CLINICAL TRIALS PROFILE FOR MAKENA

All Clinical Trials for Makena

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT01004029 ↗	Confirmatory Study of 17P vs Vehicle for Prevention of Preterm Birth in Women w/ Previous Spontaneous Preterm Delivery	Completed	AMAG Pharmaceuticals, Inc.	Phase 3	2009-10-01	As part of the continuing effort to study the benefit and risks of 17P and preterm delivery, this study is designed as a multi-center, randomized, double-blind, vehicle-controlled clinical trial of 17P for the prevention of preterm birth prior to 35 weeks, 0 days of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. The study also includes a population pharmacokinetic (PK) substudy to assess the hydroxyprogesterone caproate (HPC) exposure-response relationship and the effect of body mass index (BMI) on the PK of 17P.
NCT01004029 ↗	Confirmatory Study of 17P vs Vehicle for Prevention of Preterm Birth in Women w/ Previous Spontaneous Preterm Delivery	Completed	ResearchPoint Global	Phase 3	2009-10-01	As part of the continuing effort to study the benefit and risks of 17P and preterm delivery, this study is designed as a multi-center, randomized, double-blind, vehicle-controlled clinical trial of 17P for the prevention of preterm birth prior to 35 weeks, 0 days of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. The study also includes a population pharmacokinetic (PK) substudy to assess the hydroxyprogesterone caproate (HPC) exposure-response relationship and the effect of body mass index (BMI) on the PK of 17P.
NCT01004029 ↗	Confirmatory Study of 17P vs Vehicle for Prevention of Preterm Birth in Women w/ Previous Spontaneous Preterm Delivery	Completed	Lumara Health, Inc.	Phase 3	2009-10-01	As part of the continuing effort to study the benefit and risks of 17P and preterm delivery, this study is designed as a multi-center, randomized, double-blind, vehicle-controlled clinical trial of 17P for the prevention of preterm birth prior to 35 weeks, 0 days of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. The study also includes a population pharmacokinetic (PK) substudy to assess the hydroxyprogesterone caproate (HPC) exposure-response relationship and the effect of body mass index (BMI) on the PK of 17P.
NCT01119963 ↗	Progesterone (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM)	Completed	Obstetrix Medical Group	Phase 2/Phase 3	2011-10-01	The objective of the study is to determine if a weekly dose of 17 hydroxyprogesterone caproate (17P, Makena®) given to women with preterm rupture of the membranes will: 1. increase the probability of continuing the pregnancy until a favorable gestational age. 2. increase the interval between randomization and delivery. 3. decrease neonatal morbidity.
NCT01899846 ↗	Pharmacokinetic Study of Makena® (Hydroxyprogesterone Caproate Injection, 250 mg/mL) and Its Metabolites in Blood	Completed	Lumara Health, Inc.	Phase 1	2013-07-01	This study will evaluate the levels of hydroxyprogesterone caproate and it's metabolites in blood throughout pregnancy There will be 3 cohorts of subjects Cohort 1 (6 subjects) will have daily blood draws in the morning at approximately the same time each day for one week following their first dose of Makena and will have blood drawn immediately prior to 2 successive Makena doses during Epoch 1 (24 - 28 weeks) and Epoch 2 (32 - 36 weeks) Cohort 2 (8 subjects) will have blood drawn to determine the trough concentration 7 days after their first dose of Makena. Subjects will have daily blood draws for one week following a dose of Makena given in Epoch 1 (24 - 28 weeks) and blood drawn immediately prior to 2 successive doses during Epoch 2 (32 - 36 weeks) Cohort 3 (16 subjects) will have blood drawn to determine the trough concentration 7 days after their first dose of Makena. Subjects will have blood drawn immediately prior to 2 successive doses in Epoch 1 (24 - 28 weeks) and daily blood draws for one week following a dose of Makena given during Epoch 2 (32 - 36 weeks) A maximum of 10 subjects will be monitored on selected days following a completed course of Makena therapy to determine the terminal elimination phase.
NCT02913495 ↗	Vaginal Versus Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth	Completed	Baystate Medical Center	Phase 4	2016-09-01	The purpose of this study is to evaluate the two suggested therapies for prevention of recurrent preterm birth (PTB) in women with a prior spontaneous preterm birth, vaginal and intramuscular progesterone to determine whether vaginal progesterone is superior to intramuscular progesterone in the prevention of recurrent preterm birth.
NCT02913495 ↗	Vaginal Versus Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth	Completed	George Washington University	Phase 4	2016-09-01	The purpose of this study is to evaluate the two suggested therapies for prevention of recurrent preterm birth (PTB) in women with a prior spontaneous preterm birth, vaginal and intramuscular progesterone to determine whether vaginal progesterone is superior to intramuscular progesterone in the prevention of recurrent preterm birth.

