By Wayne Koberstein, Executive Editor, Life Science Leader magazine
Follow Me On Twitter @WayneKoberstein
The Enterprisers: Life Science Leadership In Action
The top management team at Agile Therapeutics reflects an atypical bounty of experience and expertise for a small life sciences company. That was no accident, though it came of necessity following a near calamity. The attributes of the relatively new team proved essential in helping the company survive a key clinical trial setback that might have otherwise derailed it.
Agile’s initial NDA (new drug application) for its lead product caused the FDA to issue a complete response letter that sent the company back to the drawing board in late-stage development. Then chairman Al Altomari took over the CEO role and assembled new management, which organized a confirmatory trial of the company’s new contraceptive patch, Twirla (ethinyl estradiol/levonorgestrel), now entering a confirmatory Phase 3 trial.
Sometimes, rather than creating entirely new entities, entrepreneurial enterprises innovate by leapfrogging old technology — and sometimes, by leaping ahead of their past mistakes. Agile has rallied all of its capital and resources around developing products in the almost-abandoned field of women’s health related to contraception, starting with a lower-dose, moreconvenient alternative to the only existing birth control patch on the market.
Altomari headed the division that brought to market the sole patch now available, Ortho EVRA (ethinyl estradiol/ norelgestromin), in his former job at Johnson & Johnson, but he turned to the small-company world to push for a new once-weekly patch with a safer dose and engineered for comfort. Twirla would be the only low-dose transdermal contraceptive on the market if approved and the only one containing levonorgestrel, a more tolerable form of progestin. (See “A New Patch — Agile Upgrades Contraception” on page 38.) Agile also has additional transdermal products in development that, it says, “could offer a shortened hormone-free interval and an extended-cycle regimen of consecutive use, aiming for shorter, lighter periods and/or fewer periods.”
Small companies developing new, entirely novel products all too often lose their way by focusing inwardly, without a clear plan for the long term. But almost by definition, companies like Agile, those taking an old idea and making it new, must deal early with scale-up, clinical trials design, and overall growth strategy. And their planning must include a look at external factors such as medical practice needs, reimbursement, and patient adherence. All small life sciences companies, of all types, can draw useful lessons and learn best practices from the “reengineering” enterprises.
But the ideal scenario just described does not exactly match Agile’s actual history. During the years 2010 and 2011, under previous management, the company conducted its Phase 3 trials for Twirla, but the FDA sent a complete response letter saying the NDA was insufficient for approval as originally submitted. The agency recommended an additional Phase 3 trial be conducted with a simplified clinical trial design and improved study conduct. Altomari’s new executive team had to figure out how to answer the agency’s concerns.
“We recruited this team to move Twirla across the goal line,” says Altomari. “To be candid, we could have done some things better in our previous trial, and we believe we can get this one right. We are going ahead with a blend of humility and confidence.”
TRIAL BY CONFIRMATION
In some ways, the company had tried too hard to simulate real-world conditions in its first Phase 3 trial — incorporating a wide diversity of patients including a high proportion unfamiliar with any form of birth control. The FDA found the Phase 3 data too complicated by factors extraneous to the product itself. With the new confirmatory trial, SECURE, Agile aims to minimize such elements by enrolling subjects at sites that have experience in conducting contraceptive studies and by using a more experienced CRO, thereby achieving higher compliance with the protocol.
Chief Medical Officer Elizabeth Garner, M.D., explains. “Most of the issues the FDA raised in its complete response letter had to do with how the studies were conducted at the sites — too-rapid enrollment, high discontinuation rates, loss-to-follow- up rates, and other issues affecting general compliance with the drug. Our study population largely consisted of individuals who were new to hormonal contraception, people who face a learning curve and generally will not do as well as experienced patients. The agency had a tough time interpreting our data given the number of patients we had lost from the studies.”
Some good news came out of the first Phase 3 trial, Garner says: “We believe the agency seemed sufficiently comfortable with Twirla’s dosing and its safety profile. That’s huge for us, especially with EVRA in the background. So they asked us to do another trial and focus heavily on the study conduct.”
