Rita Baron-Faust, MPH, CHES

Advancing Wellness on Many Fronts


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THE AUTOIMMUNE CONNECTION BLOG

Biosimilars -- Bargain or Boondoggle?

October 31, 2016

Tags: Biosimilar drugs, rheumatoid arthritis, Crohn's disease, psoriasis, Humira, Etanercept, Remicade, drug prices, Amjevita, Erelzi, Inflectra

IWe’ve been hearing a lot lately about new “biosimilar” drugs being approved for rheumatoid arthritis (RA) and other autoimmune diseases. While these drugs promise to be a potentially less expensive alternative to older biologics like Humira, don’t confuse the term “biosimilar” with “generic.” And don't think they'll be a bargain.

Biosimilar medications are not cheaper “generic” versions of existing biologic drugs.

Here’s what you need to know:

The three new anti-rheumatic biosims approved by the FDA -- Amjevita, Inflectra,and Erelzi – copycats of adalimumab (Humira), Remicade (Infliximab), and etanercept (Enbrel) – all target the same inflammatory molecule tumor necrosis factor-alpha (TNF-α) and are approved to treat the same autoimmune and arthritic conditions as the original biologics:

Amjevita (adalimumab-atto): a subcutaneous injection approved for moderate to severe rheumatoid arthritis (RA), Crohn’s disease and ulcerative colitis, as well as psoriatic arthritis (PsA), ankylosing spondylitis (AS), and moderate to severe plaque psoriasis.1

Erelzi (etanercept-szzs): an intravenous injection approved for treating polyarticular juvenile idiopathic arthritis (JIA) and RA, as well as PsA, AS, and moderate to severe plaque psoriasis.2

Inflectra (infliximab-dyyb): intravenous infusion approved for adults and children two years old and over with moderate to severe Crohn’s disease or ulcerative colitis for whom conventional therapies were not effective, for AS, PsA, chronic severe plaque psoriasis, and for treating RA in combination with methotrexate.3

Because these drugs are “similar” but not exact copies of older TNF-α inhibitors, your pharmacy can’t just swap them without consulting your doctor as they can with other brand-name prescription drugs and their generic versions.

Biosimilars vs. Interchangables vs. Generics

The FDA approves biological drugs in two categories: “biosimilar” and “interchangeable.”

To be approved as a biosimilar a drug must “highly similar” to an already FDA-approved biological drug (“reference drug”) and have “no clinically meaningful differences” in purity, potency, safety and effectiveness.4

A biosimilar must also have the same “mechanism of action,” route of administration, dosage form, and strength as the reference drug. They can only be prescribed for the same indications and conditions of use as the original drug.4

To be FDA-approved as an interchangeable biological, the drug must also “produce the same clinical result as the reference product in any given patient” and pose no greater risk in terms of safety and effectiveness if alternated or switched with the original.4 This is important, because many patients with RA, Crohn’s disease, and other autoimmune conditions are switched from one biologic to another if the first drug produces an inadequate response.

Generic drugs must have exactly the same active chemical components, dosage form, and route of administration as the brand-name, and produce the same effects. In pharma-speak, they’re “bioequivalent.”

Because biological drugs are very complex, it’s simply not possible to make exact copies of a drug like Remicade to produce a generic. According to the FDA, biologics are “large molecule” drugs, lab-produced proteins derived from living sources including humans, microorganisms, and yeast. In contrast, conventional prescription drugs are considered “small molecules” and compounds made from chemical formulas.4

Manufacturing a biologic medication is also more complicated. The process involves gene splicing and other techniques to produce a drug engineered to home in on and disable a specific protein that causes inflammation in the body, in this case TNF-α.

Amjevita, Erelzi and Inflectra are approved as biosimilars and not as “interchangeables.” They must be specifically prescribed by name and can’t be substituted for the original drug without permission from your rheumatologist.

