The “Endeavor” Mt-7117 trial results to be presented at a “congress” in early 2020 per press release of International Porphyria.....

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Uhohinc

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Jan 7, 2020, 11:40:39 PM1/7/20

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https://porphyria.network/IPPN/2019/11/mt-7117-endeavor-study-for-epp/

Uhohinc

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Jan 7, 2020, 11:44:22 PM1/7/20

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https://porphyria.network/IPPN/about/

Rocco Falchetto and Jamine ......

Uhohinc

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Jan 8, 2020, 2:34:22 PM1/8/20

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This excerpted quote leads me to think, even the EPP patients and patient organizations do not know anything about the drug.

“The IPPN looks very much forward to understanding more about the safety and efficacy of MT-7117 from these results as well as about the study design and the endpoints used to assess the potential of this drug candidate.”

What is still not succinct is what is the commercialization plan of Mitsubishi Tanabe management with its MT7117. Logically in a phase III trial of EPP patients the FDA will imo REQUIRE that this trial be comparisoned to the best viable therapy available........and thats Scenesse. I still can not see how they found the about 100 qualified EPP patients in USA. Perhaps the adjusted prequisites for pa tients whom previously participated on Scenesse trials

Japan (Mitsubishi Tanabe domaimed) has a relative to other countries to EPP genetics a very high prevalence to EPP, but this orphan disease EPP is not a good return on investment nor longterm commercial strategic market.

From the EC values in the patents, Mitsubishi Tanabe has VERY successfully targeted almost exclusively MCR1. Mt7117 is a very unstable chemistry and fragile to slight temperature gradients that even degrade way before 98.6 degrees farenh. Internal to human stomach etc..

So they figured out a method of getting it into the blood thru the small intestine. But they did not go subcutaneous implant nor injection to be absorbed into the blood........?

If we get to the primary endpoint, it is the basics of Clinuvels photopretection, therefore melanization .

Clinuvels plan with transdermal encapsulization imo has extremely negligible commercial competition from a oral MT7117.

But its not publicly known if MT7117 can be modified chemically for transdermal. And Mitsubishi Tanabe in oral dose with such high specificity to MCR1 has numerous and huge commercial oppurtunities in other therapies that maybe Mitsubishi Tanabe is just using EPP as a Trojan Horse thru FDA EMA.

Even if Mitsubishi Tanabe can eventually marriage future transdermal technoly to its MT7117 for photoprotective melangenisis, dna repair, anti-tumor, etc...I think there is plenty of room for Scenesse and MT7117, and therefore Mitsubishi Tanabe would have to think so too.

Uhohinc

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Jan 8, 2020, 2:40:36 PM1/8/20

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Dersimelagon mollecular weight approx 650 molar

https://www.google.com/search?q=Dersimelagon+molecular+weight&client=safari&channel=ipad_bm&prmd=inv&tbas=0&source=lnt&sa=X&ved=2ahUKEwj06PvD4PTmAhXzN30KHRnTC84QpwV6BAgDEAw&biw=1024&bih=638&dpr=2

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Uhohinc

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Aug 14, 2020, 1:27:55 PM8/14/20

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https://aad.wistia.com/medias/42kbhqkkm0

Uhohinc

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Aug 15, 2020, 3:03:06 AM8/15/20

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https://www.mitsubishichem-hd.co.jp/english/ir/pdf/00967/01092.pdf

Mitsub report ....page 28 plus......indicates 10,000 EPP global patients......indicates NDA in FY 2021........

Uhohinc

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Aug 25, 2020, 3:27:23 PM8/25/20

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Society for Pediatric Dermatology: Top news from the virtual conference

CONFERENCE COVERAGE

Novel oral drug improves sunlight tolerance in patients with erythropoietic protoporphyria

Publish date: August 24, 2020

By Bruce Jancin

FROM AAD 2020

Dersimelagon, a novel once-daily oral selective melanocortin-1 receptor agonist, significantly boosted sunlight tolerance in patients with erythropoietic protoporphyria in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.

Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.

Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.

“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.

Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.

Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.

The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.

FDA approves afamelanotide for treatment of rare condition with light-induced pain

The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.

Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.

Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.

The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.

EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.

In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.

Dr. Belangie is employed by the study sponsor.

bja...@mdedge.com

Uhohinc

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Aug 26, 2020, 12:34:14 AM8/26/20

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Theres a little more here than others.in this that MAY not be advantageous compared to Scenesse as known......note it takes 6 weeks for the medication to show significance to placebo. Compared to Sceness this makes no sense. Significance to melaninization or is this the time spent in sun increases for results of primary endpoint.

Interesting but they do not itemize that, so I must think its ALL patients in trial on both 300mg and 100mg.

Even more interesting , when the compare between the two doses is considered, the 300 mg dose more than doubled or even tripled the nevi, the freckles, the hyper pigmentation which reached 31% (verse 9% in the 100mg dose)

Is 100mg just not enough to be theraputic or is 300mg just to much.......i can presume no one wants nevi, few want freckles, and is hyperpigmentation too dark. The articledid state freckles, nevi, and hyperpigmentation are side effects.

As to hyperpigmentation in the 300mg dose only reached 31% then whats going on with the other 69%.....is not hyperpigmentation the goal ? And at where is the personal difference of the definition of hyper pigmentation or if there is even actual normal pigmentation....how measured ?

The adverse events are very high imo. Nausea, headaches and diahreea...........But we do not know if these effects are at first, or soon after oral, or continuois.

And we do not know if single patients experienced one two or all three of adverse events.

That 83 minute gain in time in sun for 300mg dose dies not look so good if one has a one in two chance of staying on a toilet or regurgitating, or geadache everyday......

Uhohinc

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Aug 26, 2020, 12:46:29 AM8/26/20

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To note, a 500% increase in trial patients dropping out if the trial at 300mg, verses the one trial patient whom dropped out on the 100mg dose. Wow.......Clinuvel to my recall had no trial patient drop out over adverse events. That extra 300mg gives alot of side effects and not nearly a significant increase in time in minutes spent in sun.

We do not know if weight dependent, male or female, age is medianed so we do not even know whom dropped out. Did the side effects adapt in other completed trial patients......we still do not know what they have encased the drug in to facilitate its intestinal crossing.

Uhohinc

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Aug 26, 2020, 1:11:07 AM8/26/20

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I will presume that of the 102 patients in trial, that 33 of them were on placebo. 33 on 100mg and 33 on 300mg.......So out of 66 patients actually on the drug, 6 dropped out for a rate of 10% did not want the side effects, yet with the oercentages of non placebo trial patients with the side effects were in 46% if 33 of the 300mg patients.....

A trial patients is more eager tobear it thru than a later patient on approved drug.

Dose of this drug I think has been rushed, or maybe they intend to let a physician adjust doseage if when approved to the peculiarities of each patient.

Since it is not an melanocyte stimulating horemone peptide, i do not know how long it survives in the blood. Nor how long does it stay in the receptor.......Since its not 50mg twice a day, I suspect the 100mg is the minimumto get a minute amount thru the intstines to the blood. But that high rate of diareaha makes me think the entire problem to this is getting it thru the intestine wall to blood. It may be the coating or what they use to get the drug there. And to consider the melanocotin receptors one on the cells that line the intestines and even facilitate the anti inflammatory and interlocking of distance between cells lining intstines to tighten (or loosen) to regulate permability between cells.

And importantly, to facilitate the drug getting by the junction of cells into blood from absrbing thru intestine, is the drug allowing fecal fauna to also get in.......and an ensuing immune response to the microbes or fungal, or viral that are there always sneeking by with nutrients

Uhohinc

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Dec 1, 2020, 5:30:33 PM12/1/20

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102.REGULATION OF IRON METABOLISM| NOVEMBER 5, 2020

Erythropoietic Protoporphyria: Phase 2 Clinical Trial Results Evaluating the Safety and Effectiveness of Dersimelagon (MT-7117), an Oral MC1R Agonist

Manisha Balwani,

Herbert L. Bonkovsky, MD,

Kirstine J Belongie, PhD,

Karl E Anderson, MD,

Fumihiro Takahashi, PhD,

Antonio Irizarry, MBA,

Mark Amster, MD,

D. Montgomery Bissell, MD,

Bruce Wang, MD,

Lydie Hazan, MD,

Charles J. Parker, MD,

Edward Cordasco, MD,

Cynthia Levy, MD,

Robert J. Desnick, MD PhD

Blood (2020) 136 (Supplement 1): 51.

https://doi.org/10.1182/blood-2020-142467

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Introduction

Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) are inborn errors of heme biosynthesis caused by the abnormal accumulation of erythrocyte protoporphyrin IX (ePPIX). These protoporphyrias are characterized by excruciating painful attacks on prolonged sunlight exposure. Before the onset of phototoxic pain, patients experience characteristic prodromal symptoms which serves as a warning signal to avoid further sun exposure. Of note, patients with higher ePPIX levels report shorter times to symptoms compared to patients with lower median ePPIX levels (JAMA Derm, 2017; 153). Here we report the safety and effectiveness of Dersimelagon (MT-7117), a novel, orally-administered, small molecule, selective melanocortin-1 receptor (MC1R) agonist that increases skin melanin without sun exposure and is being developed to increase light tolerance in EPP/XLP patients. Results of the primary, secondary efficacy endpoints, and post-hoc subgroup analyses evaluating effects of baseline ePPIX levels on treatment response will be presented.

Methods

The MT-7117-A01 (ENDEAVOR) study was a Phase 2, multi-center, randomized, placebo-controlled study with a 16-week double-blind treatment period. A total of 102 EPP/XLP patients were randomized to 3 groups: placebo once daily (QD) (n=35 [31 EPP/4 XLP]), MT-7117 100 mg QD (n=33 [31 EPP/2 XLP]), and MT-7117 300 mg QD (n=34 [31 EPP/3 XLP]). Results of the primary endpoint, increase in the average daily time (min) to first prodromal symptom during sunlight exposure, and secondary endpoints including 1) average daily duration of sunlight exposure without prodromal symptoms, 2) total number of sunlight exposure episodes with prodromal symptoms, and 3) total number of pain events, and post-hoc subgroup analyses evaluating baseline median ePPIX levels are presented here. Safety and tolerability were also assessed.

Results

There was a significant improvement in average daily time (>50 min) to first prodromal symptom [the primary endpoint] associated with sunlight exposure in subjects treated with MT-7117 100 mg (p=0.008) or 300 mg (p=0.003) compared to placebo at Week 16. Multiple secondary endpoints supported primary endpoint. There was a significant increase in average daily minutes of sunlight exposure without prodromal symptoms at Week 16 in 100 mg (p=0.009) and 300 mg (p=0.004) treated subjects compared to placebo, with an increased average exposure time without prodromal symptoms of ~50 min in MT-7117 subjects at both doses compared to placebo. There was also a 40% reduction in the total number of sunlight exposure episodes with prodromal symptoms in 100 mg (p=0.019) and 300 mg (p=0.006) subjects compared to placebo. There was a significant decrease in the total number of pain events reported in 100 mg (p=0.027, 60% reduction) and 300 mg (p=0.028, 50% reduction) subjects compared to placebo.

The post-hoc subgroup analysis evaluating the effects of baseline ePPIX levels in subjects grouped based on the baseline median ePPIX level of 1981 µg/dL. There was a statistically significant increase in average daily time to first prodromal symptom in the subgroup with ePPIX levels ≥1981 µg/dL receiving 100 mg (p=0.020) and 300 mg (p=0.003) compared to placebo. A trend to beneficial effect was also observed for the subgroup of subjects with ePPIX levels <1981 µg/dL receiving 100 mg (p=0.180) and 300 mg (p=0.216) compared to placebo.

MT-7117 had an acceptable safety and tolerability profile. The most common treatment-related treatment emergent adverse reactions were nausea (27.9%), ephelides (23.5%), and skin hyperpigmentation (20.6%).

