreme Court, sooner or later.

The attorneys general of 20 states and the District of Columbia  want that to be sooner, which makes sense. Let’s get a final ruling for the sake of US citizens and the entire healthcare system. If a workaround or a complete recontemplation of health reform needs to be done, it would be far better to find that out now, in time for the next elections (assuming that a Supreme Court decision is issued in early Fall of this year). If Medicaid expansion must be rolled back, if the exchanges must be invalidated, and if biosimilars made available to the public must be withdrawn, that could have a huge impact on the upcoming elections. That cannot happen, of course, unless the Supreme Court hears the case before this year’s session is complete.

This may be viewed in a couple of ways: (1) an opportunity/attempt by Democrats to more seriously introduce a public option or even Medicare for all, (2) an opening for Democrats to exploit that the health insurance of 20 million Americans will be immediately at stake in the upcoming elections, (3) an opportunity for Senate Republicans and the Trump administration to demonstrate real leadership in the next phase of health reform (i.e., one that does not reflect any of the lack of understanding of preexisting conditions/chronic disease/patient cost sharing demonstrated in their earlier statements on health reform), or (4) a chance for the administration shoot itself in the foot on the greater healthcare issue one more time.

The Trump administration sides with those who seek to repeal the ACA at any cost; it elected to not defend the law in the current case. The partisan divide between the House and the Senate does not inspire confidence that a quick fix can be implemented to restore by statute the needed parts of the ACA and BPCIA. Consider the nightmare of having to debate once again—from scratch—the foundational pillars of providing affordable, comprehensive health insurance to Americans. Who wants to revisit that exercise in today’s contentious environment?

The Appropriations Bill Alters Insulin Biosimilar Rules

Closing out the week before the holidays, the House and Senate’s Appropriations Bill specified two significant passages that affect the March 22, 2020 transition date for insulins being approved under the 351(k) pathway. Here’s a summary of these two points.

A TWEAK TO THE BIOSIMILAR INSULIN QUESTION

On December 17, 2019, two Food and Drug Administration senior executives released a joint statement to clarify a key point on the upcoming biosimilar insulin transition. In March of 2020, insulins will be among several drug classes that will be transitioned to the 351(k) biosimilar pathway. However, Anna Abram, Deputy Commissioner for Policy, Legislation, and International Affairs, and Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research, pointed out that this transition currently applies only to protein products that are not chemically synthesized. That is, if the insulin is a synthetic analog and not considered a human insulin, or produced through recombinant RNA technology, it will continue to be subject to the 351(a) pathway.

“Such a product would also not be able to come to market through the generic drug pathway because the originator product will have been classified as a biologic, and will not be available for copying. This exclusion could hurt potential competition because it means that if a developer were to chemically synthesize a copy of a protein product (e.g., an insulin copy), the product would not be able to come to market through the abbreviated biosimilar or interchangeable pathway,” stated Ms. Abram and Dr. Woodcock.

In the latest House and Senate appropriations bill, the notation was made to strike this exclusion from the definition of a biologic: “Section 351(i)(1) of the Public Health Service Act (42 U.S.C. 262(i)(1)) is amended by striking “(except any chemically synthesized polypeptide).” [I needed help to find the relevant passage—on page 1503.]

Dr. Woodcock and Ms. Abram explained, “Removing this exclusion will help patients because it provides the potential for chemically synthesized follow-on insulins and other protein products to come to market through more efficient abbreviated pathways, regardless of how they are manufactured. In addition to expanding access to lower-cost biosimilar and interchangeable protein products, removing this exclusion will help to promote potential innovation in manufacturing methods, which could lead to future efficiencies in manufacturing processes.”

A MERCIFUL HAND TO MYLAN AND BIOCON

Another clause in the Appropriations Bill helps Mylan and Biocon out of a big jam: The partners, which received a complete response letter in late September for its insulin follow-on agent, were facing a real issue in March 2020. If they did not receive approval by this date (that of the insulin transition to biosimilar status), they would have to resubmit their 505(b)2 new drug application as a 351(k) biosimilar and start from scratch. Instead, the Appropriations Bill includes a clause that spares them and other prospective insulin manufacturers with active applications this fate.

