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Eyes On Pharma Blog 

Eyes On the Hematology Space

Lately, we’ve had Eyes On the Hematology space. I, Robin, have worked in this area for many years and am always keeping an eye out for the latest advancements. I am from an era where folks would want to exclude potential products such as gene therapy from the competitive landscape because “it’s never gonna work” or “it’s more than 10 years away.” So needless to say, I am excited to see all of the current work coming to fruition with gene therapies, cell therapies, and advanced antibodies. Whew – maybe we are finally getting closer to truly personalized medicine and cures versus treatments.

I thought I’d provide a quick, general overview of the rare diseases in today’s article. There are links to various websites for those looking for more scientific details.

Hemophilia A (from NHF) Hemophilia A, also called factor VIII (8) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII (FVIII), a clotting protein. Although it is typically passed down from parents to children, about 1/3 of cases found have no previous family history. Hemophilia is inherited in an X-linked recessive manner. Females inherit two X chromosomes, one from their mother and one from their father (XX). Males inherit an X chromosome from their mother and a Y chromosome from their father (XY). That means if a son inherits an X chromosome carrying hemophilia from his mother, he will have hemophilia. It also means that fathers cannot pass hemophilia on to their sons. People with hemophilia A bleed longer than other people. Bleeds can occur internally, into joints and muscles, or externally, from minor cuts, dental procedures, or injuries. How often a person bleeds and the severity of those bleeds depends on how much FVIII a person produces naturally. According to the US Centers for Disease Control and Prevention (CDC), hemophilia occurs in approximately 1 in 5,617 live male births. There are between 30,000 – 33,000 males with hemophilia in the US*. More than half of people diagnosed with hemophilia A have the severe form. Hemophilia A is four times as common as hemophilia B. Hemophilia affects all races and ethnic groups. Most treatments for hemophilia A focus on replacing the missing protein, FVIII (8), so a person can form a clot, and so reduce or eliminate the bleeds associated with the disorder. Treatments that work to prevent bleeding through new mechanisms have recently come to the market or are in clinical trials. People with hemophilia A have several different medication options for treatment.

β-thalassemia (from the NORD Rare Disease Database & Cooley’s Anemia Foundation) Beta thalassemia is an autosomal recessive genetic blood disorder characterized by reduced levels of functional hemoglobin. Beta thalassemia is caused by mutations in the hemoglobin beta (HBB) gene. Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes. While the disorder is relatively rare in the USA – it is particularly prevalent in the Mediterranean, Middle East, Africa, Central Asia, the Indian subcontinent, and the Far East. Individuals with beta thalassemia minor usually do not have any symptoms (asymptomatic) and individuals often are unaware that they have the condition. Some individuals do experience very mild anemia. Individuals with beta-thalassemia major (Cooley’s Anemia) have a severe expression of the disorder; they often require regular blood transfusions and lifelong, ongoing medical care. The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small (microcytic), are not produced at normal amounts, and do not contain enough functional hemoglobin. Consequently, affected individuals do not receive enough oxygen-rich blood (microcytic anemia) throughout the body. Affected individuals may experience classic signs of anemia including fatigue, weakness, shortness of breath, dizziness, or headaches. Severe anemia (Cooley’s Anemia) can cause serious, even life-threatening complications if left untreated. Guidelines for treating affected individuals include regular blood transfusions and extensive ongoing medical care including chelation therapy to reduce the iron overload resulting from transfusions.

Sickle Cell Disease / Sickle Cell Trait (from the National Heart, Lung, and Blood Institute) Sickle cell disease is a genetic disorder caused by mutations in the beta-globin genes that leads to faulty hemoglobin protein, called hemoglobin S. Hemoglobin S changes flexible red blood cells into rigid, sickle-shaped cells. These sickle cells can block blood flow and result in pain and organ damage, and often result in the need for hospitalization to resolve the crisis. Patients with SCD inherited Hemoglobin S from each parent. If a person has Sickle Cell Trait they have one Hemoglobin S gene + one hemoglobin A [normal] gene and are generally healthy. Patients with Hemoglobin S + another faulty hemoglobin gene such as B-thalassemia, Hemoglobin C, Hemoglobin D, or Hemoglobin E have a chance of having SCD. There are blood tests for screening and genetic testing for diagnosis and genetic counseling. In the United States, most people who have sickle cell disease are of African ancestry or identify themselves as Black. About 1 in 13 Black or African American babies are born with SCT and 1 in 365 with SCD. Many people who come from Hispanic, Southern European, Middle Eastern, or Asian Indian backgrounds also have sickle cell disease. SCD is a lifelong illness and there are several medicines available to help manage the symptoms and crises. In some situations, transfusions may be recommended for the complications – particularly pain. Bone marrow transplants are also offered to some patients.