Conclusion

The results of the primary efficacy endpoint and multiple secondary endpoints in this Phase 2 study indicate that the oral, MC1R agonist dersimelagon was efficacious after 16 weeks of treatment in increasing symptom-free light exposure in patients with EPP or XLP at doses of 100 and 300 mg QD and showed an acceptable safety and tolerability profile. The post-hoc analyses showed more profound and statistically significant efficacy at both doses for the subgroup with higher baseline median ePPIX levels.

Disclosures

Balwani:Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding; Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording. Anderson:Alnylam Pahrmaceuticals: Consultancy; Recordati Rare Diseases: Consultancy; Mitsubishi Tanabe Pharma: Consultancy.

Author notes

Asterisk with author names denotes non-ASH members.

Uhohinc

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Mar 1, 2021, 1:05:20 PM3/1/21

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https://www.mt-pharma.co.jp/e/company/financial-information/pdf/e_presen210203.pdf Mitsubishi Tanabe latest report, includes Mt-7117 program and 2023 or later launch date for commercial. More press releases and APA indicative more EPP patients needed for enroll.

Two deletions above ???????????????????????????????????????

Uhohinc

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Mar 6, 2021, 1:32:26 PM3/6/21

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20 more patients needed for the trial.

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Uhohinc

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Mar 11, 2021, 11:19:39 PM3/11/21

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Study to Investigate Drug-Drug Interaction Between MT-7117 and Test Drugs in Healthy Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT04793295

Recruitment Status : Not yet recruiting

First Posted : March 11, 2021

Last Update Posted : March 11, 2021

See Contacts and Locations

Sponsor:

Mitsubishi Tanabe Pharma Development America, Inc.

Information provided by (Responsible Party):

Mitsubishi Tanabe Pharma Development America, Inc.

Study Description

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Brief Summary:

Study is to investigate drug levels in the blood after taking single or multiple doses of the study drug, MT-7117, in healthy adults when taken together with another drug. This study will also look at the safety and the body's ability to tolerate MT-7117

Condition or disease Intervention/treatment Phase
Healthy Subjects
Drug: MT-7117
Phase 1

Study Design

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Study Type  :
Interventional (Clinical Trial)
Estimated Enrollment  :
111 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Open Label
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Phase I, Open-Label, Four-Part, Single-Sequence Study to Investigate Drug-Drug Interaction Between MT-7117 and Test Drugs in Healthy Subjects
Estimated Study Start Date  :
March 2021
Estimated Primary Completion Date  :
June 2021
Estimated Study Completion Date  :
June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

U.S. FDA Resources

Arms and Interventions

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Arm Intervention/treatment
Experimental: MT-7117 Drug-drug interaction with test drug 1 and test drug 2
Drug: MT-7117

MT-7117

Other Name: Dersimelagon

Experimental: MT-7117 Drug-drug interaction with test drug 3 and test drug 4
Drug: MT-7117

MT-7117

Other Name: Dersimelagon

Experimental: MT-7117 Drug-drug interaction with test drug 5 and test drug 6
Drug: MT-7117

MT-7117

Other Name: Dersimelagon

Experimental: MT-7117 Drug-drug interaction with test drug 7
Drug: MT-7117

MT-7117

Other Name: Dersimelagon

Outcome Measures

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Primary Outcome Measures :

Maximum observed plasma concentration (Cmax) [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)
Area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC0-∞) [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)
AUC from time zero to the last measurable concentration (AUC0-last) [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)

Secondary Outcome Measures :

Time to reach maximum plasma concentration (tmax) [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)
t1/2 [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)
Apparent oral clearance [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)
Apparent volume of distribution during the terminal phase after oral administration [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products in the absence and presence of MT-7117 (Parts 1, 2, and 3) and MT-7117 in the absence and presence of test drug 7 (Part 4)
Cmax [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products metabolites in the absence and presence of MT-7117 (Parts 1, 2, and 3)
tmax [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products metabolites in the absence and presence of MT-7117 (Parts 1, 2, and 3)
t1/2 [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products metabolites in the absence and presence of MT-7117 (Parts 1, 2, and 3)
AUC0-last [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products metabolites in the absence and presence of MT-7117 (Parts 1, 2, and 3)
AUC0-∞ [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
PK parameters of IMP Test Products metabolites in the absence and presence of MT-7117 (Parts 1, 2, and 3)
MT-7117 concentrations in plasma [ Time Frame: Part 1 Day 1 to Day 19, Part 2 Day 1 to Day 15, Part 3 Day 1 to Day 17, Part 4 Day 1 to Day 13 ]
Safety and tolerability as measured by incidence of adverse events [ Time Frame: Part 1 Day -1 to Day 25, Part 2 Day -1 to Day 21, Part 3 Day -1 to Day 23, Part 4 Day -1 to Day 19 ]

Eligibility Criteria

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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:
18 Years to 55 Years (Adult)
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes

Criteria

Inclusion Criteria: Subjects will be eligible for inclusion in the study if they meet all of the following criteria:

Able and willing to provide written informed consent to participate in this study after reading the participant information sheet and Informed Consent Form (ICF) and having the opportunity to discuss the study with the Investigator or designee.
White (a person having origins in any of the original peoples of Europe, the Middle East or North Africa) male or female subjects, 18-55 years of age, inclusive, at the time of signing the ICF.
Subjects must weigh at least 50 kg (110 pounds) and have a body mass index 18-30 kg/m2, inclusive, at Screening and on Day -1.
Female subjects must not be lactating, and women of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test within 24 hours prior to receiving the first dose of IMP or IMP Test Products.
Female subjects of childbearing potential and male subjects with a partner of childbearing potential must agree to use 2 effective methods of contraception (in female subjects, one method must be highly effective). Full details of contraception in Section 4.6.5.
In the Investigator's opinion, the subject must be able to understand the nature of the study and any risks involved in participation and be willing to cooperate and comply with the protocol restrictions and requirements.

Exclusion Criteria: Any subject meeting any of the following criteria will not qualify for enrolment in the study:

Current, or history of, clinically significant (in the opinion of the Investigator) neurological conditions, endocrine, thyroid, hepatic, respiratory, gastrointestinal, renal, or cardiovascular disease, or history (within the last 2 years) of any clinically significant psychiatric/psychotic illness disorder (including anxiety, depression, and reactive depression).
Clinically relevant abnormal medical history, physical findings, or laboratory values at Screening or Day-1 that could interfere with the objectives of the study or the safety of the subjects, in the opinion of the Investigator.
A history of gastrointestinal surgery known to affect the absorption, metabolism, or excretion of the IMP or IMP Test Products such as bariatric surgery or removal of part of the bowel. A history of appendicectomy and hernia repair/herniorrhaphy/hernioplasty is permitted for inclusion in the study.
Family history of long or short QT syndrome, hypokalemia, syncope, or Torsades de Pointes.
Clinically significant 12-lead electrocardiogram (ECG) abnormalities, including subjects with corrected QC interval (QTc) using Fridericia's formula >450 ms (male) and >470 ms (female), at Screening or Day -1. A repeat assessment is allowed at each visit. If the repeat measurement is in range, the subject may be included.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 1.5 the upper limit of normal (ULN) reference range, or bilirubin ≥ 1.5 ULN at screening or Day-1. A repeat assessment is allowed at each visit. If the repeat measurement is in range, the subject may be included.
Systolic blood pressure outside the range of 90-145 mmHg, diastolic blood pressure outside the range of 50-95 mmHg, or pulse rate outside the range of 50-100 bpm, taken in the supine position at Screening or Day -1. A repeat assessment is allowed at each visit. If the repeat measurement is in range, the subject may be included.
Receipt of any prescribed of nonprescribed systemic or topical medication within 30 days (or, if relevant, 5 half-lives, whichever is longer) prior to the first dose of study drugs unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the study procedures or compromise subject safety.
1. Occasional use of paracetamol (acetaminophen) for mild analgesia is permitted.
2. Vitamins and herbal supplements are not permitted 14 days prior to dosing
Presence or history of severe adverse reaction or allergy to food or any drug or excipient or other allergy that is of clinical significance to the study drugs.
Previous receipt of MT-7117.
First-degree relative with a history of familial melanoma.
Previous use of afamelanotide or melanotan.
Female subjects planning to donate eggs (during the study and for 3 months after the last visit).
Positive test for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, or human immunodeficiency virus (HIV) 1 or HIV 2 antibodies at Screening.
Presence or history of drug abuse (as defined by Diagnostic and Statistical Manual of Mental Disorders criteria), or a positive urine test for drugs of abuse at Screening or Day -1.
Presence or history (in the last 2 years) of alcohol abuse or excessive alcohol consumption, defined as subjects who regularly, or on average, drink more than 21 units (168 g) for males or 14 units (112 g) for females, of alcohol per week (1 unit is equivalent to 8 g of alcohol).
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.
Consumption of food or drink containing oranges, grapefruit, liquorice, or cranberry within the 7 days prior to the first dose of study drug.
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.
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.
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.
Participation in more than 3 clinical studies* involving administration of an IMP in the previous year, or any study* involving administration of an IMP within 12 weeks (or, if relevant, 5 half-lives, whichever is longer) prior to the first dose of study drug.
*Disregarding any study Follow-up Periods.
Subjects with the presence of a skin lesion suspicious for dysplastic nevus or a history of histologically proven dysplastic nevus.
Subjects who have any active malignancy (including melanoma) or history of significant malignancy (including melanoma).
Subjects who have had Coronavirus Disease 2019 (COVID-19) in the 3 months prior to Screening; or suspected active COVID-19 infection, a positive COVID-19 test, contact with an individual with known COVID-19, or travel to an area with a high risk of COVID-19 infection within 14 days of Screening.
Subjects that test positive for COVID-19 at Day - 1.
Subjects who have received a COVID-19 vaccination within 14 days of Day 1. COVID-19 vaccination is not permitted during the study. Subjects may not take part in the study if they have started but not completed a COVID-19 vaccination course at the time of Screening or Day -1.
Subjects who have a history of major surgery within 3 months of Day 1.

Contacts and Locations

Go to

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04793295

Contacts

Contact: Mitsubishi Tanabe Pharma Europe Ltd General Information, To prevent mis-communication,
please e-mail
regul...@mt-pharma-eu.com

Locations

United States, Texas
Worldwide Clinical Trials

San Antonio, Texas, United States, 78217

Sponsors and Collaborators

Mitsubishi Tanabe Pharma Development America, Inc.

Investigators

Study Director:
Head of Medical Science
Mitsubishi Tanabe Pharma Development America, Inc.

More Information

Go to

Responsible Party:
Mitsubishi Tanabe Pharma Development America, Inc.
ClinicalTrials.gov Identifier:
NCT04793295 History of Changes
Other Study ID Numbers:
MT-7117-Z-102

First Posted:
March 11, 2021 Key Record Dates
Last Update Posted:
March 11, 2021
Last Verified:
March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:
No

Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No

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Erythropoietic Protoporphyria: Phase 2 Clinical Trial Results Evaluating the Safety and Effectiveness of Dersimelagon (MT-7117), an Oral MC1R Agonist

November 2020
Blood 136(Supplement 1):51-51

DOI: 10.1182/blood-2020-142467

Authors:

Manisha Balwani

Icahn School of Medicine at Mount Sinai

Herbert Bonkovsky

Carolinas Medical Center University

Kirstine J Belongie

Karl Anderson

University of Texas Medical Branch at Galveston

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Abstract

Introduction Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) are inborn errors of heme biosynthesis caused by the abnormal accumulation of erythrocyte protoporphyrin IX (ePPIX). These protoporphyrias are characterized by excruciating painful attacks on prolonged sunlight exposure. Before the onset of phototoxic pain, patients experience characteristic prodromal symptoms which serves as a warning signal to avoid further sun exposure. Of note, patients with higher ePPIX levels report shorter times to symptoms compared to patients with lower median ePPIX levels (JAMA Derm, 2017; 153). Here we report the safety and effectiveness of Dersimelagon (MT-7117), a novel, orally-administered, small molecule, selective melanocortin-1 receptor (MC1R) agonist that increases skin melanin without sun exposure and is being developed to increase light tolerance in EPP/XLP patients. Results of the primary, secondary efficacy endpoints, and post-hoc subgroup analyses evaluating effects of baseline ePPIX levels on treatment response will be presented. Methods The MT-7117-A01 (ENDEAVOR) study was a Phase 2, multi-center, randomized, placebo-controlled study with a 16-week double-blind treatment period. A total of 102 EPP/XLP patients were randomized to 3 groups: placebo once daily (QD) (n=35 [31 EPP/4 XLP]), MT-7117 100 mg QD (n=33 [31 EPP/2 XLP]), and MT-7117 300 mg QD (n=34 [31 EPP/3 XLP]).

