Products

Genetix has two products in  clinical Phase 2 trials in France: Lenti-D™ for Cerebral adrenoleukodystrophy (ALD) and LentiGlobin™ for thalassemia and sickle cell disease. Both products use lentiviral vectors to transduce bone marrow stem cells with therapeutic genes reliably and safely in the bone marrow. Lenti-D treats ALD by replacing a transporter protein that ensures a proper lipid balance in the membranes of cells of the central nervous system. LentiGlobin treats thalassemia and sickle cell disease by augmenting the patients’ defective hemoglobin with normal hemoglobin. In both cases, the patients’ own cells are transduced with the corrective gene before being reimplanted in the context of an autologous (self-derived) bone marrow transplant procedure.

 

Genetix’s therapies thus add a single step to established bone marrow transplantation schemes and enable autologous transplantation for the 70% of patients who have no matched allogeneic donor. Likeallogeneic bone marrow transplantation, these therapies are expected to provide a long-lasting lifelong benefit. Furthermore, because they involve the transplantation of autologous (self-derived) cells, they eliminate the risks of graft-versus-host disease (GVHD) (which causes 15% mortality in allogeneic transplant with matched unrelated donors) and patients have no need for lifelong immunosuppression to prevent rejection, these therapies are likely to be compelling  alternatives to  allogeneic donor bone marrow transplantation even when a donor is available.

Genetix’s gene therapy approach has the following advantages over allogeneic bone marrow transplantation:

  • Applicable to all patients and no limitation to have a matched donor;
  • No risk of death from graft-versus-host disease by using patients’ own cells;
  • More rapid engraftment/reconstitution of marrow and immune function post transplant due to perfect match between patients’ stem cells and marrow mileu.

Lenti-D

LentiD has the potential halt the progression of adrenoleukodystrophy (ALD) by providing a functional transporter gene which allows the normal processing of lipids in the monocytes and microglial cells thus preventing development of the disease.

 

To date, the two patients treated with Lenti-D have demonstrated disease stabilization or regression in both brain imaging studies and cognitive and neurological clinical findings. These results are comparable to those observed with allogeneic bone marrow transplantation and are in stark contrast to age and stage matched patients who are not treated.  This data has been covered in the prominent scientific journalNature and has been presented at scientific meetings.  A scientific paper describing the clinical results was recently published in Science.

 

Adrenoleukodystrophy (ALD)

Genetix’ lead product is Lenti-D for adrenoleukodystrophy (ALD), also known as “Lorenzo’s Oil disease.” ALD is a hereditary disease with devastating effects on the central nervous system due to lipid buildup that leads to damage of the white matter in the brain and the myelin sheath around nerve fibers. The disease afflicts 1/17,000 males with onset of severe cognitive and neurologic deficits between the ages of 5 and 12, or in adulthood.  Without allogeneic bone marrow transplantation, ALD always progresses to severe cognitive and neurological impairment with an average life expectancy of 10 years post-diagnosis. 

ALD is currently treated with allogeneic bone marrow transplantation when there is an appropriate donor.  Even so, the graft sometimes does not take and there is Graft Versus Host Disease leading to death in 15% of children and at least 30% of adults post transplant.  For those patients who survive the transplant procedure, the disease is stabilized and no longer progresses.  In 50% of the patients who survive, Graft Versus Host Disease or delayed hematological reconstitution delay the time at which disease is stabilized, allowing the disease to have progressed further before stabilization. Thus, an autologous alternative to allogeneic bone marrow transplantation would be a welcome treatment modality that has the potential to be standard of care.

 

LentiGlobin

LentiGlobin™ introduces a fully-functional human hemoglobin gene under the control of the hemoglobin-promoter into the patient's own hematopoietic stem cells in the bone marrow. By adding a single transduction step to the routine practice of bone-marrow transplantation, LentiGlobin™ thus may extend the benefit of bone-marrow transplantation to the other 80% of patients who do not have matched donors. Additionally, because it avoids the mortality associated with Graft versus host disease, it is likely to favorably influence the management of thalassemia and sickle cell disease with a one time cure via autologous bone marrow transplantation rather than chronic management of the disease with transfusion/chelation in the case of thalassemia and pain management in the case of sickle cell disease.

 

Thalassemia and Sickle Cell Disease

Genetix is conducting Phase 2 trials with its LentiGlobin™ product in Thalassemia/Sickle Cell Disease, the two most prevalent human genetic disorders. Thalassemia major and sickle cell disease are caused by inheritance of defects involving the molecular structure or the production of hemoglobin, the protein in red blood cells that carries oxygen from the lungs to the tissues of the body.

 

In Thalassemia major, the genetic defect causes reduced production of normal hemoglobin and insufficient red blood cells to sustain normal metabolism. Disease symptoms mostly due to iron build up in the organs usually begin in early childhood and tend to worsen with increasing age, often resulting in organ failure and premature death. Patients typically require repeated red blood cell transfusions to lessen effects of their disease, which over time contribute to further adverse side effects. Lack of beta-globin causes fatal anemia. Patients must also take either iv or oral chelators to remove the iron from the blood once a day.  Sickle cell disease (SCD) is characterized by clotting of improperly shaped red blood cells, which leads to significant pain which leads to hospitalization and pain management by morphine drip.  Often sickle cell disease leads to very serious health problems (e.g., stroke). SCD has a longer life expectancy than thalassemia, averaging in the fifties for patients not treated by bone marrow transplant.

 

In clinical trials, LentiGlobin has shown to potentially free thalassemia patients  from burdensome transfusion and chelation therapy. LentiGlobin provides patients with “endogenous” normal hemoglobin, which provides greater oxygen carrying capacity and increseases the half life of red blood cells by soaking up toxic free a chains.  Lentiglobin stem cell  therapy should substantially increase life expectancy following a single autologous transplant procedure.

 

Thalassemia and Sickle Cell Disease are the most prevalent inherited diseases in the world with aPrevalence is about 3M patients with350,000 born every year.   Even so, it has significant orphan drug potential in EU, US. 


Thalassemia

    • Western Europe, 25,000 patients; Italy alone has 7,000 patient1
    • 2500+ patients in Greece
    • Estimated 10,000’s in United Arab Emirates and other Middle Eastern countries (e.g. 30.4% of Qataris carry some form of thalassemia2 ; 21,000 in Iran4)
    • Estimated 450,000+ in China/India/Southeast Asia with
      100,000 born in China every year alone and 50,000 in Thailand 3,4

 

Sickle cell disease

    • 91,000 patients in the United States5
    • 75,000 patients in Europe (EU)
  1.  Tyler Medical Clinica
  2. Fawzi ZO et al. 2003
  3. Weatherall WHO 2001
  4. TIF
  5. “Orphan Products: Hope for People with Rare Diseases",

By Carol Rados, FDA Consumer magazine, November-December 2003 Issue