Expert Financial Analysis and Reporting

Key Conclusions

I believe that there is a 95% probability that Makena will remain on the market and only a 5% chance that it could be withdrawn. I think that results of PROLONG will be incorporated into the Makena label and the FDA may or may not ask for another trial. There is no approved alternative to Makena in preventing preterm birth in singleton pregnancies in women who have previously had a preterm birth and Makena has been a fixture in OB/GYN practices and incorporated into professional guidelines for some time. If Makena remains on the market as I expect, I don’t see much of a change in physician usage.

If I am correct, this is obviously a major positive for AMAG and I will have more to say on my view on this stock later. Makena SC is perhaps 20% of the current investment thesis for Antares, but concern about withdrawal has weighed on the stock. Hence, this would reinforce my buy on Antares.

Background

An FDA Advisory Committee is scheduled to meet on October 29 to discuss the implications of the PROLONG trial. The active ingredient of Makena is 17-HP (17 alpha hydroxyprogesterone caproate) was incorporated into professional guidelines in 2008. This was on the basis of the MEIS trial which was completed in 2006. MEIS demonstrated that 17-HP was effective in reducing the number of preterm births in women with a singleton pregnancy who had previously had a preterm delivery. The trial was conducted by the National Institutes of Health and in a group of 310 women on 17-HP and 153 on placebo. It reached the primary endpoint of reducing the number of preterm births in women with a singleton pregnancy who previously had a preterm birth with a very strong p value of 0.0003

Makena was approved in 2011; prior to then 17-HP was only available from compounding pharmacies. As a condition of approval, AMAG had to conduct a confirmatory phase 3 trial called PROLONG. The results of PROLONG were released in February 2019 and showed no statistically significant difference for Makena from placebo in reducing the number of preterm births in women with a singleton pregnancy. The FDA has scheduled an advisory committee for October 29 to consider what to do in light of the PROLONG failure The Briefing Documents for the AdCom were released on Friday and I have read through them in their entirety. If you wish to do the same, here is the link. I am not going to go through all of the key points of the briefing documents. Rather, I am just going to give you my key thoughts.

A Look at the PROLONG Trial

It is my strong opinion that the patients enrolled in the MEIS trial were at much higher risk than PROLONG. Rather than indicating that Makena is ineffective,I believe that the most reasonable and probable conclusion that the AdCom will reach is that the MEIS trial indicates that there is a subset of women at high risk that receive substantial benefit from Makena, but in women at lower risk, it confers no benefit.

Makena (or 17-HP) was so firmly entrenched in US physician practices that it was difficult to enroll for PROLONG in the US as physicians and patients did not want to take the risk of being in the placebo group. This meant that much of the patient enrollment took place in Russia and the Ukraine. Those patients had much lower risk profiles than women enrolled in MEIS. The key differences in the characteristics of women enrolled in MEIS, PROLONG and the US part of PROLONG are shown below.

Race/ ethnicity

MEIS: Black 60%, Hispanic 15%

Ex US PROLONG: 1 black patient, Hispanic 8%

US PROLONG: Black 14%, Hispanic 15%

Marital status (unmarried)

MEIS: 50%

Ex US PROLONG: 11%

US PROLONG: 27%

Substance use (smoking, alcohol or illicit drugs):

MEIS: 26%

Ex US PROLONG: 4%

US PROLONG: 28%

Prior spontaneous preterm birth

MEIS: 32%

PROLONG 15%

US PROLONG 27%

What Will the AdCom Recommend?

The above data persuades me that PROLONG and MEIS are essentially two different trials and that the findings of PROLONG do not invalidate the findings of MEIS. I think that the AdCom will agree on that. However, the approval of Makena was based on the PROLONG trial results confirming MEIS and clearly this was not achieved. This means that the FDA could remove Makena from the market, but this is not an absolute requirement. The quandary that the FDA faces is clearly shown in the questions it is asking the AdCom to address. Please refer to this link for the detailed questions that FDA is asking of the AdCom

1. Pursue withdrawal of approval of Makena
2. Leave Makena on the market under accelerated approval and require a new confirmatory trial
3. Leave Makena on the market without requiring a new confirmatory trial.