Results of the primary endpoint, increase in the average daily time (min) to first prodromal symptom during sunlight exposure, and secondary endpoints including 1) average daily duration of sunlight exposure without prodromal symptoms, 2) total number of sunlight exposure episodes with prodromal symptoms, and 3) total number of pain events, and post-hoc subgroup analyses evaluating baseline median ePPIX levels are presented here. Safety and tolerability were also assessed. Results There was a significant improvement in average daily time (>50 min) to first prodromal symptom [the primary endpoint] associated with sunlight exposure in subjects treated with MT-7117 100 mg (p=0.008) or 300 mg (p=0.003) compared to placebo at Week 16. Multiple secondary endpoints supported primary endpoint. There was a significant increase in average daily minutes of sunlight exposure without prodromal symptoms at Week 16 in 100 mg (p=0.009) and 300 mg (p=0.004) treated subjects compared to placebo, with an increased average exposure time without prodromal symptoms of ~50 min in MT-7117 subjects at both doses compared to placebo. There was also a 40% reduction in the total number of sunlight exposure episodes with prodromal symptoms in 100 mg (p=0.019) and 300 mg (p=0.006) subjects compared to placebo. There was a significant decrease in the total number of pain events reported in 100 mg (p=0.027, 60% reduction) and 300 mg (p=0.028, 50% reduction) subjects compared to placebo. The post-hoc subgroup analysis evaluating the effects of baseline ePPIX levels in subjects grouped based on the baseline median ePPIX level of 1981 µg/dL.

There was a statistically significant increase in average daily time to first prodromal symptom in the subgroup with ePPIX levels ≥1981 µg/dL receiving 100 mg (p=0.020) and 300 mg (p=0.003) compared to placebo. A trend to beneficial effect was also observed for the subgroup of subjects with ePPIX levels <1981 µg/dL receiving 100 mg (p=0.180) and 300 mg (p=0.216) compared to placebo. MT-7117 had an acceptable safety and tolerability profile. The most common treatment-related treatment emergent adverse reactions were nausea (27.9%), ephelides (23.5%), and skin hyperpigmentation (20.6%). Conclusion The results of the primary efficacy endpoint and multiple secondary endpoints in this Phase 2 study indicate that the oral, MC1R agonist dersimelagon was efficacious after 16 weeks of treatment in increasing symptom-free light exposure in patients with EPP or XLP at doses of 100 and 300 mg QD and showed an acceptable safety and tolerability profile. The post-hoc analyses showed more profound and statistically significant efficacy at both doses for the subgroup with higher baseline median ePPIX levels. Disclosures Balwani: Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding; Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording. Anderson:Alnylam Pahrmaceuticals: Consultancy; Recordati Rare Diseases: Consultancy; Mitsubishi Tanabe Pharma: Consultancy.

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Clinical trialsThe European Union Clinical Trials Register allows you to search for protocol and results information on:

interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.

Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.

The EU Clinical Trials Register currently displays   39256   clinical trials with a EudraCT protocol, of which   6430   are clinical trials conducted with subjects less than 18 years old.
The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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Summary

EudraCT Number:
2019-004226-16
Sponsor's Protocol Code Number:
MT-7117-G01
National Competent Authority:
Norway - NOMA
Clinical Trial Type:
EEA CTA
Trial Status:

Date on which this record was first entered in the EudraCT database:
2020-05-20
Trial results

Index

A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1
Member State Concerned
Norway - NOMA
A.2
EudraCT number
2019-004226-16
A.3
Full title of the trial

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Adults and Adolescents with Erythropoietic Protoporphyria or X-Linked Protoporphyria
A.3.1
Title of the trial for lay people, in easily understood, i.e. non-technical, language

A phase 3 trial to determine how safe, tolerable and effective MT-7117 is in adults and adolescents with Erythropoietic Protoporphyria or x-linked Protoporphyria
A.3.2
Name or abbreviated title of the trial where available

RESPITE
A.4.1
Sponsor's protocol code number
MT-7117-G01
A.7
Trial is part of a Paediatric Investigation Plan
No
A.8
EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information

B.Sponsor: 1
B.1.1
Name of Sponsor
Mitsubishi Tanabe Pharma Development America (MTDA), Inc.
B.1.3.4
Country
United States
B.3.1 and B.3.2
Status of the sponsor
Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1
Name of organisation providing support

Mitsubishi Tanabe Pharma Development America, Inc.

B.4.2
Country
United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1
Name of organisation
Mitsubishi Tanabe Pharma Development America (MTDA), Inc.
B.5.2
Functional name of contact point
Sonia J. Oosman
B.5.3
Address:
B.5.3.1
Street Address
525 Washington Blvd, Suite 400
B.5.3.2
Town/ city
Jersey City
B.5.3.3
Post code
NJ 07310
B.5.3.4
Country
United States
B.5.4
Telephone number
+1 908607-3035
B.5.5
Fax number
+1 908342-1981
B.5.6
E-mail
sonia_...@mt-pharma-us.com

D. IMP Identification

D.IMP: 1
D.1.2 and D.1.3
IMP Role
Test
D.2
Status of the IMP to be used in the clinical trial
D.2.1
IMP to be used in the trial has a marketing authorisation
No
D.2.5
The IMP has been designated in this indication as an orphan drug in the Community
No
D.2.5.1
Orphan drug designation number

D.3 Description of the IMP
D.3.1
Product name
Dersimelagon
D.3.2
Product code
MT-7117
D.3.4
Pharmaceutical form
Film-coated tablet
D.3.4.1
Specific paediatric formulation
No
D.3.7
Routes of administration for this IMP
Oral use

D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8
INN - Proposed INN
Dersimelagon
D.3.9.2
Current sponsor code
MT-7117
D.3.9.3
Other descriptive name
MT-7117
D.3.9.4
EV Substance Code
SUB181965
D.3.10
Strength
D.3.10.1
Concentration unit
mg milligram(s)
D.3.10.2
Concentration type
equal
D.3.10.3
Concentration number
100
D.3.11 The IMP contains an:
D.3.11.1
Active substance of chemical origin
Yes
D.3.11.2
Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)
No

The IMP is a:
D.3.11.3
Advanced Therapy IMP (ATIMP)
No
D.3.11.3.1
Somatic cell therapy medicinal product
No
D.3.11.3.2
Gene therapy medical product
No
D.3.11.3.3
Tissue Engineered Product
No
D.3.11.3.4
Combination ATIMP (i.e. one involving a medical device)
No
D.3.11.3.5
Committee on Advanced therapies (CAT) has issued a classification for this product
No
D.3.11.4
Combination product that includes a device, but does not involve an Advanced Therapy
No
D.3.11.5
Radiopharmaceutical medicinal product
No
D.3.11.6
Immunological medicinal product (such as vaccine, allergen, immune serum)
No
D.3.11.7
Plasma derived medicinal product
No
D.3.11.8
Extractive medicinal product
No
D.3.11.9
Recombinant medicinal product
No
D.3.11.10
Medicinal product containing genetically modified organisms
No
D.3.11.11
Herbal medicinal product
No
D.3.11.12
Homeopathic medicinal product
No
D.3.11.13
Another type of medicinal product
No

D.8 Information on Placebo

D.8 Placebo: 1
D.8.1
Is a Placebo used in this Trial?
Yes
D.8.3
Pharmaceutical form of the placebo
Film-coated tablet
D.8.4
Route of administration of the placebo
Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation
E.1.1
Medical condition(s) being investigated

Erythropoietic Protoporphyria or X-Linked Protoporphyria
E.1.1.1
Medical condition in easily understood language

Erythropoietic Protoporphyria or X-Linked Protoporphyria
E.1.1.2
Therapeutic area
Diseases [C] - Symptoms and general pathology [C23]
MedDRA Classification
E.1.2 Medical condition or disease under investigation

E.1.2
Version
21.1
E.1.2
Level
LLT
E.1.2
Classification code
10015289
E.1.2
Term
Erythropoietic protoporphyria
E.1.2
System Organ Class
100000004850
E.1.3
Condition being studied is a rare disease
Yes
E.2 Objective of the trial
E.2.1
Main objective of the trial

To investigate the efficacy of MT-7117 on time to onset and severity of first prodromal symptoms (burning, tingling, itching, or stinging) associated with sunlight exposure in adults and adolescents with Erythropoietic Protoporphyria (EPP)or X-Linked Protoporphyria (XLP).
E.2.2
Secondary objectives of the trial

- To investigate the effect on patient-reported quality of life "adult" and "adolescent" with EPP or XLP.
- To investigate the effect on the percentage of responders based on the within-subject meaningful threshold for time to first prodromal symptom in adults and adolescents with EPP or XLP.
- To investigate the effect on number and severity of sunlight-induced pain events (prodrome and phototoxic reactions) in adults and adolescents with EPP or XLP.
E.2.3
Trial contains a sub-study
No
E.3
Principal inclusion criteria

1. Subjects provided written informed consent to participate. For minor subjects, both minor assent and parental consent will be provided.
2. Male and female subjects with a confirmed diagnosis of Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) based on medical history, aged 12 years to 75 years, inclusive, at Screening.
3. Subjects have a body weight of ≥30 kg.
4. Subjects are willing and able to travel to the study sites for all scheduled visits.
5. In the Investigator’s opinion, subject is able to understand the nature of the study and any risks involved in participation, and willing to cooperate and comply with the protocol restrictions and requirements (including travel).
6. Female subjects who are non-lactating and have a negative urine pregnancy test at baseline prior to receiving the first dose of IMP.
7. Female subjects of childbearing potential and male subjects with partner of child-bearing potential currently using/willing to use 2 effective methods of contraception including barrier method as described in Section 8.7.1.
E.4
Principal exclusion criteria

