This blog was written by Jose-Carlos Gutiérrez-Ramos, CEO of Synlogic, as part of the “From The Trenches” feature of LifeSciVC.
When I was invited to contribute to this blog, I was determined to write first about patients with Rare Diseases and about Drug Development in this area. Over the last 10 years I have experienced too often lack of financial and commercial support to discover and develop a medicine in a “seemingly” small disease indication with high unmedical need – and yet collectively, rare diseases affect ~350M people worldwide, there are ~7K rare diseases found out of which <5% have approved therapies. I have listened too often to arguments stating the patients in a given disease were well served with current standard of care therapies plus life style modifications – disease was managed somewhat but not corrected. Today I want to focus on one of such diseases, Phenylketonuria (PKU), and analyze the medical need in some detail, as a clear example for a chance to “change the world” for these patients. “Wind is blowing in our backs” today to cure many rare diseases and yet it is not happening at an adequate rate. We have to change this, we can, you and me, we have to put Patients at the Center and make them the highest beneficiaries of our efforts.
Before we go into specifically into PKU, let’s review chief facts aspects of the Rare Disease Medicines Development Environment today, because it makes even more obvious the need for this call to action: First, momentum for Rare Diseases Drug Discovery and Development started a few years ago by the approval of the Orphan Drug Act of 1983 in US to facilitate development of orphan drugs. The sequence of the human genome has been transformational (>70% of rare diseases are caused by a single gene) in this area and scientific tractability is greater than in most other disease areas. Second: high unmet and pediatric medical need provides urgency; strong and motivated Patient advocacy drives patient identification and collaboration. Third: the development and commercialization costs are lower than in other indications since fewer trials in a smaller number of patients are needed for registration; Orphan tax credits defray R&D costs. In addition, there are unique meta-collaboration opportunities across multiple stakeholders (e.g. FDA, patient advocacy groups, disease experts); in fact, the challenge with natural history of these diseases provides opportunities to collaborate even in the pre-competitive space. Finally, the society in which we live, that supports us as an industry, has given us advantages for Rare disease medicines development by way of significant regulatory advantages: Expedited application review (Fast Track status); 7-10 years of market exclusivity ; higher regulatory innovation and agility. It is a good environment to operate, don’t you think?
Throughout my career in Science and in Medicines Discovery and Development, I have learned about the real meaning of disease for patients, family, caregivers and society through direct and indirect experiences. This awareness has made me personally conscious of the urgent need of better medicines, and this alertness has inspire me to “change the course” – so this is the reflection today; do we have what it takes to put patients at the center?. Don’t get me wrong: I am very proud of what we do in Biotech and Pharma: we dedicate our lives to develop medicines that can cure disease….but yet I am often disappointed by the discrepancy between how much we can do in science and drug discovery versus how little has been the impact on patients who live with disease. This paradox is particularly acute in orphan diseases, where we know the genetic cause is often monogenic. For most of these diseases, we can make a drug and yet… we haven’t. We pat ourselves on the back because there has been a wave of orphan drug approvals in the last two decades, but the number is small compared with the vast opportunity in the space, and most importantly the high unmet medical need.
Recently I started a new adventure in my career as CEO of Synlogic, a biotech company in Cambridge, Massachusetts, that powers the gut microbiome with synthetic biology approaches to correct somatic metabolic dis-regulation anywhere in the body. I do believe that our approach could transform the practice of medicine. As any biotech management team in possession of a great new technology would do, we dedicated significant effort to determine where we could have the greatest therapeutic impact. Although there was a great deal of technology focus during all these deliberations and we were constantly focused onthe need for capital efficiency to be successful …. we only found “our core, our center and our future” when we put patients at the center of all these discussions. In that moment, there was a transformation evident in our team that made the mission, journey and purpose very clear. As we were reviewing and learning more about orphan metabolic diseases, I once again found myself disappointed about the underwhelming treatment options for patients with Inborn Errors of Metabolism (IEM). IEM are a group of orphan diseases in which well understood genetic mutations impair metabolic pathways resulting in the accumulation of toxic metabolite that generate predominantly central nervous system pathology.
One of the most common IEM is phenylketonuria (PKU), a disorder of Phenylalanine (Phe) metabolism caused by an impaired conversion of Phe to Tyrosine. If left untreated, the resulting accumulation of excess blood Phe can cause physiological, neurological and intellectual disabilities. Dietary treatment successfully lowers blood Phe in most individuals with PKU. I have heard about PKU in the past and heard that dietary treatment worked well, thus when I was told: “the problem is solved, no new drugs needed, no market”, I accepted it. I thought: ”if you are unlucky enough to inherit an IEM mutation, if it is PKU, it might not be so bad after all. You just modify your diet and go on with your life. People follow diets for long periods of time, right?” This is far from the reality of the children with PKU and their parents, far from the reality of young adults living with PKU every day and in general far from the reality of living with this disease in 2016.
