Category Archives: Genetic Therapy

Age-related macular degeneration (ARMD) is a dreadful ocular disease mainly affecting people above 50 and is the result of damage to the central area of the retina called the macula, which is responsible for reading and driving vision. In conversation with THE HEALTH PIONEER, well-known OphthalmologistsDr. Rohan Chawla and Dr Mahipal Singh Sachdev throw insight into the disorder and warn that as diagnosis usually occurs in later stages when a visual loss has already occurred, no effective treatment can be given. Hence, early detection is the key to ensuring the quality of life of the eyes.

ARMD causes central irreversible vision loss in the older population, resulting in disability and significantly affecting the quality of life. It is caused due to age, genes, smoking, high blood pressure or high cholesterol, obesity, eating lots of saturated fat, being light-skinned, being female, and having a light eye color.

In Wet form, blood vessels grow from underneath your macula. These blood vessels leak blood and fluid into your retina. Your vision is distorted so that straight lines look wavy. You may also have blind spots and loss of central vision. These blood vessels and their bleeding eventually form a scar, leading to permanent loss of central vision. The wet form of macular degeneration is a leading cause of permanent vision loss. If its in both eyes, it can hurt your quality of life. Wet macular degeneration may need repeated treatments. Test your vision regularly, and follow your doctors advice.

Most people with macular degeneration have a dry form, which may lead to a wet form. Only about 10% of people with macular degeneration get the wet form.

It is extremely important for people above the age of 50 years to get regular dilated ophthalmic examinations done. The risk factors associated with ARMD are advancing age, genetic factors, cigarette smoking, comorbidities such as cardiovascular disease, hypertension, female gender, hypercholesterolemia, obesity, family history, light irides, etc.

Early on, you might not have any noticeable signs of macular degeneration. It might not be diagnosed until it gets worse or affects both eyes. But if you feel that your vision is getting blurry, and it is hard to read fine print or drive, go to an eye doctor as soon as possible.

If you are above 50 years of age, your doctor can check you for ARMD when you see them for a routine eye exam and have your eyes dilated. They'll test your vision and also examine your retina -- a layer of tissue at the back of your eye that processes light. They'll look for tiny yellow deposits called drusen under the retina. It's a common early sign of the disease.

Your doctor may also ask you to look at an Amsler grid -- a pattern of straight lines that's like a checkerboard. If some of the lines appear wavy to you or some of them are missing, it could be a sign of macular degeneration. ARMD can also be Early or Advanced, the advanced form further divided into atrophic or neovascular variants. The neovascular form is responsible for more than 90% of the vision loss associated with ARMD and causes swelling and fluid accumulation in the retina.

If your doctor finds ARMD, you may have a procedure called angiography or one called OCT. In angiography, your doctor injects dye into a vein in your arm. They take photographs as the dye flows through the blood vessels in your retina. If there are new vessels or vessels leaking fluid or blood in your macula, the photos will show their exact location and type. OCT is able to see fluid or blood underneath your retina without dye.

Its important to see your eye doctor regularly to find signs of macular degeneration early. Treatment can slow the condition or make it less severe.

According to a study, India has 23.5 per cent of global blindness, which suggests that the surveillance of various risk factors and controlling them is the need of the hour so that we can prevent this disease at an early stage before causing significant visual impairment.

The earliest symptoms of ARMD include difficulty near vision, wavy or distorted appearance of letters while reading, the appearance of black spots in the visual field, lack of vision improvement with glasses, loss of contrast, slow recovery of vision after coming from bright light, etc.

At present, there are more than 70 million people above the age of 60 years in India. The improving life expectancy means that the burden of this disease is imminent in the near future. The estimated number of people above the age of 60 years are expected to reach about 180 million by the year 2026 and so is the expected increase in age-related degenerative retinal disease. But these changes are not easily identifiable unless a thorough eye examination is carried out by an ophthalmologist.

