TalShu
19 hours ago
Post# of 426409 Go
The Amarin-Mochida Collaboration
1. Seen from Amarin’s viewpoint:
a. Amarin’s 10-K 2018 states:
“In June 2018, we entered into a collaboration with Mochida Pharmaceutical Co., Ltd., or Mochida, related to development and potential subsequent commercialization of drug products and indications based on the active pharmaceutical ingredient in Vascepa, the omega-3 acid, EPA (eicosapentaenoic acid). The potential new product and indication opportunities contemplated under this agreement are currently in early stages of development.”
b. From 2019 till 2023 all Amarin’s 10-K have reported the following INVARIABLE text:
“In June 2018, we entered into a multi-faceted collaboration with Mochida Pharmaceutical Co., Ltd., or Mochida, related to the development and commercialization of drug products and indications based on the active pharmaceutical ingredient in Vascepa, the omega-3 acid, EPA. Among other terms in the agreement, we obtained an exclusive license to certain Mochida intellectual property to advance our interests in the United States and certain other territories. In addition, the parties will collaborate to research and develop new products and indications based on EPA for our commercialization in the United States and certain other territories. The potential new product and indication opportunities contemplated under this agreement are currently in early stages of development. Upon closing of the collaboration agreement, we made a non-refundable, non-creditable upfront payment of approximately $2.7 million. In addition, the agreement provides for milestone payments from us upon the achievement of certain product development milestones and royalties on net sales of future products arising from the collaboration, if any.”
c. Nota Bene: Amarin 10-K 2019 also confirmed at the end of the above statement: “In January 2020, we achieved certain milestones under the agreement, resulting in payment of $1.0 million to Mochida.’
2. Seen from Mochida’s viewpoint:
a. Mochida Annual Review 2018 stated:
“In June 2018, Mochida also entered an agreement with Amarin Corporation Plc Group to develop and
commercialize high-purity EPA products in the US and certain other countries under Mochida’s intellectual properties, including new EPA formulation.”
b. Mochida’s Annual Review 2019 affirmed:
“Mochida also entered into an agreement with Amarin Corporation Plc for the development and commercialization of EPA-based drug products in the United States and certain other territories by Amarin Corporation Plc.”
c. Nota Bene: Mochida’s 2019 wording replaced:
- “high-purity EPA products” by “EPA-based drug products” and,
- “under Mochida’s intellectual properties, including new EPA formulation” by “certain other territories by Amarin Corporation Plc.”
d. Mochida Annual review 2020 specified:
“Mochida also entered into an agreement with Amarin Corporation Plc for the development and commercialization of high-purity EPA formulations in the United States and certain other territories by Amarin Corporation Plc.”
It also listed Amarin as part of its “alliance partner” group.
e. Nota Bene: Mochida went back to using “high-purity EPA formulations” in lieu of “EPA-based drug products” but continued to ignore “under Mochida’s intellectual properties, including new EPA formulation.”
f. Strangely, the Mochida Integrated Report for 2021, 2022, and 2023 NO LONGER MENTIONS Amarin in any way.
3. In summary:
a. It is clear that Mochida had had second thoughts as early as 2019 regarding Amarin’s ability to fulfill its part of the 2018 Agreement “to develop and commercialize high-purity EPA products in the US and certain other countries under Mochida’s intellectual properties, including new EPA formulation.”
b. Mochida has been concerned by Amarin’s inability to promote Vascepa in the U.S. and avoid the erosion of its market share in the face of generics. Cutting off its nascent advertising spending, completely eliminating its sales force, and offering rebates to maintain 75% of the market at the expense of margins only corroborate this assessment. Moreover, declarations by Karim Mikhaïl and Per Wold Olsen that the U.S. market is lost could hardly have reassured the Japanese partner. To the contrary, these will back up future attempts by Mochida to have the 2018 Agreement declared legally void and nil.
c. What concerns Mochida most is the reference to the terms “intellectual property” which were erased in its Integrated reports for 2019 and 2020. Worse, Mochida no longer mentions a word about Amarin altogether since 2021. Gone are the short days when it was looked at as a collaborator and ally.
d. In this perspective, Mochida reasserted its attachment to and defense of its “intellectual property” rights by applying for U.S. patent protection for its MND-2119 (Epadel EM) product on July 17, 2020. The latter was granted on February 27, 2024.
e. Amarin, for its part, insists yearly on stating: “Among other terms in the agreement, we obtained an exclusive license to certain Mochida intellectual property to advance our interests in the United States and certain other territories.”
f. Questions impose themselves here:
- What is the state of relationship obtaining between Amarin and Mochida and where is it heading?