Phenylketonuria was discovered by the Norwegian physician Ivar Asbjorjn Folling in 1934 when he studied two children who had been normal at birth but subsequently developed intellectual disability. The mother of the children noticed a strong smell in his urine. Dr. Følling, as a good translational physician that he must have been, obtained urine samples from the children and identified the substance causing the odor in the urine as phenylpyruvic acid. The condition came to be called phenylketonuria. For many years after and before that date, PKU caused severe disability in most people who inherited the mutations. It is difficult to grasp the drama that PKU must have been at the time. A wonderful, but intensely moving novel to read is The Child Who Never Grew, by Nobel Prize winning author Pearl S. Buck, who had a daughter who lived with PKU before treatment was available. When Phe cannot be metabolized by the body, a typical diet that would be healthy for people without PKU causes abnormally high levels of Phe to accumulate in the blood which is toxic to the brain. If left untreated, complications of PKU include severe intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder. Physical signs such as eczema, unusually light skin and hair coloration also manifest.
The outcomes of people with this disease changed largely when PKU started to be routinely diagnosed through widespread newborn screening, which was introduced in the early 1960’sand became routine by the end of that decade. Many untreated PKU patients born before 1960 screening are still alive, largely in dependent living homes/institutions. Now PKU patients who follow the prescribed dietary treatment from birth may control the extreme outcomes and may have a “manageable and almost normal” life. To achieve these good outcomes, all PKU patients must adhere to a special diet low in Phe for optimal brain development. Since Phe is necessary for the synthesis of many proteins, this amino acid is required for appropriate growth, but levels must be strictly controlled in PKU patients. That is where Patients at the Center come in focus again. Do we truly understand the limitations of current care for these patients, the reality of their medical outcomes today? We know that the catastrophic crisis that resulted in severe neurologic compromise have almost disappeared in the Western world, but how is their quality of life in 2016?
For starters, only half of patients today consider managing their PKU treatment as “easy”. PKU patients clearly state in several forums that they are in need of treatments that improve their attention span, ability to focus, ability to plan, organize and prioritize. In fact more than 60% of patients asked in a recent study (National PKU Alliance-NPKUA-, 2015 Survey) said that these are the most desired outcomes from potential new treatments. Recently, we talked to a senior executive of the National PKU Alliance and mother of two wonderful boys with PKU. Who better to ask about the level of satisfactory care for these patients? She stressed her priorities for the boys: their ability to stay alert and focused academically, while complying to the dietary limitations required by the illness.
Many parents commiserate that complying to the dietary restrictions is like walking a tightrope every day, with the balance between keeping their children’s phenylalanine levels in check while providing them with the proper nutrients to thrive socially, academically and emotionally. In fact, in the same study cited above, around half of PKU patients declared that they are hoping for treatments that “lift the fog” (improve processing speed, the ability to start and complete tasks). Recently I had a great conversation with Prof Harvey Levy from Children’s Hospital in Boston, a thoughtful and experienced leader in PKU clinical practice. He emphasized the prevalence of depression and anxiety as a key symptom experienced by PKU patients. In fact, Prof Levy runs a PKU clinical trial group that employs a clinical psychologist to evaluate and grade progress/regression of all the patients that enroll in any trial for a potential new drug.
According to Prof. Levy, “We do not know for sure the extent of psychosocial issues that PKU patients experience, but I suspect that they are significant in number and impact in their lives.” In the same NPKUA study, 50% of patients consulted stated that reducing depression and anxiety and ups/downs in overall mood was an outcome that they were seeking from new medicines. “I would like to have better mental health” was a choice that half of the patients made in the questionnaire. I also learned that the ability to control Phe is more challenging with age as only 25% of patients below 18 years were reported to be above the upper limit of normal, whereas the percentage of patients older than 18 years almost triples to 61%. In fact, social problems and work-related problems are more pronounced in adult PKU patients. We have 13,000-15,000 people in this country (the average number of new cases of PKU varies in different countries, US Caucasians are affected at a rate of 1 in 10,000) that live with these signs and symptoms. They try to combat the “fog” and depression every day. They have to eat medical foods (shakes) and special formula diets for their whole life as almost their exclusive source of food. These patients need new medicines! The company BioMarin has done serious heavy lifting for years with one drug approved (Kuvan) and one in development, but radical new approaches are needed that change the lives of PKU patients. If we, scientists in biotech and pharma, put Patients at the Center, it becomes clear that more effort should go into curing this terrible disease.
At Synlogic, we have accepted the challenge and embarked on a mission to try and develop a new therapy for PKU: a probiotic bacteria that is able to degrade Phe and is so efficient at doing so that patients should be able to eat any food regardless of the protein content without increasing the symptoms of PKU. A medicine that is safe: no needles, no nausea, no headaches or skin reactions, no bone loss, no internal bleeding. Our goal is to deliver transformational efficacy and safety.
Good news is that we have a revolutionary drug discovery platform that can deliver that promise. However, there will be many challenges ahead of us in this journey, even significant setbacks that might prevent us from reaching our goal, but I feel confident that as long as we continue to put Patients at the Center of everything we do every day, we have a good chance to change their world… and that is why you and I are here, right? To change the lives of people with disease not incrementally, but substantially.
