In this post, I share a few thoughts about erythropoietic protoporphyria (EPP), a serious debilitating condition for which there are presently no approved treatments.
EPP is a rare inherited disorder of heme biosynthesis characterized by dermal photosensitivity secondary to a partial deficiency of ferrochelatase. In a phenotypically similar X-linked protoporphyria (XLP), there is overactivity of the heme biosynthesis enzyme, erythropoietic aminolevulinate synthase (ALAS2). Both EPP and XLP result in the accumulation of the photosensitizer protoporphyrin IX (PPIX) in erythrocytes, plasma, skin and liver. The accumulated PPIX is activated by sun exposure, thus generating free radicals which damage tissue and cause severe pain.
EPP is a devastating lifelong disorder with very few evidence-based clinical management tools and no approved treatments in the United States. The number of patients affected by EPP in the US is unknown. In Europe, it is estimated that about 1 in about 75,000 to 1 in 200,000 individuals are affected. Worldwide, EPP is the third most common porphyria, with an incidence of about 2 to 5 per 1,000,000 individuals. Diagnostic delay is not uncommon due to a lack of symptom awareness among pediatricians.
Clinically, EPP is characterized by both cutaneous and extracutaneous manifestation. Phototoxicity usually begins in infancy and manifests as intolerance to sunlight, including tingling, stinging, burning, itching and pain having an onset within minutes of exposure to sun or UV light. The phototoxicity can also be accompanied by lichenification, loss of lunulae, edema, erythema and petechiae. A phototoxic reaction typically lasts from hours to a few days, although reactions lasting 10 or more days have been reported, often accompanied by social isolation, excruciating pain, anxiety and sleep impairment.
Extracutaneous manifestations include PPIX-mediated bile duct obstruction, resulting in cholestatic liver injury in 20-30%, and eventually cholelithiasis, cholestatic hepatitis, fibrosis, cirrhosis and liver failure in 3-5% of patients. Progressive liver disease can require liver transplantation, although a replacement healthy liver can start the reaccumulating PPIX. Thus, liver transplantation is not curative without a sequential liver and hematopoietic stem cell or bone marrow transplantation to correct the underlying enzymatic defect.
Photoprotection against UV-A and visible light, including sun avoidance are required to minimize cutaneous reactions and pain. Patients with EPP have to maintain a high level of vigilance about ambient and changing light conditions and undertake measures to minimize the risk of phototoxicity. Drastic lifestyle modification, including the use of protective clothing, skin foundation, shade, tinted windows and indoor living are essential to minimize the cutaneous sequelae of EPP. These symptoms, along with required behavioral modification markedly impact employment choices, socialization (sun avoidance), work and school attendance, productivity, activities of daily living and quality of life. One study reported that while most individuals with EPP were employed or attending school, almost half felt their choice of vocation had been influenced by their symptoms. Both lifestyle modification and sunlight avoidance can place a significant burden on families.
Although a number of treatments, including high dose β-Carotene, Vitamin C, N-Acetyl Cysteine and narrow band UVB have been suggested, there is little evidence to support their use. The only evidence-based treatment for preventing phototoxicity in EPP is afamelanotide (Scenesse®), a controlled release subcutaneous implant (depot) from Clinuvel Pharmaceuticals, a Melbourne, Australia headquartered company. Afamelanotide, a structural analog of α-melanocyte stimulating hormone (α-MSH) was developed, patented and initially tested by Drs. Victor Hruby, Robert Dorr and (the late) Mac Hadley at the University of Arizona more than two decades ago. It was first envisaged as a sunless tanning agent. Afamelanotide is a melanocortin receptor agonist that binds predominantly to the melanocortin-1 receptor (MC1R), activating the synthesis of eumelanin which provides photoprotection through absorption of UV and visible light, scavenging of free radicals and increased superoxide dismutase availability.
Scenesse was approved by the EMA in December 2014 for prevention of phototoxicity in adult patients with EPP as a 16 mg subcutaneous implant administered every two months. The UK marketing authorization for Scenesse is under “exceptional circumstances” for the prevention of phototoxicity in adult patients with EPP. Unfortunately, in 2017, the U.K. National Institute for Health and Care Excellence (NICE) concluded that Scenesse “is not recommended, within its marketing authorization, for preventing phototoxicity in adults with erythropoietic protoporphyria” and this ruling was upheld in 2018 on appeal. This means that the National Health Service (NHS) will not reimburse for Scenesse in England. In reaching its decision, NICE made several observations about the clinical trial design and data submitted by Clinuvel, including (i) inadvertant treatment allocation unmasking (unblinding); (ii) a "small" but statistically significant benefit in daylight exposure without pain (approximately 10 minutes per day); and (iii) the pharmaceutical sponsor's the choice, validation, and relevance for quality of life instruments. In June 2018, Clinuvel submitted an NDA for which FDA has granted a Priority Review and assigned a PDUFA date of July 8, 2019.