Thus, says Garner, the company has several reasons to think the new trial will be successful. First, its new CRO, Parexel, has sufficient “bandwidth” to handle the trial — a possible problem in the first one. Second, the few clinical sites that showed the worst compliance, dropouts, and pregnancy rates in the first trial are not participating in the second one. Third, the company has worked with Parexel to identify additional qualified investigators who can help select the patient population for the new trial. All of the measures should ensure much better compliance to give the product the best possible test of safety and efficacy as a basis for FDA review.
The centerpiece of the SECURE trial, according to Garner, is the use of new technology to gather and manage the data. For example, the trial will employ eDiaries, known to do a much better job of capturing patient responses than the old paper-based systems. (See “Direct To Data — An Electronic Solution To Patient Diaries,” August 2012.) SECURE also provides trial subjects with a host of educational materials and other compliance aids.
As with the eDiaries, supplied by PHT, almost all of Agile’s operations are virtual. In scaling up to produce the new patch for clinical trials, the company also relied on its manufacturer, Corium, for process development and production. “We are very comfortable with outsourcing,” says Altomari. “We are in a new age of virtual companies, but most of us come from Big Pharma, and we are experienced. We aim to select the best suppliers in class, with the best consultants in class, to supplement ourselves. We promise investors we will stay administratively lean. We have greatly skilled executives, but a small staff, relatively, even for a small-size company, and we like it that way.”
Altomari came to Agile from Barrier Therapeutics, where he steered the company to the point of acquisition by Stiefel Labs (later acquired by GSK). He held a variety of leadership positions at J&J from 1982 to 2003, heading the Ortho-McNeil Women’s Health Care division during the commercial planning for EVRA.
He has avoided creating multiple layers of management and only added new functions as they were needed. Chief Commercial Officer Katie MacFarlane, Pharm.D., an advisor since 2009, came on board full time in 2014, in anticipation of a Twirla launch. Her role also heralds the company’s strategy of full integration, as opposed to acquisition or licensing out.
“I come to work planning that we’re going to launch this product,” says MacFarlane. “We are doing all of the commercial prep work that needs to be done. Agile has produced more than 25 publications in the literature on this patch. We have worked with a great group of key opinion and thought leaders. We’ve done a lot of market research to identify the right messages in selling. We’ve even done a trademark. We believe we have everything we need ready to go, so that if we are granted an approval, we will be in a good position to get out into the marketplace.”
The company has even planned for the sales force, as MacFarlane explains. “The great thing about the contraceptive market is it is a true specialty market. The OB/ GYNs drive an enormous percentage of the prescriptions, so you can efficiently market a contraceptive with about 70 to 100 reps, and that’s the model we’re working under right now.”
Agile is also counting on continued support from patient groups and contraception advocates. It has longestablished relationships with all main women’s health advocacy groups, including Planned Parenthood, NOW, The Campaign to Prevent Teen and Unplanned Pregnancy, The Black Women’s Health Imperative, and the Latina Institute. MacFarlane mentions Bedsider, a popular website that presents a wide variety of birth control methods.
“These are true advocacy groups,” she says. “They are great about keeping informed about policy issues, such as insurance coverage, the Affordable Care Act, and many others that affect contraception, which enables us to stay on the cutting edge. They want women to have access to all the contraceptive options, and because the current contraceptive patch on the market is thought to be not the safest product with its high dose of estrogen, I believe they would like see an alternative contraception patch option.”
“If I were at J&J, Merck, or any of the big companies, and I said to our bosses, ‘Hey, we’re going to go down to D.C. and hang out with a bunch of lobbyists,’ I would be flung out of my job,” comments Altomari. “But as a young company, we say, why can’t we go down and talk to them? Why not? We are all on the edge of these very controversial issues because we believe we’re developing a good product, we are advocates for women, and we’re advocates for choice in contraception.”
