Teva and Celltrion Receive Rejections on Trastuzumab and Rituximab Biosimilars

Celltrion and its partner Teva were dealt a significant blow today, as the Korean manufacturer announced that the latest two biosimilar candidates were rejected by the Food and Drug Administration (FDA).

Celltrion logo1 As first reported by Dan Stanton in the Biopharma Reporter, the FDA issued complete response letters as a result of inspection problems uncovered at Celltrion’s manufacturing facility in Incheon, Korea. Celltrion initially receive the negative inspection report in January of this year, which highlighted deficiencies in aseptic practices and processing, and failure to investigate variations in batches.

Under the partners’ pact, signed in 2016, Teva would commercialize the two biosimilars. Teva has a separate concern, however, in that the same Celltrion plant cited by the FDA has been tabbed to produce its CGRP-inhibitor fremanezumab for migraine prevention. This migraine prevention antibody, which also has the potential to reach sales of $1 billion, has a PDUFA date of mid-June.

In a statement published by Mr. Stanton, a Celltrion spokesperson said, “Celltrion is making progress addressing the concerns raised by the FDA in a Warning Letter issued in January and is committed to working with the agency to fully resolve all outstanding issues with the highest priority and urgency.”

The issuance of the CRLs may be extremely poor timing for the partners. Although Mylan signed an agreement with Roche to delay the launch of its approved biosimilar version of Herceptin^®until at least 2019, the other competitors have not. Amgen/Allergan expect word on their 351(k) submission within the month, and Samsung Bioepis should hear in the fourth quarter. On the rituximab front, Sandoz should receive word early in the third quarter.

Fourth Herceptin® Biosimilar Being Evaluated by FDA

The end of 2017 has been bustling with oncology biosimilar news.

On December 20, 2017, the Food and Drug Administration (FDA) accepted Samsung Bioepis’ application for SB3, its biosimilar version of trastuzumab. The drug would be the fourth to undergo evaluation by the FDA, and may pack on the pressure for Mylan and Biocon’s product Ogivri^™, which is the only approved biosimilar trastuzumab.

Mylan/Biocon’s biosimilar was approved earlier this month. As a reminder, though, there are no plans to bring their version of trastuzumab to market immediately. Indications are that Breast Cancer owing to an agreement with Roche, they may not launch until 2019 (at the earliest). Trastuzumab biosimilar entries by Celltrion and Amgen/Allergan will not receive FDA decisions until the second quarter of next year. It is unclear whether these manufacturers will decide to launch their versions at risk, thus stealing the initiative from Mylan and its partner. In any case, competition should be vigorous when these products launch (which should be within 12 months of the first launch, assuming FDA approvals). At present, the question is open as to whether Samsung will market SB3 if it receives a positive decision sometime in the fourth quarter of 2018.

In related news…A survey of 200 oncologists revealed that their comfort levels with prescribing biosimilars is widespread. Cardinal Health published a report based on the survey on December 20.

Although these result may relate to oncologists’ multiyear experience with Zarxio^® (filgrastim), 82% of the oncologists responding to the survey specifically indicated that they would have no qualms about using biosimilars to treat patients with breast cancer in an adjuvant setting or if they had metastatic disease. As indicated above, no biosimilars are currently marketed for this indication. Furthermore, they expect significant cost savings when using biosimilars: Two thirds said that cost savings with biosimilars are either extremely or very important in their prescribing decision. That’s pretty much the point of biosimilars, isn’t it?

Fuzzy Patent Logic

Over the past week, month, year (you name it!), we’ve read too much about the trials and tribulations of patent litigation. The latest, involving Pfizer and Roche, has the latter suing Pfizer for infringing on upwards of 40 Roche patents in Pfizer’s development of a trastuzumab biosimilar. This is pretty common these days, and even the number of patents involved fails to surprise. Yet, other competitors may reach the market before Pfizer; it has not yet filed for a 351(k) approval with the Food and Drug Administration (FDA) or the European Medicines Agency.

This does not apply to other potential players. Celltrion cleared the Roche patent lawsuits in April 2017, enabling it to sell its trastuzumab biosimilar in its home country of Korea. This does not necessarily apply to sales in other countries, however.

Positive results were announced for a pivotal phase 3 study of Pfizer’s trastuzumab biosimilar PF-05280014 in Europe in September. These results will likely form the clinical backbone of its 351(k) application.

