Gene Therapy for Sickle Cell Disease

Background

Sickle cell disease (SCD) is a genetic blood disorder that results in the formation of sickled red blood cells (RBC). Sickled RBC obstruct blood vessels, causing vaso-occlusive crisis/events (VOC/VOE) - acute pain in the lower back or limbs, acute chest syndrome and stroke are frequent complications. SCD is one of the most common inherited blood disorders, resulting in > $1.1 billion in healthcare expenditure/yr in the U.S. alone. There are ~110,000 affected patients in the USA and a similar number in Europe. There are 15-20 million patients worldwide with SCD.

Currently, the only established cure is through a bone marrow transplant (BMT) from a matched donor, which is not commonly performed due to the risks involved and the difficulty of finding a matched donor. BMT is currently only approved for use in children. BMT for adults is being tried in clinical trials, using nonmyeloablative approaches to reduce mortality and partially matched donors (haplo-identical) to expand the donor pool.

Market Overview:

• During the 2020 base year, there are four approved drugs on the market, with a total market size of $277.7M across the US, with Oxbryta (voxelotor) having the largest market share of 45% ($123.8M).
• There is the impending launch of Bluebird Bio’s first-in-class gene therapy, bb1111, in 2024, which will likely occupy a 26% share of the entire SCD market by 2030 across the US.
• CHMC’s SCD technology is predicted to capture a broader patient population, potentially with a lower price tag. Therefore, it is anticipated that the sales volume may be higher than Bluebird’s therapy.
• Pfizer announced the acquisition of Global Blood Therapeutics (Oxbryta) for $5.4B in August, and Novo Nordisk acquired Forma Therapeutics for $1.1B in September 2022.
• There are several new therapies entering the SCD market, including inclacumab ($359M by 2030) and novel PDE9 inhibitor, tovinontrine, forecast to obtain an 11% market share in 2030 ($515M), potentially offering improved efficacy and significantly improved long-term outcomes for patients.
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Technology Overview

CHMC’s SCD technology is a gene therapy using lentivirus vector (LV) as the vehicle to deliver a modified gammaglobin gene to genetically correct SCD.

Value propositions of this technology include:

• Significantly reduce the conditioning (chemo) before treatment and lead to a shorter recovery time compared to the standard. This is a unique selling point because:
  • Less chemo exposure reduced the chance of chemo-induced secondary malignancy
  • Leads to a lower price tag than existing gene therapy/editing approaches
• Vector efficacy has been proven in Phase1/2 clinical trials.
• The targeted fetal hemoglobin (HbF) has a unique and potent antisickling effect with a lower threshold of LV copy number for complete correction ().

With only four therapies approved, there is an urgent need for more novel therapies to enter the market. The currently marketed therapies treat the symptoms and complications of SCD and are not curative. Therefore, there is a significant need for innovative therapies targeting the underlying cause of the disease that may offer a cure for patients with SCD.

With BlueBird’s gene therapy approved by the FDA to treat beta-thalassemia in 2022, it sets the path for upcoming gene therapy programs to enter the market. With its extremely high price point per treatment, the market is still lacking a curative and affordable treatment option for patients where CHMC’s SCD technology may be the solution.

Benefits

Benefits Proven Through Pre-clinical and Clinical Validations:

• More HbF per vector copy.
• Higher potency HbF showed in the Phase 1/2 clinical trial.
• Reduced Intensity Conditioning ‑ the only trial in hemoglobinopathies that uses RIC.
• Preserved stemness during manufacturing.
• Optimized Melphalan exposure.
• Improved homing and engraftment of genetically modified HSC.