The neovascular form however requires special injections into the eye known as anti-VEGF (vascular endothelial growth factor). However, once the swelling subsides, the consequent scarring distorts the retinal architecture. Therefore, a prompt diagnosis, early intervention is the key to preserving good vision in ARMD. Regular screening for ARMD should be conducted in people above 50 years including periodic dilated fundus examination.

Because usually women live longer than men, we find there are more women suffering from ARMD than men.

Dr Mahipal Singh Sachdev.

Professor in Ophthalmology and Padamashri Awardee

Senior Consultant, Chairman and Medical Director,

Centre For Sight Group of Eye Hospitals

There are two main types of age-related macular degeneration. One is a dry form in which people's eyes may have yellow deposits, called drusen, in their macula. A few small drusen may not cause changes in your vision. But as they get bigger and more numerous, they might dim or distort your vision, especially when you read. As the condition gets worse, the light-sensitive cells in your macula get thinner and eventually die. In the atrophic form, you may have blind spots in the center of your vision. As that gets worse, you might lose central vision.

Preventive measures to stop ARMD progression include cessation of cigarette smoking, blood pressure control with anti-hypertensives, and reduction in cholesterol levels. Eat green leafy vegetables and carrots for better health of the eyes. There are certain formulations of eye vitamins containing antioxidants and Omega 3 fatty acids that have shown to retard the progression of ARMD.

It is estimated that a total of 30-50 million people are suffering from ARMD world over, and this number is rising dramatically as age advances. According to the World Health Organization, 288 million people will suffer from ARMD by 2040, if it remains uncontrolled and untreated. Dry ARMD is more prevalent than wet ARMD in India.

Dr Rohan Chawla.

Assistant Professor of Ophthalmology,

Dr. RP Centre for Ophthalmic Sciences, AIIMS, Delhi

treatment options

Theres no cure for macular degeneration. Treatment may slow it down or keep you from losing too much of your vision. Your options might include:

Anti-angiogenesis drugs:

These medications -- aflibercept (Eylea), bevacizumab (Avastin), faricimab-svoa (Vabysmo), pegaptanib (Macugen), and ranibizumab (Lucentis) -- block the creation of blood vessels and leaking from the vessels in your eye that cause wet macular degeneration. Many people whove taken these drugs got back some vision that was lost. You might need to have this treatment multiple times.

Laser therapy: High-energy laser light can destroy abnormal blood vessels growing in your eye.

Photodynamic laser therapy: Your doctor injects a light-sensitive drug -- verteporfin (Visudyne) -- into your bloodstream, and its absorbed by the abnormal blood vessels. Your doctor then shines a laser into your eye to trigger the medication to damage those blood vessels.

Low vision aids: These are devices that have special lenses or electronic systems to create larger images of nearby things. They help people who have vision loss from macular degeneration make the most of their remaining vision.

Is New Gene Therapy a ray of hope?

Researchers from Trinity College Dublin have developed a new gene therapy approach that shows promise for treating the dry form of (ARMD). The gene therapy, ophNdi1, developed by the team in Trinitys School of Genetics and Microbiology, is the first of its kind to directly target mitochondrial function in cells that are malfunctioning in ARMD.

In adults, many diseases of aging have been found to have defects of mitochondrial function, including ARMD.

Mitochondria are known as the powerhouses of the cell because they manage the production of energy but their performance dips greatly in dry ARMD and this is linked to a deterioration in sight.

The new gene therapy cleverly uses a virus to access the cells that are suffering and deliver the code needed to give the failing mitochondria a lifeline, enabling them to generate extra energy and continue to function in supporting the vision.

The therapy has shown benefits in multiple models of dry ARMD.

Professor Jane Farrar, the senior author, said, Critically, this study provides the first evidence in models that directly modulating bioenergetics in eye cells can provide benefit and improve visual function in dry ARMD. In doing so, the study highlights the energy powerhouses of the cell, mitochondria, as key targets for dry ARMD.

Dr. Sophia Millington-Ward, first author and research fellow in Trinitys School of Genetics and Microbiology, said, The novel gene therapy targeting cellular energy, or mitochondrial function, that we explored for dry AMD consistently provided benefit in the model systems tested.