First launched in 1998, principal patent expiration of Herceptin in the US should be 2018 or 2019 and was 2014 in Europe. It may be assumed that Amgen/Allergan will wait for patent expiration before marketing their product in the US and subsist on sales in Europe in the meantime.

A similar but more protracted situation exists with Abbvie’s Humira^®, for which competition will be fierce once the patents expire fully in 2023 (if they are not found to be invalid earlier). Amgen settled with Abbvie to obtain a global license from the originator’s manufacturer, applying to sales after this time. However, Amgen’s biosimilar will still have to compete with severals once the patents expire or are ruled invalid.

I’d like to post others’ opinions as to how the marketshare wars will play out when some patent agreements are made and others are not. What do you think will happen on the Herceptin front?

News in the Courts on Biosimilars

According to a Reuters report, Janssen Biotech withdrew its patent lawsuit against Samsung Bioepis on November 10. The suit alleged infringement in the manufacture of Samsung’s infliximab biosimilar.

Related image The action, which was filed in U.S. District Court of New Jersey, means that Merck and Samsung, which launched Renflexis™ in July, is no longer at risk for revenues earned in the sale of its biosimilar. If Janssen had maintained the lawsuit and later earned a victory in the courts, it could have been awarded a large percentage of Samsung’s Renflexis revenues.

In a separate case, an appeals court found that the Southern District of Florida was correct in its decision clearing Apotex Inc of any patent infringement in its development of biosimilars of Amgen’s Neulasta^®and Neupogen^®. The initial ruling, in September 2016, helped cleared the path for the biosimilars to reach the market. However, the organization’s filgrastim biosimilar was first filed in February 2015, without an approval. Its pegfilgrastim biosimilar was filed earlier, in December 2014, but has not advanced through the Food and Drug Administration’s 351(k) approval process. Apobiologix is the Apotex subsidiary that would manufacturer and market the biosimilars in the US, should they gain approval.

Amgen/Allergan Score Positive EMA Evaluation, but Launch Will Be Delayed

A couple of noteworthy pieces of news have emerged from across the pond on the biosimilar front. The first involves progress for Amgen’s application for its bevacizumab biosimilar at the European Medicines Agency (EMA). Its drug evaluation arm, the Committee for Medicinal Products for Human Use, recommended approval of the biosimilar on November 9.

Assuming EMA final approval is received, however, Amgen and Allergan’s cancer treatment agent will not be marketed any time soon. The principal European patent is not set to expire until 2022.

Image result for avastin biosimilar In the US, Mvasi™ was approved by the Food and Drug Administration in September, but its launch is similarly delayed by patent litigation. The main US patents should expire in 2019 (Roche claims to hold 27 enforceable patents). Amgen had filed suit October 6 challenging the validity of the patents in question, but this case may not be heard until late 2018. Amgen has the option of launching “at-risk,” but it has not indicated that it will go this route. Otherwise, the earliest launch may be sometime in 2019.

Several other potential bevacizumab makers have already challenged the patents, according to other reports. These include Boehringer Ingelheim, Celltrion, Pfizer, and Samsung Bioepis.

In other related news…An announcement will be made on November 20 regarding where the EMA will relocate its headquarters as a result of the Brexit. The Agency will need to complete its move by March 31, 2019, when Britain’s divorce from the European Union is finalized.

Sandoz’s Pegfilgrastim Biosimilar Under New Review at EMA

On October 27, Sandoz announced that the European Medicines Agency has accepted its re-application for review of its biosimilar version of Neulasta^® as supportive treatment in patients receiving cytotoxic chemotherapy.

Print Sandoz’s attempt to bring its biosimilar pegfilgrastim to the market was stalled in the US in Q2 2016, when the FDA issued a complete response letter. It had withdrawn its application to the European Medicines Agency in January 2017. However, the new application seems to be bolstered by additional data, according to reports.

Sandoz is expecting to reapply to the FDA in 2019, according to its website.

As noted too often in this space, the journey to approval for a pegfilgrastim biosimilar has been marked by failure and setbacks. However, as shown in the Figure from the MarketRealist, revenues for Neulasta are considerably larger than that for its nonpegylated progenitor, Neulasta (filgrastim). This is a powerful impetus for potential biosimilar manufacturers to succeed. At close to $5 billion in annual revenues, there is little reason to think that a biosimilar pegfilgrastim will not be approved eventually.

Market Realist.png

Source: The Market Realist.

In other news… AbbVie expects its Humira sales to jump to $21 billion by 2020 from $16 billion today, evidently bolstered by its successful defense of its patents against Amgen.