In summary, there is a need for improved early diagnosis of EPP to reduce sun exposure and provide appropriate follow up, including monitoring for hepatic complications. This can be done through improved education and orphan diseases awareness. There is a need for improved treatments with robust efficacy in EPP, preferably by the oral route. There is also a need for improved study designs that leverage our increased understanding of adaptive clinical trials, quality of life and health economic outcomes, and possible integration of photoprovocation in clinical trials. Finally, it is important to appreciate the potential role of geographic and seasonal differences in natural sunlight duration and occuptaionala nd recreational time spent outdoors as potential variables in EPP clinical trials.
Dr. Najib Babul, PharmD, MBA
Neuropore announced advancement of UCB0599 to next phase. UCB0599 is an orally bioavailable, brain barrier penetrant small molecule that prevents the oligomerization of alpha-synuclein. Alpha-synuclein oligomerization and aggregation is implicated in Parkinson’s disease and other degenerative diseases. By inhibiting misfolding and oligomerization of alpha-synuclein, it is believed that the progression of Parkinson’s disease can be slowed or halted. UCB0599 belongs to a series of molecules discovered by Neuropore, which were licensed to UCB in 2014 (Press Release)
Neuropore Therapies announced that it has initiated a Phase 1 clinical trial in healthy volunteers with NPT520-34. This Phase 1 study is designed to evaluate the safety, tolerability and pharmacokinetics of NPT520-34. NPT520-34 is an orally bioavailable, blood-brain barrier penetrating small molecule. Its mode of action is attenuation of neuroinflammation and reduction of neurotoxic misfolded proteins in the central nervous system, key features of neurodegenerative diseases including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS).
Collidion, Inc. and it’s subsidiaries, Plex Pharmaceuticals & Avenlogics, Inc has an immediate full-time position open for Pharmaceutical & Medical Device Regulatory Affairs Director.
To apply, visit www.collidion.com/careers
Founded in 2015, Collidion, Inc. is a private healthcare company with two subsidiaries, Avenlogics, Inc. and Plex Pharmaceuticals. Collidion strives to improve the future of global healthcare through the acquisition, licensing, development, and commercialization of drugs and medical devices for various markets. Collidion invests industry expertise and capital to develop these technologies into recognizable solutions for patients and medical professionals. Collidion values innovation, scientific rigor, collaboration and a passion for change.
Avenlogics, Inc., Collidion’s subsidiary, is focused on the development and commercialization of several anti-infective based products. The Company’s pipeline of antimicrobial products addresses a growing need for alternative therapies to effectively treat infections caused by antimicrobial resistant pathogens. Collidion’s solutions include several antimicrobial platforms with potential applications in human and animal medicines, wound care, surface disinfection, and improved safety for the food supply chain. The company is located alongside with Collidion, Inc in Petaluma, CA.
Plex Pharmaceuticals is a scientifically-driven company with a vision to improve the lives of patients with complex diseases and conditions. The company is focused on the treatment of diseases generally caused by protein misfolding: ALS, Parkinson’s disease, and cataracts. The company was founded in 2009. Plex has a rich pipeline of drug discovery programs and a dedicated scientific team. Plex’s drug discovery lab and operations are located in San Diego, California.
PHARMACEUTICAL AND MEDICAL DEVICE REGULATORY AFFAIRS DIRECTOR
- Regulatory representation and leadership to cross-functional product development teams, development of regulatory strategies and support for clinical and non-clinical development programs and marketing applications.
- Responsible for project timelines and management of 510K, PMA, IND, NDA and global regulatory submissions.
- Lead regulatory activities including planning and reviewing of CMC, clinical and nonclinical sections of regulatory submissions.
- Plan, direct and prepare regulatory submissions (IND, NDA, IDE, 510(k), PMA) to ensure compliance with FDA and international regulations and guidelines.
- Develop and maintain SOPs with an emphasis on drug and device regulations.
- Perform research regarding regulatory strategic recommendations, and new and revised governmental regulations.
