The FDA has granted a fast track designation to LX1001 as a potential treatment for adult patients with apolipoprotein E4 (APOE4)-associated Alzheimer disease, according to a statement from LEXEO Therapeutics, the developer of the AAV-mediated gene therapy.

The fast track designation is meant to facilitate and expedite the development of treatments for serious conditions that fill an unmet need. With the Alzheimer designation, LEXEO will benefit from more frequent interaction with the FDA. Additionally, if clinical studies are successful, the company will be eligible for an accelerated approval, priority review, and the ability to submit a rolling biologic license application.

“The fast track designation granted by the FDA will expedite the development and review of LX1001 and we look forward to working closely with the Agency moving forward as we continue to advance this transformational gene therapy,” R. Nolan Townsend, chief executive officer of LEXEO Therapeutics, said in a statement. “While other treatments in development focus on the pathogenesis of Alzheimer’s disease, LX1001 is the first investigational gene therapy designed to correct the underlying genetics of the disease thereby addressing the most significant risk factor for developing Alzheimer’s disease.”

LX1001 is a single dose gene therapy that is administered as an intracisternal injection. The agent utilizes a serotype rh.10 AAV that expresses the cDNA for the 

 homozygotes in the central nervous system/cerebral spinal fluid (CSF). The goal of the gene transfer therapy is to convert 

A phase 1 study (NCT03634007) is currently exploring LX1001 for adult patients with 

 homozygote of Alzheimer disease. The primary goal of the study is currently focused on the safety of the gene therapy, with a secondary outcome of uncovering a maximum tolerated dose. The trial plans to enroll 15 participants with mild cognitive impairment.

The open-label trial will consist of 3 cohorts, each exploring a different dose of the gene therapy in the CSF. In the first cohort of the study, patients will receive LX1001 at 5.0 x 10^10 gene copies (gc)/mL CSF. In the second cohort, the treatment will be administered at 1.6 x 10^11 gc/mL CSF. The third cohort will examine LX1001 at 5.0 x 10^11 gc/mL CSF.

The company noted that recruitment was on schedule, with all 15 individuals expected to be enrolled by the end of the year. Initial clinical data from the trial are expected in the second half of 2021, according to LEXEO.

The startup gene therapy company LEXEO was launched in January 2021, following $85 million in series A funding. The initial drug pipeline includes 3 clinical stage therapies for monogenic diseases, with an additional 15 indications also under consideration. These medicines were primarily developed at Weill Cornell Medicine and the company was founded by Ronald G Crystal, MD, who is a professor and chairman of Weill Cornell’s Department of Genetic Medicine and Director of the Belfer Gene Therapy Core Facility. Crystal will act as the company's scientific advisor.

“I am excited to work with LEXEO Therapeutics to move our extensive academic portfolio into clinical development and ultimately bring it to patients,” said Crystal. “LEXEO’s AAV-mediated gene therapy programs have the potential for broad applicability across a range of therapeutic indications, and in a single company pipeline present an opportunity for the natural evolution of gene therapy from rare genetic conditions to more common diseases.”

In addition to LX1001, the company is also exploring LX2006, an IV-administered gene therapy, for cardiomyopathy associated with Friedreich ataxia. Additionally, LX1004, which is administered to the CNS, was explored in a phase 1/2 study for patients with CLN2 Batten disease. Findings from this study were published in December 2020 in 

 showing a slower loss of gray matter volume in 4 of 7 children treated with the gene therapy. Overall, LX1004 elicited a 42.4% decline of motor and language function compared to Weill Cornell natural history cohort (

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The FDA has granted a fast track designation to LX1001 as a potential treatment for adult patients with APOE4-associated Alzheimer disease.

FDA Grants LX1001 Fast Track Designation for Alzheimer Disease

Vertex Pharmaceuticals will take the lead on worldwide development, manufacturing, and commercializing of CTX001, which is a CRISPR/Cas9-based gene editing therapy in development as a potentially curative therapy for sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT).

The amended agreement was announced by Vertex and CRISPR Therapeutics. In the new terms of the agreement, CRISPR will received $900 million in upfront payments with the potential for $200 million, if CTX001 is approved by regulatory authorities. Additionally, if marketed, the companies plan to split revenue, with 60% to Vertex and 40% to CRISPR.

Based on preliminary findings for CTX001, the FDA has granted the gene editing therapy Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations for both TDT and SCD. In early findings from 7 patients with at least 3 months of follow-up, treatment with CTX001 resulted in increased fetal hemoglobin (HbF) production and total Hb overall, according to findings presented at the 2021 Transplantation & Cellular Therapy (TCT) Meetings Digital Experience.

“Our increased investment in our partnership with CRISPR is based on the compelling clinical profile of CTX001, which shows its potential to be a durable cure for patients with SCD and TDT, and the rapid progress that we and our partners at CRISPR have made toward registration and commercialization," Jeffrey Leiden, MD, PhD, executive chairman of Vertex, said in a statement. "We see a significant commercial opportunity for CTX001, and we believe we will be able to further enhance that opportunity by fully leveraging the breadth of Vertex’s capabilities – including our established and proven R&D and commercialization expertise in serious diseases – to bring CTX001 to more patients around the world, more quickly.”