The FDA Rejects Mylan/Biocon’s Pegfilgrastim; Market Still Awaits a Biosimilar for Neulasta

In the latest blow to those seeking an alternative to Amgen’s Neulasta^®, the Food and Drug Administration (FDA) sent a complete response letter to Biocon, citing manufacturing plant deficiencies, in its rejection of their biosimilar pegfilgrastim application.

Announced on October 10, this is the second biosimilar from Indian manufacturer Biocon that has been detoured by manufacturing plant problems. Its Bangalore plant, where the partners’ biosimilar trastuzumab was to be manufactured, was also cited earlier this year.

In August, Biocon and its marketing partner Mylan withdrew its European Medicines Agency applications for pegfilgrastim and trastuzumab after receiving negative reports on its manufacturing facility.

This is the second FDA biosimilar rejection relating to plant deficiencies. In June, the agency issued a complete response letter to Pfizer, resulting from a legacy Hospira plant in Kansas.

In the press release announcing the latest setback to its pegfilgrastim biosimilar, Biocon said that the complete response letter relates to “facility requalification activities post recent plant modifications. The CRL did not raise any questions on biosimilarity, pharmacokinetic/pharmacodynamic data, clinical data or immunogenicity.”

Biocon also stated that “We do not expect this [complete response letter] to impact the commercial launch timing of biosimilar pegfilgrastim in the US.” Although Mylan and Biocon had not publicly announced an intended launch date once it received approval, Amgen’s principal patents for Neulasta have expired. One might have expected a relatively quick launch of its biosimilar, considering the 180-day postlaunch exclusivity period no longer exists and the possibility of other players in the market, including Coherus, Pfizer, and Apotex (all of whom received complete response letters).

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.

Amgen Receives Approval for Bevacizumab Biosimilar

The Food and Drug Administration announced today the approval of the first biosimilar for Roche’s Avastin^®. The approval of Mvasi™ (bevacizumab-awwb) represents the first biosimilar approved in the US for the direct treatment of cancer. Amgen is partnered with Allergan in the development and marketing of the new biosimilar.

Its approved indications include:

Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.
Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate. No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.
Metastatic renal cell carcinoma, in combination with interferon alfa.
Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

Like Avastin, Mvasi will carry a black box warning involving gastrointestinal perforations, surgery and wound healing problems, and severe or fatal hemorrhage.

The FDA’s Oncology Advisory Committee had unanimously recommended approval of the agent. No announcement was made by Amgen as to pricing or availability of the new product.

Two New Trastuzumab Biosimilars Submitted for FDA Approval

The team of Mylan and Biocon may have some company in the biosimilar competition for Herceptin^® (trastuzumab). Two additional partnerships announced the filing of their 351(k) applications for trastuzumab biosimilars.

Amgen and Allergan are hoping ABP 980 will have smooth sailing through the approval system. The phase 3 study in patients with early-stage HER2-positive breast cancer was completed in January 2017, with study results reported in July 2016. This study enrolled 725 patients, and yielded positive results in terms of safety, efficacy, and similarity to the originator product.

Celltrion submitted their product application for CT-P6 (Herzuma™) to the FDA on July 30 as well. Its partner Teva will distribute and market the product in the US, upon approval. The phase 3 study for this product is ongoing, but the results of the primary outcome data from 549 patients were published in June 2017. The outcomes were found to be similar to those of Herceptin.

Mylan and Biocon had submitted their biosimilar version on November 1, 2016. The FDA Advisory Committee reviewing their product gave it their unanimous support on July 13, and the final FDA decision is expected by September 3, 2017. If approved, Mylan will have at least a 9-month time advantage to get their foot in the door of a $2.6 billion trastuzumab marketplace.

This sets up a very interesting pricing dynamic. I had originally thought that this scenario might occur first with adalimumab after the patent litigation was resolved, but it is very possible that multiple biosimilars for trastuzumab may be launched first and in a very short timeframe.

Assuming Mylan gets the nod from FDA first, they have a couple of obvious paths they can travel: (1) launch with a substantial discount in an attempt to capture as much marketshare as possible before the other market entrants arrive or (2) launch with a modest (but attractive) discount in an effort to maximize their revenue while their product remains the sole biosimilar available. It will then be a guessing game as to how Amgen/Allergan and Celltrion/Teva play their turns in this poker game. With sudden market competition, such as their launches could potentially pose, payers may play a bit of a waiting game themselves, to see where the chips fall.