Tag: Apotex

A Shakeout of Potential New Filgrastim Competition?

According to reports by Big Molecule Watch, two patent litigation suits have been dropped involving prospective filgrastim makers and the reference manufacturer Amgen. Sudden announcements like this have generally meant one of two things in the biosimilars arena.

The announcements came within days of each other: first, Accord BioPharma and Amgen announced that they jointly filed for dismissal of their ongoing suit. Then, on November 25, Big Molecule Watch reported that Kashiv Biopharma and Amgen have similarly dropped their patent litigation.

Three Scenarios Affecting Filgrastim Biosimilar Competition

Filgrastim market
Computer-Simuilation of a Filgrastim Molecule

The first potential scenario is that Amgen has come to an agreement with the respective manufacturers in terms of licensing or royalties associated with the sales of the biosimilar. We have seen this most recently with Pfizer bevacizumab biosimilar, where the Genentech and Pfizer’s filing to dismiss the patent suit came within days of an announcement of the new agreement. However, the new announcements involve filgrastim, a product that has been marketed since 2015, with ample competition (that is not subject to previous licensing arrangements). A new licensing agreement would be a bit less likely here, since Amgen owns less than 50% of the filgrastim share (Neupogen’s competitors Zarxio® and Granix® hold 31.7% and 20.3%, respectively, according to February 2019 IQVIA figures).

The second possibility is that Amgen has simply dropped the respective suits because of their lower marketshare; that is, the biosimilar genie is already out of the bottle, and litigating these ongoing lawsuits are simply a waste of resources.

A third possibility is that these prospective manufacturers, both of which have run into difficulties obtaining approval for their potential biosimilars in the US, have actually stopped development. This may be the most likely reason.

We reported back in May that Apobiologix (the US biosimilar subsidiary of Apotex) has likely ceased biosimilar development. They first filed for approval in early 2015, with no FDA action reported since that time. The lawsuit regarding this product was being defended by Accord (which was a subsidiary of Intas Pharmaceutical, a partner with Apotex in the development of the biosimilar); Accord’s name was substituted on the suit for Apotex’s in August 2019. Perhaps the rights for the filgrastim biosimilar reverted back to them.

Has Kashiv Biosciences Also Lost Interest in Filgrastim?

In the case of Kashiv Biosciences, this manufacturer purchased Adello Biologics in January 2019, which had been developing biosimilar versions of filgrastim and pegfilgrastim. Kashiv, which hasn’t issued a press release since the initial announcement of the purchase of Adello, still lists both agents on its pipeline. In January, the company stated to BR&R that it was proceeding with its development of the pegfilgrastim biosimilar, with a filing possible before the end of 2019. The filgrastim biosimilar filing in September 2017 is likely to have resulted in at least one complete response letter. No action from the FDA has been reported. One might also assume that the commercialization efforts for this product have been aborted.

If this is true for both cases, further litigation would be pointless. It may simply be additional evidence of a shakeout of the remaining competition in the first-generation biosimilar market.  

Apotex/Apobiologix: Success in Canada, but Are They Shelving Biosimilars in the US?

Apotex has recently made news in Canada, introducing biosimilars and obtaining marketshare there. However, the story of Apotex and its Apobiologix biosimilar subsidiary in the US is less positive.

Apobiologix

As we’ve listed in our updated table, Apotex had originally filed for approval for its pegfilgrastim biosimilar with the FDA in late 2014 and its filgrastim biosimilar in early 2015. In 2019, no announcement has been made with regard to the filing status of either biosimilar.

In April 2018, we spoke with Apobiologix executives, who told us that the company “were still in discussions with the FDA” about the path forward for its G-CSF biosimilars. Unfortunately, this statement has not changed at all on its website. If there were discussions, they didn’t go far. And so the mystery continues.

There is some support for the view that the parent company is seeking to shed the Apobiologix subsidiary, and has been actively seeking a buyer for some time. This would make sense to a degree, as any of its newly approved biosimilars would be facing a difficult crawl to US marketshare, being the third or fourth filgrastim or pegfilgrastim biosimilar to launch.  Realizing that its marketshare potential would be substantially limited, why spend the additional developmental dollars?

In April 2018, Canada had granted the company approval to market its pegfilgrastim biosimilar (Lapelga™), and in Canada’s provincial systems, it has become a dominant player. Filgrastim was approved in Canada in 2016 (and in the EU in 2014).