Continued here:
50 Plus and Got Blurry Vision? - Daily Pioneer

RoosterBio, a Maryland, US, supplier of human mesenchymal stem/stromal cells (hMSCs), highly engineered media, and bioprocess development services, says the partnership ties in with its aims to expand globally this year and beyond.

RoosterBios engineered media products are creating transformative impact for cell and exosome therapy developers all over the world, said Tim Kelly, CEO. One of our key objectives in 2022 is to expand global access to our best-in-class products and services, particularly in Europe and Asia. Some of the most exciting R&D in the MSC and exosome space is being conducted in China, so we have sought to partner with an industry leader in that region.

In addition to product distribution, the agreement creates an access path to RoosterBios process development and analytical services, which help advanced therapy developers move candidates into the clinic. These services, combined with media solutions, 'offers therapy developers a complete solution, addressing upstream expansion of hMSCs in 2D flasks or 3D bioreactors, optimized conditions for exosome collection, and downstream processes to achieve purity, yield, and potency of the final formulated drug product.'

Tamao Kaku, Managing Director of MBL Beijing (aJSR Life Sciences company supplying products to support life sciences), said: After evaluating the current solutions available, we determined that drug developers in China will greatly benefit from the RoosterBio technology platform and product portfolio. We are pleased to have the opportunity to support our cell and exosome therapy developers by offering this industry-leading solution.

MBL Beijing will start accepting and fulfilling RoosterBio orders in September 2022.

Go here to read the rest:
RoosterBio and MBL Beijing Biotech team up to accelerate advanced therapy manufacturing in China - BioPharma-Reporter.com

A diagnosis of autism is often followed, or preceded by, other diagnosis. Many conditions mimic autism and vice versa. Some increase the risk for autism, some are common comorbid conditions with autism.

Some children diagnosed with autism spectrum disorders are also diagnosed with Ehlers Danlos syndrome. Today I want to discuss Ehlers Danlos and autism, and how they relate to each other.

According to the Mayo Clinic, ehlers danlos syndrome is a group of inherited disorders that affect your connective tissues primarily your skin, joints and blood vessel walls. Connective tissue is a complex mixture of proteins and other substances that provide strength and elasticity to the underlying structures in your body.

EDS shares symptoms with other hypermobility related disorders such as:

The National Health Service (NHS) in the UK explains there are 13 types of EDS, most of which are very rare.

Hypermobile EDS (hEDS) is the most common type. Other types of EDS include classical EDS, vascular EDS, kyphoscoliotic EDS, and others.

People with hEDS may have:

Currently, there are no tests to confirm whether someone has hEDS.

The diagnosis is made based on a persons medical history and a physical examination.

Classical EDS (cEDS) is less common than hypermobile EDS and tends to affect the skin more.

People with cEDS may have:

Vascular EDS (vEDS) is a rare type of EDS and is often considered to be the most serious.

It affects the blood vessels and internal organs, which can cause them to split open and lead to life-threatening bleeding.

People with vEDS may have:

Kyphoscoliotic EDS (kEDS) is rare.

People with kEDS may have:

Like many other conditions, EDS is diagnosed using a specific set of criteria. The criteria are outlined in book called Gene Reviews: Hypermobile Ehlers-Danlos Syndrome as follows:

The diagnostic criteria for hEDS (and all other types of EDS) were revised by the International EDS Consortium in 2017 [Malfait et al 2017]. No underlying genetic etiology has yet been identified in hEDS, and thus the diagnosis is based entirely on clinical evaluation and family history.

Joint hypermobility is a feature of many heritable and acquired disorders (see Differential Diagnosis), and may also occur as an asymptomatic and/or nonsyndromic finding. In order to reduce heterogeneity and enhance efforts to identify the genetic etiology, a formal diagnosis of hEDS should be made only when all of the diagnostic criteria are met. Individuals with signs and symptoms suggestive of a hereditary connective tissue disorder who fail to meet diagnostic criteria for hEDS or any other described condition should be considered to have hypermobility spectrum disorder (HSD) [Castori et al 2017].

