FDA Briefing Docs Crush Agile Therapeutics Stock and Create New Concerns for Twirla

Posted on October 28, 2019 by Medtech[y] Staff

Investors woke up to a kick in the nuts this morning after Agile Therapeutics (NASDAQ:AGRX) announced their third quarter results and the FDA released the briefing documents for the AdCom meeting on October 30, 2019. Between language in the company's announcement and the briefing document, the stock is down 54% at the time of writing, trading at .50 on heavy volume.

What happened?

As with all FDA Briefing Documents, they are supposed to peel the onion back and create a fresh debate on all aspects of the product being reviewed. In these particular documents, there were a lot of questions brought up that didn't seem to be an issue the last time around.

As stated in the company's release, the FDA "expresses a number of concerns regarding Twirla’s approvability, including, but not limited to, concerns related to Twirla’s efficacy when balanced against its safety. The FDA also did not appear to agree with the Company’s proposal to include a limitation of use based on patient weight and BMI in the product label."

We previously wrote that the third time may actually be the charm for Twirla but now it's a lot less clear after reading through the briefing documents in detail.

In the company's most recent investor presentation, they only stated that the Pearl Index (PI) was 4.80 for patients ≤ 35 years of age while the FDA used 5.83 which has led many investors confused as to where that number was derived from.

Twirla Pi

Was Agile Therapeutics misleading investors or is the FDA averaging the numbers based on the results of different patient subsets in the study? The latter seems like the most obvious answer but it still causes great concern. Again, these briefing documents are supposed to open as much dialogue as possible, so there is a chance this doesn't hinder Twirla from getting a positive vote, potentially with limitations.

From the FDA briefing document:

Summary The FDA agrees with the Applicant that AG200-15 reduces the risk of pregnancy compared to not using contraception, but considers the PI and upper bound of the 95% CI unacceptable for a CHC product when considering alternative products available on the U.S. market.

The Applicant attributes the higher PI to its study population and design features (e.g., inclusion of a population that is more obese and racially/ethnically diverse, and more thorough testing for pregnancy), but it is unclear whether the findings reflect these differences or suboptimal effectiveness of AG200- 15. Even among non-obese women, the estimated PI and the upper bound of the corresponding 95% CI is higher than that of any approved CHC, and it is possible that there may be a more dramatic effect of weight on the effectiveness of a CHC transdermal system compared to CHCs that have other routes of administration.

This kind of verbiage is where the biggest concern comes from as the FDA seemingly only had an issue with adhesion in the past, yet now safety & efficacy concerns are being shared.

Is this the FDA peeling back the onion to create a dialogue or will the concerns shared in the briefing documents be points of contention in getting Twirla approved? Tough to say but that screams that the FDA has now decided to move the goal posts as safety & efficacy were never in question the last go around.

What's more likely is they are sharing these concerns for the specific subset of patients who increased the Pearl Index, which would provide less than ideal benefits when using Twirl.

Additional verbiage from the briefing documents:

FDA has the following concerns with the effectiveness of AG200-15: • AG200-15’s estimated PI in Study 23 and the corresponding 95% CI was 5.83 (95% CI 4.45, 7.21). The FDA believes that this PI and 95% CI upper bound is unacceptable from an efficacy perspective for a new CHC product.

In obese subjects in Study 23, the estimated AG200-15 pregnancy rate is almost twice that of non-obese subjects and is clinically concerning given that 28% of women between the ages of 18-44 years were classified as obese (BMI ≥30 kg/m2 ) in 2017 in the U.S. (Centers for Disease Control and Prevention 2019a). For women with a BMI ≥30 kg/m2 , the estimated PI is 8.64 (95% CI 5.79, 11.50)

To get around this, Agile Therapeutics has suggested using additional labeling to address the increased PI in these subsets of patients:

To address the increased PI, the Applicant is proposing a Limitations of Use in the INDICATIONS AND USAGE section of product labeling stating that AG200-15 has reduced effectiveness in women who weigh 202 pounds (92 kg) or more and/or have a BMI of 30 kg/m2 or more. The statement is intended to address the concerns about the higher PI reported in Study 23. The Applicant included in their statistical analysis plan a pre-specified secondary analysis in the subgroup of women with baseline BMI less than 30 kg/m2 . The statistical analysis plan did not include a planned subgroup analysis by baseline weight less than 202 pounds (92 kg). It is unclear what methodology the Applicant used to add the additional criterion of 202 pounds (92 kg).

It does seem odd that the FDA all of a sudden has an issue with safety & efficacy yet they didn't the second time around. Why now and what's changed?

Is this to create a dialogue for the AdCom on October 30 or are there bigger issues at play and the fate of Twirla has already been decided?

We currently have a position in Agile Therapeutics and have averaged down as of writing today. However, we may decide to close our position between now and adCom if new information comes out.