- Can the “exclusive license to certain Mochida intellectual property to advance our interests in the United States and certain other territories” be valid if Amarin is unable to put them to good use as well as promote its only product in terms of publicity/awareness (educating doctors, pharmacists, insurers and patients), and sales?
- To what extent is Amarin dependent on Mochida’s R&D capabilities? Does this reliance in a deteriorating relationship explain why Amarin scraped its Fixed Dose Combination program which KM and Executive Vice President, President R&D, Chief Scientific Officer Steve Ketchum had touted so much before?
- To what extent is LR-EtEPA’s development linked to Mochida’s R&D capabilities, and hence affected by this blurred and strained relationship?
- As Mochida obtained U.S. patent approval for Epadel EM who will eventually commercialize this product in the U.S. and “certain other territories”? And with what sales force?
- Mochida’s products being limited to the VHTG indication, can Vascepa’s 4mg compete against Epadel EM one-a-day in this market segment in the U.S., Europe, China and ROW?
- What do “certain other territories” cover?
- Is/are litigation(s) next to clarify the Mochida-Amarin collaboration?
g. For information:
- Mochida has 17,000+ employees.
- Mochida declared in its Integrated Report 2023: “We are also leveraging our alliances to globally expand our EPA drug with high purity in China, Thailand, Vietnam and the United States. In Thailand, the subsidiary of Meiji Seika Pharma Co., Ltd. obtained approval to import and market our EPA drug for the treatment of hypertriglyceridemia in October 2020 and commenced sales in April 2021. In Vietnam, an alliance partner of Meiji Seika Pharma is in the process of applying for approval to import and market our EPA drug.” It is worthwhile noting here Mochida does not identify who are its high-purity EPA drug marketing partners in the U.S. and China.
- Meiji Seika Pharma Co., Ltd (Japan) promotes and sells, inter alia, Mochida’s products overseas through a network of consolidated subsidiaries that cover India, most of the Far East (4 in China), Oceania (Australia & New Zealand), Europe and Africa. Production facilities are also found in India, Thailand and Spain.
- Amarin made the following payments to Mochida:
• “a non-refundable, non-creditable upfront payment of approximately $2.7 million” “upon closing the collaboration agreement” in June 2018.
• $1.0 million for “certain product development milestones achieved under the Agreement” in January 2020.
• $1.0 million for “exercising certain rights under the agreement” in December 2020.
- Amarin filed 9 U.S. provisional patent applications for LR-EtEPA during the period January 26 – June 2, 2022. It could not have done so if LR-EtEPA were the same product as MND-2119 for which Mochida had applied on July 17, 2020 – both priority claim and prior art would have impeded this.
- We do not know the status of these applications. After one year the United States Patent and Trade Mark Office (USPTO) must inform Amarin as quickly as possible if it is allowed, or not, to pursue the process. If allowed, Amarin must file a “final” so-called ‘regular” non-provisional application.
- Once the regular application is examined by a patent examiner, it is typical for the patent examiner to issue at least one Office Action. An examiner’s Office Action is a detailed report that outlines objections to the form of the application or the form or substance of the patent claims. It usually includes citations of prior art, often prior patents and published patent applications, that the examiner alleges to be relevant to the patentability of what’s claimed in the subject patent application.
- An Office Action is usually received by the applicant within 17 months of filing a regular patent application in the United States. The USPTO may request a new cycle of argumentations that would lead to a second final Office Action stating allowance or rejection of the patent application.
- Noteworthy, it took 43 months for Mochida to be granted USPTO protection for its MND-2119.
- As regards the rest of the world, Amarin used the PCT process on January 26, 2023 to ensure worldwide priority claim for LR-EtEPA based on the 9 non-provisional U.S. applications. This became effective with WIPO’s international publication of Amarin’s application on August 3, 2023.
- It is up to Amarin to move forward with applications for patent protection in certain individual countries and/or regional groupings as recognized by the PCT. Unfortunately, we lack total information regarding Amarin’s moves and intentions in this regard.
JRoon71
20 hours ago
RMB, one reason that I think they might possibly already be buying is based on trading patterns. I believe that part of the requirement for buybacks is that Cantor may not place trades in the first 30 minutes of open, or the last 30 minutes before close. They may also not buy on upticks (I forget the exact verbiage, but basically, the SEC wants to prevent momentum trades by the company buying their own shares).
I have been watching the daily trading patterns the past few weeks, and though maybe I am just seeing ghosts, it appears that there is always a bump in volume, or a block, around 10-10:30. And then often see the same thing around 3:00-3:30. Again, maybe I am just seeing things I want to see (and this is just normal trading), but it certainly seems to make sense.