The clinical diagnosis of hEDS requires the simultaneous presence of three criteria:

Multiple other clinical features including (but not limited to) sleep disturbance, fatigue, postural orthostatic tachycardia, functional gastrointestinal disorders, dysautonomia, anxiety, and depression are associated with hEDS. Some of these features were formerly included as minor diagnostic criteria for hEDS [Beighton et al 1998]. They were excluded from the 2017 hEDS diagnostic criteria because they lack specificity for hEDS [Malfait et al 2017].

We learn from the Mayo Clinic, that common symptoms of EDS can include:

Autism spectrum disorders and EDS both share various connections. Some of them include symptom overlap, and comorbid conditions.

A study called The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders concluded:

Although autism is defined neurobehaviorally and EDS/HSD by various articular and extra-articular connective tissue manifestations, these two conditions share considerable phenotypic overlap at various levels. Genetic data indicate similarities at the molecular, cellular, and tissue levels, as illustrated by numerous genetic syndromes with comorbid autism and hypermobility, which we have reviewed within this manuscript. EDS/HSD and autism comorbidity and familial co-occurrence lend further credence to this relationship, suggesting potential links via the maternal immune system

Meanwhile, these two spectrum conditions share a variety of secondary comorbidities, including similar neurobehavioral, psychiatric, and neurological phenotypes, such as ADHD, anxiety and mood disorders, proprioceptive impairment, sensory hyper-/hyposensitivities, eating disorders, suicidality, epilepsy, structural abnormalities such as Chiari I malformation and periventricular heterotopias, and sleep disordersparticularly those involving SDB. Relevant to these neurophenotypes are also common autonomic disorders (sympathetic hyperarousal, low parasympathetic tone) and immune disorders, which may influence cognition (e.g., anxiety, depression, fatigue, sleep disorders).

In the same study we learn: Although the criteria of these two complex spectrum conditions appear different on paper (one is defined by neurobehavioral symptomology, while the other is defined by structural manifestations of connective tissue impairment), they share not only comorbidity and familial co-occurrence but symptom overlap.

Shared symptoms encompass the nervous system and immune dysregulation.

Neurodevelopmental issues in EDS/HSD may also be related to proprioceptive impairment, which alters coordination and posture, and likewise may be involved in the acquisition of verbal communication and motor competence [52]. Baeza Velasco, C et al. [28,48] have proposed that in order to maintain motor competence despite proprioceptive impairment, executive function may be overwhelmed in those affected, leading to some symptoms reminiscent of ADHD.

Other psychiatric features that are common in both autism and EDS/HSD include: anxiety, depression, bipolar disorder, eating disorders, and suicidal behaviors

Other conditions that can present in ASD and EDS may include:

There is also evidence to suggest that having EDS or autism spectrum disorders may make it more likely a person may develop other conditions. One of those conditions is epilepsy.

In autism, for instance, the lifetime risk for developing epilepsy ranges between 2.7% to 44.4%, which is a seven-fold increased risk compared to the general population. Individuals with intellectual disability experience the highest rates of epilepsy at approximately 22%; however, autistic people without intellectual disability still develop epilepsy at a rate of about 8% as compared to 0.751.1% within the general population. In addition, abnormal electroencephalograms (EEG), even in the absence of epilepsy, have been reported in up to 60% of those with autism.

Seizure disorders have also been reported in EDS/HSD, particularly in association with certain subtypes such as an EDS-like disorder associated with mutations in the FLNA gene.

EDS are a group of hereditary connective tissue disorders. This means that they are passed down from parents to their children. Although rare cases have been reported of spontaneous instances of EDS, the majority are heritable disorders.

Genetic counseling can help in the quest for whether or not someone would be at risk. Genetic counseling would begin with a proband: a person serving as the starting point for the genetic study.

In the aforementioned book we learn the risk to family members for EDS.

Most individuals diagnosed with hEDS have an affected parent, although a careful history and examination of the parents is often necessary to recognize that, despite absence of serious complications, one and sometimes both parents have current or prior history of joint laxity, easy bruising, and soft skin.