Clinical Trial Conditions for Makena

Condition Name

Condition Name for Makena
Intervention	Trials
Assessing Injection Pain of Makena® (Hydroxyprogesterone Caproate Injection, 250 mg/mL) in Healthy Post-menopausal Women	1
Comparing Bioavailability When Makena® is Administered in Healthy Post-menopausal Women	1
Pregnancy	1
Premature Birth	1

Condition MeSH

Condition MeSH for Makena
Intervention	Trials
Premature Birth	3
Rupture	1

Clinical Trial Locations for Makena

Trials by Country

Trials by Country for Makena
Location	Trials
United States	48
Canada	3
Czechia	3
Czech Republic	3
Hungary	2

Trials by US State

Trials by US State for Makena
Location	Trials
California	4
Florida	3
Idaho	2
Colorado	2
Arizona	2

Clinical Trial Progress for Makena

Clinical Trial Phase

Clinical Trial Phase for Makena
Clinical Trial Phase	Trials
Phase 4	1
Phase 3	2
Phase 2/Phase 3	1

Clinical Trial Status

Clinical Trial Status for Makena
Clinical Trial Phase	Trials
Completed	5
Terminated	1

Clinical Trial Sponsors for Makena

Sponsor Name

Sponsor Name for Makena
Sponsor	Trials
AMAG Pharmaceuticals, Inc.	4
Lumara Health, Inc.	2
ResearchPoint Global	1

Sponsor Type

Sponsor Type for Makena
Sponsor	Trials
Industry	7
Other	6

Makena (Hydroxyprogesterone Caproate Injection): A Comprehensive Update on Clinical Trials, Market Analysis, and Projections

Introduction

Makena, a hydroxyprogesterone caproate injection, was approved by the FDA in 2011 under the accelerated approval pathway to reduce the risk of preterm birth in women with a history of singleton spontaneous preterm birth. However, the drug's journey has been marked by controversy and ultimately, its withdrawal from the market. Here is a detailed update on the clinical trials, market analysis, and projections for Makena.

Clinical Trials and Efficacy

Initial Approval and Accelerated Pathway

Makena was initially approved based on a trial involving 463 patients, which showed that the drug reduced deliveries before 37 weeks of pregnancy, an intermediate clinical endpoint that the FDA determined was reasonably likely to predict clinical benefit to the newborn[1][2][4].

Confirmatory Trials

As a condition of its accelerated approval, the sponsor was required to conduct a postmarketing confirmatory clinical trial to verify and describe the predicted clinical benefit to newborns. However, this trial, known as the PROLONG study, failed to show improvement in the health of babies born to mothers treated with Makena. It also did not demonstrate that Makena reduced the risk of preterm birth[1][2][5].

Analysis and Findings

The FDA conducted additional analyses to determine if differences in the study populations could explain the disparate findings between the initial and confirmatory trials. These analyses showed that factors such as the race of the mother or whether the mother was treated outside the U.S. did not explain the different outcomes. Makena was found to be ineffective across all risk groups[1].

Market Analysis

Market Presence and Sales

Makena was the only FDA-approved drug for preventing preterm birth in high-risk women, giving it a unique market position. Over its 12 years on the market, it was administered to more than 310,000 women and generated significant revenue, peaking at $387 million in sales in 2017. However, sales plummeted to $122 million in 2019 as scrutiny over its efficacy mounted[2][5].

Pricing and Accessibility

The drug was expensive, with a weekly shot costing $855. This high price, combined with its questionable efficacy, raised concerns about its value to patients and the healthcare system[2].