- Conduct successful negotiations and interactions with domestic and foreign regulatory agencies on assigned projects.
- Provide regulatory guidance with regard to preparation, review and approval of labeling and promotional materials.
- Prepare and assist with applicable regulatory audits.
- Statistical techniques.
- Minimum of B.S. in life sciences, engineering, or equivalent required.
- Advanced degree preferred.
- Minimum 5-7 years of experience in regulatory affairs for pharmaceutical and medical device biopharmaceutical companies.
- Veterinary product experience highly desirable.
- Experience with successful FDA and international agency negotiations and audits.
- Experience in developing and submitting successful 510(k), PMA, IND/NDA submissions with a thorough understanding of the drug and device development processes, FDA regulations and ICH guidelines.
- Excellent verbal and written communication skills.
- Detail oriented with well-developed organizational and analytical skills.
- Experience with submitting documents in CTD and eCTD format.
- Suited to working in a fast-paced, small company environment.
Plex Pharmaceuticals is interested in sub-leasing 1000-1500 Sq. Ft. of laboratory space on a month-to-month or long-term basis. The sub-lessee will have access to common laboratory equipment, chemical fume hood, tissue culture and other general lab instruments. Lab bench with 3-5 knee holes, dedicated office space, wi-fi, shared conference room, common kitchen and reception area. Interested parties please contact Sridhar Prasad at 858-733-0858 or email: firstname.lastname@example.org
Presentation by Dr. Tom Insel on July 24th at the Illumina Theater, Alexandria at Torrey Pines. Appetizers and drinks sponsored by Neuropore Therapies.
About the event:
Dr. Insel will talk about leading edge technologies that may one day be of impact to the care of patients suffering from psychiatric conditions. He will discuss the advent of digital phenotyping, modern cognitive and linguistic assessments, and powerful computational approaches applied to complex data which now permit a deeper analysis of behavior than would have been possible even five years ago. Will this phenomic analysis in psychiatry serve the same role as molecular profiling in oncology? Will subgroups selected by modern phenomics be predictive of treatment response or clinical course? This presentation will argue that a detailed analysis of behavior and cognition combined with functional connectomics can become a pathway to precision medicine for psychiatry.
About Dr. Insel:
Thomas R. lnsel, M.D., a neuroscientist and psychiatrist, leads the Mental Health Team at Verily (formerly Google Life Sciences) in South San Francisco, CA. From 2002-2015, Dr. Insel served as Director of the National Institute of Mental Health (NIMH). In that role he also served as Chair of the Interagency Autism Coordinating Committee (IACC) as well as co-lead of the NIH BRAIN Initiative. Prior to serving as NIMH Director, Dr. lnsel was Professor of Psychiatry at Emory University where he was founding director of the Center for Behavioral Neuroscience and director of the Yerkes Regional Primate Center in Atlanta. Dr. Insel’s research has examined the neural basis of complex social behaviors, including maternal care and attachment. A member of the National Academy of Medicine, he has received numerous national and international awards and served in several leadership roles at NIH.
Don't miss the networking event outside the Illumina Theater right after the presentation. Drinks and appetizers are sponsored by Neuropore Therapies, Inc.
Neuropore Therapies, Inc. is a San Diego, California based biopharmaceutical company that is focused on the discovery and development of novel small molecule therapeutics for the treatment Parkinson’s disease and other neurodegenerative disorders. The approaches being taken by Neuropore Therapies target the core pathological processes underlying these disorders including the intracellular accumulation of neurotoxic misfolded proteins and the associated neuroinflammation. As such, the therapeutics being developed by Neuropore may provide the first effective means for slowing the unremitting progression of these devastating diseases.
Learn more and register here
The Michael J. Fox Foundation for Parkinson's research awarded Neuropore Therapies a second grant on its TLR2 antagonist Program for Parkinson's disease. READ MORE: https://www.businesswire.com/news
The Law Offices of Michael A. Swit, devoted to Solving FDA Legal Challenges for the Life of a Life Sciences Company.
Please visit our website at www.fdacounsel.com.
An international bio-tech company is looking urgently for lab space (plus office space of 2,000-3,000 square foot) to buy or lease. They would prefer a setting where the clean room space is already built, but will consider any location where the building is properly zoned and has the utilities to support tenant improvement.
As a member of SDEE I would highly appreciate any help from the community. Please reach out to me at email@example.com if you have any information on potentially available lab space.