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Treating rare genetic disorders of obesity - Lex Van der Ploeg

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During TIDES (May 2018) we sat down with Dr. Lex Van der Ploeg, CSO, Rhythm Pharmaceuticals, for TIDES TV. Dr. Van der Ploeg discussed rare genetic disorders of obesity and ways his work is helping to diagnose and treat them.

What are rare genetic disorders of obesity?

LV: Obesity is best seen as an increase in fat mass in an individual. And it can be influenced by both genetic and environmental factors. In the rare genetic disorders of obesity there are selective underpinnings, genetic deficiencies that have occurred that leads to severe obesity. And there are examples of patients who have been identified, for instance, with leptin-receptor deficiency, Bardet-Biedi syndrome, Bardet-Biedl syndrome, Alstrom disease that fit that paradigm of the rare genetic disorders of obesity. Currently there aren't that many patients identified worldwide or in the United States and there's a largely underserved population where there is a tremendous medical need.

And what is the biological basis for rare genetic disorders of obesity?

LV: So, at Rhythm, we focus on the unique part of the causes for rare genetic disorders for obesity where we have a receptor, the melanocortin-4 receptor. And the best way to compare this is that if you consider the melanocortin-4 receptor, the city, that has different roads going into it, by the time that any of those roads are defective the traffic into the city is impaired. And essentially what happens in rare genetic disorders of obesity is there can be defects that almost are like roadblocks. And what Rhythm does is it has a neuropeptide and we typically overcome those roadblocks and thereby restore the melanocortin-4 receptor functioning. The end result of that is that there is a control of appetite, which is severe and unrelenting in individuals with these rare genetic disorders of obesity and thereby can lead to a normalization of body weight. There are quite a few different genetic mutations, different roads in the passway to the MC4 city that can be disrupted, we're evaluating those.

And how many individuals have rare genetic disorders of obesity?

LV: So the exact number of patient's identified to the United States is very limited. So it's a very early stage. We predict that there are roughly 500 patients with POMC deficiency, reportedly between 1,000 and 2,000 leptin receptor deficient patients, 1,500 to 2,500 Bardet-Biedl Syndrome patients and 1,000 patients with Alstrom Disease. So that is an initial outline of patients with deficiencies that come out of clinical studies and selected registries. We have done an extensive epidemiological study where we predict in the united States there are probably roughly 12,000 individuals that have deficiencies in the three genes that really focuses on POMC, leptin receptor and PCSK1 so that provides a patient population. It's important to realize that the majority of those patients have not been diagnosed, have not been identified, there are no treatment regimens and the treatment need is profound for these individuals.

And what are the clinical manifestations of rare genetic disorders of obesity?

LV: So the important part of these rare genetic disorders of obesity is that the patients that suffer from these have unrelenting hunger. They have a drive to appetite to eat that can take caregivers to lock up food to close cabinets. And they often compare this to the notion that there is some misconceptions about obesity. Many individuals state, it's a disease of willpower, you just, you eat too much, and I say you're absolutely right, but do me a favor and hold your breath for five minutes and tell me how your willpower is doing. You know people often answer, I cannot do that, my only response to that is, for these children's the same, not eating is like not breathing. In answer there's a unrelenting drive for access to food that we're trying to correct with therapeutics that Rhythm is developing.

So please tell me, what are some key challenges in oligo and peptide drug development and what is Rhythm Pharmaceutical doing to address, address these challenges?

LV: So the field is currently underdeveloped so we have fantastic opportunities to make progress. I always compare to we're standing at the foothills of really tall mountains and we gotta make it to the top. So working with regulatory agencies to develop the capabilities to understand the disease better, through the development of registries, and to development of capabilities that allowed it is very, very important. So Rhythm is spending a significant amount of time on the enablement of registries based on which one can learn about natural patient history, also the caregiver history so we know where to identify patients or where to look for patients those are really critical components. In addition, as it is early days, and we currently have several genes that we have identified in this passway to the MC4 city, we're applying artificial intelligence to further understand how broad the pool of genes is that we need to evaluate in order to identify those patients that will optimally benefit from Rhythm's peptide replacement therapies.

And what are drug development companies doing to differentiate themselves in the new therapeutics that they're developing from what's already on the market?

LV: There are within the field that we are developing very few treatment opportunities today. The main therapeutics that have been applied is either diet, exercise and at times bariatric surgery. And these are not very effective in the patient population we are pursuing. Rhythm has received breakthrough designation and orphan designation for the POMC deficiency and the leptin receptor deficiency and those are routes by which we can of course move the direct discovery efforts forward to the high place. So currently these passways are being further pursued and what the drug development companies are doing is learn from the progress that has been made and thereby look for novel therapeutics they may be able to make in drugs.

What are new drug therapeutic modalities do you expect to see emerging in the near future?

LV: So from the work that has been done to date mimicking an existing neuropeptide and thereby working, coming up is a neuropeptide replacement therapy. We anticipate that there will be an awful lot of opportunities as this passway becomes further and better understood. So we anticipate that there will be opportunities for compounds like the drug setmelanotide that Rhythm is developing that will find inroads and other aspects of this passway where we anticipate many different opportunities.

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