1. History or presence of photodermatoses other than EPP or XLP.
2. Subjects who are unwilling or unable to go outside during daylight hours most days (e.g., between 1 hour post sunrise and 1 hour pre-sunset) during the study.
3. Presence of clinically significant hepatobiliary disease based on Liver function test (LFT) values at Screening.
4. Subjects with AST, ALT, ALP ≥3.0 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN at Screening.
5. Subjects with or having a history (in the last 2 years) of excessive alcohol, intake in the opinion of the Investigator.
6. History of melanoma.
7. Presence of melanoma and/or lesions suspicious for melanoma at Screening.
8. History of familial melanoma (defined as having 2 or more first-degree relatives, such as parents, sibling and/or child).
9. Presence of squamous cell carcinoma, basal cell carcinoma, or other malignant skin lesions. Any suspicious lesions or nevi will be evaluated. If the suspicious lesion or nevi cannot be resolved through biopsy or excision, the subject will be excluded from the study.
10. History or presence of psychiatric disease judged to be clinically significant by the Investigator and which may interfere with the study evaluation and/or safety of the subjects.
11. Presence of clinically significant acute or chronic renal disease based upon the subject’s medical records including hemodialysis; and a serum creatinine level of greater than 1.2 mg/dL or an estimated glomerular filtration rate (eGFR) <60 ml/min as calculated by the CKD-EPI creatinine equation (2009). MDRD can be used per local recommendations.
12. Presence of any clinically significant disease or laboratory abnormality which, in the opinion of the Investigator, can interfere with the study objectives and/or safety of the subjects.
13. Female subjects who are pregnant, lactating, or intending to become pregnant during the study.
14. Treatment with phototherapy within 3 months before Randomization (Visit 2).
15. Treatment with afamelanotide within 3 months before Randomization (Visit 2).
16. Treatment with cimetidine within 4 weeks before Randomization (Visit 2).
17. Treatment with antioxidant agents within 4 weeks before Randomization (Visit 2), at doses which, in the opinion of the Investigator, may affect study endpoints (including but not limited to beta-carotene, cysteine, pyridoxine).
18. Chronic treatment with any scheduled analgesic agents including, but not limited to, opioids and opioid derivatives such as morphine, hydrocodone, oxycodone, Fentanyl or their combination with other unscheduled analgesics or non-steroidal anti-inflammatory drug (Percocet and Vicodin-like prescription drugs) within 4 weeks before Randomization (Visit 2). Acute use of scheduled narcotics greater than 3 months prior to randomization, OTCs, such as NSAIDs or aspirin for analgesia, or prior temporary use of scheduled agents within 3 months of screening are not excluded.
19. Treatment with any drugs or supplements which, in the opinion of the Investigator, can interfere with the objectives of the study or safety of the subjects.
20. Previous exposure to MT-7117 (this does not include placebo treated subjects).
21. Previous treatment with any investigational agent within 12 weeks before Screening OR 5 half-lives of the investigational product (whichever is longer).
22. Using the following drugs (including but not limited to) within 1 week of Randomization (Visit 2):
a. Drugs known to be predominantly metabolized by CYP3A4 with a narrow therapeutic index for which elevated plasma concentrations are associated with clinical safety concern or significant medical events.
b. Drugs that are known substrates of P-gp, BCRP, OATP1B1, or OATP1B3 for which elevated plasma concentrations are associated with significant medical events.
E.5 End points
E.5.1
Primary end point(s)

Change from baseline in average daily sunlight exposure time (minutes) to first prodromal symptom (burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour post sunrise and 1 hour pre-sunset at Week 26 (Visit 7).
E.5.1.1
Timepoint(s) of evaluation of this end point

To calculate the average daily duration, a 14-day window on or before a time-point (Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26) will be used. For baseline, a 14-day window before Day 1 will be used. A 14-day window will be applied to similar situations for other efficacy endpoints related to sunlight exposure diary.
E.5.2
Secondary end point(s)

1. Patient Global Impression of Change (PGIC) at Week 26.
2. Total number of sunlight-induced pain events defined as prodrome symptoms (burning, tingling, itching, or stinging) with pain rating of 1-10 on the Likert scale during the 26-week double-blind treatment period.
3. Change from baseline for total score in the domain of pain intensity in the PROMIS-57 at Week 26.
4. The percentage of subjects who are responders based on average daily sunlight exposure time to first prodromal symptom associated with sunlight exposure between 1 hour post sunrise and 1 hour pre-sunset defined by within-subject meaningful change of 66 minutes increase from baseline to Week 26.
5. Change from baseline for total score in the domain of physical function in the PROMIS-57 at Week 26.
E.5.2.1
Timepoint(s) of evaluation of this end point

1.Patient Global impression of change (PGIC), change from baseline for total score in domainof pain intensity, change from baseline for total score of physical function: at week 26

2. Total number of prodrome symptoms and percentage of subjects who are responders based on average daily sunlight exposure: from baseline to week 26.
E.6 and E.7 Scope of the trial
E.6
Scope of the trial
E.6.1
Diagnosis
No
E.6.2
Prophylaxis
No
E.6.3
Therapy
No
E.6.4
Safety
Yes
E.6.5
Efficacy
Yes
E.6.6
Pharmacokinetic
Yes
E.6.7
Pharmacodynamic
Yes
E.6.8
Bioequivalence
No
E.6.9
Dose response
No
E.6.10
Pharmacogenetic
No
E.6.11
Pharmacogenomic
No
E.6.12
Pharmacoeconomic
No
E.6.13
Others
Yes
E.6.13.1
Other scope of the trial description

tolerability
E.7
Trial type and phase
E.7.1
Human pharmacology (Phase I)
No
E.7.1.1
First administration to humans
No
E.7.1.2
Bioequivalence study
No
E.7.1.3
Other
No
E.7.1.3.1
Other trial type description

E.7.2
Therapeutic exploratory (Phase II)
No
E.7.3
Therapeutic confirmatory (Phase III)
Yes
E.7.4
Therapeutic use (Phase IV)
No
E.8 Design of the trial
E.8.1
Controlled
Yes
E.8.1.1
Randomised
Yes
E.8.1.2
Open
No
E.8.1.3
Single blind
No
E.8.1.4
Double blind
Yes
E.8.1.5
Parallel group
No
E.8.1.6
Cross over
No
E.8.1.7
Other
No
E.8.2
Comparator of controlled trial
E.8.2.1
Other medicinal product(s)
No
E.8.2.2
Placebo
Yes
E.8.2.3
Other
No
E.8.2.4
Number of treatment arms in the trial
3
E.8.3
The trial involves single site in the Member State concerned
Yes
E.8.4
The trial involves multiple sites in the Member State concerned
No
E.8.5
The trial involves multiple Member States
Yes
E.8.5.1
Number of sites anticipated in the EEA
14
E.8.6 Trial involving sites outside the EEA
E.8.6.1
Trial being conducted both within and outside the EEA
Yes
E.8.6.2
Trial being conducted completely outside of the EEA
No
E.8.6.3
If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia
Canada
Finland
Germany
Italy
Japan
Norway
Spain
Sweden
United Kingdom
United States
E.8.7
Trial has a data monitoring committee
No
E.8.8
Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1
In the Member State concerned years
1
E.8.9.1
In the Member State concerned months
2
E.8.9.1
In the Member State concerned days

E.8.9.2
In all countries concerned by the trial years
1
E.8.9.2
In all countries concerned by the trial months
2

F. Population of Trial Subjects

F.1 Age Range
F.1.1
Trial has subjects under 18
Yes
F.1.1
Number of subjects for this age range:
20
F.1.1.1
In Utero
No
F.1.1.2
Preterm newborn infants (up to gestational age < 37 weeks)
No
F.1.1.3
Newborns (0-27 days)
No
F.1.1.4
Infants and toddlers (28 days-23 months)
No
F.1.1.5
Children (2-11years)
No
F.1.1.6
Adolescents (12-17 years)
Yes
F.1.1.6.1
Number of subjects for this age range:
20
F.1.2
Adults (18-64 years)
Yes
F.1.2.1
Number of subjects for this age range:
129
F.1.3
Elderly (>=65 years)
Yes
F.1.3.1
Number of subjects for this age range:
10
F.2 Gender
F.2.1
Female
Yes
F.2.2
Male
Yes
F.3 Group of trial subjects
F.3.1
Healthy volunteers
No
F.3.2
Patients
Yes
F.3.3
Specific vulnerable populations
Yes
F.3.3.1
Women of childbearing potential not using contraception
No
F.3.3.2
Women of child-bearing potential using contraception
Yes
F.3.3.3
Pregnant women
No
F.3.3.4
Nursing women
No
F.3.3.5
Emergency situation
No
F.3.3.6
Subjects incapable of giving consent personally
No
F.3.3.7
Others
Yes
F.3.3.7.1
Details of other specific vulnerable populations

Adolescents
F.4 Planned number of subjects to be included
F.4.1
In the member state
5
F.4.2
For a multinational trial
F.4.2.1
In the EEA
50
F.4.2.2
In the whole clinical trial
159
F.5
Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

N/A

G. Investigator Networks to be involved in the Trial

G.4 Investigator Network to be involved in the Trial: 1
G.4.1
Name of Organisation
American Porphyria Foundation
G.4.3.4
Network Country
United States

N. Review by the Competent Authority or Ethics Committee in the country concerned

N.
Competent Authority Decision
Authorised
N.
Date of Competent Authority Decision
2020-08-13
N.
Ethics Committee Opinion of the trial application

N.
Ethics Committee Opinion: Reason(s) for unfavourable opinion

N.
Date of Ethics Committee Opinion

P. End of Trial

P.
End of Trial Status

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22. Using the following drugs (including but not limited to) within 1 week of Randomization (Visit 2):
a. Drugs known to be predominantly metabolized by CYP3A4 with a narrow therapeutic index for which elevated plasma concentrations are associated with clinical safety concern or significant medical events.
b. Drugs that are known substrates of P-gp, BCRP, OATP1B1, or OATP1B3 for which elevated plasma concentrations are associated with significant medical events.
E.5 End points

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CYP3A4

https://www.google.com/search?sxsrf=ALeKk031z1D-w72pQmOiOYUweNCGKiQcAg%3A1615527743702&ei=P_9KYKf8KYTbtQag37CwAw&q=cyp3a4+&oq=cyp3a4+&gs_lcp=Cgdnd3Mtd2l6EAMyBAgjECcyBQgAELEDMgcIABCHAhAUMgIIADICCAAyBAgAEEMyAggAMgIIADICCAAyAggAOgcIABCwAxBDOgcIABBHELADOgYIABAWEB46BQgAEIYDUKwdWKtAYMRJaAJwAngAgAHGAYgB2BiSAQQwLjI0mAEAoAEBqgEHZ3dzLXdpesgBCsABAQ&sclient=gws-wiz&ved=0ahUKEwjnl6bqharvAhWEbc0KHaAvDDYQ4dUDCA0&uact=5

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p-gp

https://www.google.com/search?sxsrf=ALeKk00gtNu4YLnyOcCAHqWzusOrf6uO1w%3A1615527859908&source=hp&ei=s_9KYMjFNZaDwbkPqu2Q6Aw&iflsig=AINFCbYAAAAAYEsNw53HLUYnuhL-LekMU0jPF8y2EUvF&q=P-gp&oq=P-gp&gs_lcp=Cgdnd3Mtd2l6EAMyBQgAEJECMgUIABCRAjIHCAAQhwIQFDICCAAyAggAMgIIADICCAAyAggAMgIIADICCAA6BwgjEOoCECdQix1YozNg8D9oAXAAeACAAe0BiAHyApIBBTAuMS4xmAEAoAECoAEBqgEHZ3dzLXdperABCg&sclient=gws-wiz&ved=0ahUKEwiI69mhhqrvAhWWQTABHao2BM0Q4dUDCAk&uact=5

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BCRP

https://www.google.com/search?sxsrf=ALeKk033i8lSkTTssakwcCrslZkJjn2-fA%3A1615528014228&source=hp&ei=TgBLYMPnC9Cq5wKpiZb4Aw&iflsig=AINFCbYAAAAAYEsOXt0MA2RpRYKr0P9Wp4235vvuTZMV&q=BCRP&oq=BCRP&gs_lcp=Cgdnd3Mtd2l6EAwyBQgAEJECMgIIADICCAAyAggAMgUIABCxAzICCAAyAggAMgIIADICCAAyAggAOgcIIxDqAhAnUP8oWNZNYM1gaANwAHgAgAHMAYgB8gKSAQUwLjEuMZgBAKABAqABAaoBB2d3cy13aXqwAQo&sclient=gws-wiz&ved=0ahUKEwjDxqTrhqrvAhVQ1VkKHamEBT8Q4dUDCAk

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OATP1B1

https://www.google.com/search?sxsrf=ALeKk01KaEif9cKJb29qfEFsF-1PcClEsA%3A1615528176404&ei=8ABLYIqeGJjStQbQjKbwCw&q=oatp1b1+&oq=oatp1b1+&gs_lcp=Cgdnd3Mtd2l6EAMyBAgjECcyAggAMgIIADICCAAyAggAMgIIADICCAAyAggAMgIIADICCAA6BwgAEEcQsAM6BggAEBYQHjoFCAAQhgNQwhRYsCtg3zRoAXACeACAAfgCiAHWGpIBBzAuNy44LjGYAQCgAQGqAQdnd3Mtd2l6yAEIwAEB&sclient=gws-wiz&ved=0ahUKEwiK1tC4h6rvAhUYac0KHVCGCb4Q4dUDCA0&uact=5

