Mt-7117 EPP trial participant (link ) instagram with descriptive experiences and comments, 6 pills per day, more time in sun, log book, generally positive w nausea, headaches, tiredness

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Uhohinc

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Dec 13, 2019, 1:36:53 AM12/13/19
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odi01
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https://www.instagram.com/p/BvpCAuiliZ_/?igshid=hdlsnj74petu


After personal contact to the user "livededfearless", I found out that she had complaints (nausea, tiredness, headaches) after taking MT 7117

Uhohinc

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Dec 13, 2019, 1:41:34 AM12/13/19
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42-MT-7117.

100mg
300mg
Or placebo

Uhohinc

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Dec 13, 2019, 1:47:52 AM12/13/19
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Temperature in F. 59 degrees to 86 degrees excursions
66 degrees to 77 degrees

Uhohinc

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Dec 13, 2019, 2:14:54 PM12/13/19
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With Mitsubishi Tanabe letting out very little info on this drug or trial......a piecing together some of the gathered facts and connecting these facts.

The drug is vary unstable to temperature fluctuations in storeage. Note the temperature in a human gut is 20 degrees higher than the optimal upper limit.

Six pills per day, is indicative of the difficulty in control of the therapeutic desired effect in blood levels. Correlative to this is the 100% difference in the 300mg to 600mg dose.

Now correlate the unplanned liver function or toxicity trial started or planned prior to the trial results or anticipated end.

Mt7117 definitely has a problem and they are trying to solve it.

To dramatize, could they go to 12 pills a day. I do not think they can go above 300 mg per pill as it appears to instigate or increase side effects, hence small liver trial. The liver is the blood filter which removes toxins. It appears that the perfect balance as to Mt7117 blood levels to side effects to efficacy are going to be a voodoo dependent on wildly variable factors as to each patients ever changing digestion profile.

We all move food and different foods effect how long food moves thru the gastro intestinal, and how and when the blood level is maintained.

We know melanocyte stimulating hormone lasts seconds in blood before destructing.

The antecdotal account here indicates the girl has more melanin and indicates more time in sun, so the Mt7117 is working for her, but Mitsubishi Tanabe is having to flood the blood so much the side effects are????????

Uhohinc

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Dec 13, 2019, 2:51:44 PM12/13/19
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I would also conjecture here, that at the doseages Mt7117 is using to maintain enough of the drug in the blood are raising the risk of anti-bodys and tolerance levels that it may take all or some individuals more and more of the drug to reach the same theraputic level.

The receptor desensitization probability I surmise is tremendously increased because of the fluctuations and instability and or the foods being absorbed concurrently. There is something to be said for an slow dissolving implant Scenesse is every 2 months, but the implant has pretty much dissolved within hours.
Mitsubishi is not indicating, nor is the antecdotal account indicate, if these 6 pills were every day or ...

Uhohinc

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Jan 7, 2020, 2:04:33 PM1/7/20
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http://txwd.motorradfahrer-poppenlauer.de/mitsubishi-clinical-trials.html

Uhohinc

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Jan 7, 2020, 2:14:03 PM1/7/20
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Associate Director, Supply Chain & Strategy job
MITSUBISHI TANABE PHARMA
JERSEY CITY, NJ

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JOB DESCRIPTION

Overview

Entrepreneurial Spirit, Rooted in Tradition

. At Mitsubishi Tanabe Pharma America, Inc. (MTPA), we can tout a storied reputation more than 300 years in the making. Our parent company, Mitsubishi Tanabe Pharma Corporation, is a research-driven pharmaceutical company with global reach – and one of Japan’s oldest and most respected companies.


With the recent FDA approval and availability in the U.S. of RADICAVA® (edaravone) MTPA is rapidly expanding our operation across all functional areas to launch this new product in the U.S. market. Concurrently, the company is expanding its research efforts and exploring collaborations with partners to discover and bring treatments to market for unmet medical needs including orphan diseases. We currently seek motivated professionals who share our vision of scientific excellence, innovation, and unwavering dedication to improving the lives of patients.

The Associate Director, Supply Chain & Strategy develops, establishes, and manages the supply chain activities for commercialization and launch of new products in late development related to planning, procurement, label and packaging development, distribution, importation, and vendor management. This individual will actively develop and oversee supply plans to ensure accurate and seamless supply to patients while reducing risk and minimizing waste. The Associate Director, Supply Chain & Strategy represents the supply chain function to internal stakeholders and manages relationships with external supply partners. Drawing on a working knowledge of product supply systems and best practices, as well as experience within international product shipping, this individual will work closely with management to develop and implement process improvements and helps to build the organization and systems for future products. This role is based in the North American Headquarters and will report directly into the Director, Supply Chain & Strategy

Responsibilities

Develop and establish the supply chain for the commercialization and launch for our late development stage products (MT-1186, ND0612, MT-7117 and future products) by closely working with Supply Chain Director.
Manage supply chain activities including procurement, importing product, planning and coordinating packaging, labeling, distribution of drug product, risk reduction and keeping adequate inventory level.


Work and collaborate with MTPA internal colleagues in various functions (QA, RA, Marketing, Market Access, Medical Affairs), colleagues in Mitsubishi Tanabe Pharma group, and external companies (e.g. CMO, 3PL, consultant).
Work with colleagues in Mitsubishi Tanabe Pharma group for the investigation, qualification and/or selection of CMO.
Evaluate and select 3PL and transportation venders.
Work with MTPA internal colleagues, colleagues in Mitsubishi Tanabe Pharma group, and external companies for the development of packaging, label and artwork.
Work with colleagues in MTPA Market Access to develop Trade channel of products.
Participate in supply chain related global and/or project meetings as a project member.
Lead supply chain related projects.
Attend all channel meetings and conduct business reviews with major partners.
Keep watching the new regulation and industry standard in terms of US supply chain and secure supply chain activities are fully compliant with the updated regulation.
Request and/or provide documents as needed to support regulatory filing requirements.
Prepare, maintain and distribute, as appropriate, supply chain related SOPs, reports and meeting minutes and budgets.
Prepare product forecasts as required for planning of product supply.
Monitor outside partners such as the Contract Manufacturing Organization, 3PL to ensure proper service levels, and assess ability to meet quality and delivery requirements.
Manage supply chain consultants to ensure a safe and compliant supply chain.
Negotiate prices and terms with suppliers, vendors and freight forwarders.
Develop supply chain management strategies to maximize supply efficiency, minimize waste while identifying risk and develop risk mitigation plans.
Serve as an internal lead for triaging of product complaints, temperature excursions, and deviations originating from distribution vendors.
Investigate deviations to determine root causes and implement corrective actions.
Work with Quality Assurance to establish internal SOPs for supply chain management related activities.
Support the evaluation, selection and quality audit of packaging/labeling and distribution vendors.
Cross-train departmental and/or cross-functional employees as required.
Prepare SC related budgets and manages within allocated budgets and resources as appropriate.
Completes all company-based and job-related training as assigned by MTPA within the required timeline.
Additional duties as assigned by MTPA management.


Qualifications

Bachelor’s degree required in business administration, operations management, supply chain management or similar academic major. Master’s degree preferred in business administration, operations management, supply chain management or similar academic major
Minimum 8 to 10 years of experience in supply chain coupled with expertise of supply chain activities including supply planning, procurement, label and packaging development, distribution, vendor management in US pharmaceutical industries.
3-5+ years developing and establishing the supply chain for the commercialization and launch of new products in US.
Experience handling cold chain products in US is highly preferred.
Experience handling combination products in US is highly preferred.
Must have knowledge in US regulations as they pertain supply chain activities (e.g. US Serialization, logistics).
Experience working with CMO, 3PL and other service providers is highly preferred.
Working knowledge of accounting and finance is preferred.
Broad understanding of pharmaceutical drug product development and manufacturing.
Must have knowledge of US cGMP and other regulatory guidance.
Ability to work independently with limited supervision.
Negotiation and interpersonal skills with a good awareness of global cultural differences; ability to effectively promote coordination between Supply Chain functions between US entities and Mitsubishi Tanabe Pharma Group.
Excellent oral/written communication skills including technical writing.
Proficiency with computer programs such as MS Office (Excel, PowerPoint, Word etc), SAP or similar databases.
Proficiency in project management skills, e.g. timeline, Gantt chart, critical path, checklist, flow chart, etc.
Persuasive interpersonal and communication skills including formal presentation skills; ability to work with all levels of employees up to senior executive levels.
Willingness to work off-hours during periods of peak activity.
Must embody the MTPA’s values of Respect, Communication, Teamwork, Drive for Results, Accountability, Development, Agility, and Integrity
Must be able to travel 10%-30% domestically and internationally for business and project meetings a

Uhohinc

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Jun 18, 2020, 9:03:57 PM6/18/20
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https://healthcare.utah.edu/clinicaltrials/trial.php?id=FP00012322

Note, the exclusion criteria to this gives insights as to what they think is problematic or is problematic. The gastric ph. Several drugs i recognize as immune pathway regulatory.

