After The Anti-TNFs, What’s Next In Autoimmune Disease?

With the threat of biosimilars looming closer, the leaders in autoimmune disease are scrambling to bring novel drugs to market and extend their dominance beyond the anti-TNF class. But toppling the anti-TNFs’ reign won’t be easy, especially if cheaper biosimilar copies reach the market.

The first biosimilar monoclonal antibodies are close to reaching the market and one of the primary targets for biosimilar makers are the three market-leading tumor necrosis factor inhibitors for autoimmune disease: Johnson & Johnson’s Remicade (infliximab), Amgen Inc.’s Enbrel (etanercept) and AbbVie Inc.’s Humira.

The brand leaders in the field are looking for ways to extend the life of their maturing portfolios, working to develop next-generation drugs that could topple the anti-TNFs’ reign in blockbuster therapeutic areas like rheumatoid arthritis, psoriasis and inflammatory bowel disease.

New treatments will have a daunting threshold to cross if they are to make the leap to successful commercial brands. They will have to demonstrate superior efficacy to the anti-TNFs with a safety profile that’s at least on par with the class if not better. Anti-TNFs have serious risks but the side effects are well understood by physicians after decades of experience with the drugs, and getting physicians to prescribe new drugs over the tried-and-tested won’t be simple.

The safety/efficacy hurdle alone is a high bar for new drugs to cross, but the market dynamics will be even more challenging once cheaper biosimilar versions of one or more of the leading biologics reach the market. The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) gave a green light to two biosimilars of Remicade in June, Celltrion Inc.’s Remsima and Hospira Inc.’s Inflectra, all but guaranteeing the launch of the first monoclonal antibody biosimilars in Europe (Also see "Hospira, Korea’s Celltrion Get EU Nod For First Monoclonal Antibody Biosimilar" - Pink Sheet, 28 Jun, 2013.).

And although there are still lots of uncertainties about the way the biosimilars market will unfold – from how quickly patients and physicians will be willing to adopt the new biologic treatments to how discounted their price will be – in today’s cost conscious health care environment, payers will push for the use of biosimilars, which will eventually erode brand share.

Novel Mechanisms Hold Promise

Drug makers like J&J, Amgen and AbbVie aren’t shying away from the challenge. How could they when the market is expected to grow so dramatically in the next five years, from about $35.3 billion in worldwide sales in 2012 for rheumatology, gastroenterology and dermatology to $51.8 billion in worldwide sales in 2017, according to data from EvaluatePharma.

The big three are studying new approaches to treating autoimmune disease, including new mechanisms and oral drugs, as they embrace strategies to maintain their position in a therapeutic area where they have struck gold. Humira generated $9.26 billion in 2012 and became the world’s top-selling drug after Lipitor went generic in 2011. Remicade generated $6.14 billion and Enbrel generated $4.24 billion in 2012.

“Novel mechanisms of action, while risky, are part of their strategy,” said Piet Wigerinck, the chief scientific officer at Galapagos NV, a drug discovery leader in autoimmune disease that has partnered several novel drugs with big pharmas, including J&J and AbbVie.

“During all of our discussions with companies with a big TNF franchise, it was clear that they wanted to take the risk associated with novel mechanisms of action,” he said. “That is part of their strategy, and they want to maximize the chance of finding better drugs that bring in high level of efficacy with the same level of safety, compared to the current therapies. That is what they see as the best way to extend their franchise.”

The threat of biosimilar competition appears most imminent for Remicade; it’s expected in Europe in the near-term and potentially in the U.S. in 2016, according to some industry observers, though J&J forecasts later biosimilar entry in the U.S. in 2018. Biosimilar versions of Humira could reach the market in 2017, when an important patent expires. Enbrel appears well protected. Many biosimilar makers who were developing copies of Enbrel in anticipation of a 2012 patent expiration abandoned the effort when Amgen revealed a critical new patent that extended the drug’s protection to 2028 in the U.S. (Also see "Amgen’s Stealth Enbrel Patent May Block Biosimilars; Scenario May Apply To Other Biologics" - Pink Sheet, 5 Dec, 2011.).

Despite broad use of anti-TNFs and their positive impact on patients with autoimmune diseases like arthritis, psoriasis and Crohn’s disease, drug makers say there is still plenty of opportunity for new mechanisms of action.

“We love the responses we get with the anti-TNFs, but we realize there are people who don’t respond. Even people who do respond by our clinical trial definition still haven’t gone into remission and still have some disability,” said J&J’s Dan Baker, VP-Immunology Therapeutic Area, Janssen R&D LLC. “We would like to think of new mechanisms and new approaches to that.”

Further out, the company’s ambition is to develop biomarkers that better direct the right patients to the right treatment and drugs that will intervene earlier in the course of the disease and even prevent disease.