Is the precommercial stage too early to think about marketing? Altomari believes small companies typically wait much too late to do so. “We don’t overspend on commercial planning before approval; everything is timed appropriately, but we come out of Big Pharma, and I would say our business plan is as good — maybe better, because we have had more time to work on it.”
"In my mind, every dollar we would spend in overhead could be better spent in the clinic."
Altomari credits the company’s survival and “second chance” at success with the SECURE trial to good cash management. “We have been very responsible,” he says. “We wanted to be ready to weather the financial storms if we needed to and get through some tough times. We have been able to do that.”
Resources flow to where they are needed most — clinical development. Manufacturing and commercialization, though also essential, come second. “In my mind, every dollar we would spend in overhead could be better spent in the clinic,” says Altomari. “We believe our lean operations are one reason the people who invested in this company privately also invested in the company publically. Even in our IPO, private investors came forward and supported us.”
Altomari says he is grateful the company got its second chance in life, a rare and valuable exception to the rule. At Agile, he and his team seem to have found an exhilarating balance of Big Pharma experience and small life sciences company gusto — innovating by turning the old into the new.
PUBLIC COMPANY: NASDAQ Global Market Ticker Symbol: AGRX
MARKET CAP: About $158 million
CASH: $45.7 million at Sept. 30, 2014
START-UP DATE: 1997
NUMBER OF EMPLOYEES: 12
FOCUS: Women’s health specialty pharmaceuticals; weekly, hi-tech contraceptive designed to overcome previous barriers to use of patches
A NEW PATCH – AGILE UPGRADES CONTRACEPTION
Elizabeth Garner, M.D., chief medical officer at Agile Therapeutics, describes how the company’s Twirla (ethinyl estradiol/levonorgestrel), now in a confi rmatory Phase 3 trial, differs from the only current transdermal contraceptive on the market, J&J’s EVRA (ethinyl estradiol/norelgestromin).
“Twirla contains two very well-known hormones, very commonly used in contraception: levonorgestrel, a progestin, and ethinyl estradiol, a synthetic estrogen, in combination. EVRA contains the same estrogen, but a different progestin, and it delivers substantially more of the estrogen on a daily basis. That is one of the major differences between our patch and the EVRA patch. EVRA has had notable problems with blood-clot risk, so we believe our patch may address that problem with its lower estrogen dose. Ultimately, we believe our patch will be shown to be safer than the EVRA patch in the risk of clotting.
“The Twirla patch is what we call a matrix patch, in that the hormones are interwoven with a number of enhancers that help the hormones to get through the skin. That is one of the interesting features about the patch that leads to a more consistent delivery of hormone through the skin, as opposed to older patch designs. There are six layers to the patch, including a peripheral backing. The material has a light, clothlike feel very different from the EVRA patch; it is very flexible, moving along with your activities. But the most unique aspect of this patch is this — hold it up to the light and you can see an inner ring, inside concentric circles, where the actual hormone is. You can barely feel it, too. What that means is the drug is contained in the middle of the patch with the adhesive surrounding it. That is very different from the EVRA patch, where there is drug all the way to the edges of the patch that can seep out when the patch is worn, getting on clothes and so on.
“This is also the first known patch to deliver the levonorgestrel hormone, a progestin responsible for contraceptive efficacy, at sufficient rates to reach contraceptive levels. The estrogen mainly controls bleeding. Levonorgestrel alone, like any progestin, can cause some irregular bleeding.”
CEO Al Altomari adds a comment about the innovation required in creating the new contraceptive patch:
“The engineering of this patch is as complicated as the biology and the chemistry of hormonal contraception. Imagine a piece of cloth that’s pulling and getting into folds and creases rather than settling into a nice little round circle and consistently delivering a drug. Not many companies can make patches, so there are not many drugs delivered by a patch. Our technical challenge was not to deliver estrogen, which can transport pretty easily across the skin. It is the progestin that is hard to transport. We are quite proud of this technology. We own all of the patents, so this is our product. We don’t owe any royalties; this is in-house technology.”