Tag: Herceptin

Trastuzumab Dosing May Be Given in Half the Time: Will Costs/Revenues Be Cut as Well?

An upcoming presentation at the annual American Society of Clinical Oncology (ASCO) meeting promises equal efficacy and much improved safety for patients with early-stage breast cancer receiving Herceptin®. This change in trastuzumab dosing from a 12-month to a 6-month regimen will have ramifications for patients, health systems, and manufacturers.

trastuzumab biosimilarA number of biosimilar drug makers are trying to be the first to enter the market for trastuzumab. Mylan/Biocon’s Ogivri™ (trastuzumab-dkst) is the only approved agent in the US, but it will not launch before 2019, owing to a licensing agreement with Roche. Amgen/Allergan is expecting word from the Food and Drug Administration (FDA) by May 28th on their own biosimilar version. Samsung Bioepis is also expecting a decision in the fourth quarter of this year. This new study could significantly lower anticipated revenues for these drug makers. The expected pricing pressures of the category (another 2 manufacturers are working through complete response letters from the FDA) will further add to lower revenue.

Trastuzumab Study Results: Half as Long Just as Good

This British study comprised over 4,000 women (median age, 56 yr) who were followed for more than five years. Patients were randomized to receive the originator trastuzumab for either six or 12 months, in addition to usual standard of care. The researchers found that the disease-free survival was 89.8% in the 12-month group compared with 89.4% for the 6-month group. However, the latter showed significantly fewer toxic effects of cancer therapy.

The wholesale acquisition cost for trastuzumab approaches $6,400 per month ($76,700 per 12-mo course). This may lower patients’ out-of-pocket costs, depending on how quickly they reach their cost-sharing maximums. Typically, women taking trastuzumab will be subject to a fixed copay (e.g., $300 per treatment) or a co-insurance (e.g., 20% or $1,280 per month) for this medication alone. Yet, even with the treatment duration being halved, some patients may reach their out-of-pocket maximums. This is the result of office visits, other medications to be taken, and other care related to the toxic side effects of chemotherapy.

Half the Duration but not Half the Costs

For payers and health systems, cost savings will be substantial, but not halved. Most of the costs will be incurred with the first 4 months of weekly therapy. After 12 to 18 weeks, treatments are stretched out to infusions every 3 weeks for the remainder of the regimen. For a 100-kg woman who would receive a total of 5,400 mg of trastuzumab over 52 weeks, this could be reduced to 3,666 mg over 26 weeks (–32%).

The real benefit, should these study results pass scrutiny of peer review and inclusion in practice guidelines, will be in the lower frequency of toxic adverse effects. According to its prescribing information, trastuzumab is associated with “left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling 197 cardiac failure, cardiomyopathy, and cardiac death.” This can occur during therapy (causing discontinuation) or in the years after treatment is completed.

We hope that the good news represented by these study results for patients does not dissuade other manufacturers from seeking biosimilar trastuzumab approval.

Pfizer Receives FDA Rejection on Trastuzumab, Next up Is Amgen/Allergan

When Pfizer announced that it received a complete response letter from the Food and Drug Administration (FDA), the wait for an available biosimilar to Herceptin® just got longer. According to the manufacturer, the FDA specified that the reasons for the rejection of PF-05280014 were not related to clinical questions. The rejection was not associated with manufacturing plant problems, which have tripped up biosimilar manufacturers, including Pfizer, in the past. Instead, the FDA cited the need for additional data related to “technical issues.”

The next potential team up at bat for a trastuzumab biosimilar approval is Amgen and Allergan. A decision on their biosimilar should be rendered before the end of the second quarter. To date, only Mylan/Biocon have obtained approval on this oncologic product (Ogivri™). However, the launch has been delayed by their signing an agreement with Roche, the maker of the reference product. Teva/Celltrion had received a rejection from FDA relating to manufacturing issues in early April, setting back their own marketing timetable.

Even if Pfizer did receive approval at this time, Roche had sued the company in November 2017 for patent infringement. Pfizer had elected to launch at risk with Inflectra®, despite looming legal battles with Janssen over Remicade®, so an immediate launch of their trastuzumab biosimilar could not be ruled out.