CTX001 is a first-in-human, CRISPR-Cas9-modified autologous hematopoietic stem and progenitor cell (HSPC) therapy. For the therapy, CRISPR-Cas9 is used to edit the erythroid enhancer region of BCL11A in HSPCs, which is a key transcription factor associated with HbF suppression in red blood cells.

“Working with Vertex, we have made tremendous progress with CTX001, the first CRISPR/Cas9-based therapy to demonstrate proof of concept in the clinic and together we have broken new ground in the treatment of genetic diseases," Samarth Kulkarni, PhD, chief executive officer of CRISPR Therapeutics, said in a statement. "We have now dosed more than 30 patients with CTX001, with longest follow-up beyond two years, and we are on track to complete enrollment in both clinical trials this year."

In the presented TCT 2021 data, investigators shared efficacy and safety results from all consecutive patients infused with CTX0001 and with ≥3 months of follow-up. The 7 reported patients included 5 patients with TDT with follow-up through months 15, 6, 4, 4, and 3, plus a pair of patients with SCD with follow-up through months 12 and 3. Among patients with TDT treated with CDX001, mean neutrophil engraftment was on day 32 (range, 27-36), and median platelet engraftment was on day 37 (range, 34-52).

Among the 2 patients with SCD, neutrophil engraftment was experienced with CTX001 on day 30 and 22, and platelet engraftment was on day 30 and 33, respectively. All observed patients in the follow-up reported increased in Hb and HbF over time. Patients with TDT received their last transfusion within 2 months after CTX001 infusion, with the first patient remaining transfusion free over 15 months.

Both patients with SCD reported no vaso-occlusive crises since their CTX001 infusion. The first patient has remained free of such events for over 1 year. Investigators observed a safety profile with CTX001 consistent with busulfan myeloablation, which was given as a preconditioning regimen. One patient with TDT reported 4 serious adverse events potentially related to CTX0001, including headache, HLH, ARDS, and IPS. All serious events were clinically resolved or improving at the time of assessment, however.

“Given the transformative results and momentum that we have generated with this program, we are adopting a new operating model to enable a globally coordinated launch of CTX001, leveraging Vertex’s best-in-class global capabilities and leadership in development, manufacturing, and commercialization to enable this medicine to reach all patients that can benefit from it as quickly as possible," said Kulkarni. "We remain deeply committed to the Sickle Cell and Thalassemia patient communities and look forward to continued success in our partnership with Vertex.”

Vertex Pharmaceuticals will take the lead on worldwide development, manufacturing, and commercializing of CTX001, with payments and split economics to CRISPR Therapeutics.

CRISPR, Vertex Amend Collaboration for CTX001 in SCD, TDT

Betibeglogene autotemcel (beti-cel, Zynteglo), which is approved for transfusion-dependent β-thalassemia (TDT), is being withdrawn from the German market following a breakdown in reimbursement conversations. Following the decision, the company that manufactures the gene therapy, bluebird, noted that it planned to reduce and reshape its workforce as a result of less demand and to focus on other key markets.

The company noted that German discussion did not result in a price that reflected the benefits associated with the one-time gene therapy beti-cel, which enabled durable transfusion independence in most patients with TDT across 4 studies. The company continues to negotiate the price of the therapy across other countries in Europe and anticipates further updates in the second half of 2021.

"Through our continued engagement across Europe, we are optimistic that countries will reach pricing decisions that recognize the value of one-time gene therapies and provide the necessary access to the people who need them," said Andrew Obenshain, president, severe genetic diseases, bluebird bio. "In terms of operations, we have faced challenges over the last year that have resulted in the difficult decision to reduce our workforce and say goodbye to some valued bluebirds. We want to express our gratitude for their contributions and commitment to patients. As we move into the future, we look forward to bluebird bio advancing as a strong, thriving organization that is dedicated to developing treatments for rare genetic diseases."

Beti-cel adds functional copies of a modified form of the β-globin (βA-T87Q-globin) gene into a patient’s own hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells using a BB305 lentiviral vector. Following single-agent busulfan myeloablative conditioning, beti-cel is infused, after which the transduced HSCs engraft and reconstitute red blood cells containing functional adult hemoglobin derived from the gene therapy.

In the 4 studies, the median follow-up after beti-cel infusion has been 24.8 months (range, 1.1-71.8). Of 60 patients enrolled overall, 17 of 22 (77%) treated in the 2 phase 1/2 studies were able to stop packed red blood cell transfusions. In the 2 phase 3 studies, which used a refined manufacturing process resulting in improved beti-cel characteristics, 89% (n = 31/35) of patients with at least 6 months of follow-up achieved transfusion independence for more than 6 months, according to findings presented during the virtual 2021 Transplantation & Cellular Therapy Meetings.

