Going Generic: Big Brands Poised To Lose Marketing Exclusivity In The US In 2019

With the first generic versions of blockbuster brands like Advair, Lyrica, Restasis and Sensipar and the first biosimilars of Herceptin, Avastin and Rituxan expected to launch in the US, 2019 could be a notable year for generics and biosimilars.

Several high-profile blockbuster brands are poised to lose their marketing exclusivity in the US in 2019 with the launch of the first generic versions of drugs like Advair (fluticasone/salmeterol) and Lyrica (pregabalin) and the first wave of oncology biosimilars, Herceptin (trastuzumab), Avastin (bevacizumab) and Rituxan (rituximab).

The year is expected to be a notable one for generics and biosimilars, though the commercial launch trajectory for biosimilars in the US remains unclear. The exact timing of generic and biosimilar launches is also uncertain, with the timelines tied to patent expirations, patent settlement agreements, or in some cases ongoing patent challenges. 

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"Since the end of the patent cliff, we have had essentially the same $15bn-$17bn of negative impact from expirees in the US, and our modeling suggests that it is supposed to pop this year," Research Director for the IQVIA Institute for Human Data Science Michael Kleinrock said in an interview. But, he also pointed to uncertainties, including the possibility that some launches are delayed or there is slower uptake for certain complex generics and biosimilars.

"You can have a generic approved. It can reach the market, and the originator can retain a fairly large share of the volume of sales," Kleinrock noted. That has been the experience with some recent entrants, such as the generic launch of Teva Pharmaceuticals USA Inc.'s Copaxone (glatiramer) or biosimilars to Johnson & Johnson's Remicade (infliximab).

A Big Start To The Year

The Jan. 30 FDA approval of the first generic version of GlaxoSmithKline PLC's Advair Diskus for asthma and chronic obstructive pulmonary disease (COPD) kicked off the year. The complex inhaled respiratory drug lost patent protection in 2016 when the device patents expired, but getting a generic through the FDA was challenging given the complex nature of the product. Mylan NV was the victor and launched its generic product, Wixela Inhub, in February at a 70% discount to GSK's Advair list price.

Mylan's generic had a 24% share of the fluticasone/salmeterol prescription market as of March 1.

Sales of Advair have eroded over the last few years due to pricing pressure and GSK's efforts to transition patients to newer brands like Breo Ellipta. Advair generated £1.10bn ($1.44bn) in the US in 2018 and £2.42bn ($3.16bn) globally. Mylan's generic has gotten off to a relatively strong start for a complex generic, some of which have faced challenges. The product has a 24% share of the fluticasone/salmeterol prescription market as of March 1, SVB Leerink analyst Ami Fadia said in a March 8 note.

Another drug that is facing new generic competition is Amgen Inc.'s Sensipar (cinacalcet). One version from Teva launched for a brief time Dec. 27, but Teva stopped selling the generic after reaching a patent settlement with Amgen, which is now the subject of antitrust questions. In March, Cipla Ltd. and Piramal Enterprises Ltd., through its partner Slate Run, both launched generic versions of Sensipar, despite ongoing litigation. (Also see "Generic Sensipar: Cipla Challenges Legality of Amgen/Teva Patent Settlement" - Pink Sheet, 14 Feb, 2019.) There remains a lot of uncertainty around how the generic launches for the calcium-sensing receptor agonist will play out.  (Also see "Cipla, Piramal Launch Sensipar Generics Amid Growing Antitrust Challenges to Amgen/Teva Settlement" - Pink Sheet, 12 Mar, 2019.)

Sensipar, which launched in 2004, is indicated for the treatment of secondary hyperthyroidism in chronic kidney disease patients on dialysis and hypercalcemia in patients with parathyroid carcinoma. It generated $1.43bn in the US in 2018. The composition of matter patent for Sensipar expired in March 2018, but Amgen is continuing to defend a formulation patent that expires in September 2026.

Pfizer Inc., meanwhile, has forecast a challenging 2019 as it braces for the loss of its number-two seller Lyrica to generics beginning June 30, after receiving a six-month pediatric extension from the FDA. Lyrica generated $3.59bn in the US in 2018. (Also see "Pfizer: Time To Face The Lyrica Pain" - Scrip, 29 Jan, 2019.) The loss of exclusivity for Lyrica, a popular drug for certain types of pain, will be a hit to Pfizer in 2019 and the first half of 2020, with the company generally guiding investors to expect flat growth in 2019.

Allergan PLC is preparing for a big impact as well from the launch of generic versions of its blockbuster dry eye drug Restasis (cyclosporine ophthalmic emulsion), its second best-selling drug after Botox. Restasis generated $1.2bn in the US in 2018. Four patents covering Restasis were invalidated by a US district court in 2017 and the ruling was affirmed on appeal last November. Both Teva and Mylan are aiming to launch generic versions of Restasis. Allergan's 2019 forecast assumes exclusivity for Restasis only through March 31.

Multiple Sclerosis Blockbusters On The Line

One brand that remains a question mark in 2019 is Novartis AG's multiple sclerosis pill Gilenya (fingolimod). The drug's compound patent expires in August 2019 and another patent on the dosage regimen that extends to 2027 is under attack by generic manufacturers. Novartis scored an important win last year when the US Patent and Trademark Office's Patent Trial and Appeal Board (PTAB) ruled in favor of Novartis that the 2027 patent should stand. An appeal is underway, but Novartis said a decision is unlikely before the fourth quarter.

Novartis, meanwhile, has filed a patent infringement suit against 23 generic manufacturers and expects preliminary injunction hearings in that case to begin in June.