Prescribing information for two of the new biosim drugs doesn’t indicate whether they are interchangeable or not.1,2 For Inflectra, information on switching medications cautions only that “Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.”3

The American College of Rheumatology (ACR) is calling on the FDA to specify on drug labels whether or not a biological has official interchangeable status -- and set up rules to protect patients, including guidelines for substituting medications.

“Substituting non-interchangeable biosimilars, especially without notifying the prescribing provider, poses uncertain safety risks to rheumatology patients due to the complexity of these drugs and the possibility of patients being forced to switch,” warned Angus Worthing, MD, incoming chair of the ACR’s Government Affairs Committee.5

Positive Trials Data and Price Points

All three drugs passed muster with the FDA after years of positive clinical trials among thousands of patients.

A systematic review conducted by researchers at Johns Hopkins University and Brigham and Women’s Hospital in Boston, evaluated 19 studies (including 13 clinical trials) of biosimilars to Remicade and Humira in patients with rheumatoid arthritis and inflammatory bowel disease. Phase 3 clinical trials suggest the biosims and their reference drugs produced similar clinical responses. The authors also note that four studies of patients switched from reference drugs to biosimilars suggested similar efficacy and safety outcomes.6

The analysis, published online August 2nd in the Annals of Internal Medicine, concluded that, so far, these biosim TNF blockers and their brand-name “reference drugs” do appear to be interchangeable.6

A clinical trial of an etanercept copycat, marketed in Europe asBenepali (etanercept SB4), came to the same conclusion. That 52-week study found that the drug could be safely switched in patients with moderate to severe RA. An open label extension trial lasting almost two years suggests patients could safely and effectively switch from reference etanercept to etanercept (SB4).7

While Inflectra is expected to come on the market shortly, patent disputes, especially over Humira, may delay Amjevita and Erelzi for at least five years.

Meanwhile, other questions remain to be answered.

For one thing, the three biosimilars haven’t been tested in every disease for which their reference drugs are approved. In the case of Amjevita, clinical trial results in RA and plaque psoriasis were reportedly extrapolated so the drug could be approved for all the conditions for which Humira is currently indicated.8 While experts are optimistic, there’s no way to know how these biosims will actually perform in a variety of real-world autoimmune patients outside the controlled confines of clinical trials.9

In light of that, the ACR’s Dr. Worthing called on the FDA at a public hearing October 20th, to set up a post-marketing surveillance program to watch for any adverse events related to non-interchangeable substitutions.5

Then there’s the issue of drug pricing. While industry experts expect the biosims to be priced just below the original drugs,10 it’s unclear if autoimmune patients will benefit. These days, even generic drugs can end up costing as much -- or even more -- than their brand-name equivalents.

According to a May report in the “pharmaceutical companies have been raising prices on biotech drugs about to lose patent protection to squeeze out more revenue before competition arrives… And makers of the knockoffs are setting their prices just below those marked-up ones.”10

In the case of Humira, whose patent expires December 31, WSJ.com says maker AbbVie, Inc., increased the drug’s list price eight times in the past three years -- by a total of 73% -- to $49,362 for one year’s treatment.10

So what will Amjevita cost when it’s finally launched? WSJ.com quotes an AbbVie spokesman as saying the company “prices its medicines based on the value that those medicines bring to patients and the competitive environment.”

Judging from the current pharmaceutical marketplace, that often means whatever the market will bear.

References

1 FDA approves Amjevita, a biosimilar to Humira. FDA News Announcement, September 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm.

2 FDA approves Erelzi, a biosimilar to Enbrel, FDA News Announcement, August 20, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm

3 FDA approves Inflectra, a biosimilar to Remicade. FDA News Announcement, April 5, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm

4 FDA, Information for Consumers (Biosimilars). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm

5 ACR Calls for Clearer FDA Guidelines and Increased Congressional Funding to Ensure Safe and Effective Adoption of Biosimilars in the U.S. American College of Rheumatology News Release, October 20, 2016.

6 Chingcuanco F, Segal JB, Kim SC, et al . Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic Review. Ann Intern Med. 2016;165(8):565-574. Published online 2 August 2016 doi:10.7326/M160428.