“The basis of all of this takes a real effort to understand the disease and understand the science,” said Baker.

J&J has the broadest pipeline of drugs in development for autoimmune disease of the three current leaders, a tangible sign of its commitment to building an immunology business in autoimmune disease beyond its current brands, which in addition to Remicade include Stelara (ustekinumab) for psoriasis and Simponi (golimumab) for arthritis and ulcerative colitis.

Today’s Autoimmune Disease Leaders Tomorrow
A Look At The Mid- To Late-Stage Pipeline At AbbVie, Amgen And J&J
Drug Manufacturer	Compound	Mechanism of Action	Development Stage
AbbVie	BT-061 (partnered with Biotest Pharma)	Anti-CD4 antibody	Phase II for RA Phase II for psoriasis
	GPLG0634 (partnered with Galapagos)	JAK1 inhibitor	Phase II for RA
Amgen	Brodalumab (partnered with AstraZeneca)	IL-17 inhibitor	Phase III for psoriasis
	AMG181 (partnered with AstraZeneca	Alpah4/beta7 inhibitor	Phase II for ulcerative colitis and Crohn’s
Johnson & Johnson	Sirukumab (partnered with GlaxoSmithKline)	IL-6 inhibitor	Phase III for RA
	ASP015K (partnered with Astellas Pharma)	JAK1 inhibitor	Phase IIb for RA
	JNJ-38518168	Histamine-4 receptor antagonist	Phase IIb for RA Phase II for IBD
	JNJ-527	Undisclosed novel mechanism of action	Phase II for IBD
Source: Company pipeline filings and reports

The Oral Opportunity

But even J&J has realistic expectations for how challenging it will be for new drugs, even orals, to carve out a place in the treatment paradigm.

“In RA, I think it is pretty clear that the anti-TNFs are going to remain the first line of treatment when someone fails a [disease-modifying anti-rheumatic drug],” said Susan Dillon, global therapeutic area head, Immunology, Janssen R&D. Even orals, which have a valuable convenience benefit over injectable biologics, will not have an easy entry into the market, she predicted, because of the delicate safety/efficacy balance.

“I think we are still early days for really getting to the best orals with profiles that could actually supplant the TNFs in the RA space,” Dillon said.

“I think we are still early days for really getting to the best orals with profiles that could actually supplant the TNFs in the RA space,” J&J’s Susan Dillon said.

Pfizer Inc. launched the first targeted oral drug for RA, the janus kinase 3 inhibitor Xeljanz (tofacitinib), after it was approved by FDA in November 2012. But the drug was rejected by regulators in Europe because of safety concerns and Pfizer recently said the decision will delay the launch of the product by “several years” in Europe. Xeljanz generated $22 million in its second quarter on the market, not yet a stand-out launch, though it is still early days.

Xeljanz will face new competition before long. Several companies are developing their own JAK inhibitors. Eli Lilly & Co. and Incyte Corp. are developing baricitinib, a JAK1 and JAK2 inhibitor in Phase III trials for RA. J&J acquired rights to a JAK1 inhibitor from Astellas Pharma Inc. in 2012 that is being tested in Phase IIb. AbbVie is also partnered with Galapagos on a JAK1 inhibitor, GLPG0364, which Galapagos is studying in Phase II. Based on those results, AbbVie will decide whether or not to bring the drug into Phase III.

The hope of those developing JAK1 inhibitors is that by selectively targeting JAK1, their product will have an improved safety profile with equal or better efficacy to tofacitinib, which inhibits all four proteins in the JAK family, although it has the strongest effect on JAK3 .

“We don’t think there is any added value in inhibiting JAK3 over JAK1,” said Galapagos’ Wigerinck. “If we can inhibit JAK1 to a larger extent, we hope that we can push up the efficacy higher and have good safety as well.”

Despite the oral delivery advantage of JAK inhibitors, the market research firm Decision Resources forecasts that anti-TNFs will remain the first-line treatment for patients who fail a DMARD out to the end of their forecast period in 2021. The firm predicts branded anti-TNFs’ U.S. patient share will decline slightly from 17.6% in 2011 to 15.7% in 2021, with the decline attributed to oral entrants, including tofacitinib and Lilly’s baricitinib, as well as biosimilars.

“It is an interesting dynamic because you have the branded TNF alpha inhibitors, you have the biosimilars, and you have the oral agents, which have the possibility because of their convenience and assuming their prices are at a slight decrease at least to the biologic agents, to be used over a biologic,” said Madhuri Borde, senior director, immune/inflammatory therapeutic area at Decision Resources. “Everything is happening at a similar timeframe.”

If anti-TNFs remain the backbone of treatment in RA, it leaves a much smaller market of patients for drug makers to go after with new drugs, largely anti-TNF refractory patients or patients who don’t respond to anti-TNFs.