Like the situation with pegfilgrastim, gaining competition for trastuzumab is proving frustrating for payers. Obviously, it will occur, but the latest news does not alleviate payers concerns over price increases in the oncology area.

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 logo1As 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.Teva

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.

A Profile on Lesser-Known Player in the Biosimilar Space: Alteogen Inc

On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight a South Korean-based company, Alteogen Inc.

Established in 2008, Alteogen is focused on the development of bio-betters, with an emphasis on increased half-lives. It is a fairly new player in the biosiAlteogenmilar field, however, and has  partnered with Chinese, Japanese, and Brazilian companies to advance the development of at least two biosimilars.

 

 

 

Why you may be hearing more about this company: Its lead product, a biosimilar of aflibercept (originator product Eylea®) for the treatment of macular degeneration, has just completed preclinical testing. They have announced their intention to file this year with the US Food and Drug Administration to begin the clinical trial process of ALT-L9. Additionally, Alteogen is beginning the drug characterization process for a version of trastuzumab.

Whereas both agents are several years away from potential marketing, Alteogen believes that ALT-L9 may demonstrate some distinct advantages over Regeneron’s originator product. The manufacturer believes that potential benefits include better storage and transport characteristics, including longer dates to expiration and resistance to high temperatures. The company points to proprietary technology which may help it to achieve this “bio-better” status in the biosimilar space with trastuzumab. Its website says that using “an antibody drug conjugate technology conjugating the anti-cancer chemical drugs to an antibody protein… is a technology for the next generation anti-cancer therapeutics, which increase the effectiveness and reduces side effects of the anti-cancer cells directly.” It has applied this technology to trastuzumab, and this agent (ALT-02) has completed a phase 1 trial.

Mylan/Biocon Receive First Approval for Trastuzumab Biosimilar, but First to Market?

On December 1, the team of Mylan and Biocon received their first biosimilar approval in the US, for an agent to compete with Roche’s Herceptin®. The approval decision on this product was delayed 3 months owing to potential issues involving Biocon’s manufacturing facility. However, this marks the first biosimilar approved for trastuzumab, beating entries from Amgen/Allergan and Celltrion to the 351(k) finish line.

Dubbed Ogivri™ (trastuzumab-dkst), the Food and Drug Administration (FDA) approved the biosimilar to treat human epidermal growth factor receptor (HER)–positive (HER+) breast cancer and HER2+ metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma). The FDA’s Oncology Drug Advisory Committee voted unanimously to approve the drug, and it was originally scheduled for a decision in early September.

Scott Gottlieb, MD, the recently installed FDA Commissioner, stated, “The FDA continues to grow the number of biosimilar approvals, helping to promote competition that can lower health care costs. This is especially important when it comes to diseases like cancer that have a high cost burden for patients. We’re committed to taking new policy steps to advance our biosimilar pathway and promote more competition for biological drugs.”

Ogivri will carry the same Boxed Warning as Herceptin, regarding increased risks of heart disease (cardiomyopathy), infusions reactions, lung damage (pulmonary toxicity) and harm to a developing fetus (embryo-fetal toxicity).

The launch of the product may be delayed until 2019 or 2020, based on an agreement between Mylan and Roche. This could mean that although Ogivri is first approved, it may not be first launched.

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.

BR&R Logo Transparent1.5-21-2017

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?

Mylan and Biocon Withdraw Two EMA Biosimilar Applications

The biosimilar pegfilgrastim marketplace may have taken another hit today, as Biocon announced that it was pulling its applications for both pegfilgrastim and trastuzumab from consideration by the European Medicines Agency (EMA).

The action came after Biocon was notified of the need for re-inspection of its manufacturing site by the European authorities. According to Reuters, Biocon said in a stock filing, “The European regulatory authorities had informed us of the need for a re-inspection of our drug product facility for these products,” Biocon said, without specifying when the regulator would carry out the inspection.

Herceptin“We are on track to complete our corrective action and preventive actions by the end of this quarter, and it is our intent to seek re-inspection and re-submission thereafter.”