Impact on High-Risk Patients

Covis Pharma, the sponsor of Makena, argued that the drug was particularly beneficial for high-risk patients, including Black women who have higher rates of preterm birth. However, the FDA and other experts countered that there was no evidence to support this claim, and that leaving the drug on the market could deter the development of more effective treatments[2][4][5].

Regulatory Actions and Withdrawal

FDA Advisory Committee Recommendations

The FDA’s Obstetrics, Reproductive and Urologic Drugs Advisory Committee voted multiple times on the fate of Makena. In 2019, the committee was divided, but by October 2022, it voted 14-1 to recommend withdrawing Makena from the market due to its lack of efficacy[2][5].

Final Decision

On April 6, 2023, the FDA Commissioner and Chief Scientist announced the final decision to withdraw the approval of Makena and its generic versions. This decision was based on the failure of the confirmatory trial to verify clinical benefit and the conclusion that the available evidence did not demonstrate Makena's effectiveness for its approved indication[1][4].

Market Projections and Future Implications

Immediate Impact

The withdrawal of Makena from the market means that patients and healthcare providers will no longer have access to this drug. Patients who were already using Makena were advised to consult their healthcare providers regarding alternative treatments, although none are currently FDA-approved for this specific indication[4].

Long-Term Implications

The removal of Makena highlights the need for more effective treatments for preterm birth. The FDA and the medical community recognize the importance of developing new therapies, especially given the disproportionate impact of preterm birth on communities of color. The absence of Makena is expected to drive research and development in this area, potentially leading to better treatments in the future[4][5].

Alternative Treatments and Research

The lack of an approved alternative treatment for preventing preterm birth in high-risk women underscores the urgency for further research. Covis and other pharmaceutical companies may focus on developing new drugs or conducting additional studies to fill this gap. The FDA has emphasized its commitment to supporting such research and ensuring that any future treatments meet rigorous efficacy and safety standards[3][4].

Key Takeaways

• Clinical Trials: Makena's confirmatory trial failed to verify its clinical benefit, leading to its withdrawal from the market.
• Market Analysis: Despite being the only FDA-approved drug for its indication, Makena's sales declined significantly as its efficacy was questioned.
• Regulatory Actions: The FDA withdrew Makena's approval due to lack of efficacy, emphasizing the need for a favorable benefit-risk assessment.
• Future Implications: The withdrawal of Makena highlights the need for more effective treatments for preterm birth and is expected to drive further research in this area.

FAQs

Q: Why was Makena approved under the accelerated approval pathway?

A: Makena was approved under the accelerated approval pathway in 2011 based on a trial that showed it reduced deliveries before 37 weeks of pregnancy, an intermediate clinical endpoint reasonably likely to predict clinical benefit to the newborn[1][2][4].

Q: What were the findings of the confirmatory trial for Makena?

A: The confirmatory trial, known as the PROLONG study, failed to show improvement in the health of babies born to mothers treated with Makena and did not demonstrate that Makena reduced the risk of preterm birth[1][2][5].

Q: Why did the FDA decide to withdraw Makena from the market?

A: The FDA decided to withdraw Makena due to the failure of the confirmatory trial to verify clinical benefit and the conclusion that the available evidence did not demonstrate Makena's effectiveness for its approved indication[1][4].

Q: What are the implications for patients who were using Makena?

A: Patients who were using Makena were advised to consult their healthcare providers regarding alternative treatments. However, no FDA-approved alternatives are currently available for this specific indication[4].

Q: How will the withdrawal of Makena impact future research on preterm birth treatments?

A: The withdrawal of Makena is expected to drive further research into developing effective treatments for preterm birth, particularly given the significant health disparities associated with this condition[4][5].

Sources

1. FDA: Makena (hydroxyprogesterone caproate injection) Information - FDA
2. FiercePharma: Covis agrees to sideline Makena, the lone drug for preterm birth
3. FDA: Covis Pharma GmbH's Briefing Materials - FDA
4. FDA: FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena
5. Pharmaceutical Technology: Makena Saga Shows How Hard It Is to Remove Unproven Drug from Market