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Finally, some key comments have come out straight from the horse's mouth -- Glaxosmithkline (NYSE:GSK) -- strengthening Amarin's (NASDAQ:AMRN) Vascepa's NCE prospects like never before. GlaxoSmithKline and Pronova (now a part of BASF (OTCQX:BASFY)), the two key players in the prescription grade Omega-3 fatty acid space, responded to the February 6, 2013 citizen petition filed by Crowell & Moring LLP.

The petition provided some recommendations for FDA to implement, one of which included listing EPA ethyl ester and DHA ethyl ester as active ingredients of Lovaza. Vascepa's NCE dreams would shatter if FDA is about to follow this recommendation, but that seems very unlikely as GSK/Pronova have opposed each and every request and recommendations made in the petition.

Let's have a look what the petition requested from FDA, and how GSK/Pronova has responded to it.

Requests/Arguments made Crowell & Moring LLP to FDA in the petition

GSK/Pronova's counter comments

Amend FDA's Adopted Strength for Lovaza (Omega-3-Acid Ethyl esters) Capsules, Including the Strength Listing in the Orange Book

GSK and Pronova oppose the requests made in the Citizen Petition.

the Commissioner should amend the strength adopted for Lovaza to "0.9GM" (or "900MG") (currently it is: 1-gram capsule of LOVAZA contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils)

a strength of (0.9GM) 900 mg is neither appropriate nor accurate for Lovaza, even if the strength were to be based solely on the omega-3-acid content.

factors such as excipients in an oral dosage form.... are not (should not be) part of the strength calculus

The Citizen Petition also contends that the "1GM" refers to the "overall weight of an individual capsule, including excipients."

Both contentions are mistaken.

The entire fish-oil based mixture in Lovaza-not just the ethyl esters of omega-3 fatty acids-constitutes the active ingredient.

As there is 1 gram of active drug substance in each Lovaza capsule, the strength of Lovaza is 1 gram. The clarifying language in the Orange Book stating that each gram of Lovaza "contains at least 900 mg of the ethyl esters of omega-3 fatty acids" provides important information about the characterized portion of Lovaza and is an indicator of the drug substance's identity.

The current strength listing gives undue prominence and inappropriate importance to the 1GM product weight/fill weight of the Lovaza Capsule -- a parameter which is driven by excipients and other factors presumably delineated in the Lovaza NDA that are not relevant to product strength. As a result, the current strength adopted by FDA does not plainly (and singularly) identify the amount of active ingredient per capsule.

... Vascepa (icosapent ethyl), whose active ingredient is the same as the more prominent of the two major omega-3-acid ethyl esters in Lovaza. For Vascepa, as reflected in the Orange Book, FDA adopted a strength of 1GM, which is the amount of active ingredient in an administration unit as identified in the drug labeling.

Lovaza's drug substance is not fully characterized. The mixture has been characterized such that 1 gram contains at least 900 mg of seven omega-3-acid ethyl esters.

... the active ingredient is not simply the seven omega-3-acid ethyl esters, but the entire mixture.

... when FDA made the current adoption of strength for Lovaza and listed it in the Orange Book, there might not have been sufficient data to determine whether formulation-specific factors impacted the safety and efficacy profile of new omega-3-acid ethyl esters product (Lovaza).

However, new preclinical, clinical, and bioavailability data before the Agency demonstrates that those formulation-related factors do not impact safety and effectiveness of at least one new omega-3-acid ethyl esters product that has been shown to have the same safety and efficacy profile in animals, in the target patient population, as well as in healthy volunteers in both the fed and the fasted state.

The eight pivotal clinical studies that established Lovaza's safety and effectiveness... were based on the entire mixture.

The studies were not based on capsules that contained only omega-3-acid ethyl esters, nor were they based on capsules that contained only EPA and DHA ethyl esters.

Thus, the entire composition of Lovaza's mixture-consisting of specific amounts of omega-3-acid ethyl esters, other polyunsaturated fatty acids, and other characterized and uncharacterized components-may be responsible for Lovaza's clinical effects.