Uhohinc

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Jun 24, 2020, 1:04:56 PM6/24/20
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From Odi in Germany;



In the wallstreet-online community, an EPP patient has been writing about his experiences with SCENESSE since yesterday. He also reports about Mitsubishi Tanabe, here is the article

I can report the following about MT117: Mitsubishi Tanabe employees register with a specialist (doctor) in a renowned hospital to talk about Scenesse implant and its mode of action and study findings. The corresponding specialist (doctor) will give open information! In between, the specialist (doctor) also has questions about MT117 - but these are categorically not answered by the staff (Mitsubishi Tanabe) - this raises doubts, or what do you think? This is what actually happened! To the question whether I prefer to take one tablet per day 200-360 times a year or 3-6 implants - my answer is crystal clear - IMPLANT. Why? A pill has to pass through the digestive system and puts a strain on the organism (for years to come it will surely be more poison than balsam). An EPPler already has heavy loads through the protophorphyrin, so why let additional toxins rush through the liver? Then I would rather take my implants and enjoy one or more glasses of wine. With the best will in the world, I cannot imagine that MT117 will prevail in EPP patients. Of course, the cost issue is a very important factor. Only the positive side-effects of scenesse can NEVER bring MT117 - rather counter-indicative

https://www.wallstreet-online.de/diskussion...maceuticals-ltd

Uhohinc

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Jun 25, 2020, 2:42:48 PM6/25/20
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Phase 3 clinical trial of Mitsubishi Tanabe’s investigational therapy MT-7117 (dersimelagon) for people with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) has been launched.

The study (NCT04402489) will take place at 12 clinical sites in the U.S. and will test the therapy in adults and adolescents. Locations in Columbus, Ohio, and Boston are now active, and will be followed by additional sites globally, according to the American Porphyria Foundation.

For more information, potential participants can contact the foundation to be connected with the nearest study site. Contact information is in...@porphyriafoundation.org or infor...@mt-pharma-us.com. Also, 866-APF-3635 or 301-347-7166.

MT-7117 is a man-made (synthetic) small molecule that binds to and activates the melanocortin-1 receptor (MC1R) protein. Given orally, the experimental therapy is intended to increase the production of a pigment called melanin to induce photoprotection (protection against sunlight) of the skin.

A prior Phase 2 trial, ENDEAVOR (NCT03520036), evaluated the effectiveness, tolerability and safety of MT-7117 in adults with EPP.

Participants underwent a two-week screening period, followed by a 16-week treatment, where they received either one of two daily doses (high and low) of MT-7117 or a placebo. A six-week follow-up period ended the trial at week 24.

Results showed that the study met its primary goal, with MT-7117 extending the average daily time to the first early symptom associated with sunlight exposure relative to the study’s start. MT-7117 also was generally well-tolerated.

In the double-blind Phase 3 study, participants with either EPP — the most common porphyria of childhood — or XLP will be assigned randomly to a low or high-dose of MT-7117, or a placebo, given once daily in the morning with or without food for 26 weeks. Enrolled patients may join an optional 26-week extension phase.

The study’s primary goal is to assess the effectiveness of MT-7117 in a similar way as in Phase 2. The team will evaluate whether the therapy extends the daily sunlight exposure time before participants develop the first early symptoms — burning, tingling, or stinging — associated with sun exposure in the periods between one hour post-sunrise and one hour pre-sunset.

Additional goals include assessing patients’ global impression of change and the total number of sunlight-induced pain events during the treatment period. Pain will be scored from 1 to 10 according to the Likert scale, in which increasing scores represent greater pain.

MT-7117 received fast track designation from the U.S. Food and Drug Administration for the treatment of EPP in 2018.

Uhohinc

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Jun 25, 2020, 2:58:06 PM6/25/20
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“ to a low or high-dose of MT-7117, or a placebo, given once daily in the morning with or without food for 26 weeks. Enrolled patients may join an optional 26-week extension phase.”

Interesting that its even in there that its with or without food in the morning.

That extra 26 weeks option takes it to july 2021. Tough to get a placebo patientto torture themselves to go out in sunlight. Even tougher to get the placebo patient to gp on for another 26 weeks with not only positive reinforcements, but negativereinforcements.

There must be a reason to give a 26 week extension. Maybe they do not want to lose these patients to Scenesse right after they stop getting MT7117.
If the FDA wants more data or they needto cherry pick and massage the results they have moredata.
Clearlythey had difficulty attaing enough patients and got approval for under 18, and up against Sceness rention rate nearly 99%. But they got around this by taking on use of Sceness EPP patients just about ready for their next Scenesse dose

Uhohinc

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Jan 7, 2021, 4:41:22 PM1/7/21
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reference on Share tease clinuvel of an additional trial patient on mt-7117 reference I assume from APF facebook or EPP facebook




blackm3Well-known member
(From facebook)

Hi there! Has anyone had experience with the Mitsubishi drug trial? My son is participating and we just got the real medicine after six months on the placebo. He is so sick, with vomiting since we took the first dose on Monday. We stopped taking it for now but I’m wondering if anyone has had similar experiences or advice.. Thanks!

Uhohinc

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Jan 7, 2021, 5:00:59 PM1/7/21
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It would be interesting to know the dose mg, how long after taking the pill did the nausea begin, how close in time his son had eaten before/after, and did his son experience similar to the above patients reports of tiredness and did he suffer headaches........with just what is stated, I assume his son had a reaction in the  stomach and none got to far into his intestinal, and no effect of headache nor tiredness might indicate even less or no Mt-7117 got into the blood.  There is no advantage at all imo for the actual drug Mt-7117 to be un coated with the ability to be  exposed to gastric enzymes and acidicity. Clearly it is coated to get closer intact for contact with the absorbing cells to blood farther down tract.

 I think it goes back to my original conjecture about 3 years now and still Mits Tanabe has not finessed an adjusted dose in that Mt-7117 has in general a large enough trial patient population efficacy ratio to side effects problem and it may not be possible to lower dose and still get an acceptable efficacy..............recall the massive number of pills mg per day in original posts. This may tie into the ongoing liver function tests trial. started before the phase ii was even done........His son may have been part of a subarm or even in a dose study.........

Uhohinc

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Mar 11, 2021, 10:30:50 PM3/11/21
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Johnny HWell-known member
I was waiting for this shoe to drop, but I didn't want to say anything earlier in case I was wrong...

Mitsubishi Tanabe is now investigating MT-7117 for drug-drug interactions.

I figured this was coming after the hepatic and renal investigations.

Exclusion criterion:
-Consumption of food or drink containing oranges, grapefruit, liquorice, or cranberry within the 7 days prior to the first dose of study drug. (bolding mine)

-Use of tobacco or nicotine-containing products (snuff, chewing tobacco, cigarettes, cigars, pipes, e-cigarettes, or nicotine replacement products) within 3 months prior to dosing, or a positive urine cotinine test at Screening or Day -1. (bolding mine)

-Subjects who are not willing to abstain from consumption of caffeine and methylxanthine (e.g., coffee, tea, cola, energy drinks, or chocolates) in the 48 hours before Day -1 until completion of the post-treatment assessments and in the 48 hours before the Follow-up/End of Study Visit. (bolding mine)

-Heavy physical training, labor, or excessive exercise (e.g., long-distance running, weightlifting, or any physical activity to which the subject is not accustomed) from 3 days before the administration of study drugs. (bolding mine)

-Donation of 1 or more units of blood (450 mL) in the 3 months prior to Screening, plasma in the 7 days prior to Screening, platelets in the 6 weeks prior to Screening, or the intention to donate blood within 3 months after the last scheduled visit. (bolding mine)


Grapefruit exclusion strongly implies a suspected CYP450 interaction. The other stuff.... just wow.


MT-7117 is in a lot of trouble right now.
killipso35Active member

Uhohinc

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Mar 11, 2021, 10:39:53 PM3/11/21
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https://groups.google.com/g/clinuvel/search?q=grapefruit

Uhohinc

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Jun 4, 2021, 11:05:55 AM6/4/21
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  • News
  •  MT-7117 Poised for Phase 3 Trial in Two Types of Porphyria
MT-7117 Poised for Phase 3 Trial in Two Types of Porphyria

by Patricia Inacio PhD | May 29, 2020

SHARE THIS ARTICLE:SHARE ARTICLE VIA EMAILCOPY ARTICLE LINK

A Phase 3 clinical trial of Mitsubishi Tanabe’s investigational therapy MT-7117 (dersimelagon) for people with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) has been launched.