7 Burness CB and Duggan ST, Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases. BioDrugs. 2016; 30(4):371-378. doi:10.1007/s40259-016-0188-z.

8 Clarke T. “FDA panel backs Amgen copy of AbbVie arthritis drug Humira.” Reuters Health News, July 12, 2016. http://www.reuters.com/article/us-amgen-humira-fda-idUSKCN0ZS2NC Accessed August 20, 2016.

9 Lupkin, S, “Study Bodes Well For Biosimilars, But Highlights Need For More Research.” Kaiser Health News, August 1, 2016. http://khn.org/news/study-bodes-well-for-biosimilars-but-highlights-need-for-more/ Retrieved August 20, 2016.

10 Rockcoff JD. Knockoffs of Biotech Drugs Bring Paltry Savings. Wall Street Journal. May 5, 2016. http://www.wsj.com/articles/knockoffsofbiotechdrugsbringpaltrysavings1462458209
Retrieved August 20, 2016.




Can What You Eat Help Fight Autoimmune Disease?

July 25, 2016

Tags: Anti-inflammatory foods, omega 3 fats, gluten, green tea, autoimmune diet, rheumatoid arthritis, lupus, Sjögren’s Syndrome

One of the most frequent questions I’m asked at autoimmune patient forums is about diet, anti-inflammatory foods, and autoimmunity.

There’s a lot of popular pseudo-science out there claiming that the right diet can “cure” autoimmune disease. Much of the “evidence” I’m asked about is anecdotal, largely based on reports of how patients were helped – or not – by eating -- or not eating -- certain foods (notably gluten). It’s difficult to argue with success stories and equally difficult to prove real cause and effect.

However, there’s plenty of solid scientific evidence to support the idea of an anti-inflammatory diet.

Much of what we know about the relationship between diet and inflammation comes from studies about the effects of the Mediterranean diet (and its components) in reducing inflammatory markers in cardiovascular disease (CVD)1 – a well-established risk in autoimmune diseases including rheumatoid arthritis (RA), lupus, and inflammatory bowel disease.

The Mediterranean diet encompasses many anti-inflammatory foods, notably omega-3 fatty acids found in olive and other oils, cold-water fatty fish (like salmon, mackerel, and sardines), nuts, and flax seeds. Olives and olive oil also contain compounds that act similarly to non-steroidal anti-inflammatory drugs (NSAIDs).2 Additionally, the diet includes lots of fresh fruits and vegetables rich in anti-inflammatory plant chemicals.

The diet has been shown to lower inflammatory markers in blood tied to both CVD and autoimmune diseases, including C-reactive protein (CRP), interleukins,and tumor-necrosis factor alpha (TNF-α).1 Studies also show that it helps reduce pain, joint swelling, and other symptoms of RA and other autoimmune diseases – and has beneficial effects on the immune system itself (such as moderating T-cell activity).3

It’s been suggested for years that our “Western” diet high in saturated fats and red meat may not only play a role in CVD but also in autoimmune diseases.4 Indeed, in one study, RA patients assigned to a Mediterranean diet showed a reduction in inflammatory activity and an increase in physical function compared to those assigned to a “Western” diet. 5

THE BIG FOUR INFLAMMATION FIGHTERS

•Fatty Fish & Omega 3's

Of all inflammation fighting foods in the Mediterranean diet, we know the most about fatty fish and fish oil, which contain the omega polyunsaturated fats (PUFAS) eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA).

