For years, the prescription omega-3 waters have appeared calm. While other industries are reaping the benefits of the $44 billion global omega-3 finished product market, pharma has yet to fully jump in.
On the surface, pharma applications are limited. There are just four branded drugs approved by the U.S. Food and Drug Administration with omega-3 fatty acids as active ingredients, and only two of those drugs (Lovaza and Vascepa) are commercially available in the U.S. Until recently, all approvals were restricted to the same niche patient population — adults with severely high triglyceride levels.
Yet, within the pharma industry, the waters are starting to ripple. In late 2019, Amarin’s Vascepa approval was expanded, making it the first and only drug approved to reduce cardiovascular risk among patients with elevated triglyceride levels — and greatly widening the treatment population.
But the most intriguing part of pharma’s omega-3 story may be what is churning right beneath the surface.
The Global Organization for EPA and DHA Omega-3s (GOED), currently in the final stages of creating a massive searchable clinical study database, reports that there are more than 42,000 published studies on EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) — including more than 4,000 human clinical trials.
Adam Ismail, who has spent over 20 years working in the omega-3 space, and is now serving as chief strategy officer for KD Pharma Group, recently identified 88 drugs in pharma’s preclinical and clinical pipeline that use EPA, DHA or derivatives.
Pharma’s “deep and extensive omega-3 pipelines,” says Ismail, “reach far beyond the cardiovascular space.”
Among the pipeline treatments is an orphan drug being jointly developed by KD Biopharma and SLA Pharma, currently in phase 3 trials for a rare hereditary condition that leads to colorectal cancer. That same medicine, along with a handful of other omega-3 drugs, is also being explored as a COVID-19 treatment. Additional trials evaluating omega-3 drugs as treatments and preventatives for mental health and depression, gastrointestinal diseases, eye diseases and rare genetic disorders are underway.
As pharma continues to test the waters, the clinical and financial significance of omega-3 treatments is becoming too compelling to ignore.
Approved: 2004 Launched: 2005
Developed by: Pronova BioPharma
Rights: Marketed by GlaxoSmithKline
Capsules are a combination of ethyl esters of omega-3 fatty acids, principally EPA and DHA
Developed by: Omthera Pharmaceuticals
Rights: Omthera is a wholly-owned subsidiary of AstraZeneca
Capsules are a combination of principally EPA and DHA in free fatty acid form
Developed by: Trygg Pharma
Rights: Owned (and discontinued) by Osmotica Pharmaceuticals
Capsules are a combination of ethyl esters of omega-3 fatty acids, principally EPA and DHA
Approved: 2013/Expanded approval 2019
Developed by: Amarin Corp.
Rights: Marketed by Amarin
Capsules contain an ethyl ester of at least 96 percent EPA
How many fish in the sea?
Omega-3s are a family of polyunsaturated fats (commonly referred to as “fish oils”) that the human body needs but cannot manufacture on its own. Among these critical fatty acids are two sought-after acids — EPA and DHA — which can be found in a variety of sources, including fatty or oily fish, fish body or liver oils, marine crustaceans, marine microorganisms, or even genetically modified terrestrial plants.
According to GOED, suppliers produced 111,210 metric tons of EPA and DHA omega-3 ingredients in 2018. The pharma industry takes just a small percentage of these ingredients, with the majority going to dietary supplements. Aldo Bernasconi, vice president of data science for GOED, estimates that currently, pharma only buys about 2 percent of the ingredient volume, but because pharma utilizes very highly concentrated, often pricier fish oils, pharma’s spend makes up about 13 percent of the total ingredient value.
Of the four FDA-approved drugs, three contain a mixture of EPA and DHA — two use the combo in ethyl ester form and the third (Epanova) contains the mixture as free fatty acids to aid bioavailability. Amarin’s Vascepa is made up of one active ingredient: icosapent ethyl, which is a form of EPA.
While research strongly supports the body’s need for both DHA and EPA, EPA oils tend to be less common and increasingly sought after by industries, pharma included.
“One complication is that fish have more DHA than EPA, so if you are going to produce a high concentration EPA drug, then you need to start from fish oil particularly high in EPA, and that type of oil is limited,” explains Bernasconi.
Anchovies from Morocco and Peru tend to be high in EPA. But the composition of fish is dependent upon various factors. “Fish are complicated and composition of the oils in them changes with environmental conditions such as water temperature and diet,” says Bernasconi.
“Lately, fisheries have been producing a little bit less EPA than traditionally — we will see if that changes over time. But it is a natural resource so you are somewhat dependent on what happens in the oceans,” says Ismail.
Pharma will most likely have to look beyond its established sources of APIs in order to obtain omega-3s.
“You typically don’t see a traditional pharma API manufacturer getting into the omega-3 space very often, largely because the technology required is fairly specialized,” says Ismail.