In another report, a Biocon spokesperson stated that “Whilst our drug substance facilities for trastuzumab and pegfilgrastim were approved, the European regulatory authorities had informed us of the need for a re-inspection of our drug product facility for these products. The request for withdrawal of the dossiers and re-submission is part of the EMA procedural requirements linked to this re-inspection and will be considered by the EMA’s Committee for Medicinal Products for Human Use (CHMP),” said the company spokesperson.

This action could potentially create considerable problems for the partners Mylan and Biocon. They have the opportunity to be first-to-market in the US with regard to both biosimilar products. Their biosimilar trastuzumab application received a unanimous recommendation to approve from the Food and Drug Administration (FDA) Oncology Drug Advisory Committtee in July, and a final decision is imminent (expected before September 3). The partners’ biosimilar pegfilgrastim application is expected by October 9th. Although the FDA usually rules according to its Advisory Committee recommendations, manufacturing plant problems has resulted in at least one surprising rejection, for Pfizer’s Retacrit®. Pegfilgrastim applications have not yet made it through the FDA approval process, after three previous attempts.   

Information is not readily available as to whether the Biocon plant that is subject to re-inspection would potentially be supplying products to the US. If so, the FDA may decide to review the situation, and possibly delay their decision or issue complete response letters on the two products.

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.

FDA Advisory Committee Unanimously Recommends Approval for Avastin® and Herceptin® Biosimilars

It was a good day for biosimilar manufacturers and a bad day for Roche and its Genentech unit. Following a broadly positive FDA staff review of the first products to directly treat tumors, the Food and Drug Administration’s Oncology Drug Advisory Committee took the expected step of unanimously recommending approval for agents from Amgen and Mylan.

In the morning session, Amgen and Allergan’s ABP-215 was convincingly presented as equivalent to Roche’s bevacizumab (Avastin®), based on  pharmacologic, pharmacokinetic, efficacy, and safety evaluations. Clinical studies were performed in patients with non–small cell lung cancer. The Advisory Committee voted 17-0, recommending approval of the drug for all of the originator product’s nonprotected indications:

  • As first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy
  • Combined with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line ABP 215-containing regimen
  • As first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non–small cell lung cancer in combination with carboplatin and paclitaxel
  • For the treatment of glioblastoma with progressive disease in adult patients following previous therapy as a single agent
  • For the treatment of metastatic renal-cell carcinoma in combination with interferon alfa
  • In combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix

Several questions brought up by the Committee involved the glioblastoma indication, and the drug’s passage over the blood–brain barrier. Progressive multifocal leukoencephalopathy was also mentioned, but this did not deter the Committee from its unanimous vote.

Amgen did not apply for approval for Avastin’s other orphan indications, which are “protected,” according to FDA. If they did want to obtain approval for those, an additional data package would need to be submitted.

Immunogenicity studies did not reveal any material differences between the biosimilar and originator product. In a minor twist, Amgen did the clinical testing of its biosimilar against the EU-licensed version of Avastin, and it had to conduct bridging studies to demonstrate the similarity between the EU version and the US-licensed originator drug.

In the day’s second session, Mylan’s MYL-1401O, a biosimilar version of Roche’s Herceptin (trastuzumab), was evaluated. The totality of evidence, according to the FDA staff review documents, supported the 351(k) application by Mylan. The Advisory Committee agreed, voting 16-0 to recommend the biosimilar for approval for use in Herceptin’s indications:

  • For use as adjuvant treatment of HER2 overexpressing node- positive or node-negative (ER/PR negative or with one high risk feature) breast cancer (1) as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; (2) with docetaxel and carboplatin; or (3) as a single agent following multimodality anthracycline-based therapy
  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
  • In combination with cisplatin and capecitabine or 5- fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

The FDA usually accepts the recommendation of its Advisory Committees in issuing final decisions. However, in late June, the agency rejected Pfizer’s Retacrit despite a 14–1 Advisory Committee vote to recommend, based on potential problems at a manufacturing facility. Mylan’s manufacturing partner Biocon, has recently been cited by French inspectors in connection with its European approval application, for potential problems at its Bangalore plant.

A final FDA decision is expected for Amgen’s bevacizumab biosimilar by September 14, and for Mylan’s trastuzumab biosimilar by September 3.