Agile Therapeutics (NASDAQ:AGRX) believes it has addressed the issues raised by the FDA last year about an initial pivotal trial of its Twirla contraceptive patch and is on track to treat the first patient in a new Phase 3 trial in the current quarter.
“Following a complete response letter from the FDA in early 2013, we subsequently received clear guidance from the agency about a new confirmatory Phase 3 study design that would be acceptable for approval,” president and CEO, Al Altomari, says in an interview with BioTuesdays.com.
“The results from the Phase 3 trial were affected primarily by issues with study conduct at several study sites, and the FDA could not accept those results for approval,” he adds.
Addressing issues in the complete response letter helped Princeton, NJ-based Agile raise $55-million in an initial public offering in May. The new Phase 3 trial, which should deliver data around the end of 2015, will cost some $31-million. Proceeds of the financing will also be used to develop an additional pipeline candidate and to cover principal and interest payments on a term loan that begin next February.
Mr. Altomari explains that Twirla is a low-dose, seven-day patch, containing the active ingredients, levonogestrel (LNG) and ethinyl estradiol (EE), which have over 25 years of use in contraceptives. EE is the synthetic estrogen in most currently marketed contraceptives while LNG is used as a standard for comparison of venous thromboembolism risk among progestins.
“There is no low-dose estrogen combination hormonal contraceptive patch on the market today,” he adds.
The Twirla patch employs Agile’s Skinfusion technology and consists of an inner adhesive system that delivers the two hormones at targeted levels through the skin and a peripheral adhesive system that provides patient comfort and prevents any ingredients from leaking at the outer edges of the patch.
In a report last month, Janney Capital Markets analyst, Kimberly Lee, said, “[Agile’s] value proposition lies in its once-weekly delivery of low-dose estrogen via a proprietary transdermal patch technology, which does not carry the additional safety risks associated with higher estrogen levels.”
She also said, “[Agile’s] near-term success will be correlated with a successful Phase 3 study outcome and is fairly de-risked, in our view, given several recent contraceptive approvals along with the additional clarity received from the FDA on study design following a complete response letter.”
Janney was part of the syndicate that took Agile public in May. Ms. Lee initiated coverage of Agile with a “buy” rating and $18 fair value estimate. The stock closed at $6.76 on Friday.
Mr. Altomari points out that women apply a Twirla patch once a week for three weeks followed by a fourth week without a patch when they experience a menstrual cycle. The patch is most commonly applied to the buttock or abdomen and has been designed to avoid skin irritation when removed.
More than 1,500 women have received a Twirla patch in Agile’s clinical trials, which have demonstrated favorable safety and tolerability.
Mr. Altomari moved into the executive suite at Agile in October 2010, around the time the company was completing enrollment in its original Phase 3 trial. He had previously spent 23 years with Johnson & Johnson, including a stint in Ortho-McNeil’s women’s health care franchise, where he led market preparation for the Ortho Evra contraceptive patch.
The Ortho Evra patch was the most successful contraceptive launch in history, quickly reaching an 11% market share and nearly $400-million in sales in 2004, two years after its launch. “At today’s prices, it would have been a $1-billion-plus product,” he suggests.
Ortho Evra’s meteoric rise was followed by a precipitous fall after thromboembolic events were reported to the FDA. The patch was found to deliver far more estrogen than J&J originally thought and the company stopped active promotion of the patch. Despite the risks surrounding the high dose of estrogen in Ortho Evra, the product still had sales exceeding $150-million in 2013.
“We deliver a low dose of estrogen in Twirla, with one of the safest known progestins available,” Mr. Altomari contends. “Our patch is designed to provide convenience and facilitate compliance.”
According to Mr. Altomari, in clinical testing, women have reported negligible side effects, such as nausea, site irritation, breast tenderness and headache, with the Twirla patch at about the level as one would expect to see in a low dose birth control pill. Some side effects listed on the Ortho Evra label are significantly greater and thought to be estrogen-related.
Irina Koffler, an analyst with Cantor Fitzgerald, another member of the underwriting syndicate, said in an initiation report that Twirla has demonstrated lower estrogen exposure and estrogen-associated adverse events than Ortho Evra, “so we think that doctors would easily understand the safety benefits of the product, which should facilitate its launch.”
She added that the FDA has also completed a pre-approval inspection of Twirla’s manufacturing facility, which would minimize another risk to approval.
While Mr. Altomari gives high marks to Twirla’s product development, he points to several issues that caused the first Phase 3 trial to fail. These include a contract research organization that lacked experience with large contraceptive trials, poor study conduct at several clinical sites, a study population at higher risk for non-compliance and no utilization of technology for patients.
“We believe the clinical results were affected by study conduct issues at several sites,” he points out, noting that 36% of on-drug pregnancies were reported at four of the 96 sites in the trial.
Consistent with expert opinions, the company’s analyses have suggested that the results for both the patch and oral contraceptive control arms in the Phase 3 trial were also affected in part by the study population, which comprised a disproportionately high number of new users and minority subjects, known to be at higher risk of noncompliance and pregnancy.
The primary endpoint to determine the effectiveness of a birth control device is the so-called Pearl index, which measures the number of pregnancies per 100 women-years of product use. Twirla posted a Pearl index of 5.76 in the Phase 3 trial; to date, the best Pearl score for a contraceptive that has been approved is 3.19.
In the first pivotal trial, the company found that experienced users of contraceptives had a Pearl of 3.0, while new users had a Pearl of 8.7, and black women who were new users had a Pearl of 16.0.
Mr. Altomari has high hopes for the pending confirmatory trial based on the appointment of Agile’s new chief medical officer, Dr. Elizabeth Garner; a top-tier contract research organization, Parexel; data-driven site selection, with experienced study coordinators; rigorous screening of subjects; and improved study oversight, with subjects using an electronic diary for the 52-week study.
The single-arm, open-label study will enroll about 2,000 sexually active subjects at 50-to-70 sites in the U.S.
If approved, Twirla will compete in the combination hormonal contraceptive market, which is valued at an estimated $4.2-billion a year. Mr. Altomari figures each market share point in the category represents $108-million in sales, “so getting a $500-million to $1-billion product is not unusual.”
He cites a study by Kantar Health in 2010 that estimates Ob-Gyns would use the Twirla patch in 9% of new contraceptive patients, which would represent $972-million of potential annual peak sales.
Ob-Gyns contribute nearly 50% of U.S. contraception prescriptions, and nurse practitioners and physician assistants, who are often affiliated with an Ob-Gyn practice, contribute an additional 23% of U.S. prescriptions.
“We believe that we can address this market with a specialty sales force of approximately 70-to-100 representatives,” Mr. Altomari says. “We also intend to augment our sales force through digital marketing and other techniques to market directly to patients.”
Agile has two additional combination hormonal products under development: AG200-ER that would result in fewer menstrual cycles a year; and AG200-SP that would lighten and shorten menstrual cycles. AG200-ER has the potential to move into Phase 3 testing in 2015, while AG200-SP could begin a Phase 1 study next year.
Agile also is developing a progestin-only product, AG890, for women who are unable or unwilling to take estrogen. The progestin-only contraceptive market is estimated at $1.4-billion a year.