According to its website, Apobiologix had been developing the following products for the US market:

  • Epoetin alfa (reference drug, Epogen®), in Phase 3
  • Darbepoetin alfa (Aranesp®), in preclinical study
  • Bevacizumab (Avastin®), in Phase 1
  • Rituximab (Rituxan®), in Phase 1
  • Trastuzumab (Herceptin®), in preclinical study

Although the pipeline lists the epoetin, bevacizumab, and rituximab biosimilars in clinical trials, no mention of any of these specific investigations can be found on www.clinicaltrials.gov, under Apotex or Apobiologix as a sponsor. A request for comment from Apobiologix was not answered by the time of this publication.

If this is the case, it is less the FDA than the parent drug maker who has lost faith in their biosimilars’ potential in the US. We can ill afford fewer active players in this market.

Convincing Two Main Providers the Key to Pfizer’s Retacrit® Success

An unusual market situation awaits Pfizer’s new biosimilar epoetin, one that few approved medications has to face. Not only does Retacrit® need to pass muster with payers like health plans and insurers, which we assume it will, but Retacrit will need to be accepted by the two 800-pound gorillas of the kidney dialysis field as well.

epoetin use in kidney centersRetacrit and Dialysis Centers

The different part of this discussion is that providers are not usually so concentrated except in the treatment of the rarest diseases. Cancer medications are utilized by independent treatment centers throughout the country. Biosimilar agents like infliximab are also used throughout the nation by hospitals, large medical groups, and solo practices. In the case of epoetin, its primary use is in anemia related to kidney dialysis. The vast majority (85%) of kidney dialysis centers are owned by one of two networks, Fresenius Medical Care North America and DaVita Kidney Care. According to a report by Healio, Fresenius accounted for 42.6% of the total patient market in 2017, and DaVita is just behind, with 42.0% of the 453,000 patients receiving dialysis services. In other words, get buy-in from these companies and the payers, and Pfizer would have a chance to gain significant share of the epoetin market.

kidney dialysis centers
Source: https://www.healio.com/nephrology/practice-management/news/online/%7Bd894132b-b577-435e-8dec-401cd89d1b1e%7D/the-largest-dialysis-providers-in-2017-more-jump-on-integrated-care-bandwagon

Nephrologists seem to be onboard, in general. The results of national survey of nephrologists conducted in March 2018 confirm this. According to the research, only one in five respondents would be averse to switching to the biosimilar. One barrier to use may exist, however, on the provider side. The long-acting agents may be preferred by some. These include Amgen’s darbepoetin alfa (Aranesp®) and Roche’s Mircera® (methoxy polyethylene glycol-epoetin beta). To the extent that nephrologists may be less willing to use short-acting biosimilar instead of the more expensive long-acting brand may define Pfizer’s success with Retacrit. This is somewhat similar to the situation brewing with the use of injectable biosimilar pegfilgrastim (once approved and available) and the Neulasta® Onpro® delivery system. The share of use of the long-acting erythrocyte-stimulating agents has been increasing.

On May 15, 2018, Pfizer’s epoetin biosimilar Retacrit was approved by the Food and Drug Administration (FDA), the first biosimilar competitor to Epogen® and Procrit®. Retacrit is not officially available yet.

In other related biosimilar news…Pfizer announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing approval for its biosimilar version of trastuzumab.

Apotex and its Apobiologix division has claimed a significant prize—the first pegfilgrastim biosimilar approval in Western markets. None have been approved in the US or EU to date. Health Canada granted marketing authorization to the company on June 1. The new drug will be called Lapelga™.

What Is the Biosimilar Pegfilgrastim Market Opportunity?

We’ve covered the contest to bring a biosimilar pegfilgrastim to market, with considerable depth. The progress and setbacks of Mylan/Biocon, Coherus Biosciences, Sandoz, and Apotex have been tracked. Other drug makers are also working on plans towards 351(k) applications for approval. Eventually—likely sooner than later—one or two will hit the market.