Sibs of a proband. The risk to the sibs (siblings) of the proband depends on the genetic status of the probands parents:

Offspring of a proband. Each child of an individual with hEDS has a 50% chance of inheriting the same pathogenic variant (and thus the same type of EDS). However, because of marked clinical variability, it is difficult to predict severity among affected offspring.

Other family members. The risk to other family members depends on the genetic status of the probands parents: if a parent is affected, his or her family members may be at risk.

The National Health Service says: Theres no specific treatment for EDS, but its possible to manage many of the symptoms with support and advice.

People with EDS may also benefit from support from a number of different healthcare professionals.

For example:

Your GP or consultant can refer you to these services.

Autism spectrum disorder and connective tissue disorders do co-occur. With the overlap of symptoms, there are times when EDS and autism can mimic each other. Though they are two very different conditions, they do have much in common.

Both conditions often require the same therapies and treatments as patients deal with physical impairment, mental health issues, chronic pain, and mobility struggles. Each carries risks of also being diagnosed with the other.

There is also evidence showing that EDS could worsen autism spectrum disorder symptoms as well. Therefore, a child with autism, who presents symptoms consistent with EDS should be considered for diagnosis and treatment.

Further scientific interest and study is needed to learn more about these conditions, and help the remarkable patient group who have both autism spectrum disorder and Ehlers danlos syndrome.

If your child is struggling, speak with their pediatrician, they can help guide you to get the help your family needs. Also, dont forget to take some time to invest in your own health. There are therapies and support available for parents as well.

Levy HP. Hypermobile Ehlers-Danlos Syndrome. 2004 Oct 22 [Updated 2018 Jun 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1279/

Casanova, E. L., Baeza-Velasco, C., Buchanan, C. B., & Casanova, M. F. (2020). The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders. Journal of personalized medicine, 10(4), 260. https://doi.org/10.3390/jpm10040260

https://www.mayoclinic.org/diseases-conditions/ehlers-danlos-syndrome/symptoms-causes/syc-20362125

https://www.nhs.uk/conditions/ehlers-danlos-syndromes/

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Ehlers-Danlos Syndrome and Autism: Is There a Connection? - Autism Parenting Magazine

-- Setmelanotide now FDA-approved and EC-authorized for Bardet-Biedl syndrome (BBS) --

-- EC authorization for BBS makes Rhythm eligible to receive second $37.5M tranche under Revenue Interest Agreement with HealthCare Royalty--

-- Health Canada grants Priority Review status for new drug submission for setmelanotide for treatment of obesity and control of hunger in BBS and biallelic POMC, PCSK1 or LEPR deficiencies --

BOSTON, Sept. 06, 2022 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a commercial-stage biopharmaceutical company focused on transforming the lives of patients and their families living with hyperphagia and severe obesity caused by rare melanocortin-4 receptor (MC4R) pathway diseases, today announced that the European Commission (EC) has expanded the marketing authorization for IMCIVREE (setmelanotide) to include the treatment of obesity and control of hunger associated with genetically confirmed Bardet-Biedl syndrome (BBS) in adult and pediatric patients 6 years of age and older.

Patients and families have long endured a significant need for a therapy to address the burdens of hyperphagia and severe obesity often associated with BBS, said Philip Beales, M.D., University College London, UCL Great Ormond Street Institute of Child Health. Having new treatment options available can help address the physical and emotional aspects of this devastating disease, offering patients and their families relief and improved quality of life.

BBS is a rare genetic disease that affects approximately 2,500 people in the European Union (EU) and United Kingdom (UK). People living with BBS may experience insatiable hunger, also known as hyperphagia, and severe obesity beginning early in life. Approximately 1,500 patients have been diagnosed with BBS and are now being cared for at academic settings in the EU and UK.