The company's 2019 financial forecast assumes generic versions do not launch in 2019, but the company did highlight the possibility. Nonetheless, during the company's fourth quarter earnings call, management sounded confident about the Gilenya franchise, indicating that a generic launch would likely only occur in 2019 if generic manufacturers win the preliminary injunction proceedings and then such a launch would still be considered at risk. Gilenya generated $1.77bn in the US in 2019.

Biogen's multiple sclerosis pill Tecfidera (dimethyl fumarate) also is facing challenges on several fronts, although it seems unlikely generics would launch before 2020. In February, PTAB initiated an inter partes review of Tecfidera's 8,399,514 patent, which extends to 2028, after Mylan filed a petition. Those proceedings will take some time to work through, however.

Bernstein analyst Ronny Gal expects it would take a year, likely followed by an appeal. "A win for Biogen implies 2028 generic entry while a loss implies YE2020 entry," Gal predicted in a Feb. 7 research note.

The company is heavily reliant on sales of Tecfidera, which is its top seller and generated $4.27bn in 2018, $3.25bn of which came from the US.

Biogen is moving forward with a next-generation formula through a licensing deal with Alkermes PLC, which could have improved gastrointestinal tolerability. The companies submitted an NDA in January for Vumerity (diroximel fumarate) under the 505(b)(2) pathway, referencing Tecfidera. (Also see "Keeping Track: US FDA Receives Submissions Galore As Year Ends" - Pink Sheet, 6 Jan, 2019.) Biogen hopes to transition patients to the newer product, but a generic entry could make the commercial prospects for both products more challenging.

Multiple sclerosis is one therapeutic area where payers are anxious for relief, but may have longer to wait to see new generic entries. "MS is one of those markets that a lot of payers are focused on because of its contribution to overall spend and they are focused on it because there is not a lot of payer leverage over the clinical decision," Kleinrock said.

A Biosimilar Boom On The Way

Biosimilar launches could be particularly notable in 2019. Biosimilars of Roche's blockbuster cancer drugs Herceptin, Rituxan and Avastin could all launch in the US sometime during the year, though the exact timeline is unknown. The FDA has approved biosimilars of all three drugs, though the timelines for launching remain uncertain and are based on patent settlement agreements and ongoing legal disputes.

In its annual report, Roche confirmed that biosimilar versions of all three drugs are expected to come to the market in the US in the second half of 2019. The drugs are three of the company's top sellers, with combined sales in 2018 of CHF20.6bn ($20.4bn), including CHF10.1bn ($10bn) coming from the US.

During the company's fourth quarter earnings call, Roche Pharmaceuticals CEO William Anderson told investors that it is difficult to forecast how biosimilar competition will play out, both in terms of timing and uptake. "We've baked in some impact in the second half, and it's not a huge impact, because it happens in the second half and there is only so much that can happen," he said.

Roche has developed a subcutaneous version of Herceptin that was approved by the FDA in February and is also developing a fixed-dose combination of Herceptin and Perjeta (pertuzumab) as a subcutaneous injection, which could offer a convenience advantage for patients.

Cancer biosimilars are likely to face different commercial dynamics than previous biosimilar launches. 

The biosimilar launches should be interesting to observe for the broader US market because they will represent the first wave of monoclonal antibody biosimilars for cancer, which could face different commercial dynamics than some other early biosimilar launches. Patients or physicians could have more questions about using biosimilars for the treatment of cancer early on, given the importance of efficacy, but as IQVIA's Kleinrock pointed out, there could be advantages when it comes to the physician buy-and-bill model versus pharmacy dispensing.

"Buy-and-bill has a lot to do with how the companies work with the purchasers on the discounts and pricing as they relate to the ASP model," he said, referring to the average selling price reported under Medicare Part B. "There is a way to encourage greater uptake where there is a group purchase decision, say from a cancer center for Herceptin."

Pfizer said during its fourth quarter call that it expects to launch biosimilar versions of all three drugs in 2019. The company's Herceptin biosimilar, Trazimera (trastuzumamb-gyyp), was approved by the FDA for HER2+ breast cancer and metastatic gastric or gastroesophageal cancer March 11. Pfizer's biosimilars of Avastin and Rituxan are pending at the FDA.

Pfizer’s was the fourth Herceptin biosimilar approved by the FDA, following Mylan's Ogivri (trastuzumab-dkst) in December 2017, Celltrion Inc./Teva's Herzuma (trastuzumab-pkrb) in late 2018 and Samsung Bioepis Co. Ltd.’s Ontruzant (trastuzumab-dttb) in January. (Also see "Keeping Track: FDA's Review Actions Carry On During Shutdown" - Pink Sheet, 20 Jan, 2019.) Mylan was the first to reach a settlement agreement with Roche in 2017, however, paving the way for a biosimilar launch at an undisclosed timeline. (Also see "Mylan Clears Runway For US Herceptin Biosimilar Launch" - Scrip, 13 Mar, 2017.) Pfizer also settled with Roche under undisclosed terms.

Amgen/Allergan PLC's Mvasi (bevacizumab-awwb) was the first Avastin biosimilar approved by the FDA, in 2017, while Teva/Celltrion's Truxima (rituximab-abbs) was the first Rituxan biosimilar approved by the FDA, in 2018. Novartis' Sandoz International GMBH received a complete response letter from the FDA for its product last year, and revealed that it would not develop the drug for the US market. (Also see "Novartis Gives Up On Rituxan Biosimilar For US Market" - Scrip, 5 Nov, 2018.)

While the US biosimilars market overall is starting to take more shape, the introduction of cancer biosimilars presents a greater hurdle still – and how new entries erode some of the industry's biggest brands remains to be seen.