Biosimilar Pegfilgrastim, Neulasta®, and Onpro®

Amgen, maker of the originator product Neulasta®, disclosed in its first-quarter financial report that the total sales for the product in the US is $1.0 billion, $146 million for the rest of the world, for a total of $1.15 billion. This means a US market of approximately $4 billion for one year of sales. Amgen also noted that 62% of its first-quarter Neulasta sales are associated with its Onpro® kit. Although the major patents for pegfilgrastim have expired, Onpro is still protected by patent. Onpro does have some significant advantages in that the patient does not need to go to the doctor’s office for an injection after receiving chemotherapy. The sales figures indicate that doctors prescribe it in preference to the injectable form of pegfilgrastim.

Neulasta OnproAt a current 62% marketshare for Neulasta Onpro, the initial total slice of the pie available for biosimilars may only be $1.5 billion (not considering WAC discounts). If we assume a 20% discount, this may be closer to $1.2 billion. It may not seem logical for Amgen to make great efforts to defend its share of injectable pegfilgrastim because of its successful conversion to Onpro. Also, Onpro does have marketable advantages over the injectable form.

The list price of Neulasta is upwards of $7000 per injection, and Amgen does not charge additionally for the Onpro kit. This stance may prove an incentive to health plans and insurers to not encourage biosimilar use over Onpro.

Will Physicians Resist Moving From Onpro to a Biosimilar Pegfilgrastim Injection?

The $1.2 billion to $1.5 billion estimate also assumes that Amgen cannot convert more patients to Onpro prior to approval of a new biosimilar. That would further shrink the revenue opportunity. Physicians may also resist payer efforts and not prescribe the injectable form if they favor the Onpro kit. To the extent that payers may prefer the biosimilar (or otherwise restrict the use of a more expensive originator agent) when it becomes available, that slice of the pie could increase quite a bit. Furthermore, the picture could also change in a few years as biosimilar manufacturers develop delivery systems that gain the same advantages as Onpro.

In its earnings report, Amgen indicated the sales of Neulasta have been decreasing, by 5% from the same quarter last year. This may be the result of movement to other, less-toxic cancer chemotherapies or other treatments to prevent neutropenia and its related infections.

The Onpro market for the rest of the world may be given a boost soon, as Amgen also announced that the European Medicines Agency issued a positive opinion for the drug maker to include the Onpro Kit in its EU label.

As reported in BR&R, Coherus CEO Denny Lanfear thought the pegfilgrastim market may be split in a manner similar to that for filgrastim (i.e., 30%/30%/40% shares for 2 biosimilar makers and the originator). That may possibly mean 30% of a $1.2 billion US market (not $4 billion), if payers do not emphasize the use of the biosimilar over Onpro.

Pegfilgrastim: 0 for 3 on Biosimilars at FDA

On June 12, Coherus Biosciences received word of the Food and Drug Administration’s (FDA’s) rejection of its biosimilar pegfilgrastim. Manufacturers have now taken 3 swings and misses, striking out in their quest for a biosimilar version of another blockbuster product.

In 2016, Sandoz whiffed on its version, after having the nonpegylated version approved in 2015 (Zarxio®). Although details of the FDA’s complete response letter were not released, Sandoz decided to withdraw its application to the European Medicines Agency as well. In December 2014, Apotex was the first to submit its pegfilgrastim application to the FDA, but it was similarly rejected.

The remaining biosimilar version of Neulasta® awaiting its turn at bat in the US is from Mylan/Biocon. Submitted in February of this year, the FDA decision is due October 9, 2017. Pfizer is working on its own version of pegfilgrastim (HSP-130), which is in phase 2 study. Apotex’s Apobiologix unit is still seeking approval of its biosimilar, according to its website. In Europe, 2 pegfilgrastim applications are currently awaiting decisions, but none have been approved to date.Image result for pegfilgrastim (neulasta)

On the bright side, the FDA’s complete response letter to Coherus did not indicate that the game is over. Apparently, the agency asked for a re-analysis of specific data and requested further information regarding manufacturing its biosimilar agent. The drug maker indicated its willingness to work with FDA to resolve these concerns.

There seems to be something about the pegylated version of filgrastim that makes it more difficult to obtain an approval during the first plate appearance. It may well be that Mylan’s application hits it out of the park in October. However, the batting average of drug makers pitching their other biosimilars is far better—Pfizer’s second try at approving epoetin seems to have been a hit (with a 14-1 margin by the FDA Advisory Committee).

With $4.5 billion in US sales of Neulasta last year, there will be no shortage of hitters willing to come to the plate.