After a series of legal and regulatory setbacks that nearly sunk the company, KV Pharmaceutical Co. may be regaining its footing with the approval of Makena, formerly Gestiva, Feb. 4 for prevention of pre-term birth in women carrying only one baby who have a history of spontaneous pre-term birth with singleton pregnancies.

The application has had a long, troubled history, as has the company. It was in danger of going under just weeks ago, when FDA delayed action on the NDA from January 11 to April 11. KV intends to update investors about the approval and provide a business update during a Feb. 14 conference call.

Now that Makena has won approval, KV and Bedford, Mass., women's health diagnostics firm Hologic Inc., which holds the NDA, can conclude a 2008 deal under which KV purchased full U.S. and worldwide rights to the drug pending approval ([See Deal]).

St. Louis-based KV expected to complete the transaction, which was reworked after an anticipated January 2009 approval fell through, by Feb. 11.

The firm saw its stock price grow by 140.5% on the news of the approval, to a 52-week high of $4.23 in high-volume trading. The stock opened at $2.95 that day and eventually closed at $3.68.

The drug will be marketed by KV's branded drug subsidiary, Ther-Rx Corp. It is manufactured by Baxter Pharmaceutical Solutions LLC.

Approval Based On Original Study - Six Years Later

Makena (alpha hydroxyprogesterone caproate, or 17P) is a synthetic form of progestin, a hormone produced in pregnancy. It is to be given in weekly injections to eligible pregnant women between 16 and 20 weeks gestation and continuing until 37 weeks, considered minimum for a full-term pregnancy.

The application was first submitted in 2006 - and the accelerated approval was based on the original study submitted, which was run by NIH's National Institute of Child Health & Human Development. The study enrolled 463 women with a history of preterm birth at 16 to 21 weeks of gestation, then randomized them to weekly injections of 17P or placebo until delivery or 37 weeks of gestation.

The approval was granted based on the surrogate endpoint of reducing the risk of delivery before 37 weeks. Among women treated with Makena, 37% delivered early as compared with 55% of women in the control group.

A separate study evaluating the development of children born to mothers enrolled in the NIH trial showed that the children - now 2.5 to 5 years of age - reached similar developmental targets regardless of their mother's treatment.

A follow-up study expected to include 580-750 infants is expected to be completed around 2018, while an ongoing comfirmatory study in 1,700 patients aims to win a full approval by demonstrating benefits such as reduced number of babies who do not survive or who suffer serious problems shortly after birth. That study should wind up in 2016.

The approval does not carry a Risk Evaluation and Mitigation Strategy, though certain pregnancy-related fetal and maternal complications or events were numerically increased in Makena-treated subjects, including miscarriage (2.4% versus 0%) and stillbirth (2% vs. 1.3%), admission for preterm labor (16% vs. 13.8%), preeclampsia or gestational hypertension (8.8% vs. 4.6%), gestational diabetes (5.6% vs. 4.6%) and oligohydramnios (i.e. low amniotic fluid levels; 3.6% vs. 1.3%).

The American Congress of Obstetricians and Gynecologists has recommended that physicians offer progesterone treatments to high-risk women since 2003, and prescriptions for 17P typically are filled by compounding pharmacies. However, many eligible patients faced logistical and financial barriers to access under that system, as the March of Dimes asserts in a release celebrating the approval.

FDA-approved Makena will be widely available through specialty pharmacies and access to the drug will be improved by increased coverage, the advocacy group reasons. The market is likely to be sizeable. According to the March of Dimes, late pre-term births, those at 34-36 weeks, account for nearly three-quarters of the one in eight babies born prematurely every year in the U.S.

A Lengthy Regulatory Process Completed

Makena originally was developed by Adeza Biomedical. The women's health company Cytyc acquired Adeza in April 2007, and Hologic merged with Cytyc that October, giving all rights to the drug to Hologic. But while Makena had a lot of potential, its NDA was in need of expensive remediation.

FDA had awarded Adeza's NDA a priority review in the spring of 2006, and, though it raised questions about the incidence of second-trimester miscarriages and still births seen in the pivotal study, an advisory committee voted in August to make the drug available due to the lack of alternative therapies (Also see "Gestiva Passes Cmte. Review, But Further Study Of Miscarriage Risk Requested" - Pink Sheet, 28 August, 2006.).

The agency, however, issued an "approvable" letter in October 2006 requesting an additional animal study, outlining post-approval clinical requirements related to recommendations by the advisory committee, and urging collection of long-term safety data, including a potential registry to track children exposed during pregnancy through adolescence.

FDA rebuffed the NDA again in January 2009, seeking changes in the protocol for the confirmatory study. (Hologic resubmitted the application in July 2010, receiving the January 2011 action date.) The miss crippled KV, which by then was embroiled in regulatory problems of a different stripe - involving good manufacturing abuses and SEC violations (Also see "Gestiva Approval Unlikely In FY 09; KV Pharmaceutical Admits Credit Fumbles" - Pink Sheet, 26 January, 2009.).

In November 2008, the company delayed filing its second quarter financial report because its audit committee was proving allegations of misconduct by management. It subsequently halted the manufacture of all its products, terminated its CEO and general counsel, announced it might default on a $30 million line of credit, reported that it was slashing 700 jobs, and announced that the launch of then-Gestiva would be again delayed ([A#1409032006]).

After that, KV shed another 289 employees, and though FDA began allowing it to ship two products it does not manufacture in-house, it was clearly in financial distress and said it might not be able to fund operations after Sept. 30, 2010, if it couldn't raise funds (Also see "KV Pharmaceutical Cleared To Resume Some Drug Shipments, But Cash Crisis Looms" - Pink Sheet, 10 September, 2010.). With the Makena approval in hand, KV now can look forward to a revenue stream.

[Editors note: This story was updated Feb. 14 to clarify descriptions.]

-Shirley Haley (s.haley@elsevier.com)

KV's Gestiva Reemerges With New Name, Makena, And A Long-Sought FDA Approval

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