Making a good thing better

Thomas Edison

Legend has it that Thomas Edison “failed” 1,000 times before he managed to create the incandescent lightbulb. Edison says he didn’t get discouraged, instead he looked at each unsuccessful experiment as being one step closer to finding the method that really worked. That’s a lesson in optimism and persistence for all of us.

Lineage Cell Therapeutics has that same spirit. Lineage is trying to develop a stem cell therapy to help people with spinal cord injuries. CIRM invested $14.3 million in the first version of this approach which produced encouraging results. But encouraging is not enough. So, Lineage set about doing a complete overhaul of the therapy known as OPC1.

The idea behind it is to turn embryonic stem cells into oligodendrocyte progenitor cells (OPCs). These OPCs are precursors to cells that play an important role in supporting and protecting nerve cells in the central nervous system, the area damaged in a spinal cord injury. By transplanting these cells at the injury site it’s hoped they will help restore some of the broken connections, allowing patients to regain some movement and feeling.

In the original trial many patients, who had been paralyzed from the chest down, regained some use of their arms, hands and even fingers. This was better than any previous therapy had managed. But for Lineage it wasn’t good enough. So, they set about redesigning their whole manufacturing process, making improvements at every step along the way.

In a news release they outlined those improvements:

  • A new ready-to-inject formulation of OPC1, which enables clinical use at a much larger number of spinal cord treatment centers, accelerating enrollment for a larger and potentially registrational clinical trial.
  • Elimination of dose preparation, reducing overall preparation time from 24 hours to 30 minutes and cutting logistics costs by approximately 90%.
  • A 10 to 20-fold increase in OPC1 production scale, sufficient to support late-stage clinical development and which can be further scaled to meet initial commercial use.
  • A 50-75% reduction in product impurities.
  • Improvements in OPC1 functional activity, as assessed by cellular migration and secretion of key growth factors.

They also came up with new quality control tests to make sure everything was working well and eliminated all animal-based production reagents.

Brian Culley, Lineage CEO was, understandably, enthusiastic about the changes and its prospects for helping people with spinal cord injuries:

“Manufacturing is the foundation of cell therapy and the significant enhancements we have achieved with OPC1 marks the second time we have successfully transformed a research-grade production process into one capable of supporting a successful commercial product. Our objective is to be the premier allogeneic cell therapy company and our dedication to manufacturing excellence allows us not only to reduce or eliminate certain regulatory and commercial hurdles, but also establish strong competitive barriers in our field.”

Lineage are now hoping to go back to the Food and Drug Administration (FDA) in the near future and get permission to run another clinical trial.

Here are stories of the impact the first generation of this approach have already had on people.

CIRM-funded kidney transplant procedure eyeing faster approval

Kidney transplant surgery.

Medeor Therapeutics, which is running a CIRM-funded clinical trial to help people getting kidney transplants, just got some really good news. The US Food and Drug Administration (FDA) has just granted their product Regenerative Medicine Advanced Therapy (RMAT) designation. That’s a big deal because it means they may be able to apply for faster review and approval and get their therapy to more patients faster.

Here’s why that RMAT designation matters.

Over 650,000 Americans suffer from end-stage kidney disease – a life-threatening condition caused by the loss of kidney function. The best available treatment for these patients is a kidney transplant from a genetically matched living donor. However, patients who receive a transplant must take life-long immunosuppressive drugs to prevent their immune system from rejecting the transplanted organ. Over time, these drugs are toxic and can increase a patient’s risk of infection, heart disease, cancer and diabetes.  Despite these drugs, many patients still lose transplanted organs due to rejection.

To tackle this problem Medeor is developing a stem cell-based therapy called MDR-101. This is being tested in a Phase 3 clinical trial and it’s hoped it will eliminate the need for immunosuppressive drugs in genetically matched kidney transplant patients.

