Veru has completed a successful comparative bioavailability study and is moving forward with the Pre-NDA and NDA preparation for TADFIN®.

TADFIN® (5mg Tadalafil and 5mg Finasteride tablet) for BPH

Veru is also advancing new drug formulations in its specialty pharmaceutical pipeline addressing unmet medical needs in urology. The clinical trial of the Company’s proprietary TADFIN® (5mg Tadalafil and 5mg Finasteride tablet) for BPH met FDA requirements for bioavailability and bioequivalence for the co-administration of tadalafil 5mg and finasteride 5mg dosed daily for benign prostatic hyperplasia (BPH). Tadalafil (CIALIS®) is currently approved for treatment of BPH and erectile dysfunction and finasteride (PROSCAR® and PROPECIA®) is currently approved for treatment BPH and male pattern hair loss. The co-administration of tadalafil and finasteride has been shown to be more effective for the treatment of BPH than finasteride alone. The Company anticipates submitting an NDA for its Tad-Fin Combination Capsule under the 505(b)(2) regulatory pathway by the end of 2020.

Scientific Overview

  1. Description, Indications, and Usage-Finasteride (based on FDA-approved product label for PROSCAR®)
    1. Finasteride Description:
      Finasteride is a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT). Finasteride is N-tert-Butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is:Finasteride structural formulaFinasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in chloroform and in lower alcohol solvents but is practically insoluble in water. PROSCAR® (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of finasteride and the following inactive ingredients: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.
    2. Finasteride Indications and Usage:
      Finasteride is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

      • Improve symptoms
      • Reduce the risk of acute urinary retention
      • Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.

      PROSCAR® administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of symptomatic progression of BPH (a confirmed ≥4 point increase in AUA symptom score).

    3. Finasteride Dosage and Administration
      1. The recommended dose is 5 mg orally once a day. PROSCAR® can be administered alone or in combination with the alpha-blocker doxazosin (see label CLINICAL PHARMACOLOGY, Clinical Studies).
      2. PROSCAR® may be administered with or without meals.
      3. No dosage adjustment is necessary for patients with renal impairment or for the elderly (see Label CLINICAL PHARMACOLOGY, Pharmacokinetics).
    4. Finasteride (PROSCAR) Clinical Pharmacology, Clinical Studies, Nonclinical Studies, and Additional Information
      Refer to PROSCAR® Product Insert
  2. Description, Indications, and Usage-Tadalafil (based on FDA-approved product label for CIALIS®)
    1. Tadalafil (CIALIS®) Description:
      Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is:
      Tadalafil structural formula
      The chemical designation is (2R,8R)-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. CIALIS® is available as almond-shaped tablets for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
    2. Tadalafil (CIALIS®) Indications and Usage:
      Tadalafil is indicated for the treatment of:

      • Erectile dysfunction (ED) (1.1 in product label)
      • The signs and symptoms of benign prostatic hyperplasia (BPH) (1.2 in product label)
      • ED and the signs and symptoms of BPH (ED/BPH) (1.3 in product label)
    3. Tadalafil (CIALIS®) Dosage and Administration
      Do not split CIALIS® tablets; entire dose should be taken.

      1. CIALIS® for Use as Needed for Erectile Dysfunction
        • The recommended starting dose of CIALIS® for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.
        • The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients.
        • CIALIS® for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of CIALIS®, this should be taken into consideration.
      2. CIALIS® for Once Daily Use for Erectile Dysfunction
        • The recommended starting dose of CIALIS® for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
        • The CIALIS® dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability.
      3. CIALIS® for Once Daily Use for Benign Prostatic Hyperplasia
        • The recommended dose of CIALIS® for once daily use is 5 mg, taken at approximately the same time every day.
      4. CIALIS® for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia
        • The recommended dose of CIALIS® for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
      5. Use with Food
        • CIALIS® may be taken without regard to food.
    4. Tadalafil (CIALIS®) Clinical Pharmacology, Clinical Studies, Nonclinical Studies and Additional Information
      Refer to CIALIS® Product Insert

TADFIN® (5mg Tadalafil and 5mg Finasteride tablet) for BPH

Current Status

Veru’s clinical trial of the Company’s proprietary Tadalafil and Finasteride Combination Capsule met the U.S. Food and Drug Administration’s (FDA) requirements for bioavailability and bioequivalence for the co-administration of tadalafil 5mg and finasteride 5mg dosed daily for benign prostatic hyperplasia (BPH) (TADFIN® Combination Capsule).

Stability testing of commercially manufactured batches (GMP) of the TADFIN® Combination Capsule required for submission of a New Drug Application (NDA) is in progress.

The Company has also requested a Pre-NDA meeting with FDA and anticipates submitting an NDA under the 505(b)(2) regulatory pathway in the second half of calendar year 2020.

TADFIN® Combination Capsule combines two of the most popular medicines, tadalafil and finasteride, that are currently prescribed separately to treat lower urinary tract symptoms caused by an enlarged prostate also known as BPH. The co-administration of tadalafil and finasteride has been shown clinically to be more efficacious in treating BPH symptoms than either tadalafil or finasteride alone.* Our TADFIN® Combination Tablet is proprietary and is designed to improve patient compliance and safety.

According to current FDA approved labeling, Tadalafil (CIALIS®) (PDE5 inhibitor) is approved to treat both BPH and erectile dysfunction, and Finasteride (PROSCAR®) (5 alpha-reductase inhibitor) is approved to treat symptoms of BPH, prevent the progression of BPH, reduce the risk of acute urinary retention and decrease the potential need for prostate surgery. Finasteride (PROPECIA®) is also approved to treat male pattern hair loss.

*Casabe A et al. J or Urol 2014; 191:717-733

TADFIN® (5mg Tadalafil and 5mg Finasteride tablet) for BPH

Clinical

Clinical studies conducted since 2010 have demonstrated that the co-administration of tadalafil with finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement (Casabé et al, 2014; Olesovsky & Kapoor, 2016). In addition, tadalafil/finasteride co-administration was also shown to improve erectile function in men who have comorbid erectile dysfunction. Elkelany et al concluded that combination therapy with daily tadalafil and finasteride is ideally suited for men with moderate to severe BPH-LUTS and a prostate volume >30 g. In addition, they conclude that men with coexisting erectile dysfunction will benefit from PDE5 inhibition (Elkelany et al, 2016).

Adverse reactions related to the use of tadalafil and finasteride (separately and co-administered) in clinical trials and from post-marketing experience have been well documented in the approved labeling.

coadministration of Tadalafil and Finasteride

TADFIN® (5mg Tadalafil and 5mg Finasteride tablet) for BPH

Market

TADFIN® targets men with BPH whose prostate >30cc. No combination Proscar and Cialis product currently exists. Veru intends to target urologists. TADFIN® will be an attractive product for the multi-billion-dollar global market for BPH and substantially increase compliance and safety in men who suffer from BPH or BPH and erectile dysfunction.