And as for volume, keep in mind that Cantor is limited to buying about 350,000 shares per day (25% of average 30-day volume). There is an exception to that rule once a week (you can place an uncapped block trade once a week), but this is the daily limitation. So it is very easy to bury 350,000 shares (or less) each day.
JRoon71
22 hours ago
Announcement of Submission of New Drug Application for Epadel in China
https://firstwordpharma.com/story/5872291
July 2, 2024 Mochida Pharmaceutical Co., Ltd.
Mochida Pharmaceutical Co., Ltd. (Head office: Tokyo, Japan, President: Naoyuki Mochida, hereinafter: Mochida) announced that Mochida submitted a New Drug Application to the China National Medical Products Administration (NMPA) for Epadel S (development code: MND-21), a highly purified eicosapentaenoic acid (EPA) ethyl ester formulation that is being jointly developed in China by Mochida and Sumitomo Pharma (Suzhou) Co., Ltd., a Chinese subsidiary of Sumitomo Pharma Co., Ltd. As the clinical phase III trial conducted in patients with severe hypertriglyceridemia in China has shown positive results, Mochida has submitted a New Drug Application for Epadel S. Additionally, Mochida has entered into a distribution agreement for Epadel S in China with Meiji Seika Pharma Co., Ltd. (hereinafter: Meiji) in 2024. After approval, Mochida will supply the product to Meiji, which will distribute it through its affiliated partner in China, MAXMIND Bio-Technology (Hainan) Co., Ltd. Mochida is committed to contributing to the improvement of the quality of life for Chinese patients with hypertriglyceridemia through Epadel S. About Epadel Epadel (generic name: icosapent) is a highly purified EPA ethyl ester formulation developed by Mochida as the world's first medical drug. The product is available in Epadel Capsules, Epadel S, and Epadel EM Capsules forms. Epadel S is indicated for "Hyperlipidemia" and "Ulcer, pain and chilliness associated with arteriosclerosis obliterans" in Japan. The active pharmaceutical ingredient is supplied by Nissui Corporation, which has advanced EPA purification technology and mass production capability. Since its launch in 1990, it has been taken by many patients.
Dancing in the dark
1 day ago
Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE-EPA)
ClinicalTrials.gov ID NCT02719327
Claude can make mistakes. Please double-check responses.
Assessing the likelihood of success for a clinical trial like BRAVE-EPA is complex and involves considering multiple factors. While I can't provide a definitive prediction, I can offer some insights based on the study design and current knowledge in the field:
Factors that may increase the likelihood of success:
1. Strong scientific rationale: Omega-3 fatty acids, particularly EPA, have shown promise in cardiovascular and neurological health in previous studies.
2. Well-defined target population: The study focuses on a specific group (Veterans) with known risk factors for Alzheimer's disease.
3. Comprehensive outcome measures: Using multiple biomarkers (MRI, CSF, cognitive tests) increases the chances of detecting meaningful changes.
4. Appropriate duration: 18 months is a reasonable timeframe to observe potential effects on brain health markers.
5. Use of a purified, pharmaceutical-grade compound (icosapent ethyl) rather than over-the-counter fish oil supplements.
Factors that may decrease the likelihood of success:
1. Complex nature of Alzheimer's disease: AD is multifactorial, and a single intervention may have limited impact.
2. Previous mixed results: While some studies on omega-3s have shown promise, others have had inconclusive or negative results in cognitive health.
3. Relatively small sample size: 150 participants may limit the power to detect subtle effects.
4. Focus on prevention in healthy individuals: It can be challenging to demonstrate preventive effects in cognitively healthy people over a relatively short timeframe.
5. Potential for confounding factors: Despite careful exclusion criteria, there may be unforeseen variables affecting the results.
Overall, I would characterize the likelihood of success as moderate. The study is well-designed and based on solid scientific reasoning, but the complexity of Alzheimer's disease and the challenges of preventive studies make success not guaranteed. Even if the primary endpoints are not met, the study is likely to provide valuable data for future research directions.
It's important to note that in medical research, even studies that don't meet their primary endpoints often provide crucial information that guides future investigations and ultimately contributes to medical progress.
+Let's delve deeper into the scientific rationale behind omega-3 fatty acids, particularly EPA (eicosapentaenoic acid), and their potential benefits for
neurological health:
1. Anti-inflammatory properties: EPA has potent anti-inflammatory effects in the brain. Neuroinflammation is a key factor in the development and progression of various neurodegenerative diseases, including Alzheimer's disease (AD). EPA can help reduce the production of pro-inflammatory cytokines and promote the resolution of inflammation.
2. Neuroprotection: EPA has been shown to protect neurons from oxidative stress and apoptosis (programmed cell death). This neuroprotective effect may help preserve brain function and structure over time.