The company takes blood-forming stem cells and immune cells from the organ donor and infuses them into the patient receiving the donor’s kidney. Introducing the donor’s immune cells into the patient creates a condition called “mixed chimerism” where immune cells from the patient and the donor are able to co-exist. In this way, the patient’s immune system is able to adapt to and tolerate the donor’s kidney, potentially eliminating the need for the immunosuppressive drugs that are normally necessary to prevent transplant rejection.

So how does getting RMAT designation help that? Well, the FDA created the RMAT program to help speed up the development and review of regenerative medicine therapies that can treat, modify, reverse, or cure a serious condition. If MDR-101shows it is both safe and effective RMAT could help it get faster approval for wider use.

In a news release Giovanni Ferrara, President and CEO of Medeor, welcomed the news.

“This important designation underscores the tremendous unmet medical need for alternatives to today’s immunosuppressive therapies for transplantation. We have the potential to help people live longer, healthier lives without the need for high dose and chronic immunosuppression and we thank the FDA for this designation that will assist us progressing as efficiently as possible toward a commercially available product.”

This is the seventh CIRM-supported project that has been granted RMAT designation. The others are jCyte, Lineage, Humacyte, St. Jude’s/UCSF X-linked SCID, Poseida, Capricor

Good news for two CIRM-supported therapies

Jake Javier, a patient in the spinal cord injury stem cell therapy clinical trial

It’s always satisfying to see two projects you have supported for a long time do well. That’s particularly true when the projects in question are targeting conditions that have no other effective therapies.

This week we learned that a clinical trial we funded to help people with spinal cord injuries continues to show benefits. This trial holds a special place in our hearts because it is an extension of the first clinical trial we ever funded. Initially it was with Geron, and was later taken up by Asterias Biotherapeutics, which has seen been bought by Lineage Cell Therapeutics Inc.

The therapy involved transplanting oligodendrocyte progenitor cells (OPCs), which are derived from human embryonic stem cells, into people who suffered recent spinal cord injuries that left them paralyzed from the neck down.  OPCs play an important role in supporting and protecting nerve cells in the central nervous system, the area damaged in a spinal cord injury. It’s hoped the cells will help restore some of the connections at the injury site, allowing patients to regain some movement and feeling.

In a news release, Lineage said that its OPC therapy continues to report positive results, “where the overall safety profile of OPC1 has remained excellent with robust motor recovery in upper extremities maintained through Year 2 patient follow-ups available to date.”

Two years in the patients are all continuing to do well, and no serious unexpected side effects have been seen. They also reported:

– Motor level improvements

  1. Five of six Cohort 2 patients achieved at least two motor levels of improvement over baseline on at least one side as of their 24-month follow-up visit.
  2. In addition, one Cohort 2 patient achieved three motor levels of improvement on one side over baseline as of the patient’s 24-month follow-up visit; improvement has been maintained through the patient’s 36-month follow-up visit.

Brian M. Culley, CEO of Lineage Cell Therapeutics called the news “exciting”, saying “To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence.”

Evie, cured of SCID by a therapy licensed to Orchard Therapeutics

The other good news came from Orchard Therapeutics, a company we have partnered with on a therapy for Severe Combined Immunodeficiency (SCID) also known as “bubble baby diseases” (we have blogged about this a lot including here).

In a news release Orchard announced that the European Medicines Agency (EMA) has granted an accelerated assessment for their gene therapy for metachromatic leukodystrophy (MLD). This is a rare and often fatal condition that results in the build-up of sulfatides in the brain, liver, kidneys and other organs. Over time this makes it harder and harder for the person to walk, talk, swallow or eat.

Anne Dupraz-Poiseau, chief regulatory officer of Orchard Therapeutics, says this is testimony to the encouraging early results of this therapy. “We look forward to working with the EMA to ensure this potentially transformative new treatment, if approved, reaches patients in the EU as quickly as possible, and continuing our efforts to expand patient access outside the EU.”

The accelerated assessment potentially provides a reduced review timeline from 210 to 150 days, meaning it could be available to a wider group of patients sooner.