KD Pharma, the largest manufacturer of omega-3 APIs for pharma in the world, has a deep portfolio that includes multiple state-of-the-art purification technologies, which allow for the production of high-quality, pure omega-3s with EPA concentrations as high as 99 percent.
While pharma’s participation in the omega-3 ingredient market will likely not cause a supply shortage, the demand for high EPA oils may shift the price of ingredients for other industries.
“I think that the oils that exist that are high in EPA are going to increasingly end up in the pharma market,” says Bernasconi. If the supply of these oils starts dwindling and ingredient manufacturers have to reach into other oils, it could change the price of the ingredients.
“This might also increase the price of high EPA oils for the dietary supplements industry, and potentially lead to changes in dietary supplement formulations,” says Bernasconi.
Catching the big fish
While the U.S. did not see its first omega-3 drug approval until 2004, prescription EPA has been marketed in Japan for over three decades. In 1990, Epadel, developed and marketed by Mochida Pharmaceutical and EPA supplier Nippon Suisan Kaisha, became the first prescription drug in the world to successfully extract high purity EPA from omega-3 fatty acid.
The drug is credited for opening a new field in the treatment for arteriosclerosis obliterans and hyperlipidemia (cardiovascular conditions) and was the leading drug in its class in Japan for 20 years. Epadel reached peak sales of $481 million in 2012, after which it faced government price cuts and generic competition.
In June 2018, Mochida announced a partnership with Amarin focused on the development and commercialization of EPA-based drug products in the U.S. and certain other territories.
The biggest fish in the U.S. sea is currently still the first out of the gate. Lovaza, a drug developed by Norway’s Pronova BioPharma, was launched in the U.S. as well as in major European markets (under the brand name Omacor) in 2005. In 2008, as the drug’s global sales reached $778 million, GlaxoSmithKline spent $1.65 billion to buy Reliant Pharmaceuticals, the company that was licensing the rights to Lovaza in the U.S. and Puerto Rico. Lovaza rose to blockbuster status in 2010, maintaining annual sales of approximately $1.1 billion until facing generic competition in 2014.
Investors had high hopes for Vascepa, the sole product from Dublin-based Amarin. Last year, analysts anticipating the FDA’s favorable decision on Vascepa’s label expansion were abuzz about a potential buyout of the small biopharma company. Big names in pharma were added to the possible suitor list, all chasing Amarin’s potentially game-changing omega-3 treatment.
This scenario, of course, is not unusual in pharma.
“Over the last few years, Big Pharma has shown high interest in smaller niche companies with novel promising therapies,” says Arda Ural, PhD, the Americas Industry Markets Leader for Health Sciences and Wellness at EY. “For example, smaller companies with their omega-3 products can be potential targets for Big Pharma companies for M&A deals and partnership/collaboration agreements.”
After a huge first-quarter revenue bump, Amarin hit a snag this April, losing a patent trial against two generic drugmakers. This ruling subsequently cleared the way for Hikma Pharma’s approval for a generic version of Vascepa in late May. Amarin has appealed the court decision, so it remains to be seen if any generic company takes the risk of launching a generic version during the patent litigation appeal process.
Despite some uncertainly, market experts at Evaluate Pharma estimate that worldwide sales of omega-3 drugs will reach close to $1.4 billion in 2021 — a 40-50 percent increase over 2019.
Sea of potential
The year kicked off with news from two promising late-stage omega-3 trials — unfortunately both outcomes were less than ideal.
Krill-oil derived combination of EPA and DHA
Company: Acasti Pharma | Québec, Canada
Target indication: Severe hypertriglyceridemia
Status: Acasti submitted its briefing package, which included results from a double-blind, placebo-controlled, 26-week, two-trial phase 3 clinical program, to the FDA on April 29, 2020. Acasti is currently awaiting comments, and expects a formal response from the FDA by June 30, 2020.
Small molecule drug containing a combination of salicylic acid and DHA
Company: Catabasis Pharmaceuticals | Boston, MA
Target indication: Duchenne muscular dystrophy
Status: Currently being studied in a one-year, randomized, double-blind, placebo-controlled phase 3 trial, as well as in an open-label extension study. Top-line results from the phase 3 trial are expected in late 2020 and the trial is anticipated to support an NDA filing in 2021. Catabasis is also planning a clinical trial to study edasalonexent in the non-ambulatory Duchenne population.
Highly purified EPA in gastro-resistant capsule
Company: KD Pharma, SLA Pharma | Bioggio, Switzerland; Liestal, Switzerland
Target indication: Familial adenomatous polyposis; secondary indications for ulcerative colitis and sporadic polyps
Status: Successfully completed phase 1 and phase 2 studies and in the process of conducting phase 3 trials in the EU for the orphan drug indicated for the treatment of FAP. A phase 2 trial testing Alfa in ulcerative colitis and preclinical testing in sporadic polyps is underway. The drug, under the name EPAspire, is also entering trials to mitigate the severity of COVID-19.