Under the Bill’s language, “With respect to an application for a biological product submitted under subsection (b) or (j) of section 505 of the Federal Food, Drug, and 12 Cosmetic Act (21 U.S.C. 355) that is filed not later than March 23, 2019, and is not approved as of March 23, 2020, the Secretary shall continue to review such application under such section 505 after March 23, 2020.”

In other words, if the application for a new insulin follow-on agent was already underway before March 22, it can continue as such throughout the approval process. This new language does not resolve the problem of a “gap year” as Gillian Woollett of Avalere terms it; it will still take around a year after March 22 for new 351(k) applicants to receive an FDA decision on their insulin biosimilar. However, it does mean that we may see a new follow-on insulin approved during that time.

In Other Biosimilar News…Partners Amgen and Allergan have submitted a 351(k) application for their rituximab biosimilar ABP 798 to the FDA. The clinical studies for this drug were conducted in patients with rheumatoid arthritis and in those with non-Hodgkins lymphoma, which would differentiate the agent somewhat from the other rituximab biosimilar approvals, which focus only on Rituxan’s oncology indications. Based on the submission date, an FDA decision can be expected in Q4 2020.

And with that, we’ll be disconnecting for a couple of weeks. From all of us at BR&R, we wish you a happy and safe holiday season!

The Drug Importation Follies

With much of the Administration, the House, and the Senate’s bills meant to lower drug pricing being postponed well into 2020 (if not dropped altogether), the one initiative that is still alive is the one that has been around the longest—drug importation. This is now being planned as a pilot program driven by the Trump administration and Department of Health and Human Services.

Drug importation

I can’t remember when I started writing about drug importation, though it must have been nearly 10 years ago, when it was first raised as a novel way of gaining access to lower priced drugs. The problem then, as it is now, is that few outside the pharma industry seem to understand what a short-term fix this is.

Today, a small number of Americans obtain their small-molecule medicines (not biologics) from Canada (or Mexico) for substantial discounts. However, the pharmaceutical supplies of Canada or Mexico cannot fulfill the needs of millions of US residents; obviously, the manufacturers do not send all of their stock to these countries. For example, Canada currently buys approximately 2% of all pharmaceuticals sold. On the other hand, the US utilizes more than 40% of all pharmaceuticals produced. Once the supply runs low in Canada, what happens next?

Once drug makers see that a significant percentage of their North American supply is being sold at a discount relative to before large-scale importation started, they will have two very basic choices: (1) cut the supply to Canada, which will leave Americans without drugs to import and perhaps threaten Canada’s supply for its own population or (2) increase the supply to Canada but raise prices close to what they charged in the US. The business decision is as simple as that. The latter choice likely is less workable, because Canada has a single-payer system with the power to push back strongly against large, sudden price increases. Either way, drug importation will result in significant discounts to Americans for a very short time (perhaps months). Does it sound like this hasn’t been thought through?

The value of this drug importation law is limited further in that it would apply to only small-molecule agents—not very high cost drugs, like biologics. Opioids would be excluded as would any drugs that are subject to Risk Evaluation and Mitigation Strategies (REMS) programs.

Under the pilot plan, pharma companies can voluntarily relabel their Canadian supply for reimportation to the US. The Trump administration did not describe any reasons why a drug maker would be incentivized to sell more of their Canada-bound drugs at a lower cost to Americans. If someone has a coherent explanation about how this can be successful, I’m willing to consider it.

I remain skeptical that this will go beyond a pilot program. Earlier this year, we were discussing the potential impact of a Medicare International Pricing Index, drug price negotiations by the federal government, and other initiatives. This seems like a pointless political gesture in comparison.