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Glossary

Safety, Tolerability, PK and PD of MT-7117 in Healthy Subjects

Research type
Research Study
Full title
A Randomised, Double-blind, Placebo-controlled Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of MT-7117 in Healthy Subjects
IRAS ID
208020
Contact name
Muna Albayaty
Contact email
muna.a...@parexel.com
Sponsor organisation
Mitsubishi Tanabe Pharma Corporation (MTPC)
Eudract number
2016-001326-33
Clinicaltrials.gov Identifier
NCT02834442
Duration of Study in the UK
0 years, 8 months, 1 days
Research summary
This is a phase 1, randomised, double-blind, placebo controlled clinical study being conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of MT-7117. The study is comprised of 8 study parts all of which will enrol healthy volunteers of different ages, races, genders and skin types. \n\nThis will be the first time MT-7117 is given to human participants and is a First in Human (FiH) clinical trial. MT-7117 is being developed by Mitsubishi Tanabe Pharma Corporation (MTPC) for the treatment of Erythropoietic protoporphyria (EPP). EPP is an inherited genetic disorder (i.e. it is caused by a fault in the person’s DNA) which causes sensitivity to the sun which results in stinging, itching, burning and severe pain. It can also cause redness and swelling of the skin and red / purple spots called petechiae. Liver effects are also seen in some patients.\n\nThe main purpose of the study is to see how safe the drug is after single and multiple doses, and how well the body tolerates the drug after single and multiple doses. The study will also investigate how the drug is absorbed (taken up into the body), metabolised (chemically broken down), distributed through the body, and excreted (removed from the body). The study will also look the effect of the following on the study drug:\n- Gender\n- Race\n- Food\n- Age\n- Differences between drug taken as tablet or oral solution\n- Molecules and genes in the skin as well as pigmentation of the skin
REC name
London - Brent Research Ethics Committee
REC reference
16/LO/0813
Date of REC Opinion
30 Jun 2016
REC opinion
Further Information Favourable Opinion

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2595 Erythropoietic Protoporphyria: Phase 2 Clinical Trial Results Evaluating the Safety and Effectiveness of Dersimelagon (MT-7117), an Oral MC1R Agonist

Program: Oral and Poster Abstracts
Session: 102. Regulation of Iron Metabolism: Poster III
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, Therapies, Genetic Disorders, Clinically relevant, pharmacology, Quality Improvement

Monday, December 7, 2020, 7:00 AM-3:30 PM

Manisha Balwani1*, Herbert L. Bonkovsky, MD2*, Kirstine J Belongie, PhD3*, Karl E Anderson, MD4*, Fumihiro Takahashi, PhD5*, Antonio Irizarry, MBA6*, Mark Amster, MD7*, D. Montgomery Bissell, MD8*, Bruce Wang, MD9*, Lydie Hazan, MD10*, Charles J. Parker, MD11, Edward Cordasco, MD12*, Cynthia Levy, MD13* and Robert J. Desnick, MD, PhD14*

1Icahn School of Medicine at Mount Sinai, New York
2University of Connecticut, Farmington, CT
3Mitsubishi Tanabe Pharma Development America, Jersey city, NJ
4University of Texas Medical Branch, Galveston
5Mitsubishi Tanabe Pharma Cooperation, Tokyo, Japan
6Mitsubishi Tanabe Pharma Development America, Jersey city
7Dermatology Associates Rogers Outpatient Center, Mashpee
8UCS, San Francisco, CA
9University of California, san francisco
10Axis Clinical Trials, Los Angeles
11University of Utah School of Medicine, Salt Lake City, UT
12Remington Davis clinical research, Columbus
13University of Miami, Miami
14Mount Sinai School of Medicine, New York, NY

Introduction

Methods

Results

Conclusion

Disclosures: Balwani: Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding; Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording. Anderson: Alnylam Pahrmaceuticals: Consultancy; Recordati Rare Diseases: Consultancy; Mitsubishi Tanabe Pharma: Consultancy.

See more of: 102. Regulation of Iron Metabolism: Poster III
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Review Porphyrias in the Age of Targeted Therapies Angelika L. Erwin 1,* and Manisha Balwani 2 Citation: Erwin, A.L.; Balwani, M. Porphyrias in the Age of Targeted Therapies. Diagnostics 2021, 11, 1795. https://doi.org/10.3390/ diagnostics11101795 Academic Editor: Chung-Che (Jeff) Chang Received: 1 September 2021 Accepted: 27 September 2021 Published: 29 September 2021

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Center for Personalized Genetic Healthcare, Cleveland Clinic & Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA 2 Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; manisha...@mssm.edu * Correspondence: erw...@ccf.org; Tel.: +1-216-444-9249

Abstract: The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as the chemical characteristics of the accumulating substances, the clinical features of different porphyrias vary substantially. Heme precursors are neurotoxic, and their accumulation results in acute hepatic porphyria, while porphyrins are photoactive, and excess amounts cause cutaneous porphyrias, which present with photosensitivity. These disorders are clinically heterogeneous but can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life. Medical management consists mostly of the avoidance of triggering factors and symptomatic treatment. With an improved understanding of the underlying pathophysiology and disease mechanisms, new treatment approaches have become available, which address the underlying defects at a molecular or cellular level, and promise significant improvement, symptom prevention and more effective treatment of acute and chronic disease manifestations. Keywords: porphyria; heme biosynthesis; acute porphyria; cutaneous porphyria; siRNA; small molecule; chaperone; hematin; givosiran; afamelanotide; MT-7117; ciclopirox 1. Introduction The porphyrias are a group of rare inherited metabolic disorders that are caused by deficiencies of specific enzymes involved in the heme biosynthetic pathway (Figure 1) [1]. The symptoms observed in the different types of porphyria result from the excessive accumulation of porphyrins or heme precursors in different tissues (Table 1) [2]. While heme synthesis is present in all cell types, the majority (~80%) occurs in erythroblasts in the bone marrow, followed by ~15% in hepatocytes. Based on the primary source of heme precursor or porphyrin overproduction and accumulation, the porphyrias are classified as either hepatic or erythropoietic [3]

. From a clinical perspective, the hepatic porphyrias commonly present with acute neurovisceral symptoms and include acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and delta-aminolevulinic acid dehydratase deficiency porphyria (ADP). Erythropoietic porphyrias, which include erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), and congenital erythropoietic porphyria (CEP), are characterized mainly by cutaneous manifestations due to phototoxicity. This difference in clinical presentation explains an additional grouping into either acute or cutaneous porphyrias, with two types (HCP and VP) falling into both categories (Table 1).

In addition, two types of hepatic porphyrias, porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP), present mainly with cutaneous symptoms and do not have neurovisceral involvement [4]. Diagnostics 2021, 11, 1795. https://doi.org/10.3390/diagnostics11101795 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 1795 2 of 18 Diagnostics 2021, 11, x FOR PEER REVIEW 3 of 19 Figure 1. The heme biosynthetic pathway:

Eight enzymatic steps lead to the conversion of succinyl-CoA and glycine to the end product, heme, which is then transported out of the mitochondrion and used for the formation of various hemoproteins. Especially in the liver, heme exerts a negative feedback on the first enzyme of the heme biosynthetic pathway, ALAS1. While ALAS1 is ubiquitously expressed, its isoform, ALAS2, is erythroid specific and is regulated by erythroid-specific transcription factors. Four catalytic reactions of the heme biosynthetic pathway occur in the mitochondrion and the other four steps in the cytosol. Dysfunction of each enzyme (in blue boxes) results in a different type of porphyria (in red boxes) due to accumulation of the different heme precursors and porphyrins in various tissues. Abbreviations: enzymes of the heme biosynthetic pathway: ALAS1/ALAS2, delta-aminolevulinic acid synthase 1/2; ALAD, delta-aminolevulinic acid dehydratase; HMBS, hydroxymethylbilane synthase; UROS, uroporphyrinogen III synthase; UROD, uroporphyrinogen decarboxylase; CPOX, coproporphyrinogen oxidase; PPOX, protoporphyrinogen oxidase; FECH, ferrochelatase. Different types of porphyria: XLP, X-linked protoporphyria; ADP, delta-aminolevulinic acid dehydratase deficiency porphyria; AIP, acute intermittent porphyria; CEP, Congenital erythropoietic porphyria; PCT, porphyria cutanea tarda; HCP, hereditary coproporphyria; VP variegate porphyria; EPP, erythropoietic protoporphyria. Diagnostics 2021, 11, 1795 3 of 18 Table 1. Overview of the different porphyrias with respect to certain distinguishing key elements, affected enzymes, inheritance patterns and most common biochemical porphyrin findings.

Porphyria Clinical Presentation Tissue Site of Porphyrin Origin Dysfunctional Enzyme Inheritance Most Significant Biochemical Findings * Acute Hepatic Porphyrias ALA-dehydratase deficiency porphyria (ADP) Acute neurovisceral Hepatic Delta-aminolevulinic acid dehydratase (ALAD) AR Urine: ALA, copro III Plasma: Zn-PPIX Acute intermittent porphyria (AIP) Acute neurovisceral Hepatic Hydroxymethylbilane synthase (HMBS) AD Urine: ALA, PBG, uro Hereditary Coproporphyria (HCP) Acute neurovisceral and cutaneous Hepatic Coproporphyrinogen oxidase (CPOX) AD Urine: ALA, PBG, copro III Feces: copro III Variegate Porphyria (VP) Acute neurovisceral and cutaneous Hepatic Protoporphyrinogen oxidase (PPOX) AD Urine: ALA, PBG, copro III Feces: copro III, PPIX Cutaneous Erythropoietic Porphyrias Erythropoietic protoporphyria (EPP) Cutaneous, rarely hepatic complications Erythropoietic Ferrochelatase (FECH) AR Plasma: free PPIX X-linked protoporphyria (XLP) Cutaneous, rarely hepatic complications Erythropoietic Delta-aminolevulinic acid synthase 2 (ALAS2) X-linked Plasma: free and Zn-PPIX Congenital erythropoietic porphyria (CEP) Cutaneous, hemolytic anemia Erythropoietic Uroporphyrinogen III synthase (UROS) AR Plasma & urine: uro I, copro I Feces: copro I Cutaneous Hepatic Porphyrias Porphyria cutanea tarda (PCT) Cutaneous Hepatic Uroporphyrinogen decarboxylase (UROD) Sporadic, AD Urine: uro, heptacarboxylporphyrin Feces: iso-copro Hepato-erythropoietic porphyria (HEP) Cutaneous Erythropoietic, hepatic Uroporphyrinogen decarboxylase (UROD) AR Urine: uro, heptacarboxylporphyrin Feces: iso-copro *: Additional biochemical testing that can aid in establishing a diagnosis of porphyria includes plasma porphyrin measurement with fluorescence emission spectroscopy. If AIP or ADP are suspected, the determination of HMBS or ALAD enzymatic activity, respectively, can be performed to corroborate the diagnosis. Abbreviations: AR, autosomal recessive; AD, autosomal dominant; ALA, delta-aminolevulinic acid; copro, coproporphyrin; Zn-PPIX, zinc-bound protoporphyrin IX; PBG, porphobilinogen; uro, uroporphyrin. Diagnostics 2021, 11, 1795 4 of 18 With the exception of PCT, which in most cases is sporadic, porphyrias are caused by pathogenic variants in the genes encoding the different enzymes involved in the heme biosynthetic pathway. Inheritance can be autosomal dominant, autosomal recessive, or X-linked. Especially in the acute hepatic porphyrias, disease penetrance and severity are significantly influenced by a combination of genetic, environmental and physiologic factors, which can lead to disturbance of the tightly regulated heme biosynthesis [5]. Heme Biosynthesis Heme is the end product of a metabolic pathway that involves eight enzymatic steps (Figure 1). The first and rate-limiting step is the formation of delta aminolevulinic acid (ALA) from glycine and succinyl-Coenzyme A [1,4]. This step is catalyzed by the enzyme ALA-synthase (ALAS), which has two isoforms—the ubiquitously expressed ALAS1 and the erythrocyte-specific ALAS2. These two different isoforms are encoded by two separate genes—ALAS1, which is located on chromosome 3, and ALAS2, on the X-chromosome [6,7]. The first and the last three enzymatic steps of the pathway are located in the mitochondrion, whereas the other four enzymes occur in the cytoplasm (Figure 1). The first two catalytic reactions in the pathway lead to the formation of heme precursors delta aminolevulinic acid (ALA) and porphobilinogen (PBG), followed by the production of porphyrin metabolites. These intermediate substrates do not have a physiologic function and do not accumulate under normal conditions.

