Innovation and Perseverance: Bringing a New Delivery Method to Market

The market for testosterone replacement products has expanded rapidly over the past couple of decades, with patients having access to numerous options from injectables to patches to gels. “When you look at what’s available, it almost screams, ‘Where’s the oral option?” says Robert E. Dudley, PhD, chairman, chief executive officer and president at Clarus Therapeutics, Inc.

In 2019, the FDA approved a testosterone replacement therapy from Clarus Therapeutics, Inc. that is designed for oral delivery to avoid certain administration challenges that exist with other therapies. Here, Dudley speaks with Pharmaceutical Executive about the long road to developing and commercializing JATENZO® (testosterone undecanoate) capsules, CIII, the first and only FDA-approved oral softgel testosterone replacement therapy for the treatment of men with certain forms of hypogonadism. He also talks about what it has been like to launch a new product amid the COVID-19 pandemic.

Pharmaceutical Executive: How did you become involved in men’s health as a focus for your career?

Dudley: I trained in pharmacology and toxicology at the University of Kansas Medical School and my background is in drug development. And then, quite serendipitously, I joined a small entrepreneurial company as head of R&D, where I made my first foray into the world of testosterone replacement with a sublingual testosterone product.

From there, I went on to develop a testosterone gel product, the first gel product that was approved and marketed in the United States. In 2004, I founded Clarus Therapeutics, Inc. to take my experience and develop a safe and effective oral testosterone prodrug, which received FDA approval in 2019.

Pharmaceutical Executive:What challenges did you face in your quest to create an oral testosterone replacement therapy (TRT)?

Dudley: We faced several challenges. It took the greater part of 16 years to develop and receive FDA approval on an oral TRT, which is a testament to why no one else has managed to do what we’ve been able to do.

The first obstacle was that you cannot give testosterone orally by itself. It is metabolized too efficiently by the liver, so we needed to have a testosterone prodrug. This led to a second obstacle: testosterone prodrugs are very lipophilic, and thus are very insoluble, difficult to formulate, and challenging to keep in solution. In fact, we looked at 80 different formulations before we ultimately settled on one that we took into the clinic and used in the approved
oral testosterone.

A third obstacle was the pharmacokinetics. Transdermal patches and the gels produce fairly flat testosterone levels in the blood, but the oral prodrug creates peak-and-valley levels of testosterone in the blood, like any oral drug. You have to get to the right average testosterone concentration in the normal range without excessive peaks, which is a challenge.

These were our three biggest challenges, which, along with a few others, consumed a lot of our time and effort as we brought the product forward.

Pharmaceutical Executive:With so many TRT options available, why did you investigate a new format?

Dudley: The short answer is there was a void in the market. The available products at the time were deep muscle injectables, a newer subcutaneous injectable, transdermal patches, an initial gel product that I co-invented and brought to market, other similar gels, and a nasal product. What was clearly missing was an oral TRT option. The only oral TRT ever approved by the FDA before our product was methyltestosterone, which can be toxic to the liver and is rarely used.

Pharmaceutical Executive:How has the TRT landscape evolved since you’ve developed the first testosterone gel?

Dudley: First and foremost is the availability of delivery methods that were more convenient than the deep muscle injectable products that made up the market before the late 1990s.

The second thing that occurred more broadly in the scope of men’s health was the approval of Viagra. This product increased awareness of low testosterone as a real medical condition with real symptoms, helped men open up about their issues, and provided an opportunity for people to begin looking at therapies to address it. The market dramatically expanded in the early 2000s, and continued to grow quite steadily, growing considerably around 2009–2013. Arguably then, too many men were being prescribed testosterone and that raised concerns with FDA that it was not being used as properly as it should be.

Around 2013–2014, the FDA raised the possibility that there could be increased cardiovascular risk associated with testosterone products, particularly in older men. The agency began to look more closely at testosterone products in development and tightened the regulations on them.

So, by the time our oral testosterone product was up for approval, FDA’s regulatory requirements had tightened up pretty significantly. We not only had to address the average peak concentrations I mentioned earlier, but we also had to show very strong evidence that if a healthcare provider decided to adjust the dose, it would result in a testosterone level in the normal range.

That was the first time that we are aware of that these strict criteria were applied to testosterone products of any kind. It was just another example of the evolution within the agency and the requirements that we needed to meet. In the end, we were able to provide FDA with all of the information it needed and received approval.

Pharmaceutical Executive: How did the COVID-19 crisis affect your plans to go to market?

Dudley: After overcoming so many obstacles to get our product to market, one could not have imagined that we would be dealing with the COVID-19 pandemic, which surfaced four to five weeks after we launched our product. We never fathomed that we would suddenly have to pull back our clinical sales specialists in the field because so many healthcare providers’ offices were either closed or were severely limiting the number of patients they were seeing.

Clarus is not a huge pharmaceutical company that can just throw massive resources at these problems. So, we looked quickly and carefully at how we could pivot to interacting with healthcare professionals from a virtual perspective. We quickly retooled promotional materials so they could be used in virtual presentations. We went through immense amounts of new training with our sales professionals about these new technologies. When the dust settles, it will show that we have handled this current COVID crisis amazingly well and maintained some forward momentum in some pretty clever and ingenious ways when I think a lot of companies, particularly bigger ones, cannot move as quickly. I’m really, really proud of the team.

Pharmaceutical Executive:What sets Clarus Therapeutics apart from other companies in the men’s health space?

Dudley: I founded Clarus for the sole purpose of developing men’s health products, starting with an oral testosterone replacement product. It has been my passion and my drive. I love the entrepreneurial environment of a smaller company. I excel in providing leadership in that kind of environment.

Pharmaceutical Executive: How would you describe your leadership style?

Dudley: I’m a planner and all about execution. I’m not afraid of challenges. I thank my parents for raising me never to quit. No matter what the challenges are, you simply have to find your way around them. That upbringing and my ability to bring together and empower teams and individuals within the organization are hallmarks of my leadership. I hire people that are really great at what they do, and my job is to support them.

I’m very keen on transparency, integrity, and being honest. We are in a very important business of treating, in our case, men. All of us in the healthcare field have a real moral obligation to be men and women of high integrity.