Highly potent combination that includes a sizable dose of EPA, low amounts of DHA and the addition of DPA, delivered via gelatin capsule
Company: Matinas Biopharma | Bedminster, NJ
Target indication: Severe hypertriglyceridemia
Status: Currently in phase 2 clinical development, with one completed study evaluating the drug’s bioavailability and potency against Vascepa. In March, the company initiated a pharmacodynamic study of MAT9001 against Vascepa in patients with elevated triglycerides. Topline results expected late 2020. Pending discussions with the FDA, the company plans to conduct a placebo-controlled phase 3 study assessing the efficacy of MAT9001 in patients with severe hypertriglyceridemia.
AstraZeneca, which had acquired Epanova along with developer Omthera Pharmaceuticals in 2013 in a $443-million deal, made the decision in January to shutter a trial after disappointing preliminary data.
Hoping to reach a broader patient population, the drugmaker had launched a large, five-year phase 3 outcomes trial shortly after Epanova won FDA approval in 2014 for patients with severe hypertriglyceridemia. But then preliminary data showed Epanova had a low likelihood of benefiting patients with an increased risk of cardiovascular disease, so AstraZeneca pulled the plug.
The second trial fail came from Canadian drugmaker Acasti Pharma. In January, Acasti announced that the phase 3 trial testing its drug hopeful CaPre, a krill-oil derived combination of EPA and DHA for the treatment of severe hypertriglyceridemia, had missed its primary endpoint.
But all may not be lost for CaPre. The company believes that EPA and DHA are more efficiently transported by phospholipids sourced from krill oil than the EPA and DHA contained in fish oil transported by ethyl esters in other prescription omega-3 drugs. Undeterred by the trial results that Acasti attributed to a highly unusual placebo effect, the company submitted a briefing package to the FDA for review, and are now awaiting a formal response on CaPre.
Current trials are not limited to the cardiovascular space, either.
Boston-based Catabasis is studying a small molecule drug that contains two active substances, salicylic acid and DHA, as a potential novel treatment for Duchenne muscular dystrophy (DMD). The FDA has granted the drug, called Edasalonexent, Orphan Drug, Fast Track and Rare Pediatric Disease designations for the treatment of DMD. Results from the phase 3 study are expected by the end of this year, and Catabasis hopes to file its New Drug Application (NDA) in 2021.
KD Biopharma and SLA Pharma’s highly purified EPA formulation, called Alfa, is in a phase 3 trial in the EU for the treatment of familial adenomatous polyposis (FAP). Currently, there are not safe treatments for FAP and a partial or full removal of the colon is considered the “gold standard” of care. Alfa has been granted Orphan Drug designation in the EU and U.S. Early stage trials are also testing Alfa in patients with ulcerative colitis and sporadic polyps.
The varied and wide exploration of omega-3 treatments is not surprising, according to Bernasconi. “Omega-3s have, among other biological functions, anti-inflammatory properties and inflammation is in some way connected to most common chronic diseases,” he says.
Omega-3 fatty acids can reduce the production of molecules and substances linked to inflammation, such as inflammatory cytokines. It’s for this reason that numerous omega-3 drugs are being explored as possible COVID-19 treatments.
Data from the late-stage KD Pharma/SLA Pharma FAP trial suggests the drug candidate could suppress the expression of inflammatory cytokines believed to contribute to the progression of more serious COVID-19 symptoms. The Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK has already given the trial a green light.
A Canadian non-profit physician organization, the Canadian Medical and Surgical Knowledge Translation Research Group, is sponsoring a trial to test the potential anti-inflammatory effects on lung tissue as well as the potential antiviral/antimicrobial effects that Amarin’s Vascepa could offer COVID-19 patients. Again, the goal is mitigating severity in COVID-19 infection.
Beyond the seas
In the U.S., commercialized omega-3 drugs are still part of an exclusive club — but all signs point to an expanding membership.
There are large markets for omega-3 products around the world — so products approved in the U.S. have opportunity beyond FDA borders. “Approval in China, for example, will have a big impact on demand for omega-3 pharmaceuticals,” says Ismail.
There are currently no prescription omega-3 products in China. The country’s large population and high prevalence rates of hypertriglyceridemia suggest that China could greatly benefit from the introduction of omega-3 pharmaceuticals. Amarin recognized this need in 2015, forming a $169 million partnership with Eddingpharm to develop and commercialize Vascepa in China; trials are currently underway.
Researchers are also exploring other omega-3s, such as DPA (docosapentaenoic acid) and ETA (eicosatetraenoic acid), as well as fatty acids beyond the omega-3 space.
“Omega-3 pharmaceuticals have triggered new research in a lot of other fatty acid areas,” says Ismail.
For example, omega-6 fatty acids, which typically come from vegetable oils and seeds, appear to help keep good and bad cholesterol in a favorable balance.
“There is certainly more to come,” says Ismail. “Not only is there growing interest in the space, the landscape is constantly changing.”