As far back as 1991, researchers suggested that the omega-3 fats in fish may help reduce disease severity in lupus.6 More recently we’ve learned that omega 3’s may help protect against RA. A prospective study of more than 32,000 older Swedish women in 2013 found that eating one or more servings of fatty fish a week was associated with a 29% lower risk of developing RA and long-term intake of high-dose fish oil decreased the risk of RA by 52%).7

A recent British review reported that eating more fish high in omega-3s modestly reduced joint swelling, pain and morning stiffness in RA, leading to less use of NSAIDs.8 A randomized, controlled trial in people with early RA found that around 40% of those given high-dose fish oil to take with their conventional disease modifying anti-rheumatic drugs DMARDs)were in remission after a year.9

However, fairly high amounts of fish oil are needed to achieve an effect (about 3 grams of EPA and DHA in a concentrated fish oil supplement). Fish oil is also an anticoagulant and doesn’t agree with everyone.10 So consult your doctor before adding it to your diet.

Other types of omega-3 fats can be are found in olives, flax seeds, pumpkin seeds and walnuts.

•Olives & Olive Oil

Certain anti-inflammatory properties in olives and olive oil may be a big reason why the Mediterranean diet helps in autoimmune diseases.

Olives and virgin olive oil have been found to contain a polyphenol compound called oleocanthal, which blocks production of the pro-inflammatory enzymes and cyclooxygenase-2 (COX-1 and COX-2) much as NSAIDs do. In fact, research shows oleocanthal has properties similar to ibuprofen.11

The fruit of the olive tree, Olea europaea, also contains oleic acid, a monounsaturated fatty acid which also helps modulate the immune system.12

Olive oil, as well as nuts, sunflower and flax seeds, and avocados are also packed with vitamin E, which helps prevent cell damage in joints and may have anti-inflammatory properties as well.

•Fresh Fruits & Vegetables

The Mediterranean-style diet includes plenty of fresh fruits, vegetables, and beans rich in fiber plus inflammation-fighting plant chemicals (phytochemicals) and antioxidants such as vitamin A, beta carotene, vitamin E, zinc and selenium.

In particular, raspberries and cherries are packed with antioxidants called anthocyanins and vegetables containing flavonoids like onions and garlic are thought to regulate expression of key inflammatory enzymes.

•Green Tea

I meet many autoimmune patients who swear by green tea, which is a good source of antioxidant polyphenols.

Its active ingredient, epigallocatechin-3-gallate (EGCG), has been shown to improve symptoms and reduce the pathology in some animal models of autoimmune diseases.

The effects of EGCG help suppress production of autoreactive T cells and also pro-inflammatory cytokines (such as interleukin-1).13 A recent study showed that EGCG improved rheumatoid arthritis in mice, while another showed effects in lab rats. But there’s an unfortunate lack of research in humans for this healthy beverage.

GLUTEN: GUILTY AS CHARGED?

There are a number of experts who claim that any anti-inflammatory diet must exclude gluten.

There’s no question that gluten, a naturally-occurring protein in wheat, barley and rye, causes celiac disease in genetically susceptible individuals. Gluten triggers an autoimmune inflammatory reaction that damages the small finger-like projections in the small intestine (villi) which absorb many nutrients.

The only treatment for celiac disease is eliminating gluten. It can stop the symptoms of chronic diarrhea, stomach pain, bloating, and gas and help repair damage to the villi. Intestinal healing can take three to six months in children and several years in adults, according to the National Institutes of Health.14

Some people are allergic to wheat or have non-celiac gluten sensitivity and experience severe GI symptoms. While neither problem damages the small intestine, for these people going gluten-free also makes sense.

What’s not so clear is gluten’s effects elsewhere in the body (like the brain) and whether going gluten-free helps other autoimmune diseases, prevents or even “cures” them.

“There is no evidence that a gluten free diet helps autoimmune diseases such as Hashimoto's thyroiditis. Celiac disease is the one autoimmune disease that is appropriate for the gluten-free diet,” Peter H.R. Green, MD, director of the Celiac Disease Center at Columbia University told me in an email. “It is as though celiac disease has given the gluten-free a medical legitimacy that other diet trends lack.”

As a result of what he terms a “media epidemic,” “almost a third of all American and UK consumers are trying to avoid gluten,” many of them unnecessarily, he writes in a new book, “Gluten Exposed,” (2016, William Morrow, NY).15

VEGETARIAN AND VEGAN DIETS

Any elimination diet can have adverse effects, Dr. Green adds, cutting out crucial nutrients such as fiber and essential vitamins and minerals.