The study (NCT04402489) will take place at 12 clinical sites in the U.S. and will test the therapy in adults and adolescents. Locations in Columbus, Ohio, and Boston are now active, and will be followed by additional sites globally, according to the American Porphyria Foundation.

For more information, potential participants can contact the foundation to be connected with the nearest study site. Contact information is in...@porphyriafoundation.org or infor...@mt-pharma-us.com. Also, 866-APF-3635 or 301-347-7166.

MT-7117 is a man-made (synthetic) small molecule that binds to and activates the melanocortin-1 receptor (MC1R) protein. Given orally, the experimental therapy is intended to increase the production of a pigment called melanin to induce photoprotection (protection against sunlight) of the skin.

A prior Phase 2 trial, ENDEAVOR (NCT03520036), evaluated the effectiveness, tolerability and safety of MT-7117 in adults with EPP.

Participants underwent a two-week screening period, followed by a 16-week treatment, where they received either one of two daily doses (high and low) of MT-7117 or a placebo. A six-week follow-up period ended the trial at week 24.

Results showed that the study met its primary goal, with MT-7117 extending the average daily time to the first early symptom associated with sunlight exposure relative to the study’s start. MT-7117 also was generally well-tolerated.

In the double-blind Phase 3 study, participants with either EPP — the most common porphyria of childhood — or XLP will be assigned randomly to a low or high-dose of MT-7117,  or a placebo, given once daily in the morning with or without food for 26 weeks. Enrolled patients may join an optional 26-week extension phase.

The study’s primary goal is to assess the effectiveness of MT-7117 in a similar way as in Phase 2. The team will evaluate whether the therapy extends the daily sunlight exposure time before participants develop the first early symptoms — burning, tingling, or stinging — associated with sun exposure in the periods between one hour post-sunrise and one hour pre-sunset.

Additional goals include assessing patients’ global impression of change and the total number of sunlight-induced pain events during the treatment period.  Pain will be scored from 1 to 10 according to the Likert scale, in which increasing scores represent greater pain.

MT-7117 received fast track designation from the U.S. Food and Drug Administration for the treatment of EPP in 2018.

About the Author
Patricia Inacio PhD Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.

Uhohinc

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Jun 4, 2021, 11:08:06 AM6/4/21
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and adolescents. 

Uhohinc

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Sep 17, 2021, 8:29:36 AM9/17/21
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blackm3Well-known member
Interesting comments from the Epp fb page:



“I experienced an abnormal liver reaction to a drug over the past summer. I went from no liver problem to a liver problem in 3 weeks”


I dont know what drug she was referring to but i do know she took part in the Mitsubishi trial in June

Uhohinc

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Nov 10, 2021, 10:51:28 PM11/10/21
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johnnytechModerator Sharetease
Staff member
Competitor AGM Question

Most of us here are not worried about MT-7117, but I transcribe out the CEO's answer from the 2021 AGM for those reporters that are visiting.

Shareholder Question: If the Mistubishi Tanabe MT-7117 drug makes it to market, is it likely to have an impact on Clinuvel's margin on Scenesse sales?

Dr. Wolgen Response: So, how long is a piece of string? (pause) The area of EPP was never of interest to any pharma company. This is part of our selection criteria when we look at a market or a serviceable market. And a competitor will always emerge.

And whether this particular competitor is going to be successful, is to be seen.

Whether the patients wish to see a different formulation, is to be seen.

Whether the competitor will reach successful agreement with insurance companies and payors, is to be seen.

Whether the drug is going to stand the scrutiny of safety of regulators and pharma vigilance, is to be seen.

There are so many unknowns and ifs. But, we keep an eye on every competitor in the world. It is not a concern, it is part of our business. And what is also important is to realize that the EPP market is still not highly penetrated. So, we believe there is room for 2 or even 3 competitors without eroding our market.

I hope to have... finally answered your question... we've seen it over the years.

My comment: By best estimates around these parts, MT-7117 is at least 2.5 years, and likely closer to 4 years away for market approval. Further, who wants to take a pill everyday and stress the liver. Lastly, 7117 works down the MC1R chain, wherease Scenesse works at the MC1R receptor. To go any further up the chain above where Scenesse acts is to reach the very source of the defect... at the genes themselves.

When prescribing doctors are aware of the options, the obvious choice will be the safe natural one at the top of the chain.

Uhohinc

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Dec 5, 2021, 3:40:22 AM12/5/21
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VerharvenWell-known member
@sharelooker So, they've increased their planned numbers from 120 to 175 but left their 'anticipated' completion date at September 2023. They're an optimistic bunch there at Mitsubishi Tanabe.

The only clear reason I can see for increasing patient numbers mid trial is they've had some realisation from prelim data that their study is underpowered. But in this case when you're trying to prove safety, you don't want to see statistically significant differences, but instead no difference between groups. But you can't just run a say "n=4" trial (two people in each group) to show the regulator: "Look, there was no statistical difference between groups in terms of liver damage" - you would be laughed at and told to go back and do it again with more patients. So, you need to have enough people in the study to be confident that there really is no 'hidden' liver damage happening that is being masked by the small sample size relative to the normal biological variation of liver damage in the whole population.
Last edited: Today at 6:18 AM
More patients to be recruited, looking for 175 within this month!
And only 2 out of 32 global locations are recruiting, the other 30 show a status „not yet recruiting.
Seems not plausible, but don‘t know if it is mandatory for them to update all details of the study status on the „clinicaltrials.gov“ web site.

However, any delay keeps competition at bay. ……oh, that rhymes

Uhohinc

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Jan 27, 2022, 1:33:21 AM1/27/22
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Melanogenic effect of dersimelagon (MT‐7117), a novel oral melanocortin 1 receptor agonist
  • November 2021
Authors:
Abstract
Background The activation of melanocortin 1 receptor (MC1R) on melanocytes stimulates the production of eumelanin. A tridecapeptide α melanocyte-stimulating hormone (αMSH) is known to induce skin pigmentation. Objectives We characterised the properties of a novel oral MC1R agonist dersimelagon (MT-7117) with respect to its specific binding to MC1R, downstream signalling and eumelanin production in experimental models. Methods The competitive binding and production of intracellular cyclic adenosine 3′, 5′-monophosphate in cells expressing recombinant melanocortin receptors were examined. A mouse melanoma cell line B16F1 was used for the evaluation of in vitro melanin production. The in vitro activity of MT-7117 was determined with αMSH and [Nle⁴, D-Phe⁷]-αMSH (NDP-αMSH) as reference comparators. The change of coat colour and skin pigmentation were evaluated after repeat administration of MT-7117 by oral gavage to C57BL/6J-Ay/+ mice and cynomolgus monkeys, respectively. Results MT-7117 showed the highest affinity for human MC1R compared to the other melanocortin receptors evaluated and agonistic activity for human, cynomolgus monkey and mouse MC1R, with EC50 values in the nanomolar range. In B16F1 cells, MT-7117 increased melanin production in a concentration-dependent manner. In vivo, MT-7117 (≥0.3 mg/kg/day p.o.) significantly induced coat colour darkening in mice. MT-7117 (≥1 mg/kg/day p.o.) induced significant skin pigmentation in monkeys and complete reversibility was observed after cessation of its administration. Conclusions MT-7117 is a novel oral MC1R agonist that induces melanogenesis in vitro and in vivo, suggesting its potential application for the prevention of phototoxic reactions in patients with photodermatoses, such as erythropoietic protoporphyria and X-linked protoporphyria. Abstract