3. Synaptic plasticity: Omega-3 fatty acids, including EPA, are crucial components of neuronal membranes. They play a role in maintaining synaptic plasticity, which is essential for learning, memory, and overall cognitive function.
4. Cerebral blood flow: EPA has been associated with improved cerebrovascular function. It can enhance endothelial function and reduce arterial stiffness, potentially leading to better brain perfusion. This is particularly relevant to the BRAVE-EPA study, which is measuring cerebral blood flow as one of its primary outcomes.
5. Amyloid-ß reduction: Some studies have suggested that EPA might help reduce the accumulation of amyloid-ß plaques, a hallmark of Alzheimer's disease pathology. This could potentially slow down the progression of AD.
6. Neurotrophic effects: EPA may promote the production of brain-derived neurotrophic factor (BDNF), which supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses.
7. Mitochondrial function: EPA has been shown to improve mitochondrial function in neurons. Mitochondrial dysfunction is increasingly recognized as a factor in neurodegenerative diseases.
8. White matter integrity: Some research suggests that omega-3 fatty acids, including EPA, may help maintain white matter integrity in the brain, which is crucial for efficient neural communication.
9. Neurogenesis: While more research is needed, there's some evidence that EPA might support adult neurogenesis, particularly in the hippocampus, a region critical for memory formation and often affected early in AD.
10. Interaction with genetic risk factors: EPA may have a protective effect against cognitive decline in individuals carrying the APOE e4 allele, a major genetic risk factor for AD.
It's important to note that while these mechanisms have been observed in various studies (including cell cultures, animal models, and some human trials), the overall picture is complex. The BRAVE-EPA study is valuable because it aims to investigate several of these potential benefits in a well-defined human population using rigorous methods.
The use of icosapent ethyl, a purified form of EPA, allows for a more controlled investigation of EPA's specific effects, as opposed to the mixed omega-3 supplements used in some previous studies. This approach could provide clearer insights into EPA's role in neurological health and its potential as a preventive strategy for Alzheimer's disease.
+The blood-brain barrier (BBB) is indeed a crucial consideration when discussing the neurological effects of any compound, including EPA. Here's an overview of how EPA relates to the blood-brain barrier:
1. BBB Permeability:
o EPA can cross the blood-brain barrier, although the efficiency of this process is still a subject of research.
o The lipophilic nature of EPA allows it to pass through the BBB more easily than some other nutrients.
2. Mechanisms of Transport:
o EPA can enter the brain through passive diffusion due to its lipid-soluble nature.
o There's also evidence of active transport mechanisms, including specific fatty acid transport proteins that can facilitate EPA's passage across the BBB.
3. Incorporation into Brain Tissue:
o Once across the BBB, EPA can be incorporated into brain cell membranes, particularly in the gray matter.
o It can also be metabolized into various bioactive compounds within the brain.
4. Effects on BBB Integrity:
o EPA may actually help maintain and improve BBB integrity.
o It has been shown to reduce BBB permeability in some studies, which could be protective against neuroinflammation and the entry of harmful substances.
5. Indirect Effects:
o Even if only a small amount of EPA crosses the BBB, it can have significant effects by modulating systemic inflammation and vascular health, which indirectly impact brain health.
6. Chronic vs. Acute Administration:
o Long-term supplementation with EPA (as in the BRAVE-EPA study) may lead to gradual accumulation in brain tissue over time.
7. Individual Variability:
o The efficiency of EPA crossing the BBB can vary between individuals due to factors like age, overall health, and genetic differences.
8. BBB in Alzheimer's Disease:
o It's worth noting that BBB integrity is often compromised in Alzheimer's disease, which could potentially alter the brain's exposure to EPA in at-risk individuals.
9. Metabolites and Derivatives:
o Some of EPA's neuroprotective effects may be mediated by its metabolites or derivatives, some of which may cross the BBB more readily than EPA itself.
10. Dosage Considerations:
o The dose used in the BRAVE-EPA study (likely high-dose icosapent ethyl) is important, as higher plasma concentrations of EPA could potentially increase its penetration across the BBB.
The BRAVE-EPA study's focus on CSF biomarkers is particularly relevant here. By analyzing cerebrospinal fluid, researchers can get a more direct measure of how EPA supplementation affects the brain environment, providing insights into its ability to cross the BBB and influence brain biochemistry.
While EPA can cross the BBB, the extent and efficiency of this process, as well as its direct versus indirect effects on brain health, are areas of ongoing research. The BRAVE-EPA study may provide valuable data on these questions in the context of Alzheimer's disease prevention.
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CaptBeer
13 hours ago