Under the terms of the Revenue Interest Financing Agreement with HealthCare Royalty Partners announced on June 16, 2022, Rhythm is now eligible to receive an additional investment of $37.5 million following EC marketing authorization for setmelanotide for BBS. Rhythm had received an initial investment amount of $37.5 million from HealthCare Royalty as a result of the approval of setmelanotide by the U.S. Food and Drug Administration (FDA), and the Company remains eligible for an additional investment amount of $25 million, which would be payable upon the achievement of certain agreed sales milestones in 2023.

Priority Review Status Grantedfor New Drug Submission forSetmelanotide in CanadaRhythm also announced today that Health Canada has granted Priority Review for Rhythm's New Drug Submission for setmelanotide, indicated in adult and pediatric patients 6 years of age and older with impairments in the MC4R pathway due to genetic diseases, for the treatment of obesity and control of hunger in BBS or biallelic pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.

Priority Review shortens Health Canadas submission review performance target to 180 days, in comparison to 300 days for non-priority review. Priority Review may be grantedfor drug submissions inCanada for a serious, life-threatening or severely debilitating disease or condition for which there is substantial evidence of clinical effectiveness that the drug provides effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada or a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.

These two important regulatory milestones underscore the global unmet need to treat the hyperphagia and severe obesity associated with these rare MC4R pathway diseases, said David Meeker, M.D., Chairman, President and Chief Executive Officer of Rhythm. We are working closely with Health Technology Assessment bodies and payers throughout the EU on a country-by-country basis to achieve market access and reimbursement in order to make IMCIVREE available to eligible patients as rapidly as possible. Taken together with the recent FDA approval for BBS in June, we are making significant advances in our mission of delivering the first precision medicine for MC4R pathway diseases to patients across the world.

AboutRhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients and their families living with hyperphagia and severe obesity caused by rare melanocortin-4 receptor (MC4R) pathway diseases. Rhythms precision medicine, setmelanotide, is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). The European Commission (EC) has authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above.The UKs Medicines & Healthcare Products Regulatory Agency (MHRA) authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare genetic diseases of obesity and is leveraging the Rhythm Engine and the largest known obesity DNA database -- now with approximately 45,000 sequencing samples -- to improve the understanding, diagnosis and care of people living with severe obesity due to certain genetic deficiencies. Rhythms headquarters is in Boston, MA.

Setmelanotide IndicationIn the European Union, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed Bardet-Biedl syndrome (BBS) or genetically confirmed loss-of-function biallelic pro-opiomelanocortin (POMC), including PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 6 years of age and above.

IntheUnited States, setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) or BBS.

Limitations of UseIn the United States and Europe, Setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology.

Setmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective:

WARNINGS AND PRECAUTIONS

Skin Monitoring:Setmelanotide may lead to generalized increased skin pigmentation and darkening of pre-existing naevi because of its pharmacologic effect. Full body skin examinations should be conducted annually to monitor pre-existing and new skin pigmentary lesions before and during treatment with setmelanotide.

Heart rate and blood pressure monitoring:Heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide.

Prolonged penile erection:Spontaneous penile erections have been reported in clinical trials with setmelanotide. Patients who have a penile erection lasting longer than 4 hours should be instructed to seek emergency medical attention for potential treatment of priapism.

Depression:In clinical trials, depression has been reported in patients treated with setmelanotide. Patients with depression should be monitored at each medical visit during treatment with setmelanotide. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviors.

Paediatric Population:The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. The prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves.

Excipients:This medicinal product contains 10 mg benzyl alcohol in each ml. Benzyl alcohol may cause allergic reactions. Patients who are pregnant or breastfeeding should be advised of the potential risk from the excipient benzyl alcohol, which might accumulate over time and cause metabolic acidosis. This medicinal product should be used with caution in patients with hepatic or renal impairment, because of the potential risk from the excipient benzyl alcohol which might accumulate over time and cause metabolic acidosis.

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium-free.

ADVERSE REACTIONS

The most frequent adverse reactions are hyperpigmentation (51%), injection site reaction (39%), nausea (33%), and headache (26%).