The Baby, Biosimilars, and the Bath Water, Part 2

Exactly one year ago, we covered the ruling by Texas District Court Judge Reed O’Connor, which threatens the existence of the Affordable Care Act (ACA), and along with it, the statutory legislation that founded biosimilar regulation and approval. As the nefarious character Vizzini often said in The Princess Bride, “inconceivable!

inconceivable
Wallace Shawn as Vizzini in “The Princess Bride”

On December 14, 2018, Judge O’Connor decided that in State of Texas vs. USA, the ACA without the individual mandate should not be allowed to stand, and although worried, we expected that the appeals court would take a more measured view. Its ruling should be issued very soon, but as Kaiser Health News warns, two of the three appellate court judges hearing the case in July 2018 seemed to be leaning towards repeal of the ACA. This may invalidate the entire ACA legislation. Potentially, the Court of Appeals could take a surgical view, applying its knife to only the ACA’s exchanges and financing. If the court upholds Judge O’Connor’s ruling, it is doubtful that the justices will want to wade neck high into a quagmire that includes not only the BPCIA, but also the Centers for Medicare and Medicaid Innovation (think accountable care organizations and value-based contracting), the Medicare part D coverage gap, the Patient-Centered Outcomes Research Institute (to conduct comparative-effectiveness research), and work done to advance prevention in public health. Inconceivable!

Of course, a ruling upholding the District Court will be appealed to the US Supreme Court, where it will likely be overturned, right? Based on the composition of the Supreme Court, anything can happen. Even if the Supreme Court affirms the lower court’s ruling, surely the Senate and House of Representatives will quickly develop and pass new legislation that separates and saves the bipartisan biosimilar pathway, among these other important features of the BPCIA? Inconceivable!

Well, here’s a couple of things we do know. If the ACA is upended as a whole, Capitol Hill will not be able to move swiftly to alleviate the ensuing chaos—not with its current divide. Even if there is general agreement to reinstate the BPCIA, this could open up an opportunity for not only changing BPCIA provisions (for good or bad) but also for attaching other unrelated legislative priorities that could slow the process for passage to a standstill.

Second, if the Appellate Court rules against the ACA, it will likely be some time before the Supreme Court can hear the case and then decide on it. In the meantime, this will detract confidence from both the ACA and biosimilar regulatory processes. In fact, if the Supreme Court repeals the ACA, what would happen immediately to any biosimilar applications already filed with the Food and Drug Administration? Does it affect the parties litigating patent infringement and market exclusivity? I’m guessing this would also throw the long-simmering interchangeability issue into chaos. Inconceivable!

Even stranger, how does that affect the status of the 26 biosimilars approved to date in the US? It would make Vizzini’s head spin.

If I were leading a biosimilar development company, what are my options? Conduct business as usual and hope for the best? Turn your attention towards other, more stable global markets? Or delay further expenditures until some semblance of rationality becomes evident?

It is very difficult to believe that the present administration has been so blind as to allow this suit to continue on. It has nothing at all to gain and only chaos to sow. Very conceivable.

Amgen’s Infliximab Biosimilar, Avasola, Receives FDA Approval

On December 6, 2019, the US Food and Drug Administration (FDA) gave Amgen its approval to market the fourth biosimilar infliximab medicine.

Dubbed Avasola (infliximab-axxq), a launch date was not announced, but one can assume that Amgen intends to launch this agent as soon as possible. This infliximab biosimilar was approved for all of the autoimmune indications of the reference product Remicade®.

Avasola will be the third infliximab biosimilar agent to be marketed, as Pfizer’s Ixifi®, though approved, is not sold in the US, as it would compete directly with another Pfizer-marketed biosimilar (Inflectra®). Pricing for the Avasola was not yet available.

Avasola was approved based on clinical studies involving patients with inflammatory bowel disease, rheumatoid arthritis, and other indicated conditions (over 4,800 patients taking the drug), including a phase 3 investigation pitting the biosimilar against the reference product in patients with rheumatoid arthritis.

The US market for infliximab is shrinking somewhat, based on falling sales numbers caused by biosimilar competition and prescriptions lost to other biologics. According to Johnson & Johnson, parent of Remicade’s manufacturer (Janssen Biotech), US revenues shrank 24% (to $1.14 billion) in the third quarter of 2019 compared with the same quarter of 2018.