Will FDA pursue withdrawal of approval of Makena?

Clearly, PROLONG does not confirm the MEIS trial and this confirmation was a condition for approval of Makena. While the MEIS trial shows clearly that in a subset of patients that the incidence of preterm births is reduced, it is of concern that this is a surrogate endpoint. It does not establish a clinical benefit for the infant in terms of reduced morbidity or mortality. Of course, there is almost universal belief that preterm birth does increase the risk of infant morbidity and mortality both among physicians and the lay public.

There would be a vexing question for physicians and the FDA if Makena is withdrawn. Because there is clear clinical evidence that in a sub-group of high risk women that that Makena does reduce the number of preterm births, could a woman have legal recourse against the FDA or physicians if the therapy is withheld and they have a preterm birth with associated infant mortality or morbidity.

Will FDA leave Makena on the market under accelerated approval and require a new confirmatory trial

What kind of a trial would this be? Clearly repeating a trial like PROLONG would be a waste of time. It might be possible to conduct a trial in which only high risk patients comparable to the MEIS trial were enrolled. This would be an apples to apples comparison to MEIS, which clearly PROLONG was not. This seems logical, but it could be very difficult to enroll patients in the placebo arm. Another possibility is that the trial could have a different endpoint intended to show a benefit in infant morbidity or mortality. This would also be difficult to enroll and might take some years to complete as the babies might have to be watched for months or more likely years.

Will FDA leave Makena on the market without requiring a new confirmatory trial?

The FDA could elect to just include the results of the PROLONG trial in the label and let physicals decide based on their own experience and the considered opinion of leadership groups whether and in which patients to use Makena. I favor this option, but I am not a voting member of the AdCom

What I Think FDA Will Do?

For what it is worth, here is my guesses at the probability of FDA action on these three questions.

1. Leave Makena on the market without requiring a new confirmatory trial--- 65%
2. Leave Makena on the market under accelerated approval and require a new confirmatory trial----30%
3. Pursue withdrawal of approval of Makena-----5%

In both 1 and 2, the results of PROLONG would be incorporated into the label. In the case of the FDA requiring another trial, it would take years to produce results. Hence, physician behavior would be the same in either case.

What Will Physicians Do If Makena Remains on the Market?

I think that there is a very strong view in the OB/GYN community that Makena is an effective drug. It is strongly integrated into their practices and is incorporated into professional guidelines. I think that most will conclude as I do that PROLONG results don’t invalidate MEIS findings. In point of fact, we already have a preview of what they will do as PROLONG results were released in February 2019. Since that time the demand for Makena (Makena SC and IM generics) does not seem to have been much effected. If Makena remains on the market, it might be the case that physicians would restrict use to patients most at risk and perhaps this could reduce usage; this would be their call. However, because there is no alternative to Makena and the drug is safe, I think that most physicians will not change their current usage patterns for Makena.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Preterm birth defined as birth prior to 37 weeks of gestation , currently affects 10% of all births and 8% of singleton pregnancies. Current professional guideline recommend progesterone treatment starting in the second trimester of pregnancy to reduce the risk of preterm birth in women with a singleton pregnancy and who have had a prior spontaneous preterm birth. There are no controlled trials showing a direct clinical benefit such as improvement in neonatal mortality and morbidity. AN NIH study completed in 2003 showed a highly statistically significant decrease in preterm birth prior to 37 weeks gestation, which is believed to be a atrong surrogate endpoint suggesting reduction in infant morbidity and mortality. HPC was approved in 2006. There was no drug sponsor so the drug was onloy available through compounding pharmacies.

 

There was a question as to the applicability of this study to a broader population because:

• 60% of population was black,
• Patients were recruited from academic centers with 25% from one center alone
• There was a 55% rate or preterm birth in the control arm.

The patients in the Meis trial were obviously high risk. In order to assess the efficacy in a broader population, a condition of approval was to do another trial in a broader population which was PROLONG. The trial was to be a worldwide trial. However, because of the widespread acceptance of Makena by the OB/ GYN community, it was difficult to recruit in the US.

 

 

 

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