Also, in concluding that Lovaza was entitled to five-year exclusivity as a new chemical entity, FDA determined that Lovaza is a single active ingredient product, comprised of a single, complex mixture.

Alternatively, the Commissioner could adopt a strength for Lovaza based upon the fixed amount of major omega-3-acid ethyl esters specified in the Lovaza reviews and labeling.

According to its currently-approved labeling, "at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils" "are predominantly a combination of ethyl esters of

  1. eicosapentaenoic acid (EPA - approximately 465 mg) and
  2. docosahexaenoic acid (DHA - approximately 375 mg)."

Adopting a strength of 840 mg would be consistent with the emphasis (reflected in the publicly-accessible NDA reviews) on the 840 mg mixture of the major omega-3-acid ethyl esters in Lovaza.

Commissioner could also choose "840MG" as FDA's adopted strength for Lovaza.

The Citizen Petition mistakenly presumes that the established name for Lovaza, "omega-3-acid ethyl esters," proves that the active ingredient in Lovaza is only the seven ethyl esters of omega-3 fatty acids.

NDA review process indicates that FDA chose "omega-3-acid ethyl esters" as a fallback name, for lack of any more fitting options.

In a November 1, 2004 facsimile to Lovaza's sponsor, FDA noted that the sponsor had requested that the established name for Lovaza be changed from "omega-3-acid ethyl esters" to a combination of ... two main components of Lovaza, EPA ethyl ester and DHA ethyl ester.

FDA rejected this approach, noting that the sponsor's proposed name did not correspond to the drug substance of Lovaza, as it "implies that there are no other components to the drug substance, when, in fact, there are."

... Orange Book... listing .... describes.... the overall weight of an individual capsule, including excipients.

the Citizen Petition's argument that Lovaza's strength improperly describes "the overall weight of an individual capsule, including excipients" is not correct.

Lovaza's strength is based on its active ingredient, the naturally-sourced mixture, and is not based on any "capsule properties," such as excipients or inactive ingredients.

The Citizen Petition's argument reflects a misunderstanding of the unique character of naturally derived products.

The comments by GSK/Pronova give me a feeling like they wanted to say, "hey look, all we know is that the whole mixture is the active ingredient. We don't really know if EPA ethyl ester is active."

GSK's comments may prove to be barriers to entry for some Wanna-be-Lovaza-Generics

In layman's terms, what GSK is arguing is:

  1. LOVAZA generics should contain 1gm of Fish Oil...
  2. ... out of the 1gm Fish oil, at least 900mg should be ethyl esters of omega-3-fatty acids.

And that's exactly what the current Orange Book (OB) description of LOVAZA conveys.

If FDA finds that they have made no mistake in listing the current description of Lovaza on OB since May 2011, and finds that the Citizen Petition lacks merit after weighing in GSK/Pronova comments, FDA would likely deny taking actions on the requests made by the petition. It may mean that any generic that is not able to get at least 900 mg of esters within 1gm of fish oil may not qualify as a LOVAZA generic.

GSK/Pronova comments support Amarin arguments

Amarin Corporation stated its arguments for AMR101 (now Vascepa) in a Letter to Shareholders back in 2012. Let's compare those with GSK/Pronova comments.

Complementary stances of Amarin and GSK over Vascepa's NCE status

Amarin's Arguments (made in January 2012) on why FDA should grant NCE marketing exclusivity to AMR101 (Vascepa)

GSK/Pronova's counter comments (made in August 2013) on a Citizen Petition

In the United States, we believe that there are strong arguments for AMR101 to be awarded FDA five-year new chemical entity (NCE) marketing exclusivity. ... Our optimism for NCE exclusivity is based on the following factors:

First, there is precedent at FDA for granting NCE status to a previously uncharacterized active moiety that was part of a previously approved product.

Lovaza's drug substance is not fully characterized.

