By Lisette Hilton, contributing writer, August 01, 2012
Dermatologists who treat severe psoriasis call the advent of biologic treatments a revolution. U.S. patents for these medications, including adalimumab, alefacept, etanercept, infliximab and ustekinumab, will expire during the next 11 years, opening the door for generic biosimilars.
The topic of biosimilars is of such concern to dermatologists around the globe that members of the International Psoriasis Council (IPC), including Craig Leonardi, MD, clinical professor of dermatology at Saint Louis University, wrote a commentary summarizing current knowledge about biosimilars in dermatology, published in the February 2012 Journal of the American Academy of Dermatology (66 (2):317-322).
The authors explain what could happen by citing an example outside dermatology. Epogen (erythropoietin) is a medicine used to treat anemia, initially manufactured by Amgen (Thousand Oaks, Calif.). Amgen licensed Epogen to Ortho Biotech (Bridgewater, N.J.), under the trade name Eprex. The drugs were made of the same cell formulations, but because of variation between the companies’ manufacturing processes, patients were much more likely to have significant clinical issues on Eprex than Epogen.
Dr. Leonardi elaborated on these clinical issues. “Patients on Eprex developed anti-Eprex antibodies. To make matters worse, the Eprex antibodies also reacted with Epogen, so when doctors took some of these patients back to the parent compound, it, too, was rendered inactive,” Dr. Leonardi said.
Biosimilars could increase psoriasis patients’ access to the drugs, which now cost between $12,000 and $35,000 annually, according to Dr. Leonardi. [pagebreak]
The solution, however, is not as simple as developing a like drug for less money. Creating biologic equivalents for psoriasis patients is not easy, and even small variations could result in big safety and efficacy issues. While most prescription drugs are made through chemical processes, biological products are usually made from human or animal materials.
“When trying to mimic these [psoriasis medications], you’re depending on random events to come out exactly the same,” said Kenneth B. Gordon, MD, professor of dermatology at Northwestern University Feinberg School of Medicine in Chicago. “It involves protein structure, post-translational modification, and various other processes that have a big impact on the structure of the proteins that are biologic medicines. And so the likelihood of being able to make something exactly like the biologic medicine, designed as a substitute, is very low. It’s almost impossible to make something identical.”
Dr. Leonardi feels similarly, and said that the drugs themselves are actually proteins grown inside living cells. Mimicking the amino acid sequence that makes up the drug, he said, is only part of the process.
“There are other things that happen, like the way the proteins are cross-linked, folded, and glycosylated. These are all steps that have more to do with the cells and the conditions in which these cells grow than with the actual primary sequence of the protein,” Dr. Leonardi said. “Part of the concern is that we’ll create cells that will encode for the drug but very little testing will be done on the finished product.” [pagebreak]
Regulations in the works
The FDA is in the process of regulating biosimilars in a way that aims to simplify the approval process, yet ensure safety and bioequivalence, according to JAAD commentary co-author Alan Menter, MD, chief of dermatology, Baylor University Medical Center, Dallas, and immediate past president of the IPC.
“It’s going to be more rigid than what we currently have for our generic drugs. The question with biologics is, can there be interchangeability based on similar structure, similar manufacturing processes, or do they have to undergo a rigid clinical trial to show the same effect as the biologic agents that are currently approved?” Dr. Menter said.
On Feb. 9, 2012, the FDA issued three draft guidance documents on biosimilar product development for which the government agency is seeking public comment.
The Patient Protection and Affordable Care Act, signed into law by President Obama March 23, 2010, amended the Public Health Service Act to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product, according to an FDA news release. “A biosimilar is a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency,” according to the FDA. [pagebreak]
Will access go up? Costs down?
It is extremely complex — and hence, expensive — to manufacture and produce biologic medications, according to Dr. Menter. Whether competitors can meet regulatory guidelines, maintain the plants necessary for manufacturing the drugs, and still make enough of a profit to call it a business is hard to predict, experts agree.
This is because most of the cost of biologic medications is in development and manufacturing, according to Dr. Menter.
“The structure of a U.S. biologic manufacturing plant is incredibly complex, with multiple floors, multiple divisions, the most scrupulous hygiene, and other tight controls,” Dr. Menter said. “Everyone has the opinion that the biosimilars are going to be approximately 10 to 20 percent less expensive. Obviously, we’d all like cheaper drugs, but we want to make sure that these drugs are manufactured correctly, completely equivalent, and safe.”
What’s next for biosimilars?
Biosimilars for psoriasis will have to gain FDA approval if they are to be sold legally in the U.S., according to Dr. Mark Lebwohl, MD, professor and chairman of the department of dermatology at Mount Sinai School of Medicine in New York. However, it could be years until patients have access to FDA-approved biosimilars for psoriasis, according to Dr. Leonardi.
Etanercept, the first psoriasis biologic expected to go off patent in October 2012, might not be off patent at all. Enbrel maker Amgen announced in November 2011 that it had been granted a new U.S. patent for Enbrel, which could protect the drug from biosimilar competition for another 17 years. Infliximab is the next of the five biologics now on the market for psoriasis that is expected to go off patent on Dec. 29, 2014. [pagebreak]
In the meantime, dermatologists are advised to warn patients — those who might try to get non-FDA-approved bioequivalents from other countries — of their potentially serious side effects. Additionally, at some point in the future when the biosimilars become available to U.S. patients, dermatologists should not only proceed with caution when prescribing them but also continue to gather data specific to psoriasis, according to Dr. Menter. Why? Because biologic registries in dermatology are only a few years old compared to those in rheumatology and gastroenterology.
“We can’t just build on other data, because psoriasis is a different disease with its own comorbidities. The more patients we have in our psoriasis registries the better,” Dr. Menter said.
Reality versus ideal
Dermatologists agree that having safe, FDA-approved biosimilars available would be the ideal outcome.
“At this point, there are approximately 100,000 psoriasis patients on biologics and the drugs have turned around their lives,” Dr. Lebwohl said. “So, it’s very important to make sure that the severe patients have access to biologics. There are still many severe patients who are not able to get them because they’re so expensive.”
Insurance companies often make prescribing biologics difficult, he added. Some demand that psoriasis patients fail multiple treatment modalities or exhibit high levels of severity of the disease before being prescribed biologics.
As to the reality of whether the generic medications will work as well as their original counterparts, Dr. Leonardi predicts a mixed bag of results. [pagebreak]
“I think it’s going to be a can of worms. I think we’re going to find that sometimes this strategy works out just fine. At other times it creates problems and takes other options off the table. It’s going to be very difficult to predict how this goes,” Dr. Leonardi said.
In the end, it’s not a question of whether or not biosimilars will exist. Dermatologists, such as Dr. Gordon, are sure that they will be a part of the future of dermatology treatment.
“The controversy is what level of testing will be required of companies that make biosimilars. If you look at generic medications in general, the level of testing required is at a much lower level than the original approval of the medication.” Dr. Gordon said.”
For dermatologists, time will provide more answers. Much of the courses of treatment and options available to them will be determined by how the FDA rules on biosimilars.
Relevant disclosure information
Dr. Menter has been principal investigator for phase 3 studies of adalimumab (Humira) and infliximab (Remicade). He has done research, lectured, and has consulting agreements with all the pharmaceutical companies that manufacture biologics currently approved for psoriasis as well as those under investigation. He does not, however, own stock in any of those companies. Like Dr. Menter, Dr. Leonardi has worked as an investigator or advisor for all the companies that make biologics for psoriasis. Dr. Lebwohl has been an investigator or consultant for all companies that make biologics for psoriasis.