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Public Full-text 1
Available via license: CC BY 4.0
Content may be subject to copyright.
Received: 3 September 2021
-
Revised: 5 November 2021
-
Accepted: 6 November 2021
DOI: 10.1002/ski2.78
ORIGINAL ARTICLE
Melanogenic effect of dersimelagon (MT‐7117), a novel
oral melanocortin 1 receptor agonist
T. Suzuki
|Y. Kawano |A. Matsumoto |M. Kondo |K. Funayama |
S. Tanemura |M. Miyashiro |A. Nishi |K. Yamada |M. Tsuda |A. Sato |
K. Morokuma |Y. Yamamoto
Sohyaku Innovative Research Division,
Mitsubishi Tanabe Pharma Corporation,
Yokohama, Japan
Correspondence
Tsuyoshi Suzuki, Sohyaku Innovative
Research Division, Mitsubishi Tanabe Pharma
Corporation, Yokohama, Japan.
Abstract
Background: The activation of melanocortin 1 receptor (MC1R) on mela-
nocytes stimulates the production of eumelanin. A tridecapeptide α
melanocyte‐stimulating hormone (αMSH) is known to induce skin
pigmentation.
Objectives: We characterised the properties of a novel oral MC1R
agonist dersimelagon (MT‐7117) with respect to its specific binding to
MC1R, downstream signalling and eumelanin production in experimental
models.
Methods: The competitive binding and production of intracellular cyclic
adenosine 30, 50‐monophosphate in cells expressing recombinant mela-
nocortin receptors were examined. A mouse melanoma cell line B16F1
was used for the evaluation of in vitro melanin production. The in vitro
activity of MT‐7117 was determined with αMSH and [Nle
4
, D‐Phe
7
]‐αMSH
(NDP‐αMSH) as reference comparators. The change of coat colour and
skin pigmentation were evaluated after repeat administration of MT‐7117
by oral gavage to C57BL/6J‐A
y
/+mice and cynomolgus monkeys,
respectively.
Results: MT‐7117 showed the highest affinity for human MC1R compared
to the other melanocortin receptors evaluated and agonistic activity for
human, cynomolgus monkey and mouse MC1R, with EC
50
values in
the nanomolar range. In B16F1 cells, MT‐7117 increased melanin
production in a concentration‐dependent manner. In vivo, MT‐7117
(≥0.3 mg/kg/day p.o.) significantly induced coat colour darkening in
mice. MT‐7117 (≥1 mg/kg/day p.o.) induced significant skin pigmentation
in monkeys and complete reversibility was observed after cessation of its
administration.
Conclusions: MT‐7117 is a novel oral MC1R agonist that induces mela-
nogenesis in vitro and in vivo, suggesting its potential application for the
prevention of phototoxic reactions in patients with photodermatoses, such
as erythropoietic protoporphyria and X‐linked protoporphyria.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2021 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
Skin Health Dis. 2021;e78. wileyonlinelibrary.com/journal/ski2
-
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1
|
INTRODUCTION
The melanocortin receptor (MCR) family belongs to the
class A family of G‐protein‐coupled receptors and
consists of five members: MC1R, MC2R, MC3R, MC4R
and MC5R with different tissue distribution and func-
tions.
1
Expression of MC1R has been reported on
various cell types including melanocytes, keratinocytes,
monocytes, endothelial cells and fibroblasts.
2
The
activation of MC1R on cutaneous melanocytes by an
endogenous ligand, αmelanocyte‐stimulating hormone
(αMSH), after solar irradiation results in a switch from
red‐yellow pheomelanin to brown‐black eumelanin
pigment synthesis.
3,4
On the other hand, αMSH is
known to exhibit anti‐inflammatory effects in inflam-
matory cells.
2,5
A number of naturally occurring single‐
nucleotide polymorphisms of the MC1R gene have
been identified globally,
6,7
and variants such as R151C,
R160W and D294H in humans are associated with red
hair colour and pale skin,
8
indicating that functional
MC1R is crucial in eumelanin synthesis. The major
biological functions of eumelanin are absorption of
sunlight (photoprotection) and scavenging of free radi-
cals (chemoprotection).
9,10
Thus, MC1R plays a critical
role in the ability of melanocytes to provide an anti‐
oxidative defence mechanism against cell damage
from harmful solar irradiation.
1,11
Following activation with agonistic ligands, the Gα
s
protein dissociates from MC1R and stimulates adenylyl
cyclase leading to the intracellular accumulation of the
second messenger cyclic adenosine 30,50‐mono-
phosphate (cAMP).
2
Consequently, cAMP activates
protein kinase A, which further induces phosphorylation
of the transcription factor, cAMP response element‐
binding protein and upregulation of transcription fac-
tors related to regulation of melanin biosynthetic en-
zymes including tyrosinase (TYR), tyrosinase‐related
protein 1 (TRP1) and dopachrome tautomerase
(DCT).
3,12
The synthetic peptide [Nle
4
, D‐Phe
7
]‐αMSH (NDP‐
αMSH), also known as afamelanotide, binds predomi-
nantly to MC1R and induces skin pigmentation that
prevents phototoxic reactions and it has been approved
in several countries for the treatment of adult patients
with erythropoietic protoporphyria (EPP). EPP is a
lifelong disorder, and photosensitivity that affects EPP
patients has a significant impact on their quality of life.
However, NDP‐αMSH is not a selective MC1R agonist
and thus this may lead to concerns about potential
adverse effects, such as nausea, which may be due to
binding to MC3R.
13,14
It is a peptide and thus unsuitable
for oral administration due to liability to degradation; it
has the limitation of a short half‐life and it needs to be
implanted subcutaneously by a healthcare professional
every two months. Therefore, there is a need for a se-
lective, safe and orally available MC1R agonist.
We have designed MT‐7117 (dersimelagon phos-
phoric acid), a novel oral MC1R agonist that is currently
in development as a photoprotective agent for patients
with EPP and X‐linked protoporphyria (XLP). In this
study, we describe the biological profile of MT‐7117 and
show its agonistic activity for MC1R in cellular assays,
and pigmentation effects in mice and monkeys.
2
|
MATERIALS AND METHODS
2.1
|
Test substances
MT‐7117 (Figure 1) synthesised at our institute was
dissolved in dimethylsulphoxide for in vitro assays or
suspended in 0.5% methylcellulose solution or 0.5%
methylcellulose plus 0.1% Tween 80 aqueous solution,
pH 2.0, for studies in mice and monkeys, respectively.
The synthetic method of MT‐7117 is reported sepa-
rately (manuscript in preparation). αMSH was pur-
chased from PEPTIDE INSTITUTE, INC. NDP‐αMSH
was synthesised at PH Japan Co., Ltd.
What is already known about this topic?
Activation of melanocortin 1 receptor (MC1R)
by agonistic peptide αmelanocyte‐stimulating
hormone increases eumelanin synthesis in
melanocytes.
Since the common cutaneous manifestation
of both erythropoietic protoporphyria (EPP)
and X‐linked protoporphyria (XLP) is painful
photosensitivity, treatment is based on sun-
light avoidance.
What does this study add?
We generated dersimelagon (MT‐7117), a
novel orally available and selective agonist
for MC1R.
MT‐7117 increased skin pigmentation in
monkeys and darkened coat colour of C57BL/
6J‐Ay/+mice.
What is the translational message?
Increased pigmentation by MT‐7117 may
protect patients with photodermatoses, such
as EPP and XLP, from phototoxic reactions.
An oral agent would be a convenient new op-
tion for patients with such photodermatoses.
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SUZUKI
ET AL.
2.2
|
Cell lines
Human embryonic kidney 293 (HEK293) cells stably
expressing melanocortin receptors were established by
our institute, including expression of mouse MC1R
(mMC1R), rat MC1R, cynomolgus monkey MC1R
(cmMC1R), human MC1R (hMC1R) wild type, hMC1R
V60L, hMC1R V92M, hMC1R R151C, hMC1R R163Q
and human MC4R (hMC4R). The site‐specific integra-
tion of each MCR gene was carried out in accordance
with the Jump‐In
TM
TI
TM
Gateway® Targeted Integration
System user guide (www.lifetechnologies.com) except
replacement of tetracycline‐induced CMV promoter into
SV40 promoter in MCR expression vector as previously
described.
15
This technology enables stable single copy
integration at the same location in the genome, equal-
ising expression levels. CHO‐K1 cells expressing human
MC2R and accessory protein MRAP were prepared by
EuroscreenFast (Gosselies, Belgium). The B16F1
mouse melanoma cell line was purchased from the
American Type Culture Collection.
2.3
|
Cyclic AMP assays
Hanks' balanced salt solution containing 1% bovine
serum albumin and 10 mmol/l HEPES was prepared
and used as an assay buffer. Cells were suspended in
the assay buffer containing 0.5 mmol/l 3‐isobutyl‐1‐
methylxanthine (Calbiochem) and plated into a micro-
plate. Serially diluted test substances were then added