Second, the FDA required Amarin to conduct non-clinical and clinical work consistent with the characterization of a new active moiety and approval of an NCE product.

The eight pivotal clinical studies that established Lovaza's safety and effectiveness...were based on the entire mixture.

The studies were not based on capsules that contained only omega-3-acid ethyl esters, nor were they based on capsules that contained only EPA and DHA ethyl esters.

Thus, the entire composition of Lovaza's mixture -- consisting of specific amounts of omega-3-acid ethyl esters, other polyunsaturated fatty acids, and other characterized and uncharacterized components -- may be responsible for Lovaza's clinical effects.

The only other omega-3 based product approved by the FDA is Lovaza™; however, we believe the active moiety in Lovaza and the active moiety in AMR101 are different, which we believe is reflected in the decision to establish different molecular family names for icosapent ethyl (AMR101) and omega-3 acid ethyl esters (Lovaza).

... FDA determined that Lovaza is a single active ingredient product, comprised of a single, complex mixture.

In a November 1, 2004 facsimile to Lovaza's sponsor, FDA noted that the sponsor had requested that the established name for Lovaza be changed from "omega-3-acid ethyl esters" to a combination of the International Nonproprietary Names ("INNs") for the two main components of Lovaza, EPA ethyl ester and DHA ethyl ester. FDA rejected this approach, noting that the sponsor's proposed name did not correspond to the drug substance of Lovaza, as it "implies that there are no other components to the drug substance, when, in fact, there are."

... and we believe the EPA in Lovaza was not required to be separately characterized as an active moiety in Lovaza.

Lovaza's drug substance is not fully characterized.

FDA determined that Lovaza is a single active ingredient product, comprised of a single, complex mixture.

Prior to GSK's comments, I was a believer who feared that GSK may challenge FDA if they grant NCE exclusivity to Amarin's Vascepa. But now I have a sigh of relief as it seems I was wrong.

Does NCE still Matter?

Joseph S. Zakrzewski, CEO of Amarin Corp., commented when asked about NCE during the Q4 2012 Earinings Call:

Yeah, I think probably on the NCE I think to simply put, it's a heck of a lot less important than it was a year ago. We were having discussions with people and people wanted to know when we were going to get the first patent. Now we're sitting on 18 with several others, even more broad than the ones we have now coming.

.. So.. as we continue those discussions with people it's really less and less about NCE than it's ever been. Don't get me wrong, but I love to have NCE in addition to all the patents and the trade secrets and everything else we have.

..I think people are getting more and more comfortable that it's about the patents and that's really going to drive where this goes ultimately.

The number of patents issued or allowed relevant to Vascepa in the United States has grown to 27, per the company's very recent press release. With such a gigantic number of patents and undisclosed trade secrets, NCE has become a "nice to have" than a "must have." Moreover, Vascepa is likely to get 3 years of added exclusivity based on its successful clinical trial data in ANCHOR population upon approval for ANCHOR, but, there is no alternative of NCE when it comes to blocking generic makers from filing an ANDA (Abbreviated New Drug Application) to FDA. NCE means delayed generic competition, and that matters.

Curtailing the Extended Overhang

The Crowell & Moring LLP petition might have significantly contributed to the overhang (state of no decision) over the NCE status of Vascepa as both decisions could overlap/contradict the other. Possibly, the petition has put the FDA into a situation from where it can't give a decision on NCE until it completely responds to the petition, for which they are bound to follow defined timelines (180 days from the date of receipt of the petition). If FDA goes with GSK/Pronova viewpoint, the wait for Vascepa NCE decision may end sooner than later.

Time will tell the real tale.

Source: GlaxoSmithKline Clearing The Clouds Over NCE Prospects Of Amarin's Vascepa

Additional disclosure: This article contains several assumptions. Readers are advised to do the relevant due diligence on their own prior to drawing any conclusions. Also it is assumed that readers are familiar with Amarin Corporation PLC and NCE issue regarding Vascepa.