• About Clarus Therapeutics
• Tuclar
• Testosterone Deficiency
• Partnering and Licensing
• Investors and Media

Formulation

Historically, there are numerous physiologic and formulation challenges that have made the development of a commercially viable oral testosterone (T)-replacement therapy difficult.  Oral T is metabolized rapidly and extensively by the intestine and the liver, a process known as first-pass metabolism.

Consequently, an inadequate amount of T reaches the bloodstream. While it is possible this limitation could be overcome with an extremely large oral dose of T, such a dose potentially would be harmful to the liver.

One approach to oral T delivery is to chemically modify T in a way that dramatically retards its metabolism by the liver.  This method was used over 40 years ago when methyl-T and related compounds, such as oral anabolic steroids, were developed.  However, methyl-T has been associated with potentially serious liver toxicity and, although it is approved in the United States, is rarely prescribed. In fact, some countries, such as Germany, have banned the use of methyl-T.

Another oral T delivery approach, originally developed in the late 1960s, is to create orally active T prodrugs by attaching fat-like molecules, or fatty acids. Although these T prodrugs sufficiently avoid first-pass liver metabolism, there have been a number of challenges related to their clinical use, including inconsistent absorption into the lymphatic system, insolubility issues and the influence of fat content in food, all of which can inhibit the intended increase of circulating T.  These issues often create unpredictable clinical responses. Finally, even when target levels of circulating T are achieved, T is rapidly cleared by the body once it reaches the bloodstream, therefore requiring either frequent dosing or high and unsafe levels of T in order to maintain the desired therapeutic effect throughout the day.  For example, we believe these limitations have had a negative effect on the clinical and commercial success of Andriol®, an oral T undecanoate (TU) product marketed outside the United States by Schering-Plough.  The published literature indicates average serum T levels in response to Andriol are highly variable notwithstanding that multiple Andriol capsules are required to be taken three times per day.

Our Solution — Tuclar

We believe our proprietary oral T-replacement therapy, Tuclar, overcomes many of the problems associated with earlier attempts to formulate and deliver oral T for therapeutic treatment. We have developed Tuclar by using the T prodrug TU and applying our proprietary technology to achieve optimal formulation characteristics for twice-daily oral delivery with food.  Tuclar, if approved, will be a first-in-class T-replacement therapy in the United States as the first oral formulation of a T prodrug, namely TU. Specific Tuclar formulation attributes include:

• the ability to increase amount of dissolved TU per softgel capsule;
• rapid and complete solubilization of TU after oral administration to foster bioavailability;
• the ability to dose TU with meals that contain a wide range of dietary fat levels;
• significant TU absorption even when taken in the absence of food; and
• demonstrated preliminary clinical efficacy in Phase II testing.

Tuclar will require twice-daily dosing because a single oral T dose sufficient to overcome the rapid clearance of T after it enters the bloodstream would yield a peak serum T level far above the 1,000 ng/dL upper limit of normal.  Such high peak T levels pose safety and FDA regulatory approval concerns.  As a result, we believe twice-daily dosing is a safe way to achieve clinical efficacy while avoiding concerns about peak serum T levels.

We believe Tuclar, if approved, will offer men and prescribing physicians a safe and effective oral T-replacement treatment for men suffering from low T.  We believe Tuclar will have many advantages over the currently approved T-replacement therapies, including:

• Convenient Dosing:  Tuclar is an easy-to-swallow softgel capsule expected to be taken twice daily with a meal, which we believe will be easier to use than T-replacement therapies currently on the market.
• No Inadvertent T Exposure:  Tuclar is an oral product and thereby avoids the potential transference to women and children and related secondary exposure issues associated with the market leading T-gels.
• Normalized T Levels:  77% and 87% of men treated with Tuclar in our Phase II studies, respectively, obtained serum T levels within the normal range, defined as 300-1,000 ng/dL.
• No Liver Toxicity:  Because of the different chemical composition of TU, we did not observe any liver toxicity in our Phase II studies, particularly the kind of liver injury associated with oral methyl-T.
• Safe Pharmacokinetic Profile:  In our Tuclar Phase II repeat-dose studies, the FDA guidance for acceptable peak serum T levels was met without any dose adjustment. In contrast to sustained high serum T levels observed for several days after dosing with injectable T, only three men treated with Tuclar had an average serum T above the 1,000 ng/dL upper limit of normal. We believe avoiding T levels above this threshold can decrease the risk of potential side effects associated with high T levels, such as an increased risk of stroke and gynecomastia.