and incubated for 30 min at 37°C. Concentrations of
cAMP in the cells were quantified using the cAMP
dynamic 2 kit (Cisbio Bioassays) by measuring fluo-
rescence. The maximum responses (E
max
) and EC
50
values (50% effective concentration of the Emax value
of αMSH) were calculated.
2.4
|
Radioligand binding assays
Determination of binding affinities for human recombi-
nant MCRs (MC1R, MC3R, MC4R and MC5R) were
performed by using [
125
I] NDP‐αMSH radioligand
binding. The material of receptors, MC1R (Cat.# ES‐
195‐M), MC3R (Cat.# RBXMC3M), MC4R (Cat.#
RBHMC4M) and MC5R (Cat#. RBXMC5M) were pur-
chased from PerkinElmer. In brief, test substances and
[
125
I] NDP‐αMSH were mixed with human recombinant
MCRs in incubation buffer containing 25 mmol/l
HEPES, pH 7.0, 100 mmol/l NaCl, 1 mmol/l 1,10‐phe-
nanthroline, 1.5 mmol/l CaCl
2
, 1 mmol/l MgSO
4
and
protease inhibitors for 60 or 120 min at 37°C. After
separation of bound and free ligand with washing,
radioactivity was measured by a scintillation counter
(PerkinElmer, TopCount NXT
TM
). The IC
50
values were
determined with non‐linear regression analysis. The Ki
values were calculated using the following formula:
Ki ¼IC50=ð1þ ½concentration of radioligand=KdÞ
Kd is the dissociation constant calculated from his-
torical value on assay validity.
2.5
|
Melanin production in B16F1 cell
line
Dulbecco's modified Eagle medium without phenol red
(Life Technologies), containing 10% foetal bovine serum
(Gibco) and 100 U/ml of penicillin‐streptomycin (Gibco),
was used as the assay medium. Cells (1.5 10
4
) were
seeded into a 96‐well culture plate. Serially diluted test
substances were added to the plate and incubated at
37°C in a humidified 5% CO
2
incubator for 3 days. The
melanin concentration in the supernatant was deter-
mined from the optical density (405 nm) measured by
VersaMax
TM
microplate reader (Molecular Devises)
using a standard curve of eumelanin (Sigma‐Aldrich,
M8631). The EC
50
values (50% effective concentration
of the Emax value of NDP‐αMSH) were calculated.
2.6
|
Coat colour darkening in Ay/a
mice
Unless noted otherwise, 3‐week‐old male C57BL/6J‐
A
y
/+mice (Ay/a mice) were purchased from Japan
SLC, Inc. Mice were housed under specific pathogen‐
free conditions, and all animal experiments were
conducted according to the Guidelines for Animal
Experimentation at our institute. On day 0, the coat of
the lower back was shaved, and animals were allocated
to experimental groups. MT‐7117 was administered
orally or NDP‐αMSH was subcutaneously injected once
daily for 6 consecutive days. Assessment of coat colour
of the shaved area on day 6 was performed macro-
scopically in a blinded manner. The dorsal skins were
dissected and fixed in a neutralised formalin then
embedded in paraffin. Melanin production in the hair
FIGURE 1 Chemical structure of MT‐7117
SUZUKI ET AL.
-
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roots of the dorsal skin was histologically evaluated by
Fontana‐Masson staining. For gene expression anal-
ysis, pinnae were dissected after single dosage of
MT‐7117 to 7‐week‐old male Ay/a mice.
2.7
|
Quantitative real‐time PCR
Total RNA was extracted using the Qiagen RNeasy
Mini Kit (Qiagen), and quantitative real‐time PCR for
Tyr,Trp1 and Dct was performed using the One Step
SYBR PrimeScript PLUS RT‐PCR Kit (Takara Bio).
Hypoxanthine phosphoribosyltransferase 1 (Hprt) was
used as an endogenous control for normalisation. The
ΔCT method was used to determine the relative
expression levels. All PCR primers were purchased
from Takara Bio with following product codes,
MA153806 (Tyr), MA129755 (Trp1), MA118342 (Dct)
and MA031262 (Hprt).
2.8
|
Pigmentation on the facial skin of
cynomolgus monkeys
This study was conducted in compliance with the ‘Act
on Welfare and Management of Animals’ in Japan and
the ‘Guidance for Animal Care and Use’ and in accor-
dance with the protocol reviewed by the Institutional
Animal Care and Use Committee of the test facility,
which is fully accredited by AAALAC International.
Female cynomolgus monkeys (Macaca fascicularis)
aged 2–3 years were assigned to experimental groups
to ensure homogenous distribution of the skin colour
(L* value) at pre‐test among the groups. The mea-
surement site (cheek) was the same site on the face for
all animals. MT‐7117 was administered by oral gavage
at dose levels of 0 (vehicle), 1, 3 and 10 mg/kg/day
once daily for 4 weeks, and 30 mg/kg/day once daily for
3 weeks (N=5). The skin colour on the face was
measured 3 times by Colorimeter (Konica Minolta) and
the mean of the 3 measurement values was regarded
as the L* value. The ΔL* represents the differences of
individual L* values between each time point and pre‐
test.
2.9
|
Pharmacokinetic studies
Blood was collected after single oral dosing of MT‐7117
was administered to 7‐week‐old male Ay/a mice (N=4)
and after 4‐weeks’ repeated oral dosing of monkeys in
the facial skin colour study (N=5). Plasma concen-
trations of MT‐7117 were determined using a high‐
performance liquid chromatography/tandem mass
spectrometry system (AB Sciex, API 4000 or 4000
QTRAP).
2.10
|
Statistical analysis
To evaluate the effects of the test substances, Dunnett's
multiple comparison test, Williams' multiple comparison
test or Fisher's exact test were performed to compare the
treated groups with the controls. To estimate the EC
50
values and their 95% confidence intervals, nonlinear
regression analysis was performed. The geometric
mean and 95% confidence interval of the EC
50
value
were determined from the data obtained in the 3 exper-
iments. All analyses were done using the SAS system,
and tests were two‐tailed with a significance level of
<0.05 or one‐tailed with a significance level of <0.025.
3
|
RESULTS
3.1
|
Binding afnity and agonistic
activity of MT‐7117 for MCRs
The binding affinity of MT‐7117 for a series of human
MCRs was evaluated using a competitive binding assay
with [
125
I] NDP‐αMSH. MT‐7117 showed the highest
affinity for hMC1R with a Ki value of 2.26 nmol/l
(Table 1). The Ki values of MT‐7117 for hMC3R,
hMC4R and hMC5R were 1420, 32.9 and 486 nmol/l,
respectively, demonstrating selectivity of MT‐7117 for
MC1R (Table 1). In contrast, while NDP‐αMSH showed
the highest affinity for MC1R with a Ki value of
0.028 nmol/l, its binding affinity for hMC3R, hMC4R and
hMC5R were 0.17, 0.20 and 0.21 nmol/l, respectively,
indicating its affinity across MCRs was also in the sub‐
nanomolar range (Table 1).
Agonistic activities of MT‐7117 and αMSH were
evaluated on the basis of their ability to increase intra-
cellular cAMP in HEK293 cells that stably express
hMC1R with wild‐type or representative single‐
nucleotide polymorphisms. Both test substances
increased cAMP in a concentration‐dependent manner
in cells with variants of MC1R and wild type, although the
response of V60L and R151C mutants were weaker than
that of the wild type MC1R (Figure 2). The Emax values of
MT‐7117 reached similar levels to those of αMSH,
TABLE 1Binding activity of MT‐7117 for human recombinant
melanocortin receptors
Human recombinant receptor
Ki value for receptor
binding (nmol/l)
MT‐7117 NDP‐αMSH
MC1R 2.26 0.028
MC3R 1420 0.17
MC4R 32.9 0.20
MC5R 486 0.21
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SUZUKI
ET AL.
indicating that the agonistic efficacy of MT‐7117 is
comparable with that of αMSH (Figure 2).
To reveal species difference in agonistic activity, the
EC
50
values of MT‐7117, αMSH and NDP‐αMSH were
determined for MC1Rs of several species. Agonistic
activity for hMC4R was also evaluated since this re-
ceptor showed certain affinity to our compound
(Table 1). MT‐7117 showed agonistic activity for
hMC1R, cmMC1R and mMC1R, with EC
50
values of
8.16, 3.91 and 1.14 nmol/l, respectively (Table 2). In
contrast, the EC
50
value of MT‐7117 for hMC4R was
79.6 nmol/l (Table 2) and the EC
50
value for hMC2R
was >10 000 nmol/l (data not shown). The agonistic
activity of MT‐7117 for rat MC1R was also determined,
with an EC
50
value of 0.251 nmol/l (data not shown).
3.2
|
Melanin production in B16F1 cells
To evaluate the ability of MT‐7117 to induce eumelanin
production, B16F1 cells were incubated for 3 days with
MT‐7117 or NDP‐α‐MSH, and the melanin concentration
in the supernatant was determined. Both MT‐7117 and
NDP‐αMSH at concentrations of ≥3 pmol/l significantly
increased eumelanin production in a concentration‐
dependent manner, with EC
50
values (95% confidence
interval) of 13.00 (0.2865–590.2) and 8.455 (0.4249–
168.3) pmol/l, respectively (Figure 3).
3.3
|
Coat colour darkening of Ay/a
mice
MC1R agonists, such as αMSH, increase melanogen-
esis in the hair root and change the colour of the emer-
gent coat from a normal yellow into dark brown in Ay/a