USE IN SPECIFIC POPULATIONS

PregnancyThere are no data from the use of setmelanotide in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. However, administration of setmelanotide to pregnant rabbits resulted in decreased maternal food consumption leading to embryo-foetal effects. As a precautionary measure, setmelanotide should not be started during pregnancy or while attempting to get pregnant as weight loss during pregnancy may result in fetal harm. If a patient who is taking setmelanotide has reached a stable weight and becomes pregnant, consideration should be given to maintaining setmelanotide treatment as there was no proof of teratogenicity in the nonclinical data. If a patient who is taking setmelanotide and still losing weight gets pregnant, setmelanotide should either be discontinued, or the dose reduced while monitoring for the recommended weight gain during pregnancy. The treating physician should carefully monitor weight during pregnancy in a patient taking setmelanotide.

Breast-feedingIt is unknown whether setmelanotide is excreted in human milk. A nonclinical study showed that setmelanotide is excreted in the milk of nursing rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from setmelanotide therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

FertilityNo human data on the effect of setmelanotide on fertility are available. Animal studies did not indicate harmful effects with respect to fertility.

To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337. See Summary of Product Characteristics APPENDIX V for a list of European national reporting systems to communicate adverse reactions.

Please see the full Prescribing Information for additional Important Safety Information.

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide, the potential benefits of setmelanotide for patients with BBS, and our expectations surrounding potential regulatory submissions, approvals and timing thereof, and our business strategy and plans, including regarding commercialization of setmelanotide in Europe, Canada, the United States and other international regions. Statements using word such as expect, anticipate, believe, may, will and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our liquidity and expenses, the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies, clinical trials and commercialization prospects, and general economic conditions, and the other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2022 and our other filings with the U.S. Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise.

Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com

Investor Contact:Hannah DeresiewiczStern Investor Relations, Inc.212-362-1200hannah.deresiewicz@sternir.com

Media Contact:Adam DaleyBerry & Company Public Relations212-253-8881adaley@berrypr.com

OMX, source GlobeNewswire - EU Press Releases

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Rhythm Pharmaceuticals Announces IMCIVREE (setmelanotide) Granted Marketing Authorization by European Commission for Treatment of Obesity and Control...

Novartis has acknowledged that two patients have died of acute liver failure following treatment with its Zolgensma (onasemnogene abeparvovec-xioi), a one-time gene therapy indicated for some forms of spinal muscular atrophy (SMA).

As a result, the company said, it will revise Zolgensmas label to specify that fatal acute liver failure has been reported.

While this is important safety information, it is not a new safety signal and we firmly believe in the overall favorable risk/benefit profile of Zolgensma, Novartis said in a statement emailed to GEN and other news organizations.

Mani Foroohar, MD, Senior managing director, Genetic Medicines, and a senior research analyst with SVB Securities, wrote in a research note today that the deaths are expected to touch off renewed public discussion over the safety of adeno-associated virus (AAV) gene therapies such as Zolgensma.

We expect these events to rekindle broader debates on safety and management of systemic AAV therapies in fragile or very young patients, one contributor to the overhang on gene therapy stocks across our coverage, which have underperformed the biotech sector as a whole YTD [year to date], Foroohar wrote.

The labelincluding a Boxed Warning in the U.S. Prescribing Information for the gene therapyhas until now included acute liver failure as a known side effect that has been reported following treatment.

A 2020 paper published in The Journal of Pediatrics detailed two cases of transient, drug-induced subacute liver failure following treatment with Zolgensma. A 2021 study in Nature-published Gene Therapy showed that of nine children treated with the gene therapy in Qatar, none experienced failurebut all patients experienced elevated levels of the liver enzymes aspartate aminotransferase (AST) or alanine transaminase (ALT), two experienced high prothrombin time, and one experienced elevated bilirubin. One patient experienced vomiting after infusion.

The deaths are the first fatal cases of acute liver failure that have been linked to Zolgensma, a gene therapy developed by AveXis. Novartis acquired AveXis for $8.7 billion in a deal completed in 2018.

A year later in May 2019, the FDA approved Zolgensma for the treatment of SMA in pediatric patients less than two years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Zolgensma was the second gene therapy authorized by the FDA for an inherited disease.

