Pazopanib Clinical Trial: Q&A

The Pazopanib clinical trial has launched, and the road to reach this breakthrough milestone has been more involved and hard-fought than many may realize.

Cure HHT is one of the few patient advocacy organizations that not only helps to facilitate and drive research forward but is directly sponsoring a Phase II/III clinical trial of an investigational new drug product which they own. I wanted to take this moment to 1) explain what this means, 2) reflect on how we reached this point, and 3) share more on why it’s monumental for our community.

What is pazopanib?

Currently, there are no FDA-approved drugs to treat HHT. Some patients with HHT are receiving FDA-approved therapies to treat HHT-related bleeding (like Avastin), but these therapies are what we call ‘off-label’, or approved by the FDA to treat another disease that is not HHT.

Pazopanib (pa-zah-pa-nib) is an antiangiogenic therapeutic (works to stop blood vessel growth) that is typically given orally to patients with cancerous tumors. When given off-label at a greatly reduced dose than the chemotherapeutic dose, pazopanib has had positive effects in HHT patients with outcomes like a reduced need for blood transfusion, iron infusion, and a decreased amount of nose and gastrointestinal bleeding.

Why do a clinical trial for a therapy that already exists?

It sounds like some patients have gotten pazopanib and had success. Why can’t we just give this drug to any patient out there who could benefit from it? Since pazopanib has not been through a clinical trial for safety and efficacy in patients with HHT, it is not approved by the FDA to treat HHT. This makes the drug much harder to be covered by insurance programs and it is very expensive. HHT is an ‘equal opportunity’ disease that affects all races and ethnicities, whether rich or poor. We need for patients to have equitable access to therapies AND we need to ensure it is safe for a wide range of patients to take. Therefore, we need to do a clinical trial for pazopanib for the treatment of HHT-related bleeding.

Didn’t this trial process start a long time ago?

Yes, this started in 2015! The pharmaceutical company, Glaxo-Smith-Kline (GSK) owned the drug product Votrient™ which is the market name for their formulation of pazopanib (dose = 200mg) -given at 800 mg for treating patients with kidney cancer. Dr. Marie Faughnan, the Director of the Toronto HHT Center of Excellence, led the multi-center clinical trial studying pazopanib to treat HHT-related bleeding at a dose of 50mg (taking that 200mg tablet and ‘quartering’ it). The good news is that the trial enrolled 7 patients and all showed some improvement in nosebleeds and/or anemia. The bad news is that another pharmaceutical company bought the drug from GSK. This happens a lot in the world of industry. Drug products can change from one company to another, or a company’s objectives and missions can change based on the marketplace and economy. Unfortunately, the new company was not interested in continuing the use of Votrient™ in HHT-related clinical trials, the study was closed, and we lost access to this drug product.

So you took matters into your own hands?

Yes! HHT researchers and clinicians still believed in the potential for pazopanib to make an impact for HHT patients. Marianne Clancy, the executive director of Cure HHT, made the bold call to invest in manufacturing the drug product – meaning to remake the pazopanib compound in a capsule at the lower dose necessary for the study – and to begin talks with the FDA and other funding agencies to secure the dollars and resources needed to finish what GSK, a 75 Billion Dollar company, started.

What goes into making a drug and running a trial?

In short, a whole lot! Cure HHT assembled a small team of experts to begin engaging the FDA. You need to do this for them to consider granting something an ‘investigational new drug’ status. Pazopanib isn’t a new drug, per se, but it was made and tested for safety and stability at 200mg before and now we need to make it at 25mg. This, by definition, makes it ‘new’ and like we are starting from scratch. Once we received the IND status, Cure HHT funded manufacturing of this 25mg version of pazopanib. Rigorous standards and testing (which also means a lot of money and time) goes into making a new drug. It must be stable at certain temperatures and up to a certain humidity. It needs to absorb correctly and be ‘bioavailable’ in your system, so you are actually getting the drug that is supposed to help you. To determine these things, stability testing and pharmacodynamic and pharmacokinetic testing must be done (pharmacodynamic = studying what the drug does to the body; pharmacokinetic = what the body does to the drug).

During this process, Cure HHT was working hard in the background writing study protocols, research proposals, gathering evidence, and appealing to the FDA. With the positive evidence of pazopanib use off-label in patients with HHT, and a plan in place to continue the drug through a clinical trial, the FDA granted two things: an orphan drug designation and a breakthrough therapy designation (a pretty big deal) for pazopanib in HHT! These two wins were major milestones that gave us certain ‘red-tape’ advantages in our pursuit of getting FDA approval of this product.

Simultaneously, Cure HHT was applying for funding through the Department of Defense Peer Reviewed Medical Research Program (see more information about this here) and through the FDA. In 2020, our organization received $5.2 million from the DOD an $800k from the FDA to begin clinical trials again with pazopanib! Of course, we only have ten employees and none of us know how to run a phase II/III clinical trial, so we have to use this money to contract the kinds of people who work at pharmaceutical companies to help us execute this trial. This includes a clinical research organization to oversee the clinical sites, study operations, and data, statisticians, device companies, labs, auditors, regulatory experts, and management professionals in clinical trial operations.

All of this was of course affected by COVID-19. Prices nearly doubled for making the drug product and there were price hikes in almost every other area along with delays and shortages. We persevered through it, and after a bit of a delayed start, we are now open to recruitment for this clinical trial!

What do you do after the trial is over?

During the trial, results are analyzed carefully along the way for safety, tolerability, and effectiveness of the drug product. If the results at the end of the trial are positive (which we hope they are!), Cure HHT will apply for a ‘New Drug Application’ with the FDA. The trial data and results will be scrutinized, evaluated, and hopefully the FDA will determine this dose of pazopanib is appropriate for treating HHT-related bleeding and they will grant FDA approval. Cure HHT owns this drug product and with FDA approval, we can find a partner for manufacturing of this drug product on a larger scale and it will be much more accessible for our patient community and become the first FDA approved therapy in treating HHT