mice.
16,17
The effects of MT‐7117 and NDP‐αMSH on
coat colour were examined in this study. MT‐7117 was
administered orally or NDP‐αMSH was subcutaneously
administered for 6 consecutive days. The colour of the
newly grown coat was assessed as yellow or black. The
coat colour of all mice was determined as black in the 0.3
and 3 mg/kg MT‐7117‐ and 2 mg/kg NDP‐αMSH‐treated
groups with statistical significance, indicating that MT‐
7117 induced coat colour darkening in Ay/a mice
(Figure 4a). To verify such an effect, histological exam-
ination of the hair root in the dorsal skin was performed
and melanin was stained by the Fontana‐Masson pro-
cedure. The pigmentation in hair roots of representative
animals in the vehicle group was brownish yellow
(Figure 4b), in contrast, that in 3 mg/kg MT‐7117‐treated
group was black (Figure 4c). These results suggest that
MT‐7117 elicited synthesis of eumelanin rather than
pheomelanin in hair roots in Ay/a mice.
3.4
|
Pharmacodynamic markers of
melanisation
To better understand how MT‐7117 influences melani-
sation in mice, the time course of gene expression
related to eumelanin synthesis was examined in pinnae
after single administration of MT‐7117. Tyr,Trp1 and Dct
are mainly involved in eumelanin biosynthesis.
1
Expression of all three genes were significantly upregu-
lated at 24, 48 and 72 h in the 3 mg/kg MT‐7117‐treated
group, while a tendency towards gene upregulation was
detected at 24 h after 0.3 mg/kg MT‐7117 (Figure 5).
3.5
|
Skin pigmentation in cynomolgus
monkeys
The induction and reversibility of pigmentation of facial
skin of cynomolgus monkeys induced by MT‐7117 was
measured by a colorimeter. During the dosing period,
statistically significant decrease of ΔL* values as
compared with the vehicle group were noted in the 30 mg/
kg‐treated group after 1 week, in the 10 mg/kg‐treated
group from after 3 weeks and in the 1 and 3 mg/kg‐treated
FIGURE 2 Effects of MT‐7117 on intracellular cAMP production in HEK293 cells transfected with stable expression of human MC1R
variants. αMSH was used as the reference. Data are mean SEM of triplicate wells. Results are representatives of three independent
experiments with similar findings
SUZUKI ET AL.
-
5 of 10
groups after 4 weeks (Figure 6). Pigmentation dimin-
ished 4 weeks after cessation of treatment in the 1, 3 and
10 mg/kg groups and 16 weeks after cessation in the
30 mg/kg group (Figure 6). These results indicate that
pigmentation induced by MT‐7117 was dose proportional
and its minimum effective dose was 1 mg/kg, and it was
reversed after cessation of administration.
3.6
|
Pharmacokinetic studies
Plasma concentrations of MT‐7117 were determined
after a single dose in Ay/a mice and after 4 weeks’
repeated dosing in cynomolgus monkeys. Pharmacoki-
netic parameters are summarised in Table 3. Plasma
levels of MT‐7117 in mice increased in a dose‐
proportional manner, while the rise in levels in monkeys
was greater than a dose‐proportional increase (Table 3).
4
|
DISCUSSION
We have described the pharmacological profile of a
novel oral MC1R agonist, MT‐7117, in experimental
models of melanin production. MT‐7117 behaved as a
full agonist for hMC1R in the recombinant cell assays
as demonstrated by the observation that Emax of MT‐
7117 reached the same level as that of the endoge-
nous agonist αMSH (Figure 2). Interestingly, MT‐7117
induced melanin production in B16F1 cells with an
EC
50
value close to that of NDP‐αMSH (Figure 3), while
the EC
50
value of cAMP production by MT‐7117 was
approximately 20‐fold less potent than that seen with
NDP‐αMSH in mMC1R‐transfected cells (Table 2). For
clarification, we examined cAMP production by MT‐
7117 or NDP‐αMSH in B16F1 cells and found that the
EC
50
value of MT‐7117 was similarly 19‐fold less potent
than that of NDP‐αMSH (Figure S1), which was
consistent with the result from mMC1R‐transfected
cells. We speculate that distinct intracellular signalling
pathways such as Erk1/2 and Akt phosphorylation other
than cAMP production reported in the literature
12
are
involved in MT‐7117‐induced melanisation in B16F1
cells. Further analysis will be needed to clarify the
precise mechanism of agonistic signalling of MT‐7117
to learn how it is different from peptide agonists.
The minimum effective doses of MT‐7117 were 0.3
and 1 mg/kg for the darkening of coat colour of mice
TABLE 2Comparison of agonistic
activity of MT‐7117 with αMSH and NDP‐
αMSH for stably expressing melanocortin
receptors on HEK293
EC
50
(nmol/l)
hMC1R cmMC1R mMC1R hMC4R
αMSH 0.203 9.84 3.17 45.1
(0.166–0.250) (3.10–31.2) (2.01–5.01) (10.8–188)
NDP‐αMSH 0.0564 0.205 0.0524 0.764
(0.0426–0.0748) (0.0670–0.628) (0.0274–0.100) (0.429–1.36)
MT‐7117 8.16 3.91 1.14 79.6
(6.74–9.88) (1.77–8.63) (0.259–5.06) (44.3–143)
Note: The EC
50
values were expressed as the geometric mean (95% confidence interval) of three
independent experiments.
Abbreviations: cmMC1R, cynomolgus monkey MC1R; hMC1R, human MC1R; hMC4R, human MC4R;
mMC1R, mouse MC1R.
FIGURE 3 Effects of MT‐7117 on melanin
production in B16F1 cells. Cells were treated
with the indicated concentrations of test
substances for 3 days. The % value is the
percentage of melanin production relative to
the maximum melanin production induced by
NDP‐αMSH calculated by nonlinear
regression analysis. Data are mean SEM of
three independent experiments. *p<0.05 and
**p<0.01 versus vehicle by Dunnett's
multiple comparison test
6 of 10
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SUZUKI
ET AL.
and skin pigmentation of monkeys, respectively
(Figures 4and 6). When we measured the serum levels
of MT‐7117 after single oral dosing in mice, Cmax
reached 5.6 ng/ml (=8.3 nmol/l) at 0.3 mg/kg (Table 3).
In regards to the plasma levels of MT‐7117 after
repeated oral dosing to monkeys, Cmax reached 53 ng/
ml (=78 nmol/l) at 1 mg/kg (Table 3). These results
indicate that the level of systemic exposure of MT‐7117
reasonably exceeded the EC
50
values of MC1R
agonistic activity, which represent the target level
necessary to exhibit efficacy in the body. Moreover, the
extent of darkness of skin pigmentation of monkeys
became greater and quicker dose‐proportionally up to
30 mg/kg of MT‐7117 without reaching saturation
(Figure 6). Once the administration was stopped,
reversal of skin pigmentation was observed over the
course of 19 weeks with the degree of reversal
dependent on the dosage. Skin turnover period is re-
ported to take 4–5 weeks.
18
Thus, the degree of
pigmentation induced by MT‐7117 will be influenced by
several factors such as dosage, frequency, duration
and kinetics of epidermal turnover, suggesting that
FIGURE 4 Effects of MT‐7117 on the coat
colour darkening of Ay/a mice. MT‐7117 and
NDP‐αMSH were administered for 6 days
and, then, the coat in the dorsal area was
shaved and the colour of the newly grown
coat was assessed as yellow or black.
##
p<0.01 versus vehicle by Fisher's exact
test, **p<0.01 versus vehicle by Fisher's
exact test with multiplicity adjusted using fixed
sequence procedure. (a) Representative
image of each group on day 6 (above) and the
number of mice with the emergent coat colour
determined as yellow or black (below).
(b) Representative image of Fontana‐Masson
staining of dorsal skin in the vehicle‐treated
group on day 6. The pigment in the hair root
was brownish yellow. (c) Similar image to
(b) from the MT‐7117 group treated at 3 mg/
kg. The pigment in the hair root was black
FIGURE 5 Effects of MT‐7117 on expression of genes related to melanogenesis in the pinnae from Ay/a mice. MT‐7117 was single
administered orally to mice at 0.03, 0.3 and 3 mg/kg; thereafter, the pinnae were dissected at the time points indicated. The time point for the
vehicle‐treated group was 72 h. Expression of Tyr,Trp1 and Dct genes was determined relative to hypoxanthine phosphoribosyltransferase 1
(Hprt). Data are mean SEM (N=5). *p<0.025 and **p<0.005 versus vehicle by Williams' multiple comparison test
SUZUKI ET AL.
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optimal administration for therapeutic usage should be
explored in clinical studies in order to maintain sufficient
levels of melanin over time to prevent phototoxic re-
actions caused by sunlight.
There is concern about the risk of melanoma by
overstimulation of pigmentation. In nonclinical, αMSH
showed neither increase cell proliferation nor invasion
of mouse melanoma in vitro.
19
We found that MT‐7117
showed no effect on cell proliferation in 5 human
melanoma cell lines in vitro (data not shown). More-
over, there was no histopathological change for mela-
nocytes in face, melanocyte abundant region in chronic
toxicity study in non‐rodent species (data not shown).
