*Several years ago I wrote a blog post called Anti-Kell Antibodies: Dr. Moise’s New Treatment and I promised to update the blog when there were new developments. This is the update 3 years in the making!

*Disclaimer: I am not a medical professional. This is what I understand about M281 and the phase 2 trial currently underway.

I like to think in pictures and stories, so I’ll share the scenario that comes to mind when I think of M281, a new drug currently being tested to treat severe alloimmunization and HDFN in pregnancy. Imagine a busy train track with trains coming and going every hour or so. Now imagine a toddler walking around exploring the train tracks, picking up rocks, stumbling and righting himself, following a passing airplane overhead with wide eyes. I’ll use a picture of my 20 month old, Callum just for a cute visual.

You hear a train approaching in the distance. What is your first reaction? Go get that baby off the tracks, right? It seems logical to protect the toddler from being hurt or killed before the injury happens. What if someone nearby said, “Oh, it’s fine. Let him do his thing and if he gets hit by the train we have medical professionals who can treat his wounds. There is a possibility of death but hopefully we can save him after he gets hit by the train.” No one in their right mind would stand by and let that scenario play out. Why not remove the baby from the area or at least put up a fence or other barrier to keep the baby away from the train track?

Sometimes it feels like the methods used at the moment to treat alloimmunization during pregnancy/HDFN are similar to the train track scenario. Instead of protecting the baby from the antibodies to begin with, the protocol is to wait until the baby is attacked by the antibodies and becomes anemic before stepping in to help. But this way of treating the disease has proven dangerous far too many times. Sometimes the baby dies before the doctors detect the fetal anemia or the anemia is so severe by the time they discover it that the baby can’t be saved (like in Lucy’s case.) Sometimes the fetal anemia is discovered but the doctors wait too long to do a transfusion and the baby dies. There can be complications from the IUT which can lead to premature delivery or death. Another complication is hyperbilirubinemia after birth which can lead to permanent brain damage if not treated quickly and aggressively. All of these tragedies could be avoided if we could figure out a way to “put up a fence” between the antibodies and the baby BEFORE the baby is attacked by the antibodies. What if there was a way to protect the baby from the injury in the first place instead of trying to treat the wounds afterwards? Well, Dr. Moise and some other brilliant people might have figured it out!

M281 is a drug that can potentially block a mother’s antibodies from going through the placenta to her baby during pregnancy. If the antibodies don’t get to the baby then there should be no fetal anemia, no IUTs, no fetal hydrops, no hyperbilirubinemia after birth, no death. This drug is still in the trial phase but it looks very promising and I am so excited to see how it might save lives in the future.

Since my original blog post in 2016, researchers have done drug studies on pregnant primates and non-pregnant humans to test for safety and efficacy of M281. They have studied the drug in human placentas in the lab too. To learn more about these studies you can check out these links:

Human Ex Vivo Placental Perfusion Model:

transplacentalarticle.pdf

http://ir.momentapharma.com/static-files/71c4376f-4984-419e-a0b1-430326783e99

First Human Study:

firstinhuman.pdf

Right now the phase 2 trial for pregnant women is open and they are accepting 15 trial participants worldwide. This trial is the first one to test M281 on pregnant women with severe HDFN/alloimmunization. Here is the link to the study details: https://clinicaltrials.gov/ct2/show/NCT03842189?cond=m281&rank=3

I wanted to answer some of the most common questions I have received about M281 here so that the information is easy to find. If you have other questions about the new treatment or about the drug trial you can come join our M281 Discussion Group on Facebook or you can email me at bethanysk55@yahoo.com or just ask your question here in the comments section. If you have specific questions about the trial here is the contact information for Momenta Pharmaceuticals:

Here are some of the most commonly asked questions:

How does the drug protect the baby from the antibodies?

M281 works in two ways to protect baby from the mother’s antibodies while in the womb. It lowers the mother’s overall antibody count and it blocks the antibodies from getting through the placenta to the baby.

How is the drug administered?

M281 is given via IV infusion once every week and the infusion takes about two hours.

Does the drug work for any antibody or just for certain ones?

The drug trial is only for women with anti-D or anti-Kell antibodies since those two are usually the most aggressive ones when it comes to HDFN and the study wants to specifically target the worst case scenarios before declaring that it works. But the drug does block all red cell antibodies from going through the placenta so if it does get approved and go on the market it will work for anyone with a red cell antibody.