So What’s New in Therapies??

BioMarin resubmits Hemophilia A gene therapy, Roctavian, to the FDA after approval in EU. The resubmission comes 2 years after the initial rejection that came with a request for longer-term data showing continuing benefits. BioMarin expects an FDA decision on submission acceptance in 4Q22. The current data shows that the therapy, which replaces a defective gene with a functional copy, restores Factor VIII levels to the limits defined as “Mild” hemophilia A and prevents breakthrough bleeds. Note: A patient in the trials did develop leukemia – but further studies indicate it may be naturally occurring and not due to the gene therapy. Gene Therapy Trials have long been scrutinized for cancer, with some of the first efforts appearing to cause cancers in some patients. An additional supporting piece of data is ICER’s updated HemeA Draft Report. This report suggests Roctavian is cost-effective and provides a slightly higher QALY benefit than HEMLIBRA. [About $4.2M lower total lifetime cost + slightly higher QALY benefit of 17.62 vs 17.49]. Note: HEMLIBRA from Genentech/Roche is a subcutaneously administered bi-specific factor IXa and factor X directed antibody for prophylaxis to prevent or reduce the frequency of bleeding in patients with Hemophilia A. It can be administered once a week, once every 2 weeks, or once every 4 weeks depending on patients’ needs. More details can be found from BioPharmaDive here, and the PharmaTell Studio here and here. Bluebird bio received approval for ZYNTEGLO (beti-cel), a one-time gene therapy custom designed to treat the underlying genetic cause of β-thalassemia in adult and pediatric patients who require regular red blood cell transfusions. This is the first gene therapy for this patient group and offers a potentially curative benefit through the achievement of durable transfusion independent and normal or near normal total hemoglobin levels. Bluebird bio estimates that there are between 1,300 and 1,500 patients in the US with transfusion-dependent β-thalassemia and the lifetime cost of treatment can reach $6.4M per patient. Pricing for the therapy is stated to be $2.8M upfront, with an agreement that there will be a rebate of 70%- 80% if the patient fails to achieve and maintain transfusion independence up to 2 years after infusion. Vantage reports that Zynteglo was approved in the EU in September 2021 and priced at $1.8M per patient. When none of the payers would agree to cover the therapy bluebird bio withdrew the product from that market. In the US, bluebird announced on October 4, 2022, that they have partnered with Real Endpoints to facilitate reimbursement and rebates.

Real Endpoints is a leading market-access platform and advisory firm and will provide multiple health plans with access to Zynteglo through the Real Endpoints Marketplace. The Real Endpoints Marketplace platform provides members of mid-sized and smaller health plans speedier access to innovative treatments such as rare disease drugs, cell and gene therapies, and digital medicines. From four founding member plans, Real Endpoints Marketplace now represents mid-sized and regional plans approaching nearly 16 million beneficiaries across all lines of business. Hopefully, the novel program bluebird now has in place in the US will help Zynteglo get to the patients looking for curative options for their disease. Vertex & CRISPR Therapeutics announced a rolling review for Exa-cel (CTX-001) for Sickle Cell Disease beginning in November 2022. They expect the submission to be complete at the end of March 2023. The EMA and MHRA submissions are still on track for 4Q22. This news puts them into a competitive race with bluebird bio’s Zynteglo for SCD. Some analysts postulate that exa-cel will have an advantage over Zynteglo due to their different CAS9 editing system. The Zynteglo lentivirus system had a partial clinical hold at one point causing some to be wary of the long-term effects of the therapy. For more thoughts from our partners on the approval timing and competitive landscape see articles on PharmaTell Studio here and here. We’ll be keeping our eyes on this sector and post updates. It is truly exciting to watch these trials and see the opportunities for long-term/curative therapies that will enable patients to live their best lives.

Tip of the Week Third Quarter reporting season is almost here. Just a reminder you can search in multiple ways:

  • In the keyword search type in “3Q22” or “quarterly results” and limit the timing from 15 September 2022 to present.

  • We will include transcripts of calls when we can and you can search for these by typing “transcript” into the keyword search function and limit the dates from 15 September to present.

If you haven’t activated your PharmaTell Studio account, or can’t access the links, or if you are interested in a free trial of PharmaTell, please send us an email to, and we will be happy to assist you.


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