The final step in the pathway leads to the synthesis of heme, which is then further used for the formation of hemoproteins such as hemoglobin, myoglobin, cytochrome P450 enzymes and mitochondrial respiratory cytochromes [2,4,8]. Heme biosynthesis is tightly regulated through different mechanisms. In the liver, regulation occurs through feedback control of the rate-limiting enzyme ALAS1. ALAS1 gene expression is induced by various factors that increase heme demand, including stress and nutritional status, as well as medications and substances that activate the cytochrome P 450 system in the liver. Heme, on the other hand, exerts a negative feedback on ALAS1 activity via the suppression of ALAS1 transcription, destabilization of ALAS1 mRNA, repressed translocation of the enzyme into the mitochondrion, and direct inhibition of the ALAS1 enzyme activity [9]. Heme was also shown to induce the protease Lon peptidase 1, which plays a role in breaking down the ALAS1 enzyme [10]. In erythroid cells, heme biosynthesis is modulated primarily via the synthesis of the erythroid-specific enzyme ALAS2. ALAS2 expression is regulated by erythroid-specific transcription factors, such as GATA1, as well as by the availability of iron via an iron-responsive element/iron regulatory protein binding system. While iron deficiency leads to inhibition of the ALAS2 mRNA translation, increases in the intracellular iron levels cause degradation of the ironresponsive elements, which allows for the activation of ALAS2 mRNA translation and in turn increases synthesis of the ALAS2 enzyme [11]. All porphyrias are caused by decreased activity of one of the enzymes in the heme biosynthetic pathway, with the exception of XLP, which is a consequence of gain-of-function variants in the ALAS2 gene, leading to increased ALAS2 activity [12]. Nevertheless, the clinical presentation of the different types of porphyrias is distinct due to differences in pathophysiology, accumulating heme precursors or porphyrins, and affected tissues. Hence, the treatment and management of clinical manifestations also differ significantly, depending on the underlying condition. Historically, the avoidance of symptom-triggering factors and supportive management were the standard of care. Significant disease burden, impact on quality of life, comorbidities, chronic disease complications, and shortened life span are observed in all porphyrias. With growing knowledge of the disease mechanisms and advances in molecular medicine, progress has been made with respect to medical management, and recent developments as well as ongoing investigative approaches are reviewed in this manuscript (Table 2). Diagnostics 2021, 11, 1795 5 of 18 Table 2. Overview of recently approved drugs, current clinical trials and emerging therapies for the treatment of the different types of porphyria. N/A = not applicable.

Porphyria Recently Approved Drugs Ongoing Clinical TRIALS Emerging Therapies Acute Hepatic Porphyrias AIP, VP, HCP Givosiran (Givlaari™, Alnylam Pharmaceuticals, Boston, MA, USA), subcutaneous injection: siRNA targeting ALAS1, resulting in downregulation of ALAS1 and decreased production of heme precursors ALA and PBG in addition to improved annualized acute porphyria attack rate [13,14].

N/A Gene therapy with recombinant adeno-associated vector expressing porphobilinogen deaminase (rAAV2/5-PBGD), phase I clinical trial: no change in the concentration of ALA and PBG [15]. Optimization of gene therapy approach is being investigated [16,17]. Human PBGD mRNA packaged into liquid nanoparticles, administered intravenously: proved to be safe and efficacious in non-human primates [18].

Erythropoietic Cutaneous Porphyrias EPP, XLP Afamelanotide (Scenesse™, Clinuvel Pharmaceuticals, Melbourne, Australia), intracutaneous implant: α-melanocyte stimulating hormone analogue, leading to increased production of eumelanin and photoprotection [19].

MT-7117 (Dersimelagon™, Mitsubishi Tanabe Pharma America, Jersey City, NJ, USA), oral medication: selective melanocortin-1 receptor agonist, increased cutaneous melanin production. Phase 3 clinical trial (NCT04402489) currently underway [20].

Antisense oligonucleotide (AON-V1), increased production of functional FECH mRNA and, therefore, function protein with decreased PPIX concentration in cell cultures [21,22]. CEP N/A N/A Ciclopirox: stabilizes UROS enzyme, improving catalytic function and leading to decreased porphyrin concentration in cell cultures and murine CEP models [23,24]. Hepatic Cutaneous Porphyrias PCT N/A Ledipasvir/sofosbuvir (Harvoni™, Gilead Sciences, Foster City, CA, USA), direct-acting antiviral used for treatment of chronic hepatitis C. Currently investigating time to resolution of PCT symptoms and porphyrin levels. Phase 2 clinical trial (NCT 03118674) currently underway. N/A 2. Acute Hepatic Porphyrias The acute hepatic porphyrias (AHP) include AIP, VP, and HCP, which are caused by loss-of-function variants in specific enzymes of the heme biosynthetic pathway and have autosomal dominant inheritance. AIP is the most common of the AHPs with an estimated prevalence of approximately 5.9 patients with symptomatic AIP per 1,000,000 individuals.

VP is thought to be half as common, and HCP is the rarest form of the autosomal dominant AHPs [25,26]. The fourth type of AHP is ADP, which has autosomal recessive inheritance, is characterized by a very severe clinical presentation and is extremely rare, with less than 10 cases reported worldwide [27]. Diagnostics 2021, 11, 1795 6 of 18 It is notable that the autosomal dominant forms of AHP have decreased penetrance, and it is thought that less than 1% of all pathogenic variant carriers will remain asymptomatic throughout their life. The carrier frequency for pathogenic HMBS variants has been reported to be as high as approximately one in 1700 individuals, and the cause for the significant phenotypic variability even among carriers of the same pathogenic HMBS variant is unclear [28,29].

One report showed that penetrance may be higher in families with symptomatic AIP [30]. AIP is caused by deficiency of porphobilinogen deaminase (PBGD) or hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. The etiology for VP and HCP is decreased enzyme activity of protoporphyrinogen oxidase (PPOX) and coproporphyrinogen oxidase (CPOX), respectively [1]. The deficiency of these enzymes leads to accumulation of the heme precursors ALA and PBG, which are neurotoxic and responsible for the neurovisceral phenotype observed in the AHPs [31]. Precipitating factors that can trigger acute porphyria attacks including stress, excess alcohol intake, smoking, fasting, acute illness, steroids, hormonal preparations and other certain medications [32]. 2.1. Clinical Presentation Symptomatic AHP is characterized by acute neurovisceral attacks, which are characterized by diffuse abdominal pain accompanied by nausea, vomiting and constipation, back and chest pain, proximal muscle weakness and polyneuropathy. Tachycardia, hypertension and hyponatremia are often observed, and patients frequently report insomnia and anxiety. Cutaneous manifestations are not present in AIP or ADP but develop in up to 50% of individuals with VP and less frequently in HCP [2,33]. Acute porphyria attacks can either occur as an isolated episode or become recurrent in some individuals [34]. Long-term complications of AHP include hypertension, chronic pain, autonomic dysfunction, renal insufficiency, and in rare cases hepatocellular carcinoma [33,35,36]. The diagnosis of AHP is made by demonstrating significant elevation of urinary ALA and PBG levels. Determination of total porphyrins with fractionation in urine, feces, and plasma can aid in distinguishing between the different types of AHP (Table 2). With easier access to molecular analysis, genetic testing is often performed to definitively determine the specific type of AHP and identify other at-risk family members [32,37]. 2.2.

Contemporary Approaches to Management The treatment of acute porphyria attacks consists of symptomatic therapy, including medication for pain control and nausea, seizure control, correction of electrolyte disturbances, hemodynamic stabilization and mechanical ventilation if indicated [32]. The only curative treatment approach for AHP is orthotopic liver transplantation (OLT), which has been shown to lead to rapid normalization of ALA and PBG levels and effectively prevent further acute porphyria attacks [38,39]. However, due to high morbidity and mortality, OLT is usually only considered as a last resort in individuals with very frequent recurring acute attacks who cannot be sufficiently well controlled using other treatment approaches. In an attempt to downregulate hepatic ALAS1 activity and subsequently decrease the production of ALA, PBG, and porphyrin metabolites, carbohydrate loading, dextrose infusion, and intravenous hematin administration are frequently used in individuals experiencing acute porphyria attacks [32,33,40]. Carbohydrates and glucose are thought to decrease ALAS1 activity by suppressing PGC1a and are usually less efficient than hematin, which directly inhibits ALAS1 activity by replenishing hepatic heme stores. Hematin is available as lyophilized hematin (Panhematin™, Recordati Rare Diseases, Northfield, IL, USA) in the US and heme arginate (Normosang™, Orphan Europe, Paris, France) in Europe. During acute porphyria attacks, three to four intravenous hematin treatments on consecutive days are often necessary to effectively lower elevated ALA and PBG concentrations and achieve symptom control [41–43]. Individuals who experience frequently recurrent acute attacks may benefit from off-label, regular prophylactic hematin infusions on a weekly or monthly basis in an attempt to regularly suppress increasing Diagnostics 2021, 11, 1795 7 of 18 porphyrin precursor concentrations [33,44]. Complications of frequent hematin administration include damage to vasculature (the substrate can irritate the vessels and needs to be given through a large bore intravenous catheter or a central line) as well as chronic iron overload [45]. In 2019, the Food and Drug Administration (FDA) and, in 2020, the European Medicines Agency (EMA) approved givosiran (Givlaari™, Alnylam Pharmaceuticals, Cambridge, MA, USA), a synthetic small interfering RNA (siRNA) molecule that targets and downregulates ALAS1 mRNA. The double-stranded siRNA molecule is conjugated to N-acetylgalactosamine (GalNAc) and administered subcutaneously in the form of a lipid nanoparticle, which allows for liver-specific delivery. After uptake into the hepatocytes, the siRNA molecules are trimmed into ~20 base pair strands by the endoribonuclease Dicer and subsequently further separated into single strands within the siRNA-induced silencing complex (RISC). Due to perfect base pair complementarity, the ALAS1 mRNA is then targeted and cleaved by the argonaute-2 endonuclease, leading to effective knock-down of the gene [46,47]. In the phase I/II study, a significant decrease in ALAS1 mRNA levels along with sustained near normalization of urinary ALA and PBG concentration was demonstrated with monthly givosiran injection [13]. This was confirmed in the phase III clinical trial, in which a significant reduction in the annualized acute porphyria attack rate (74% reduction in the treatment versus the placebo group) decreased the need for hemin use, and improved daily pain scores were observed with the monthly administration of givosiran at a dose of 2.5 mg/kg. Common side effects in the treatment group included injection-site reactions, nausea, rash, and fatigue. Notably, 15% of individuals treated with givosiran experienced transient elevation of liver transaminases, which led to treatment discontinuation in one trial participant. Furthermore, an increase in the serum creatinine level or reduction in eGFR was observed in seven (15%) individuals in the treatment cohort versus two (4%) in the placebo group. There was no correlation with baseline renal function, and resolution of the temporarily worsened kidney function over time without treatment discontinuation or dose adjustment was observed [14]. Real-world data collected after regulatory agency approval of givosiran shows an increased prevalence of hyperhomocysteinemia in individuals with AHP treated with the new siRNA drug. While increased homocysteine concentrations have been reported previously in AHP, initiation of therapy with givosiran seems to lead to a further increase in plasma levels, raising concern for potential cardiovascular or neurologic complications.

