Amgen Inc. put the biopharma world on notice by disclosing positive findings from the first phase III study evaluating efficacy and safety of its lead biosimilar candidate. The randomized, double-blind, active-controlled study of ABP 501, whose reference drug is Humira (adalimumab, Abbvie Inc.), met its primary endpoint: improving the Psoriasis Area and Severity Index (PASI) within a prespecified equivalence margin, compared to adalimumab, from baseline to week 16 in patients with moderate to severe plaque psoriasis.

Officials at Amgen said the safety and immunogenicity of ABP 501 also were comparable to adalimumab. The study was the first of two phase III trials designed to move ABP 501 into global regulatory submissions.

The phase III trial enrolled 350 patients at sites in Canada, Australia and Europe, randomized to ABP 501 (n = 174) or adalimumab (n = 173). One patient in the ABP 501 group and two in the adalimumab group were randomized but did not receive any investigational product. Amgen said assessments of PASI percent improvement for any given patient were made by the same observer whenever possible.

Patients with a PASI 50 or above response at week 16 will remain on the study for up to 52 weeks so the company can collect data on key secondary safety endpoints, according to Scott Foraker, Amgen's vice president and general manager of biosimilars. Those include the occurrence of any adverse and serious adverse events, clinically significant changes in laboratory values and vital signs and the incidence of anti-drug antibodies, according to Cortellis Clinical Trials Intelligence (CTI).

Patients who continued on the study beyond week 16 were re-randomized in a blinded fashion. Those initially randomized to ABP 501 are continuing to receive the study drug, while those on adalimumab either continued on adalimumab or switched to ABP 501 in a 1-to-1 fashion. Patients will receive the last dose at week 48, with final efficacy assessments conducted at week 50. The study is expected to be completed at the end of the first quarter of 2015, according to Cortellis CTI.

An anti-TNF-alpha monoclonal antibody (MAb), adalimumab is approved in numerous countries to treat inflammatory diseases, including rheumatoid arthritis (RA), plaque psoriasis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and ulcerative colitis. RA is the target of Amgen's second phase III for ABP 501, with the fully enrolled study also expected to be completed next year. Once Amgen has data from both studies in hand, it will seek meetings with regulatory agencies and submit global filings, according to Richard Markus, Amgen's executive medical director for global biosimilars development.

"We thought it important to satisfy global stakeholders to have some data available in both of these indications," Markus told BioWorld Today, citing Amgen's desire to provide a compelling data package not only to regulators but also to payers and prescribing physicians.

Based on discussions with regulators, Amgen is confident that it can extrapolate data from the phase III studies to seek broad approval for ABP 501 without having to study "every single labeled indication that Humira enjoys," Foraker added.

The active ingredient of the Amgen biosimilar is an anti-TNF-alpha MAb with the same amino acid sequence as adalimumab. The drug also has the same pharmaceutical dosage form and strength as adalimumab, as approved in the U.S. and European Union.

"This is a really, really exciting day for us on the biosims team and for the company, in general," Foraker said. "After all, this is the largest-selling drug in the world right now."

'WE'VE GOT TO OVERCOME STAKEHOLDER UNCERTAINTY'

And ABP 501 is just the beginning for Amgen. The Thousand Oaks, Calif.-based biotech has five additional biosimilars in development. According to Biosimilars: A Global Perspective of a New Market – Opportunities, Threats and Critical Strategies 2014, a report compiled by Thomson Reuters BioWorld, they include molecules targeting a handful of additional blockbuster drugs: Avastin (bevacizumab, Genentech Inc.), Erbitux (cetuximab, Bristol-Myers Squibb/Eli Lilly & Co./Merck KGaA), Remicade (infliximab, Janssen Biotech Inc./Mitsubishi Tanabe Pharma Corp./Xian Janssen/Merck & Co. Inc.), Mabthera/Rituxan (rituximab, Biogen Idec Inc./Genentech) and Herceptin (trastuzumab, Genentech).