Hence, there is no evidence of melanoma risk for MT‐
7117 in nonclinical, although further studies are
needed to warrant the safety. Epidemiological evidence
indicates that mutations in MC1R are genetic risk fac-
tors for melanoma in humans that are thought to act by
loss of function.
20,21
The αMSH/MC1R agonism has a
role of prevention of skin cancer including melanoma by
up regulating two important photo‐protective mecha-
nisms, DNA repair and pigmentation.
10,22
Therefore,
impaired function rather than activation of MC1R may
increase the vulnerability of melanocytes to UV‐induced
transformation to malignant melanoma.
Apart from pigmentation, various biological effects
of endogenous ligand αMSH have been reported in
nonclinical settings, such as anti‐inflammatory ef-
fects,
2,23
anti‐fibrotic effects,
24,25
wound healing ef-
fects,
26
and enhancement of nucleotide excision
repair.
10,22
These effects suggest that αMSH plays a
broad protective role in homoeostatic maintenance in
the body. Future studies will determine if MT‐7117 can
elicit similar biological effects.
MT‐7117 showed high selectivity for MC1R, and to
some extent agonistic activity for MC4R (Table 2). MT‐
7117 was less likely to be distributed into the brain,
which is the predominant tissue of MC4R expression, in
a tissue distribution study in rats (data not shown).
Hence, based on specificity and distribution, we expect
MT‐7117 to act as a selective MC1R agonist in the
body. In contrast, NDP‐αMSH binds predominantly to
MC1R but still behaves as a pan‐MCR agonist, which
may cause unfavourable side effects such as nausea
and this could be explained by its binding to MC3R.
14
Although NDP‐αMSH is currently used to treat adult
patients with EPP, there remains a high medical need for
new effective, safe and more conveniently administered
treatments for EPP and XLP, especially for pediatric/
adolescent patients who have had no options to date.
The oral route of administration of MT‐7117 is a salient
FIGURE 6 Effect of MT‐7117 on skin pigmentation in
cynomolgus monkeys. MT‐7117 was administered orally to
monkeys at 0 (vehicle), 1, 3 and 10 mg/kg for 4 weeks and 30 mg/
kg for 3 weeks. Thereafter, the administration was stopped.
Changes in ΔL* values, the differences of individual L* values
between each time point and pre‐test, are shown. Data are
mean SEM (N=5). *p<0.025 versus vehicle by Williams'
multiple comparison test
TABLE 3Pharmacokinetic parameters of MT‐7117 after oral administration to Ay/a mice and cynomolgus monkeys
Species/strain Dose (mg/kg) Day Sex C
max
(ng/ml) t
max
(h) AUC
0–8 h
(ng·h/ml) AUC
0–24 h
(ng·h/ml)
Mouse/Ay/a 0.03 1 M 0.668 0.5 2.62
0.3 1 M 5.62 2 31.8
Monkey/cynomolgus 1 28 F 53.0 2.6 428
3 28 F 401 1.0 2510
10 28 F 1510 1.8 14 100
Note: Pharmacokinetic parameters in mice are expressed as the mean of four animals. Pharmacokinetic parameters in monkeys are expressed as the mean of five
animals.
Abbreviations: AUC
0–8 h
, area under the plasma concentration–time curve from zero up to 8 h after dosing; AUC
0–24 h
, area under the plasma concentration–time
curve from zero up to 24 h after dosing; C
max
, maximum plasma concentration after administration; F, female; M, male; t
max
, time to reach maximum plasma
concentration after administration.
8 of 10
-
SUZUKI
ET AL.
feature that provides ease of administration and results
in consistent therapeutic levels of the compound. In
conclusion, we have designed MT‐7117, a novel and
selective oral MC1R agonist. MT‐7117 is currently being
assessed in a phase 3 trial (NCT04402489) as a potential
new therapeutic option to permit an increase in pain‐free
light exposure for adults and adolescents with a history of
phototoxic reactions from EPP or XLP.
ACKNOWLEDGEMENTS
We thank Mr. Yasushi Horai for his contribution to his-
tological evaluation. We thank Mr. Ryosuke Ide and Ms.
Miho Kamezawa for their contribution to pharmacoki-
netic studies.
CONFLICT OF INTEREST
All authors are employees of Mitsubishi Tanabe
Pharma Corporation.
AUTHOR CONTRIBUTIONS
T. Suzuki: Conceptualization; Data curation; Formal
analysis; Investigation; Methodology; Project adminis-
tration; Supervision; Validation; Visualization; Writing –
original draft; Writing – review & editing. Y. Kawano:
Conceptualization; Data curation; Investigation; Meth-
odology; Project administration; Software; Validation;
Writing – original draft; Writing – review & editing. A.
Matsumoto: Data curation; Formal analysis; Investi-
gation; Methodology; Software; Validation; Visualiza-
tion; Writing – original draft; Writing – review & editing.
M. Kondo: Conceptualization; Data curation; Formal
analysis; Investigation; Methodology; Project adminis-
tration; Software; Validation; Visualization; Writing –
original draft; Writing – review & editing. K. Funayama:
Investigation; Methodology; Software; Validation. S.
Tanemura: Investigation; Methodology; Software;
Validation. M. Miyashiro: Conceptualization; Investi-
gation; Methodology; Project administration;
Resources; Software; Supervision; Validation; Writing –
review & editing. A. Nishi: Conceptualization; Investi-
gation; Methodology; Project administration; Re-
sources; Software; Supervision; Validation; Writing –
review & editing. K. Yamada: Investigation; Methodol-
ogy; Software; Validation; Writing – review & editing. M.
Tsuda: Investigation; Methodology; Software; Valida-
tion; Writing – original draft; Writing – review & editing.
A. Sato: Investigation; Methodology; Validation.
K. Morokuma: Investigation; Methodology; Validation.
Y. Yamamoto: Investigation; Methodology; Project
administration; Resources; Supervision; Validation.
DATA AVAILABILITY STATEMENT
Research data are not shared.
ORCID
T. Suzuki
1. Wolf Horrell EM, Boulanger MC, D'Orazio JA. Melanocortin 1
receptor: structure, function, and regulation. Front Genet. 2016;
7:95.
2. Getting SJ. Targeting melanocortin receptors as potential novel
therapeutics. Pharmacol Ther. 2006;111(1):1–15.
3. Beaumont KA, Wong SS, Ainger SA, Liu YY, Patel MP, Mill-
hauser GL, et al. Melanocortin MC(1) receptor in human
genetics and model systems. Eur J Pharmacol. 2011;660(1):
103–10.
4. Hunt G, Kyne S, Wakamatsu K, Ito S, Thody AJ. Nle4DPhe7
alpha‐melanocyte‐stimulating hormone increases the eumela-
nin:phaeomelanin ratio in cultured human melanocytes. J Invest
Dermatol. 1995;104(1):83–5.
5. Brzoska T, Luger TA, Maaser C, Abels C, Bo
̈hm M. Alpha‐
melanocyte‐stimulating hormone and related tripeptides:
biochemistry, antiinflammatory and protective effects in vitro
and in vivo, and future perspectives for the treatment of
immune‐mediated inflammatory diseases. Endocr Rev. 2008;
29(5):581–602.
6. Gerstenblith MR, Goldstein AM, Fargnoli MC, Peris K, Landi
MT. Comprehensive evaluation of allele frequency differences
of MC1R variants across populations. Hum Mutat. 2007;28(5):
495–505.
7. Nakayama K, Soemantri A, Jin F, Dashnyam B, Ohtsuka R,
Duanchang P, et al. Identification of novel functional variants of
the melanocortin 1 receptor gene originated from Asians. Hum
Genet. 2006;119(3):322–30.
8. Wong TH, Rees JL. The relation between melanocortin 1 receptor
(MC1R) variation and the generation of phenotypic diversity in the
cutaneous response to ultraviolet radiation. Peptides. 2005;
26(10):1965–71.
9. Riley PA. Melanin. Int J Biochem Cell Biol. 1997;29(11):1235–9.
10. Swope V, Abdel‐Malek Z. MC1R: front and center in the bright
side of dark eumelanin and DNA repair. Int J Mol Sci.
11. D'Orazio JA, Nobuhisa T, Cui R, Arya M, Spry M, Wakamatsu K,
et al. Topical drug rescue strategy and skin protection based on
the role of Mc1r in UV‐induced tanning. Nature. 2006;443(7109):
340–4.
12. Pillaiyar T, Manickam M, Jung SH. Downregulation of melano-
genesis: drug discovery and therapeutic options. Drug Discov
Today. 2017;22(2):282–98.
13. Langendonk JG, Balwani M, Anderson KE, Bonkovsky HL,
Anstey AV, Bissell DM, et al. Afamelanotide for erythropoietic
protoporphyria. N Engl J Med. 2015;373(1):48–59.
14. Minder EI. Afamelanotide, an agonistic analog of alpha‐
melanocyte‐stimulating hormone, in dermal phototoxicity of
erythropoietic protoporphyria. Expet Opin Invest Drugs. 2010;
19(12):1591–602.
15. Ohgaki R, Wei L, Yamada K, Hara T, Kuriyama C, Okuda S,
et al. Interaction of the sodium/glucose cotransporter (SGLT) 2
inhibitor canagliflozin with SGLT1 and SGLT2. J Pharmacol Exp
Therapeut. 2016;358(1):94–102.
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Hruby VJ, et al. Stimulation of follicular melanogenesis in the
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1987;89(3):269–73.
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invasion of reconstituted basement mambrane (Matrigel) by
SUZUKI ET AL.