It is hypothesized that heme depletion could interfere with cystathionine-beta-synthase, which is the enzyme primarily responsible for the conversion of homocysteine, although alternative mechanisms could also be involved. Supplementation with pyridoxal phosphate (vitamin B6) led to improved or normalized homocysteine levels in some cases [48–51]. 2.3. Emerging Therapies With recent advances in vector-mediated gene therapy for inherited conditions, this approach also seems promising for AHPs. A phase I clinical trial (NCT02082860) was conducted in Europe, using a recombinant adeno-associated vector expressing porphobilinogen deaminase (rAAV2/5-PBGD), the enzyme deficient in AIP [15]. In an open-label dose escalation study, a total of eight participants received a one-time intravenous administration of this vector construct in different doses. While a trend towards symptom improvement (with respect to hospitalizations and hemin use) was noted, no change in the concentration of the porphyrin precursors ALA and PBG was observed. While all participants developed neutralizing anti-AAV5 antibodies, no cellular immune response against the transgene or the virus capsid occurred. It is thought that even the highest dose of rAAV2/5-PBGD administered in this study was not high enough to achieve a therapeutic effect. This result prompted further investigational efforts to optimize the gene therapy approach by altering the PBGD sequence to create a protein with increased enzymatic activity without having to administer a higher vector dose. In addition, different Diagnostics 2021, 11, 1795 8 of 18 approaches to decrease the immune system response and thereby improve the efficacy of rAAV-vector mediated gene therapy are underway [16,17]. In a different approach, human PBGD mRNA is packaged into liquid nanoparticles, which are administered intravenously and taken up by hepatocytes via receptor-mediated endocytosis. Preclinical studies showed dose-dependent protein production in an AIP mouse model, and rapid normalization of the porphyrin precursors was achieved during induced acute porphyria attacks. Repeat administration proved to be safe and efficacious, and the fact that safety has also been shown in non-human primates raises hope that this approach may also be translatable into humans [18]. 3. Erythropoietic Cutaneous Porphyrias Erythropoietic porphyrias present primarily with cutaneous photosensitivity and a distinct clinical presentation. These include the non-blistering porphyrias, EPP and XLP as well as CEP, which presents with blistering skin lesions. 3.1. Erythropoietic Protoporphyria and X-Linked Protoporphyria EPP is the third most common porphyria overall and the most frequent type in children [1]. Prevalence estimates of EPP range from 1:75,000 in the Netherlands to 1:200,000 in the UK [25,52]. A recent study that analyzed exome sequencing data from the UK Biobank determined that the prevalence of EPP is 1.7–3.0 times higher than previously thought in the UK [53]. EPP is an autosomal recessive condition caused by deficiency of ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway, which catalyzes the insertion of iron into protoporphyrin to form heme. This enzyme also affects the insertion of zinc into those protoporphyrin molecules that are not used for heme formation, leading to the production of zinc protoporphyrin [4,54,55]. The FECH enzyme is encoded by the FECH gene, and to date, more than 190 pathogenic FECH variants causing significant protein instability and loss of enzymatic function have been described [56]. A common lowexpression polymorphism (FECH IVS3-48C > T) affects splicing and leads to a decrease in enzyme activity of 20–30% [57]. The carrier frequency for this hypomorphic FECH allele varies among different ethnicities; it is present in up to 40% of Asians, approximately 10% of Caucasians, and very rarely present in individuals of African descent [58]. In most cases, EPP is caused by coinheritance of one copy of the low-expression allele and a pathogenic FECH variant in trans, which decreases the overall FECH activity to <35% of normal and results in photosensitivity. The presence of two pathogenic FECH variants is observed in approximately 5% of EPP patients [52,59]. Decreased FECH activity leads to the accumulation of protoporphyrin in bone marrow reticulocytes from where it enters the plasma via mature erythrocytes and is transported to the skin and liver [60]. Since FECH catalyzes the insertion of iron and zinc into protoporphyrin, the majority (>85%) of accumulating protoporphyrin is metal free [61,62]. XLP is caused by gain-of-function alleles in exon 11 of the ALAS2 gene and is X-linked in inheritance. These ALAS2 variants lead to activation of the erythrocyte-specific ALAS enzyme and result in the overproduction of protoporphyrin in excess of what is required for heme synthesis in bone marrow [63]. Since there is normal function of the FECH enzyme, a larger proportion of the accumulating protoporphyrin is zinc bound, and the rest is metal free (~50–85%) [12]. Given the X-linked inheritance, males are usually more severely affected, whereas the phenotype in females can be variable and range from asymptomatic to severe. 3.1.1.

Clinical Presentation Cutaneous photosensitivity in EPP/XLP is caused by protoporphyrin presence in the small blood vessels of the skin, leading to photoactivation upon sun exposure. This phototoxic reaction results in swelling, itching, burning, erythema and severe pain in sun-exposed areas. Symptom onset usually first occurs in early childhood, and the condi- Diagnostics 2021, 11, 1795 9 of 18 tion persists throughout life. Bullous skin lesions, skin fragility and hirsutism are absent, and symptoms resolve after several days of sun avoidance without scarring. Most frequently affected areas include the dorsal aspect of the hands and the face [1,64]. Mild iron deficiency anemia may occur in some individuals with EPP/XLP, but hemolysis is typically absent [65]. Vitamin D deficiency is a common finding in EPP/XLP [66]. Hepatic involvement with elevated serum aminotransferases can be observed in approximately 20–30% of individuals with EPP/XLP, and in rare cases (~1–5%), rapidly progressive liver failure may occur [67–69].

Approximately 25% of EPP/XLP patients have been reported to form gallstones consisting of crystallized protoporphyrins [70]. 3.1.2. Contemporary Approaches to Management Acute phototoxic reactions improve after several days of avoidance of sun exposure and cooling measures. Pain medication including narcotics is usually not efficient in alleviating pain. Antihistamines and steroids may improve symptoms, although a beneficial effect has not been clearly documented [71]. Sun avoidance and sun-protective clothing are the mainstay of EPP/XLP management. Tinted car windows and sunscreens containing zinc oxide or titanium dioxide help decrease sun exposure, and affected individuals often adjust their lifestyle to minimize sun exposure as much as possible [71]. Prophylactic treatment with oral beta-carotene can lead to mildly improved tolerance of sunlight if plasma levels are sufficiently high. This usually requires intake of high doses of beta-carotene, which tend to cause orange skin discoloration as an unpleasant side effect [72,73]. Other approaches, such cysteine, N-acetyl cysteine and vitamin C, have been tried but there are no data that show a beneficial effect on sun tolerance [74]. Afamelanotide (Scenesse™, Clinuvel Pharmaceuticals, Melbourne, Australia), an analogue of the human α-melanocyte stimulating hormone (α-MSH), was approved by the EMA in 2014 and by the FDA in 2019. Afamelanotide is administered in the form of a subcutaneous implant and binds to the dermal melanocortin-1 receptor, leading to increased production of the photoprotective substance eumelanin in the skin. In addition to producing a tan, eumelanin induces antioxidant activities, enhances DNA repair processes, and modulates inflammation [75,76]. Two multicenter, double-blind, placebo-controlled phase 3 clinical trials in Europe and the US with a total of 168 EPP/XLP patients showed increased pain-free time after sun exposure as well as a lower number of phototoxic reactions in the treatment versus the placebo group. In addition, patient-reported quality of life improved in participants who received afamelanotide. The most common side effect that could unequivocally be attributed to the afamelanotide implant was skin discoloration at the injection site. Other reactions such as nausea and nasopharyngitis were equally frequent in the placebo group [19,77]. In cholestatic liver disease, the use of cholestyramine and ursodeoxycholic acid has been described in an effort to increase protoporphyrin excretion [78,79]. In addition, plasmapheresis, red cell exchange transfusions and intravenous hemin administration have been trialed, but there is insufficient evidence to strongly support these measures [80,81]. For end-stage liver failure, orthotopic liver transplantation (OLT) is indicated. However, given the high risk of recurrent liver disease in EPP and the fact that protoporphyrin is produced in bone marrow, hematopoietic stem cell transplant (HSCT) has been reported as a curative approach either sequentially after OLT or as a primary intervention in cases without progressed liver fibrosis [79,82,83]. 3.1.3.

Emerging Therapies MT-7117 (Dersimelagon™, Mitsubishi Tanabe Pharma America, Jersey City, NJ, USA) is an orally administered small molecule that acts as a selective melanocortin-1 receptor agonist and increases dermal melanin production in the absence of ultraviolet radiation exposure, which is usually the main stimulus for melanin synthesis. In the recently completed multicenter, randomized, placebo-controlled phase 2 clinical trial (NCT03520036), Diagnostics 2021, 11, 1795 10 of 18 which included 102 EPP/XLP individuals, placebo was compared to treatment with lowdose (100 mg daily) and high-dose (300 mg daily) MT-7117 [20]. The primary outcome measure was the change from baseline in relation to the average daily duration of sunlight exposure tolerated without symptoms, which were defined as the prodromal symptoms that frequently precede a phototoxic reaction and include tingling, itching, burning and stinging. Patients in both treatment groups showed a significant increase in average daily time (>50 min) to first prodrome at week 16 (100 mg group: p = 0.008; 300 mg group: p = 0.003).

The overall side effect profile in the treatment groups was reported as favorable, with the most commonly reported events being nausea (27.9%), ephelides (23.5%) and skin hyperpigmentation (20.6%) [20]. A multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial (NCT04402489) assessing the same primary endpoint and measuring patient-reported outcomes regarding pain and physical function is currently underway. The majority (~90%) of individuals with EPP carry the hypomorphic FECH polymorphism IVS3-48C > T, which leads to the increased use of a cryptic splice site between exons 3 and 4. This results in the transcription of unstable mRNA with a premature stop codon and, therefore, overall decreased ferrochelatase enzyme activity [57]. Gouya et al. identified a sequence within intron 3 that, when targeted by an antisense oligonucleotide (AON-V1), led to redirection from the cryptic to the physiologic splice site and increased the production of wild-type mRNA [21]. Transfection of lymphoblastoid cell lines derived from symptomatic EPP patients with AON-V1 resulted in increased production of functional FECH mRNA. In developing erythroblasts from an EPP patient, erythrocyte protoporphyrin IX (PPIX) concentration after adding ASO-V1 decreased to the level observed in an asymptomatic pathogenic FECH variant carrier but did not normalize [21].

Thus far, no data are available on using this approach in vivo, but the development of a nanocomplex in which AON-V1 is coupled to a bifunctional peptide that facilitates delivery of the AON construct to erythroid cells and helps prolong redirection of splicing towards the physiological splice site offers a promising outlook [22].

The exact etiology of microcytic anemia and iron deficiency is not known, and individuals with EPP/XLP seem to have normal iron absorption and hepcidin response [65,84]. Similarly, the role of iron supplementation in the treatment of EPP and XLP remains unclear.