The Arthritis Foundation, the Sjögren’s Syndrome Foundation, and other organizations, report that studies since the 1990s have found vegetarian diets to be beneficial for some autoimmune patients. However, you need to get plenty of plant protein from legumes and beans, among other things.

A vegan diet -- which excludes meat, fish, dairy or other animal products -- may also be helpful, possibly because of the types of polyunsaturated fatty acids included in the diet, say British arthritis researchers.10

However, if you go vegan make sure you get vital nutrients you need, especially calcium, vitamin B12, vitamin D, zinc, and selenium.

References


1 Giugliano D, Ceriello A, and Esposito K, The Effects of Diet on Inflammation. Journal of the American College of Cardiology. 2006;48(4):677–85. doi:10.1016/j.jacc.2006.03.052.

2 Rahmani AH, Abutti AS, and Ali SM. Therapeutics role of olive fruits/oil in the prevention of diseases via modulation of anti-oxidant, anti-tumour and genetic activity. Int J Clin Exp Med. 2014. 7(4 ):799-808. PMCID: PMC4057827. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057827/ Accessed July 20, 2016.

3 Shepshelovich D and Shoenfeld Y.Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity. Lupus. 2006. 15(3):183-190. doi: 10.1191/0961203306lu2274rr s

4 Manzel A, Muller DN, Hafler DA et al., Role of “Western Diet” in Inflammatory Autoimmune Diseases. Curr Allergy Asthma Rep. 2014;14:404. DOI 10.1007/s11882-013-0404-6.

5 Sköldstam L, Hagfors L, Johansson G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:208–214.

6 Walton AJ, Snaith ML, Locniskar M, et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis. 1991; 50:463–466.

7 Di Giuseppe D, Wallin A, Bottai M, et al., Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: a prospective cohort study of women. Ann Rheum Dis. 2014 Nov;73(11):1949-53. doi: 10.1136/annrheumdis-2013-203338.

8 Miles EA, Calder PC, Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2012 Jun;107 Suppl 2:S171-84. doi: 10.1017/S0007114512001560.

9 Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis. 2015. 74:89-95 doi:10.1136/annrheumdis-2013-204145.

10 Arthritis Research UK, Diet and Supplements. http://www.arthritisresearchuk.org/arthritis-information/complementary-and-alternative-medicines/complementary-therapies/diet-and-supplements.aspx#sthash.g3ajjiyB.dpuf Accessed July 19, 2016.

11 Lucas L, Russell A, Keast R. Molecular mechanisms of inflammation. Anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal. Curr Pharm Design. 2011;17(8):754–68. DOI: 10.2174/138161211795428911. http://www.ncbi.nlm.nih.gov/pubmed/21443487 Accessed July 19, 2016.

12 Sales-Campos H, Souza PR, Peghini BC, et al., An Overview of the Modulatory Effects of Oleic Acid in Health and Disease. Mini Reviews in Medicinal Chemistry. 2013;13(2):201-210. DOI: 10.2174/13895575113130220003.

13 Wu D, Wang J, Pae M, Meydani SN. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol Aspects Med. 2012 Feb;33(1):107-18. doi: 10.1016/j.mam.2011.10.001. Epub 2011 Oct 14. http://www.ncbi.nlm.nih.gov/pubmed/22020144. Accessed July 19, 2016.

14 Treatment for Celiac disease. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/celiac-disease/Pages/treatment.aspx Accessed July 19, 2016.

15 Green PR, Jones R. “Gluten Exposed: The Science Behind the Hype and How to Navigate A Healthy, Symptom-Free Life,” (2016, William Morrow, NY).

16 The Arthritis Foundation: Eat Right for Your Type of Arthritis. http://www.arthritis.org/living-with-arthritis/arthritis-diet/anti-inflammatory/eat-to-beat-inflammation.php Accessed July 19, 2016