“Of patients that are eligible for biologics, somewhere around 15% of them who have tried a TNF will wind up on something else,” said J&J’s Dillon. “But that market, as more and more patients have been on the drugs for longer period of time, is going to evolve over the next five to seven years so that as many as half of the patients who are eligible for a biologic will have already failed an anti-TNF.”

Segmenting The Market By Disease

The story could play out differently in disease areas outside of RA, however. While the anti-TNFs have broad labels that extend across multiple diseases from RA to ulcerative colitis (Remicade is approved for eight indications, Humira is approved for seven indications), as the understanding of autoimmune disease advances, it is becoming clear that a one-size-fits-all approach may not be the best treatment. The market will become even more fragmented by disease in the future, in which case there may be some opportunities for new drugs to differentiate themselves from the anti-TNFs on efficacy.

“These different areas may evolve a little bit differently in terms of whether TNFs remain the first treatment for DMARD failures versus either another biologic mechanism or orals,” said J&J’s Dillon. Indeed, J&J has had success with Stelara, an interleukin-12/23 inhibitor, in psoriasis. The product has demonstrated superiority to Enbrel in head-to-head clinical trials. Stelara joined the blockbuster drug club in 2012 with sales of $1.03 billion. J&J launched the drug in 2009.

Building off the knowledge of Stelara, J&J is now studying a monoclonal antibody specific for IL-23, guselkumab, which the company believes will offer improved efficacy over Stelara on skin clearing. The company recently completed Phase II testing of guselkumab, and earlier in development is exploring a small molecule approach to targeting the IL-12/23 pathway.

But lots of other drug makers are looking to launch new biologics for psoriasis (Also see "Psoriasis Market Snapshot: An Area Drug Makers Are Itching To Get Into" - Pink Sheet, 23 Jul, 2012.). The market represents a significant opportunity alone. Sales of the anti-TNFs in psoriasis were $1.9 billion in 2011, according to Decision Resources, and are expected to grow to $2.4 billion by 2015.

The biggest change to the market in the near term will be the introduction of the first IL-17 blocker, which could be Novartis AG’s secukinumab, which completed Phase III testing and is poised for a near-term regulatory filing. In July, Novartis reported that secukinumab demonstrated superior efficacy to Enbrel in Phase III testing. Close on Novartis’ heels is Amgen/AstraZeneca PLC’s brodalumab and Lilly’s ixekizumab, both in Phase III. Brodalumab represents Amgen’s nearest-term opportunity in immunology to extend its portfolio beyond Enbrel.

The IL-17 blockers have demonstrated strong efficacy but concerns about safety, especially among safety-conscious dermatologists, are likely to relegate the drugs to later lines of treatment, at least initially. That could change over time if the safety profile of the drugs holds up in the real world setting.

Inflammatory bowel disease is another potential big opportunity that drug makers have their eye on.

“If you look to the ulcerative colitis market, the number of patients that still show a suppression of the disease after two years of treatment is more than 40%,” said Wigerinck. “I think there is a huge opportunity for compounds with novel mechanisms, whether they are oral or novel antibodies against novel targets. Any treatment that could suppress the disease longer in patients will take over the TNFs easily because these drugs are used due to a lack of better treatments, not for their high efficacy.”

Galapagos has a first-in-class drug candidate in inflammatory bowel disease, an oral small molecule that inhibits free fatty acid receptor 2 (FFA2), which reduces migration of neutrophils, a critical part of the inflammatory process. The company is planning to bring the drug through proof-of-concept independently and expects to report top-line results from a Phase II study in patients with ulcerative colitis early next year. If the data read out positively, the drug is not likely to remain unpartnered for long.

AbbVie has also taken interest in a drug that could work specifically for irritable bowel disease. AbbVie invested in startup Avaxia Biologics Inc. in June, joining the biotech’s $11.4 million Series B round and taking a seat on the board (Also see "AbbVie Joins Avaxia Board, Becomes An Early Investor In The Gut Therapy Biotech" - Pink Sheet, 7 Jun, 2013.). Avaxia’s lead drug AVX-470 is an oral anti-TNF but it is a gut-targeted therapeutic that works specifically in the gastrointestinal tract. Because it is absorbed minimally systemically, it could be safer than injectable anti-TNFs, though its efficacy is limited to gastrointestinal diseases. Avaxia is testing the product in a Phase Ib trial in ulcerative colitis and hopes to partner the drug early in development.

Anti-TNFs may dominate the market and biosimilars may be on the horizon, but more drug makers are flocking to autoimmune disease and no one seems to be running away. There is a big commercial opportunity at stake and patients stand to benefit from improved treatments. Whether new drugs will become blockbusters – let alone $9 billion brands – in the highly fragmented market seems doubtful, but today’s leaders seem confident they can strike gold twice.