During the first half of this year, Zolgensma generated $742 million in net sales, up 17% from JanuaryJune 2021. Zolgensma finished last year with $1.351 billion in net sales, up 47% from 2020. Novartis considers Zolgensma among its key growth brands.

In trading today, Novartis shares dipped 1.16% on the SIX Swiss Exchange, to CHF 80.10 ($85.06).

To date, Novartis stated, Zolgensma has been used to treat more than 2,300 patients worldwide across clinical trials, managed access programs, and commercially.

We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities, Novartis added.

Novartis has long asserted that Zolgensmas benefits in halting SMA and facilitating infant development milestones justify its $2.1 million list price, though the company has also long cited its discounted patient-access programs with insurers.

Novartis did not reveal information about the patientswho were both children according to STAT News, which first reported the deaths. However, the company did disclose that one of the fatal cases of acute liver failure took place in Russia and the other, in Kazakhstan.

Both cases occurred at approximately five to six weeks post Zolgensma infusion, and approximately 110 days following the initiation of corticosteroid taper, Novartis stated.

See the article here:
Novartis Confirms Deaths of Two Patients Treated with Gene Therapy Zolgensma - Genetic Engineering & Biotechnology News

The Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) updated its Guidance Agenda in June 2022,1which provides that the agency plans to issue 18 guidance documents in 2022, including eight guidance documents on tissues and advanced therapies. In this alert, we highlight some key considerations from three draft guidance documents on human gene therapy products that incorporate gene editing (GE) components, chimeric antigen receptor (CAR) T cell products, and regenerative medicine therapies that can benefit biopharmaceutical developers and sponsors. Recognizing the challenges of developing such complex, multi-component biologic drug products, including unanticipated risks associated with on-target and off-target activities, these draft guidance documents describe the FDA's recommendations for preclinical and clinical testing, chemistry, manufacturing, and controls (CMC), as well as information that should be included in investigational new drug (IND) applications to ensure proper identity, potency/strength, quality, and purity of the investigational drug products. FDA recommends sponsors of such complex products to communicate with the Office of Tissues and Advanced Therapies (OTAT) in CBER early in product development before submission of an IND, to discuss the product-specific considerations in preparation for transitioning to the clinical phase.

FDA expects detailed information and data IND applications before sponsors can transition to clinical testing. We recommend biopharmaceutical developers and sponsors review the applicable FDA draft guidance documents early in their product development process to identify these needs. Work closely with both FDA regulatory counsel and intellectual property/patent counsel to ensure there is sufficient data to support an IND application, including adequate testing and quality control measures, and that CMC, preclinical, and clinical development plans are coordinated with intellectual property and patent strategies to ensure robust protection of their intellectual property and to maximize the benefits of their patents and FDA regulatory exclusivities. We also encourage interested persons to submit comments to shape the policies proposed in FDA's draft guidance documents prior to finalization.

Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing2

Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products3

Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies4

Stakeholders have until September 14, 2022, to submit comments to this draft guidance to ensure they are considered by FDA before finalization of the guidance.

For More Information

For questions regarding FDA strategy, approval, and regulatory compliance, please contact any member of Wilson Sonsini'sFDA regulatory, healthcare, and consumer productspractice. For questions regarding intellectual property and patent counseling, please contact any member of Wilson Sonsini'spatents and innovationspractice.

Andrea Chamblee,Paul Gadiock, andEva Yincontributed to the preparation of this Wilson Sonsini Alert.

[1] FDA, Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2022 (Updated June 2022), available at https://www.fda.gov/media/120341/download.

[2] FDA, Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing (March 2022), available at https://www.fda.gov/media/156894/download.

[3] FDA, Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, available at https://www.fda.gov/media/156896/download.

[4] FDA, Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies (June 2022), available at https://www.fda.gov/media/159237/download.

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FDA Issues Draft Guidance to Facilitate Development of Human Gene Therapy, CAR T Cell, and Regenerative Medicine Products - Wilson Sonsini Goodrich...