Uhohinc

unread,
Jan 27, 2022, 1:48:10 AM1/27/22
to Clinuvel Afamelanotide SCENESSE senescence CUV ASX.CUV CLVLY ur9
https://docplayer.net/215588621-Mitsubishi-tanabe-pharma-corporation-medium-term-management-plan-minutes-of-investor-meeting-presentation-q-as.html

Mitsubishi Tanabe Mt 7117 is seeking a "precision" dose  selective to strata of patients, and looking for "biomarkers" to facilitate proper doseages to the individual.

Uhohinc

unread,
Jan 31, 2022, 9:21:12 AM1/31/22
to Clinuvel Afamelanotide SCENESSE senescence CUV ASX.CUV CLVLY ur9
Hiroaki Ueno is not really "seeking" a "precision" dose and customizing his Mt 7117 desmerlagon melanocortin 1 stimulation for the benefit of patients for a more efficacous therapy..............I think his drug is a problem in that not all patients are responding favorably to his drug and some have side effects to doseage to efficacy issues. He has put a good public relations on a problem.

Uhohinc

unread,
Mar 9, 2022, 1:13:11 PM3/9/22
to Clinuvel Afamelanotide SCENESSE senescence CUV ASX.CUV CLVLY ur9
https://www.youtube.com/watch?v=zAiR1wniF_U at 3 minutes in Dr. Wolgen addresses intrepid stock analysts opines to competitive pharma candidates at the time, pertinent to Forskholin, and then Prostroglandin E2 which were circa 2007 2013 as melanin inducers that were not practical for numerous reasons.
At 6 minutes Dr. Wolgen addresses the Mt-7117 generic Desmergolen which also has been around for decades and until Mitsubishi Tanabe all other pharma, including the big ones, pulls off the shelf and puts back on the shelf.

Dr. Wolgen emphasizes the owned and conducted by Mitsubishi comparisons in pharmkinetics released December 2021 and the 81 times more binding affinity of Clinuvel's Afamelanotide relative to Desmergolen at Mcr1, as well as incredulous affinity at Mcr4. 
Dr. Wolgen also points to the doseage now at 300mg of Mt-7117 per day, propensity for recreational abuse, and the implications of this humongous dose, which in the above  posts does appear to be a humongous problem.....and the Ceo of Mitsubishi putting a rosey and positive about Mt-7117 as to how the company has the drug planned for individualized custom dose and monitoring to structure a personalized therapy for EPP patients with their own unique dose.................imnshopinion..............this is really silly words play to cover up a chaotic drug interaction variables and pecuniaries individualized to the drug to patients interaction all different in each patient.

Outside of this, to note, Desmeragolen does not appear to use the cAMP pathway as Afamelanotide does...................just wondering what does the Mitsubishi Tanabe management game plan for a succcessful revenue generating Desmeragolen. I think they must have a goal and a alternative drug for the Porphyria population does not look good as a poor number 2 choice for a therapy with convenience of oral but a high rate of side effects not tolerated by a high rate of trial patients, and long term side effects and the gastro intestnianl issues in a high rate.

As with any human endeavor, perseverence and tenacity are incredible advantageous personality character traits, but not knowing when to jump into a rabbit hole or quit chasing something down a dead end is a balance. Reminds me of Smitty's Tunnel in the California desert in the middle of no where.

Uhohinc

unread,
Mar 9, 2022, 1:14:58 PM3/9/22
to Clinuvel Afamelanotide SCENESSE senescence CUV ASX.CUV CLVLY ur9
https://en.wikipedia.org/wiki/Burro_Schmidt_Tunnel

Uhohinc

unread,
Mar 20, 2022, 8:03:18 AM3/20/22
to Clinuvel Afamelanotide SCENESSE senescence CUV ASX.CUV CLVLY ur9
investekWell-known member
WO2022053570 - PYRROLIDINE COMPOUNDS TO TREAT XERODERMA PIGMENTOSUM

- PYRROLIDINE COMPOUNDS TO TREAT XERODERMA PIGMENTOSUM

WO2022053570 PYRROLIDINE COMPOUNDS TO TREAT XERODERMA PIGMENTOSUM
The present invention relates to pyrrolidine compounds for treatment of Xeroderma Pigmentosum (XP), specifically for enhancing DNA repair in a subject suffering from XP.

Claims
1. Pyrrolidine compound for use in the treatment of a human subject suffering from Xeroderma Pigmentosum (XP), wherein the pyrrolidine compound is represented by formula :



wherein

ring A represents an optionally substituted aryl group or an optionally substituted heteroaryl group;



R1 represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group that may be partially hydrogenated, an optionally substituted heteroaryl group, or an optionally substituted carbamoyl group;



R2 represents a halogen atom, an alkyl group, or an optionally substituted alkoxy group;



R3 is an alkyl group substituted with an optionally substituted aryl group, or an alkyl group substituted with an optionally substituted heteroaryl group and R4 is a hydrogen atom or an alkyl group; or R3 and R4are terminally attached to each other, and together with the nitrogen atom to which they are attached, form an optionally substituted nitrogen-containing aliphatic heterocyclic ring that may partially contain a double bond;

or a pharmaceutically acceptable salt thereof.



2. Compound for use according to claim 1, wherein the compound is used in enhancing DNA repair in the treatment of a human subject suffering from Xeroderma Pigmentosum (XP).



3. Compound for use according any of claims 1-2, wherein the compound is a 3,3-di-substituted pyrrolidine compounds with 2 substituents in the 3-position of pyrrolidine and wherein the compound preferably has substituents in the 1-, 3-, and 4-positions.

4. Compound for use according to any of claims 1 to 3, wherein the pyrrolidine compound is 1-{2-[(3S,4R)-l-{[(3R,4R)-l-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.



5. Compound for use according to any of claims 1 to 4, wherein the compound is administered orally.



6. Compound for use according to any of claims 1-5, wherein the compound is administered daily.



7. Compound for use according to any of claims 1 to 6, wherein the compound is administered at least 3 times consecutively to the human subject.



8. Compound for use according to any of claims 1 to 7, wherein XP is selected from complementation group A (XP-A), complementation group B (XP-B), complementation group C (XP-C), complementation group D (XP-D), complementation group E (XP-E), complementation group F (XP-F), complementation group G (XP-G), and variant type (XP-V).



9. Compound for use according to any of claims 1 to 7, wherein the compound is used for treatment of complementation group C (XP-C).



10. Method of treating Xeroderma Pigmentosum (XP) by administering a pyrrolidine compound.



11. Method according to claim 10, wherein the compound is administered to a human subject with an interval between subsequent administrations of the pyrrolidine compound is between 1 to 15 days.



12. Use of a pyrrolidine compound for the manufacture of a medicament for the treatment of Xeroderma Pigmentosum.

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