Based on single case reports, iron administration in patients with XLP seems to improve anemia as well as protoporphyrin levels and have a positive effect on liver disease [85]. In EPP, however, there are conflicting reports with some individuals experiencing improvement and others exacerbation of their photosensitivity upon iron supplementation [86,87]

. A clinical trial (NCT 02979249) assessing a change in protoporphyrin levels after starting iron supplementation was recently conducted, but no data have yet been reported. 3.2. Congenital Erythropoietic Porphryia CEP is extremely rare with approximately 250 described cases in the literature, affecting individuals of all ethnic backgrounds. It is caused by a deficiency of uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway, which is encoded by the UROS gene [88]. Inheritance is autosomal recessive, and there is broad phenotypic variability ranging from intrauterine demise due to non-immune hydrops fetalis to later-onset disease with mild cutaneous involvement. Deficiency of UROS leads to accumulation of the enzyme’s substrate, hydoxymethylbilane, which is then converted nonenzymatically into uroporphyrinogen I and subsequently coproporphyrinogen I. These porphyrin metabolites cannot be further metabolized since the next enzyme in the pathway, coproporphyrinogen oxidase (CPOX), is stereospecific for the isomer III coproporphyrinogen. Accumulation of the non-physiologic and phototoxic isomer I porphyrinogens ensues in erythroid precursors in bone marrow, where they undergo auto-oxidation to the corresponding porphyrins and cause damage to the erythrocytes, resulting in hemolysis [89,90]. Deposition of the photocatalytic and cytotoxic porphyrins in the skin leads to the cutaneous symptoms observed in CEP upon exposure to sunlight and other sources of long-wave Diagnostics 2021, 11, 1795 11 of 18 ultraviolet radiation. The porphyrinogen I isomers are excreted in large amounts in urine and feces, resulting in pink to dark-reddish discoloration of the urine, which is often observed as early as in the newborn period [91–93]. In three male individuals with CEP, beta-thalassemia and thrombocytopenia, a pathogenic variant in the X-linked GATA1 gene, was identified as an underlying cause. The pathogenic variant associated with the CEP phenotype is located in an area that is critical for the formation of an N-terminal zinc finger, which is thought to interfere with the binding affinity of the gene to the erythroid-specific UROS promoter region and thereby alter UROS gene expression [94,95]. 3.2.1.

Presentation The first sign in many individuals with CEP is reddish discoloration of urine, which frequently occurs in infancy or early childhood. Photosensitivity tends to be severe with vesicle formation in sun- or light-exposed areas. Blisters are prone to rupture and have a high risk of superinfection. The healing process frequently leaves scars, and deformities with loss of digits and facial features, such as eyelids, lips and ear and nose cartilage can occur (photomutilation). Thickening of the skin, hypertrichosis of the face and extremities and brown discoloration of the teeth (erythrodontia) are common [91,96,97]. If not protected from light exposure, eye involvement, such as necrotizing scleritis, keratoconjunctivitis, blepharitis and ectropion, can develop [98–100]. Most individuals with CEP experience chronic hemolytic anemia, which can be severe and require blood transfusion, splenomegaly, secondary thrombocytopenia and leukopenia. Porphyrin deposition in the bones can lead to demineralization and severe osteoporosis [101,102]. 3.2.2. Contemporary Approaches to Management Protection from exposure to sunlight, ultraviolet light and light emitted by fluorescent sources is the most important aspect of the prevention of cutaneous manifestations. Skin blisters and lesions need to be addressed promptly to prevent secondary infections, which frequently require topical or systemic antibiotic therapy. Other complications, such as ophthalmologic manifestations, are treated symptomatically. Vitamin D supplementation is crucial to avoid osteopenia and osteoporosis [5,103]. If hemolytic anemia is severe, frequent blood transfusions may be necessary to maintain the hematocrit above 32%. Chronic hypertransfusion leads to suppression of erythropoiesis and simultaneously decreased porphyrin production, which can result in improved photosensitivity. However, complications of long-term blood transfusions, such as iron overload, can occur [104]. Splenectomy can be considered in individuals with significant splenomegaly, hemolytic anemia and pancytopenia [103]. The only curative approach in CEP consists of hematopoietic stem cell transplant (HSCT), which is usually reserved for very severe cases given the high risk of morbidity and mortality [105,106]. 3.2.3. Emerging Therapies Similarly to EPP/XLP, the role of iron and iron metabolism in CEP is not yet completely understood. Recently, some CEP patients were reported to show an improvement in hemolysis and photosensitivity after successive phlebotomies or off-label treatment with an iron chelator, effectively inducing iron deficiency [107–109]. A beneficial effect of iron chelation on photosensitivity and hemolysis was recently demonstrated in a murine CEP model as well as in a human erythroid cell line from a CEP patient, in which inhibition of iron-dependent erythroid-specific ALAS2 expression and iron-responsive element-binding protein 2 led to decreased porphyrin production [110]. Thus far, the experience in humans is based on single observations and isolated case reports, and no clinical studies have been performed. Millet et al. discovered that the known antifungal medication ciclopirox binds to the UROS protein and stabilizes its folded form, thereby effectively acting as a chaperone. In a CEP mouse model treated with ciclopirox, UROS enzyme activity was restored, and a Diagnostics 2021, 11, 1795 12 of 18 decrease in uro- and coproporphyrinogen I in red blood cells as well as improvement of splenomegaly were measured. It was demonstrated that ciclopirox targets an allosteric site, which is removed from the active center, and there is no interference with the enzyme’s catalytic center. Given this mechanism, it is thought that ciclopirox would be suitable for approximately 75% of missense variants and would not have any effect on intronic variants or splicing defects [23]. While no clinical trials in individuals with CEP have been performed to date, a phase I study in patients with hematologic malignancy revealed that ciclopirox was well tolerated at low and medium doses and had a stabilizing effect on the malignant disease state. The mechanism behind this phenomenon is thought to be intracellular iron chelation and disruption of iron-dependent pathways, such as Wnt signaling, which results in decreased expression of the antiapoptotic gene SURVIVIN [111]. Even though iron chelation is thought to improve photosensitivity and hemolysis in individuals with CEP, this does not seem to be the mechanism through which the effect of ciclopirox is conferred in this condition since the mRNA expression of genes involved in the heme biosynthetic pathway remained unchanged in the CEP cell line treated with ciclopirox. In addition, the uroporphyrinogen I concentration in cells treated with ciclopirox was not influenced by large amounts of iron, which is possibly explained by the fact that ciclopirox has only weak affinity for iron binding and rather acts as a stabilizer of heme than a competitor for metal chelation [23]. Additional studies to improve the toxicity and pharmacologic profile of ciclopirox are underway in preparation for potential clinical trials in individuals with CEP [24]. 4. Hepatic Cutaneous Porphyrias Hepatic cutaneous porphyrias include Porphyria Cutanea Tarda (PCT) and Hepatoerythropietic Porphyria (HEP). PCT is the most common type of porphyria with a prevalence of approximately 50 per one million and an incidence of 2–5 per million [26]. Most cases of PCT are acquired (PCT I), and only around 20% of individuals with PCT carry a pathogenic variant in the UROD gene (PCT II), which acts as a predisposing factor [1,2]. HEP is very rare, with less than 100 cases described in the literature and is caused by bi-allelic UROD variants, leading to significantly decreased urodecarboxylase (UROD) enzyme activity [112]. The sporadic form (PCT I) develops in the setting of liver-specific inhibition of the UROD enzyme activity, which can occur in the presence of several susceptibility factors, such as HFE variants, excess alcohol consumption, hepatitis C, end-stage renal disease, HIV and hormonal influences. Decreased UROD activity leads to the accumulation of uroporphyrinogen as well as the intermediate metabolites hepta-, hexa- and pentacarboxylporphyrins, which are then oxidized and excreted as their corresponding porphyrins. Circulation of these porphyrins in the skin capillaries causes cutaneous symptoms upon sun exposure due to photoactivation. The penetrance of PCT II is very low, and typically, no familial clustering is observed [1–3]. 4.1. Clinical Presentation Individuals with PCT experience bullous lesions and fluid-filled vesicles, which easily rupture and heal with crusting and scarring. These findings are present in sun-exposed areas such as the face, neck, ears and dorsal aspect of hands and forearms. In addition, marked skin fragility, milia, hypertrichosis, hyperpigmentation and severe thickening of the skin occur frequently. A mild to moderate increase in serum aminotransferases is present in >50% of PCT patients, and ferritin levels are either normal or elevated. The clinical picture in HEP is characterized by symptom onset in early childhood and severe phototoxicity with blistering, scarring and in some cases photomutilations [113]. 4.2. Current Management Approaches Iron is known to play a significant role in the pathogenesis of PCT, and reduction in iron stores and hepatic iron content is the mainstay of symptomatic treatment. This can be achieved by serial phlebotomies or oral iron chelator therapy if phlebotomy is Diagnostics 2021, 11, 1795 13 of 18 contraindicated or poorly tolerated. Antimalarial agents, such as hydroxychloroquine or chloroquine, at low doses are an effective alternative if phlebotomy is not an option, although the mechanism of action is poorly understood. Susceptibility factors should be addressed or removed as much as possible. The treatment of HEP is based mostly on photoprotection since neither phlebotomies nor low-dose antimalarial agents have been shown to improve symptoms [114,115]. 4.3. Emerging Therapies and Investigations Chronic hepatitis C is one of the most common susceptibility factors for sporadic PCT [116]. Since PCT symptoms are often more debilitating than manifestations of chronic hepatitis C, PCT treatment was recommended before starting therapy for hepatitis C. However, recent advances in the treatment of hepatitis C and availability of the highly effective direct-acting antiviral (DAA) medications may lead to a paradigm shift, since some case reports showed that PCT-directed therapy was unnecessary after the use of DAAs in patients with PCT and hepatitis C. A phase 2 clinical trial (NCT 03118674) is currently underway, evaluating if the treatment of individuals with chronic hepatitis C and PCT with ledipasvir/sofosbuvir (Harvoni™, Gilead Sciences, Foster City, CA, USA) leads to resolution of PCT determined by porphyrin concentrations, as well as clinical manifestations. 5.

Conclusions and Future Directions Porphyrias are a heterogeneous group of disorders characterized by phenotypic variability, chronic disability, and decreased quality of life. Treatment options have been limited with primarily symptomatic management. Curative approaches consist of hematopoietic stem cell transplant (in CEP and EPP) or liver transplantation (in AHP), which is a treatment of last resort for patients with severe, progressive disease who are at high risk for complications and mortality. There is a large unmet need for disease-modifying therapies for both acute and cutaneous porphyria. In recent decades, a better understanding of the underlying disease mechanisms as well as advances in molecular therapeutics have given rise to novel treatment approaches that are targeting the underlying pathomechanisms rather than merely addressing symptoms. With further advances in the area of targeted therapies, more definitive or even curative treatment approaches, such as gene therapy, gene editing and alternate modes of gene or drug delivery, are being investigated for the different types of porphyria, with the goal to ameliorate the disease course as well as the quality of life of affected individuals. Author Contributions: Conceptualization, A.L.E. and M.B.; writing—original draft preparation, A.L.E.; writing—review and editing, M.B. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded in part by The Porphyrias Consortium (U54DK083909), which is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the NIDDK. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: A.L.E.: consultancy for Alnylam Pharmaceuticals and Mitsubishi Tanabe Pharma America. M.B.: consultancy for Recordati Rare Diseases and Alnylam Pharmaceuticals; clinical trial support from Mitsubishi Tanabe Pharma America. Diagnostics 2021, 11, 1795 14 of 18 References 1. Anderson, K.E.; Sassa, S.; Bishop, D.; Desnick, R.J. Disorders of heme biosynthesis: X-linked sideroblastic anemias and the porphyrias. In The Metabolic and Molecular Basis of Inherited Disease; Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D., Eds.; McGraw-Hill: New York, NY, USA, 2001; pp. 2991–3062. 2. Puy, H.; Gouya, L.; Deybach, J.C. Porphyrias. Lancet 2010, 375, 924–937. [CrossRef] 3. Bissell, D.M.; Anderson, K.E.; Bonkovsky, H.L. Porphyria. N. Engl. J. Med. 2017, 377, 862–872. [CrossRef] [PubMed] 4. Desnick, R.J.; Balwani, M.; Anderson, K.E. Inherited Porphyrias. 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Nov 10, 2021, 10:50:28 PM11/10/21

to Clinuvel Afamelanotide SCENESSE senescence CUV ASX.CUV CLVLY ur9

johnnytechModerator. Sharetease

Staff member

Today at 5:09 AM

#11,075

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.

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