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In 2013, Big Sellers in PGx Market Remain Herceptin, Gleevec with Newer Agents Poised to Take Over

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In 2013, the top selling pharmacogenetically targeted drugs were well-known personalized medicine products, Herceptin and Gleevec.

Both of these drugs are slated to face generic competition soon, however, and when they do, drugmakers have newer agents in their pipelines to take their place. Meanwhile, across the PGx market, as new drugs are launched addressing smaller and smaller patient subsets, it raises the question whether any other personalized drugs will be able to match Herceptin or Gleevec's revenue success.

For the full year 2013, Roche's HER2 breast cancer franchise sales, comprising Herceptin (trastuzumab), Perjeta (pertuzumab), and Kadcyla (ado-trastuzumab emtansine), rose 14 percent year over year to CHF 6.6 billion ($7.44 billion). During the past year, Roche expanded the US indication for Perjeta into the neoadjuvant setting and EU regulators approved Perjeta in late-stage cancer, and gained regulatory approval for Kadcyla in the US and EU.

Herceptin is Roche's flagship HER2 breast cancer treatment that will lose patent protection in Europe this year and in the next three years in the US. To take its place in the market, Roche in 2012 gained approval for Perjeta from the US Food and Drug Administration for the first-line treatment of HER2-positive metastatic breast cancer, and garnered European regulatory approval in March 2013. Then, in October 2013, the FDA also granted accelerated approval for Perjeta in the neo-adjuvant setting, making it the first cancer drug to receive the agency's nod for this early-stage indication before patients receive surgery. Kadcyla was also approved last year for later stages of HER2-positive metastatic breast cancer.

Worldwide sales for Herceptin in 2013 were CHF 6.1 billion, a 6 percent jump from 2012. The company attributed the increase to "good sales growth" in the US and strong sales in the international market. Meanwhile, Perjeta brought in CHF 326 million, marking a nearly 500 percent increase from the previous year, and Kadcyla netted CHF 234 million. Due to Kadcyla's recent launch there is no year-over-year sales comparison.

With regard to Perjeta, Roche Molecular Diagnostics CEO Daniel O'Day said during the company's recent 2013 earnings call that the drug was "really paving the way for potentially a new regulatory path for products with a significant [partial complete response] effect in patients." In clinical trials, up to 40 percent of patients treated with Perjeta in the neoadjuvant setting "really had no evidence of tumors by the time they hit surgery," he noted.

"So when you think about the period of time it took for Herceptin to go from metastatic to the first use in adjuvant setting, that was close to eight or nine years," O'Day said. "And this was 1.5 years [in the case of Perjeta]. So, [that's] pretty phenomenal."

He estimated that by year end, Perjeta had captured half of new patients in the first-line HER2-positive metastatic breast cancer market, while Kadcyla had netted 40 percent of the new patient market for second-line metastatic breast cancer and in later stages. Roche is studying Kadcyla in combination with Perjeta as a first-line treatment for metastatic HER2-positive breast cancer in a Phase III trial.

Additionally, in September Roche received approval from the European Commission for a subcutaneous formulation of Herceptin. In the PrefHer study, Roche showed that 92 percent of patients preferred the less-invasive form of the drug, and that the new form of the drug was able to cut the time early-stage breast cancer patients spent on chemotherapy regimens by 58 percent.

During the earnings call, O'Day said that the subcutaneous version of Herceptin has been launched in Germany, UK, and several other markets. "What we find is when a center adopts Herceptin subcu, they tend to convert all the patients in the clinic because they change their workflow. So, they tend to convert not just adjuvant but also metastatic patients [on] Herceptin subcu," he said. "This is going to be a very convenient strategy for patients, for healthcare systems, and [will] continue to support our franchise in relation to biosimilar competition that will come."

Newer pharmacogenetically-targeted drugs, such as Roche's Zelboraf (vemurafenib) for BRAF-mutated metastatic melanoma patients, continued to be adopted last year, having gained approval in a total of 81 countries. The drug brought in CHF 354 million in 2013 global sales, a 52 percent increase. In a Phase III study called co-BRIM, Roche is studying Zelboraf in combination with investigational MEK-inhibitor cobimetinib in BRAF V600-mutation positive metastatic melanoma.

Last year, FDA approved two new PGx-guided melanoma drugs from GlaxoSmithKline – Mekinist (trametinib) and Tafinlar (dabrafenib) – which will compete with Zelboraf in the BRAF-mutated melanoma space. GSK reported that last year Tafinlar brought in £16 million ($26.7 million) in sales, while Mekinist contributed £10 million.

Meanwhile, although these drugs have been on the market a short time, GSK is already working on expanding their indications. The FDA just last month approved Mekinist in combination with Tafinlar for the treatment of advanced, unresectable melanoma with BRAF V600E and V600K mutations. The agency the same month also granted breakthrough designation to Tafinlar as a treatment for non-small cell lung cancer patients with BRAF V600E mutated tumors.