The six reference products accounted for some $42 billion in global 2013 sales, Foraker pointed out. "That shows the great potential that exists with respect to biosimilars," he said.

Having pioneered the biologics pathway, Amgen is eager to broaden its stride and sprint down the track in biosimilars, as well, according to the Thomson Reuters BioWorld biosimilars report – a notion Foraker did not disavow.

Biosimilars "have the opportunity to provide meaningful revenue and profit growth for Amgen, which is not so easy to do growing off the large base that we have," he told BioWorld Today. "This is one of the few opportunities to move the needle."

Biosimilars also represent "a good hedge" against the inherent risk of developing innovative drugs and the challenges of biosimilar competition against the company's legacy products. Biosimilar products are launched or are in development to compete with Amgen's anemia products Aranesp (darbepoetin alfa) and Epogen (epoetin alfa), the osteoporosis drug Xgeva/Prolia (denosumab), the arthritis drug Enbrel (etanercept), and Neupogen (filgrastim [G-CSF]), used to treat neutropenia, according to the Thomson Reuters BioWorld report.

That's not to say development of biosimilars has been a cakewalk, even for Amgen. In fact, the development process for the company's initial biosimilars pipeline was strikingly akin to that of its branded biologics business, according to Foraker. Biosimilar drugs are complex to design and difficult to manufacture, the cost is relatively high, the regulatory environment is ambiguous and the supply chain is not always reliable, he said.

On top of that, "we've got to overcome stakeholder uncertainty" Foraker added, especially perceptions about quality as the U.S. market encounters biosimilars for the first time.

"Biosimilars are not all the same, and each will represent a distinct therapeutic choice," Foraker conceded. "But we feel that, in each challenge, we have unique and significant competitive advantages."

Some of the early lessons learned from Amgen's biosimilars development involved technical applications "that have spilled over into the innovative side of our business," he added. "We have two-way learning going on."

From a regulatory perspective, Foraker praised the FDA's "thoughtful and deliberate" approach toward biosimilars. Regulators "want to be cautious, because they know what can go wrong with biologics, and that makes perfect sense," he said. But Amgen's discussions with the agency have offered reassurance that reviewers understand the distinctions among biosimilar molecules and the scientific underpinning of the company's approach.

"Even though people complain that there are draft guidelines, we're getting enough direction from the FDA to give us confidence to invest many millions of dollars in these drugs," Foraker said.

Amgen's initial biosimilars are in development with partner Actavis Inc. (formerly Watson Pharmaceuticals Inc.), which, under a 2011 deal, agreed to provide up to $400 million in co-development costs and to share development risks for seven to eight years. (See BioWorld Today, Dec. 21, 2011.)

Amgen is "absolutely" looking at expanding that pipeline, Foraker said. He declined to say whether the company will take new assets forward on its own or with Actavis but said "we'll have some exciting news coming out in the coming weeks."

The company's biosimilars news generated sufficient buzz to move the stock (NASDAQ:AMGN), which gained $4.04 Wednesday, to close at $140.07.

Analysts also were enthused. In a note on the company published in November 2013 following her attendance at a biosimilars conference, Deutsche Bank analyst Robyn Karnauskas "came away with a greater understanding" of the impact of biosimilars and the market opportunity for Amgen. She subsequently projected that biosimilars could contribute approximately $8 more to the company's stock price.

Karnauskas remained bullish following the release of phase III data on ABP 501, projecting the future value of biosimilars at up to $18 per Amgen share, based on 100 percent probability, with the company's manufacturing expertise "a key for success in biosimilar competition."

And in a hot comment, Piper Jaffray analyst Joshua Schimmer noted that Amgen's biosimilar franchise "is generally not included in consensus estimates and we believe the pipeline overall is under-modeled, which is the core premise for AMGN being one of our top large-cap picks."

Editor's note: For a copy of BioWorld's report,Biosimilars: A Global Perspective of a New Market Opportunities, Threats and Critical Strategies 2014, call: +1-800-336-4474 in the U.S. and Canada; outside the U.S.: +44-203-684-1796.