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First in Human: Rare diseases pose particular challenge in early drug research

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First in Human: Rare diseases pose particular challenge in early drug research

This is a recurring column on clinical research in the early stages of development, what is referred to as phase 1. These are treatments that are being used for the first time in a small number of human patients to determine safety, dosing and general pharmacological activity.

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Researchers of rare diseases face a number of challenges, from ailments that have few patients, less attention by pharmaceutical companies, to complex gene mutations that are barely understood.

"There are many rare diseases for which there are no approved treatments," said Emily Cutting, a research officer at Ataxia UK, a charity that funds research in treatment for Friedreich's ataxia.

Friedreich's ataxia affects multiple body systems, particularly the brain and the heart, impairing patients' ability to walk, talk and swallow. The disease impacts one in every 50,000 people in the U.S. and is classified as a rare disease. Heart disease is the most common cause of death for Friedreich's ataxia patients, according to the National Institute of Neurological Disorders and Stroke.

A mutation in the FXN gene causes Friedreich's ataxia. The deficiency reduces the body's production of frataxin protein, which is found throughout the body with the highest levels in places including the heart and spinal cord. There is no cure or effective treatment for the disease yet.

Cutting said part of the reason the disease is hard to treat is that researchers do not yet fully understand how to effectively target the FXN gene. The blood-brain barrier that protects the brain from getting infections from blood circulation complicates the delivery of drugs for the condition. Moreover, gene therapies themselves are still young, she said.

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Chondrial Therapeutics' Friedreich's ataxia therapy CTI-1601 aims to treat the disease by delivering human frataxin protein to the body.

Source: Thinkstock

The small patient population also makes Friedreich's ataxia less acknowledged by pharmaceutical companies, though the situation is improving, according to Cutting. However, she said because the progression of the disease is quite slow, changes in patients' bodies can be slow to detect, which becomes a big challenge for clinical trials.

"Some trials in the past have been too short, or not designed appropriately to detect changes," Cutting said.

Bala Cynwyd, Pa.-based orphan-drug developer Chondrial Therapeutics Inc. is one company trying to find a solution for Friedreich's ataxia. The company commenced a phase 1 study for CTI-1601, which aims to treat the disease by delivering human frataxin protein to the body.

"That's the first time [such a measure] is being tried," Cutting said. However, one big challenge for the trial is how to deliver the protein to the right tissue while not reducing the drug's effectiveness in the process.

The double-blind study will enroll patients over 18 years old randomly and assign them to take either the drug or a placebo to evaluate the safety of CTI-1601. Researchers will also observe how well patients tolerate the treatment and the drug's absorption into the body. Dosage will be increased during the study to figure out appropriate dosing.

Chondrial expects to reveal results from the study by the end of 2020.

Rare disease gene therapy advances

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Ornithine transcarbamylase deficiency is a genetic disorder that can lead to excessive ammonia in the body.

Source: AP Photo

Patients with another genetic disease called ornithine transcarbamylase deficiency, or OTC deficiency, are closer to having a new treatment.

The disease is a rare inherited genetic deficiency caused by complete or partial lack of an enzyme called ornithine transcarbamylase, which helps break down and remove nitrogen in the body. Without the enzyme, nitrogen can build up and boost levels of ammonia, which is toxic to the neuro system. Excess ammonia can cause vomiting and coma.

Current approved therapies for OTC deficiency must be taken multiple times a day throughout a patient's life, but still do not prevent future metabolic illnesses. Liver transplant is the only curative treatment for the disease right now, according to a Jan. 9 release from Ultragenyx Pharmaceutical Inc. More than 10,000 patients are affected by OTC deficiency worldwide, the company said.

Novato, Calif.-based Ultragenyx recently reported results for a phase 1/2 study of the gene therapy DTX301, which aims to deliver stable expression and activity of OTC into the body.

Three more patients responded to a DTX301-steroid combination, making a total of five responders to the treatment out of nine patients taking the therapy in three different dosages. No severe side effects have been reported in the trial.

One patient who responded to the treatment reported after 52 weeks that she has weaned off of medicine that removes ammonia from the body and has been "liberalizing" her diet to include more protein, Ultragenyx said during a Jan. 9 call to discuss the results.

Ultragenyx will enroll three more patients to the trial's higher dose group and plans to provide more updates on the trial in the second half of 2020. CEO Emil Kakkis said during the call that the company is discussing with the U.S. Food and Drug Administration a phase 3 study design, and the trial's goal will likely be reducing ammonia levels.