Linerixibat (GSK2330672), a drug that is being developed for PBC patients who experience itchiness, has recently been granted “orphan” status by the FDA. This is wonderful news for patients who are suffering from itchiness (pruritus) which is one of the main symptoms of Primary Biliary Cholangitis.
Orphan status is a special designation given by the FDA for drugs that target rare diseases. With orphan status companies are encouraged to develop treatments for a rare diseases. Rare disease patients benefit from orphan status as the drug development process is shortened and treatments become available sooner.
Itch is common in people with PBC. Currently available treatments are not always effective and may have side effects. In PBC, the bile ducts in the liver become damaged which causes the build-up of bile acid salts in the body. This may cause some patients to experience persistent itching (pruritus).
The drug being developed by GSK is currently called GSK2330672. Itis being developed as a tablet to treat the PBC itch. Bile passes from the liver into the intestines where it helps with the digestion of food. Some of the bile is then taken back up into the blood and returned to the liver. GSK2330672 blocks the uptake of bile from the intestines. It is anticipated that this will allow the chemicals that cause the itch to be lost from the body in a person’s stool.
How to get involved in the study
GSK2330672 has already been tested in PBC patients in a small study. This larger study aims to find out which dose and dose frequency improves itch and if it has an effect on the underlying PBC disease. The study will test a range of doses to compare the effect, safety and how well it is tolerated by patients with moderate to severe itch due to PBC.
In Canada, the study is based in 5 research centres in Montreal, Winnipeg, Calgary, Edmonton and London. The study involves 7 visits at the study site and 1 final telephone contact with the study doctor or nurse. Patients participating in this study will receive reimbursement of their travel expenses and compensation for meals and refreshments for 2 of the visits which are expected to last between 2 and 5 hours.
GSK2330672 is currently being evaluated in a Phase 2b study. When the study is completed at all the study sites, the data will be analyzed. Read more about this study here.
Currently enrolling patients for Phase 2 Study in Canada, USA, UK and Germany. No placebos will be used, while dosages may differ between participants. Health Canada and FDA approve this 52 week study. Principal investigators in Canada: Dr. Mark Swain (Calgary); Dr. Hemant Shah (Toronto)
An Update from Cymbay
CymaBay Therapeutics is a small biotech company located in the San Francisco Bay Area. So far, we have 22 employees. The company is publicly traded on the NASDAQ market (ticker symbol CBAY). For the last two years we have conducted two studies with seladelpar (formerly known as MBX-8025) for the treatment of primary biliary cholangitis (PBC).
The so-called ‘CB8025-21629’ is our second study evaluating the effects and safety of seladelpar on PBC patients. Its main objective is to define what is the appropriate dose of seladelpar to be used. The study is open to patients who have high alkaline phosphatase (AP), a marker of liver function, and are not responding well enough to UDCA (sometimes also called ‘urso’ or ‘ursodiol’) or who cannot tolerate UDCA. All patients receive treatment with seladelpar, there is no placebo, but the dose is chosen at random (5 or 10 mg/day, orally). The study treatments are not masked, so patients and physicians know the dose they receive.
When the first 24 patients enrolled in ‘CB8025-21629’ reached 12 weeks of treatment we evaluated their progress while the study is continuing. This is called an ‘interim analysis’. The goal was to get an early look to see if the dose is correct, if seladelpar is well tolerated and effective and, eventually, speed-up the program and plan its next stage.
We compared patient results before treatment and during treatment. At 12 weeks, significant AP decreases were seen in the seladelpar 5 mg and 10 mg groups, 39% and 45%, respectively. This suggests that the liver is functioning better. Total bilirubin and gamma glutamyl transferase (GGT), other tests of liver function, also improved. These results also suggest that seladelpar, at the doses used, exerts a favorable impact on cholestasis (the retention of bile). Cholestasis is a prominent issue in PBC. We also saw a decrease in an important marker of inflammation called the C-reactive protein. This protein is secreted by the liver when it is faced with an inflammatory injury such as PBC.
Overall, there were no indication of increased pruritus with seladelpar. This was something we already knew from our first study, but which was important to confirm in this second study. In addition, seladelpar seemed well tolerated. For instance, no patient reported a serious adverse event.
Based on these results, Health Canada and the US-FDA agreed that we can treat patients with seladelpar 5 mg and 10 mg for longer than six months. The CB8025-21629 study now has a 52-week seladelpar treatment period. We are also planning to extend seladelpar treatment beyond one year with a new long-term extension study that will be open to patients who have participated in a seladelpar study, assuming that they tolerate the drug well. Treatment in the long-term study will continue until seladelpar is approved in Canada or the program is discontinued.
Canadian Study Sites
Study ‘CB8025-21629’ is currently enrolling patients in 4 countries (Canada, United States, United Kingdom and Germany). We have two sites open in Canada:
University of Calgary Liver Unit, Calgary, Alberta, Canada, T2N 4Z6
Principal Investigator: Mark Swain, M.D.
Study Coordinators: Pam Crotty, Shirley Cole
Toronto Centre for Liver Disease, Toronto, Ontario, Canada, M5G 2C4
Principal Investigator: Hemant Shah, MD
Study Coordinator: Teresa Bianco
With these developments, we are now looking to the next phase of the seladelpar program. This next phase is called the ‘confirmatory’ phase, or phase 3. We need to reproduce these encouraging data on a bigger scale, with a larger study and a treatment duration of at least one year. This study is sometimes also called the ‘registration’ study. A similar study served as the basis for the registration of Ocaliva (the ‘POISE’ study).
If the results of this confirmatory study are positive, the data collected will be submitted to health authorities to file a registration package and request an authorization for physicians to prescribe seladelpar to their PBC patients outside of a clinical study. The registration package is a very comprehensive dossier that includes data from clinical studies but also data from multiple non-clinical studies (e.g. toxicology) as well as data on how the drug is made and prepared (manufacturing process).
CymaBay’s intent is to use the coming month to present its plan for the confirmatory study to health authorities. This includes Health Canada, as well as the US-FDA, the European Medicine Agency and potentially other countries around the world.
CymaBay is very thankful to the PBC patients who participated and continue to participate in our studies. We totally appreciate their dedication and we all do our best to conduct the best research possible. We will use the results of the ongoing study to justify starting the agreed upon confirmatory study as quickly as possible. Our wish, if everything goes well, is to start this study in the second part of 2018. We’ll probably need to grow beyond 22 employees to achieve this challenge!