Does the drug cause birth defects or dangerous side effects?

This is part of what they are trying to determine with the phase 2 trial on pregnant women but the previous studies did not find any evidence of birth defects or major negative side effects. The drug will be administered once the woman is in her second trimester so that alone is safer in regards to birth defects since those typically happen in the first trimester. Also, previous studies show little to no transfer of the drug to the fetus.

How is M281 different from IVIG?

If you read my post about Titers, Antigens and Sharks you might remember that the “shark cage” was IVIG which can be used in severe cases to protect the baby in utero from the antibodies early in pregnancy before IUTs are possible. IVIG stands for “intravenous immunoglobulin” and it is made up of thousands of people’s antibodies concentrated into a liquid given intravenously. Doctors still aren’t sure exactly how IVIG works to protect the baby but most doctors think the IVIG protects the baby in one or more of these three ways:

1. It lowers the titer so that there are fewer antibodies present in the mother’s blood to attack the baby.
2. It slows/prevents the antibodies from going through the placenta and attacking the baby’s red blood cells.
3. It helps the baby fight off the antibodies that are attacking his red blood cells.

IVIG doesn’t completely block the antibodies from getting to the baby like M281 could but it does delay the attack. With my second and third sensitized pregnancies I had plasmapheresis and IVIG treatments which delayed the antibodies’ attack and saved my babies’ lives. Even with those life saving treatments Nora had seven transfusions total and Callum had six transfusions total as well as other interventions and medications, NICU, etc. The antibodies still wreaked havoc on my babies both in the womb and in the weeks following birth. IVIG is also very expensive and most countries will not approve it as a treatment for our disorder. Another down side of IVIG is that it usually comes with some pretty severe side effects for the mother. I had debilitating migraines, vomiting, rapid heart rate, difficulty breathing, back pain, muscle weakness, eczema and more. I also had to take more medications (mostly class C drugs for pregnancy) to manage the side effects. For the people who were given M281 in the previous human studies (non-pregnant) there were no significant side effects.

When will the drug be ready for public use?

I’m not sure if or when the drug will be available to the public. The next step is to complete the phase 2 trial which means following 15 women through their pregnancies and for six months after birth. Only once the drug is deemed effective and safe will they consider making it available to the public. Right now the estimated trial completion date is 2022.

If the drug blocks all maternal antibodies from going through the placenta, how does the baby get the good antibodies from the mother? Is the baby born without an immune system?

The drug does block even the “good” maternal antibodies from getting to the baby but the doctors have a solution for this. The plan is to induce labor/deliver at 37 weeks, so at 35 weeks they will stop the weekly M281 infusions to allow maternal IgG antibodies to transfer to the baby. The woman will receive IVIG to boost her antibody count (NOT her red cell antibody count though.) During the two weeks without the M281 infusions the MFMs will watch baby very closely to make sure he isn’t getting anemic. If baby is showing signs of anemia they will deliver. The baby will get mom’s antibodies for two weeks before birth. Once baby is born the doctor will test the cord blood to make sure baby’s IgG antibody levels are high enough. If they aren’t, they will give baby IVIG infusions to boost the antibody count and baby will have an efficient immune system.

Who can be included in the trial?

The doctors have very specific requirements for trial participants, all for good reasons. If you are interested in joining the study, contact your OB or MFM and have them contact Momenta Pharmaceuticals at +1 617-491-9700 or have them email Dr. Ken Moise at kenneth.j.moise@uth.tmc.edu  Here are SOME of the requirements for trial participants:

• Age >18
• English speaking
• Singleton pregnancy
• Gestation 8-13 weeks
• Anti-D alloimmunization with a titer of at least 32 or Kell with a titer of at least 4.
• Previous pregnancy with one of the following at 24 weeks or earlier- severe anemia at time of transfusion with hemoglobin less than 0.55, Hydrops Fetalis with elevated MCA over 1.5 MoM, fetal demise with pathology of the placenta/fetus consistent with severe HDFN (need records)
• Evidence of immunity to certain diseases
• No history of a clinically significant medical complication that would jeopardize the safety of the patient or her fetus (ex: pre-eclampsia, pregnancy induced hypertension, drug or alcohol abuse, etc.)

I will try to keep everyone updated on the new drug’s progress here on the blog and definitely on the M281 Discussion Group on Facebook so come join us there if you’re interested in following along!