In lung cancer, in the first quarter of 2013 the FDA approved Roche's Tarceva (erlotinib) for the first-line treatment of NSCLC in those with EGFR-mutation positive tumors. This added an indication for Tarceva, as it is already approved for NSCLC patients with advanced or previously treated disease. In 2013, Tarceva brought in CHF 1.3 billion in global sales, a 4 percent year-over-year bump.

AstraZeneca's Iressa (gefitinib), an NSCLC drug for EGFR-mutated patients available only outside the US, saw an 11 percent increase in 2013 sales from the previous year, from $611 million to $647 million. The company is also developing AZD9291, a third-generation irreversible EGFR inhibitor in advanced NSCLC patients with EGFR-mutation positive tumors.

Boehringer Ingelheim's Gilotrif (afatinib), approved by the FDA in July 2013, will also compete with Tarceva and Iressa in the first-line EGFR-mutated NSCLC market. Boehringer is slated to hold its annual press conference on April 15.

Also in the personalized lung cancer treatment space, Pfizer's personalized lung cancer drug Xalkori (crizotinib) during 2013 had worldwide revenues of $282 million, up 129 percent from 2012, when the drug had revenues of $123 million.

Novartis, meanwhile, has filed for regulatory approval in the US for LDK378 or ceritinib for advanced ALK-positive NSCLC, and eventually might end up competing with Pfizer's Xalkori. Certinib received breakthrough designation from the FDA last year as a treatment for patients with metastatic ALK-positive NSCLC tumors who have progressed or are intolerant to Xalkori.

The leukemia market last year was dominated by Novartis, which markets Gleevec (imatinib) and Tasigna (nilotinib), together bringing in nearly $6 billion in total sales, marking a 5 percent increase from 2012. Gleevec, approved for Philadelphia chromosome-positive chronic myelogenous leukemia and KIT-positive gastrointestinal stromal tumors, is still Novartis' top-seller with $4.7 in 2013 sales, even though year-over-year sales remained flat.

Gleevec has already lost patent exclusivity in Brazil, Russia, Canada, Turkey and Mexico, and is slated to lose exclusivity in the US next year. Tasigna, which Novartis hopes will take Gleevec's place in the leukemia market, brought in $1.3 billion last year, a 27 percent increase from $998 million in sales in 2012.

Novarits has shown in three large Phase III trials that, compared to Gleevec, Tasigna achieves "deeper molecular responses" in Ph-positive CML patients, including in newly diagnosed patients, those with residual disease who received Tasigna after longterm Gleevec use, and those who failed to respond to frontline Gleevec. Novartis also recently announced it is partnering with MolecularMD to develop a test to track in clinical trials how well CML patients are able to maintain their response in terms of durable minimal residual disease.

Novartis' CML drugs will compete in the market with Pfizer's Bosulif (bosutinib) and Bristol-Myers Squibb's Sprycel (dasatinib). Pfizer still hasn't reported sales of Bosulif after it received FDA approval in September 2012 as a treatment for chronic, accelerated, or blast phase Ph-positive CML in adult patients with resistance or intolerance to prior therapy.

BMS's Sprycel had $1.2 billion in worldwide revenues last year, up 26 percent from $1 billion in revenues in 2012. The drugmaker is focused on convincing healthcare providers of the advantages of its drug over Gleevec. At the American Society of Hematology's annual meeting in December, researchers reported four-year follow-up data from the Phase III DASISION study of Sprycel 100 mg once daily versus Gleevec 400 mg daily in the first-line treatment of adults with Ph-positive CML.

The study results showed that at four years, 76 percent of patients on Sprycel versus 63 percent of Gleevec-treated patients experienced a major molecular response. Additionally, 84 percent of Sprycel-treated patients compared to 64 percent of those on Gleevec had an optimal molecular response at three months. Patients with these responses on Sprycel also lived longer than those who didn't have these responses.

Finally, in the personalized colorectal cancer market, Amgen's Vectibix (panitumumab) had global sales of $389 million in 2013, compared to $359 million in 2012, an 8 percent increase. BMS's Erbitux (cetuximab) had $696 million in worldwide revenues in 2013, a 1 percent decrease from $702 million in 2012.

BMS also markets Plavix, which saw its worldwide revenues last year plummet by 90 percent due to generic competition, from $2.5 billion in 2012 to $258 million in 2013. Plavix lost patent protection in May 2012. The FDA in 2010 placed a black box warning on Plavix's label informing doctors that patients with certain CYP2C19 mutations are poor metabolizers for the drug and that they should consider alternative treatments or Plavix dosing strategies for these patients.

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