Watson May Bypass Progesterone Gel 8% For Second-Generation Product

The extent of additional clinical work required pursuant to an FDA “complete response” letter will have to be balanced against the remaining patent life on the product, for which Watson was seeking an indication to prevent preterm birth in women with a short cervix.

Facing a short patent life and an FDA “complete response” letter for its progesterone vaginal gel 8%, Allergan PLC may choose to forego further clinical work toward a preterm birth prevention indication and instead focus on developing a second-generation pipeline product or abandon the category entirely.

In a move that came as little surprise, FDA issued a “complete response” letter requesting additional clinical data for Watson and Juniper Pharmaceuticals Inc.’s progesterone vaginal gel 8% for reducing the risk of preterm birth in women with a singleton gestation and a short uterine cervical length in the mid-trimester of pregnancy. The product is frequently referred to as Prochieve, the brand name used in other countries.

In the U.S., Watson markets progesterone gel 8% under the brand name Crinone; it is indicated for use as part of an Assisted Reproductive Technology treatment for infertile women with progesterone deficiency.

The “complete response” letter was expected given the negative evaluations by FDA reviewers and an advisory committee, which raised concerns about geographic inconsistencies in the pivotal trial data.

Watson gained full rights and regulatory obligations for the preterm birth NDA in mid-February, when Columbia transferred the application to its partner. Columbia maintains a financial interest in the product and its role in the companies’ joint development committee.

The “complete response” letter was expected given the negative evaluations by FDA reviewers and the Reproductive Health Drugs Advisory Committee at a Jan. 20 meeting. The committee voted 13-4 against approval due, in part, to concerns about geographic inconsistencies in the data, including a lack of a statistically significant benefit in the U.S. subpopulation (Also see "Columbia/Watson’s Progesterone Gel For Preterm Births Needs Additional Studies, Advisory Panel Says" - Pink Sheet, 20 Jan, 2012.).

At the meeting, the sponsors’ representatives asserted that FDA was imposing new requirements, demanding statistically significant results by geographic region and subjecting the data to inappropriate post-hoc sensitivity analyses. The perceived unfairness of the advisory committee proceeding led Watson to complain directly to FDA Commissioner Margaret Hamburg (Also see "Watson Pulls Prochieve From Guidance, But Pushes For Approval" - Pink Sheet, 25 Jan, 2012.).

Watson and Columbia described the contents of the “complete response” letter in a Feb. 27 news release. The letter “stated that the effect of treatment with progesterone vaginal gel 8% in reducing the risk of preterm birth in women with a short uterine cervical length at ≤32 6/7 weeks gestation (p=0.022) did not meet the level of statistical significance generally expected to support the approval of the product in the U.S. market from a single trial,” the companies said.

“Although not part of the requirements communicated to the sponsor during pre-Phase III meetings, the FDA also raised the issue of robustness in efficacy in the U.S. sub-cohort as compared to the overall efficacy of the trial. In the complete response letter, FDA stated that additional clinical work would be required to support the approval.”

Looking For A Path Forward

Watson President and CEO Paul Bisaro discussed the FDA action during separate investor conference presentations.

At the Citi Global Healthcare Conference on Feb. 27, Bisaro said the company intends to discuss with FDA whether the accelerated approval mechanism could be a viable pathway to approval (Also see "Watson Hopes Accelerated Approval For Progesterone Gel Remains Option" - Pink Sheet, 27 Feb, 2012.). This was the route followed by Lumara Health Inc.’s Makena (alpha hydroxyprogesterone caproate, or 17P), which was approved in February 2011 for prevention of preterm birth in women carrying only one baby who have a history of spontaneous preterm birth with singleton pregnancies (Also see "KV's Gestiva Reemerges With New Name, Makena, And A Long-Sought FDA Approval" - Pink Sheet, 7 Feb, 2011.).

Bisaro expanded on those thoughts Feb. 28 at the RBC Capital Markets Health Care Conference. “There was some discussion in the letter … that there may be a viable option for us to get this product through,” he said.

However, Watson will have to weigh the amount of work needed for approval against the very limited patent life left on progesterone gel 8%. According to FDA’s Orange Book, the patent protecting Crinone expires on Sept. 15, 2013.

“We know there is a limited amount of life left on the Prochieve asset because of the patent expiry that’s coming up. So if it requires a full clinical trial that we have to start all over again, with no product in the market, it’s very likely that that particular molecule won’t be the one that we carry forward with,” Bisaro said. “If there was a way to get it to market and then do a study, well, that might change that statement.”

The CEO was asked whether the company might ditch further development of progesterone gel 8% in favor of a follow-on product. Pipeline information on Watson’s website describes that product as “Prochieve 2^nd Generation,” currently in Phase I development.

Bisaro said the company will have to consider whether it would be worth the effort and resources needed to bring the second-generation product forward. “We have to look at it and see is it a viable option for us to spend whatever clinical work we have to do – does the ROI work? And if it does, then we’ll do it. If it doesn’t, then we may be in a situation where we just simply abandon the opportunity.”

The Watson exec described a scenario in which the company would choose not to pursue the second-generation product. “If it requires multiple studies over the next five or six years, I don’t think we would be willing to spend that kind of money, particularly in this environment,” where the practice of medicine is shifting toward off-label use of progesterone in women with a short cervix, he said.

Issues surrounding off-label progesterone therapy in this population were discussed at the advisory committee meeting, with some panelists disagreeing with the view that the standard of care is appropriately moving in this direction (see sidebar).

Off-label use also was cited as one reason why conducting further placebo-controlled trials in this indication might not be feasible. At the RBC conference, Bisaro said that in the “complete response” letter, FDA “recognized that doing a placebo-controlled study could be difficult. …They appear to be willing to consider non-placebo controlled study options.”

A Lesson About U.S. Subgroup Results?

The Prochieve experience has dinged Watson’s efforts to further diversify its portfolio into the branded side of the pharmaceutical business and has placed the company in a defensive posture as it seeks to explain the NDA failure to investors.

During the recent investor presentations, Bisaro reiterated the view that FDA’s refusal to approve resulted from its imposition of new requirements on the sponsors and not from any failings in the sponsors’ handling of the application.

“There clearly was a fundamental disconnect between what we thought the agency was willing to accept, and what the agency ultimately was willing to accept,” Bisaro told the RBC audience. “And in fairness to our team, we have documented meeting minutes that show what the agency, at least at that particular time, had told us they would be willing to accept. That, for whatever reason, changed, and that changed very late in the game. And it is certainly the prerogative of the FDA to change its position.”

He suggested the lessons to be learned from the Prochieve experience go beyond Watson, extending to any sponsor that seeks to use foreign data to support a drug application.

“You need to make sure … you can show clinical significance in the U.S. population and you can’t rely on an ex-U.S. population set,” Watson CEO Bisaro said.

“Everybody needs to obviously look at their clinical study programs. And at least it appears now that if you have a clinical study program, you need to make sure that if you have a U.S. population, you can show clinical significance in the U.S. population and you can’t rely on an ex-U.S. population set. That … clearly was one of the outcomes of this meeting. … I don’t know if it’s a requirement, but it clearly was a requirement in this case.”

However, the need to prove a statistically significant benefit in the U.S. subpopulation has not been an across-the-board requirement at FDA.

The most notable case in point involved AstraZeneca PLC’splatelet inhibitor Brilinta (ticagrelor). Despite a robust showing of efficacy across a large, multinational pivotal trial, the drug not only failed to show a statistically significant benefit in the U.S. subpopulation, it even showed a negative trend. AstraZeneca attributed the anomaly to concomitant use of high-dose aspirin in U.S. patients, but FDA issued a “complete response” letter, seeking further analyses of aspirin doses to support this hypothesis.

Ultimately, FDA was satisfied with the additional analyses submitted by AstraZeneca and it approved Brilinta (Also see "Multiple Aspirin Dose Analyses Reassured FDA On Brilinta’s U.S. Efficacy" - Pink Sheet, 1 Jan, 2012.).