Patients who achieved transfusion independence experienced a 38% median reduction in liver iron concentration (LIC) from baseline to month 48. The median reduction in LIC was 59% in patients with a baseline LIC more than 15 mg/g dw. A total of 21 of 37 (57%) patients who achieved transfusion independence have stopped iron chelation for 6 months or longer, with a median duration of 18.5 months from stopping iron chelation to last follow-up.

Persistent vector-positive hematopoietic cells and durable HbaT87Q levels supported stable total hemoglobin over time. In phase 3 trials, the median peripheral blood vector copy number was 1.2 c/dg at month 12 and 2.0 c/dg at month 24, and the median total hemoglobin was 11.5 g/dL at month 12 and 12.9 g/dL at month 24.

All patients were alive at the last follow-up (March 3, 2020). Eleven of 60 (18%) of patients experienced at least 1 adverse event (AE) considered related or possibly related to beti-cel, the most common being abdominal pain (8%) and thrombocytopenia (5%). Serious AEs were those expected after myeloablative conditioning: veno-occlusive liver disease (8%), neutropenia (5%), pyrexia (5%), thrombocytopenia (5%), and appendicitis, febrile neutropenia, major depression, and stomatitis (3% each).

Of the 7 patients experiencing veno-occlusive liver disease, 3 were of grade 4 and 2 were of grade 3. Two other patients had grade 2 veno-occlusive disease. There were no cases of insertional oncogenesis.

"We remain committed to our pioneering mission to deliver one-time gene therapies with life-long benefits to our patients," said Obenshain. "We are grateful for the clinical investigators and healthcare providers helping us better understand the recent safety events in our sickle cell disease studies. We are confident that working with the FDA and EMA, we will be able to determine a positive path forward as we seek to re-open our clinical studies."

Betibeglogene autotemcel is being withdrawn from the German market following a breakdown in reimbursement conversations, which has resulted in bluebird reducing and reshaping its European workforce.

Beti-Cel Withdrawn From Germany, bluebird Reduces Workforce

A recent report from Avalere outlines patient access challenges to accessing chimeric antigen receptor (CAR) T-cell therapies due to geographic distance and a complete understanding of what their insurance benefits will cover.

Disparities in health care could worsen these access issues, the report said.

“The growing cell therapy market highlights an imminent need to address patient access barriers unique to these therapies, including the limited number of treatment sites, high drug and non-drug costs, complex logistics associated with travel, post-treatment monitoring, and long-term-care follow-up,” the report said.

Manufacturers seeking FDA approval for additional CAR T-cell therapies will need to examine these financial and logistical burdens and consider how to revamp patient support service offerings to address these challenges, the report said.

Five cellular therapies are approved; another 54 are in late-stage development worldwide.

To get a better understanding of the geographic challenges to access cell therapies, Avalere used the 100% sample of Medicare fee-for-service (FFS) claims between 2017 and 2019; the final population included in the analysis was less than 20% of the total Medicare FFS population.

In the Southern and Western parts of the country, patients had to travel significantly longer distances, compared with the densely populated Middle Atlantic and Northeast.

Given that some patients may need to travel across state lines to access treatment sites—CAR T is only given in approved cancer centers—patients may not have a clear understanding of their insurance benefits, including parameters for out-of-state or out-of-network treatment and any possible additional costs, including drug cost sharing.

Transportation and lodging costs could also be a burden for some patients, especially in parts of the country where median income is low.

The report recommended 5 ways that payers and manufacturers could increase access for these patients during their treatment:

Improving patient support program services to include the cost of the procedure, patient travel, non-drug expenses, long-term follow-up, and care coordination

Assistance with compliance challenges with regards to free or reduced-price drugs in the inpatient bundled payment system

Patient reported outcomes tracking longitudinal patient engagement

Given that some patients may need to travel out of state to access CAR T sites of care, some may not have a clear understanding of their insurance benefits, including requirements for out-of-state or out-of-network treatment, as well as adequate assistance with the costs of medical-related travel.

Avalere Report Looks at Geographic Challenges to Accessing CAR T-Cell Therapies

 (AMCP) 2021 meeting, 2 researchers from Prime Therapeutics reviewed new specialty therapies that may reach the market this year, including biologics and cell and gene therapies.

Catherine Starner, PharmD, BCPS, senior principal health outcomes researcher, and Nicole Kjesbo, PharmD, BCPS, clinical program development director-pipeline, said the drugs in their forecast (except for the cell and gene therapies) have been submitted to the FDA and are expected to have a high impact based on per member per month (PMPM), given their internal claims data, which draw from commercial lines, Medicare, and Medicaid, depending on the proposed indication.

In cell and gene therapies, Prime starts observing the drugs before they are submitted to the FDA. For their presentation, they reviewed 3 candidates they thought had the highest likelihood of being submitted:

Eladocagene exuparvovec, for aromatic l-amino acid decarboxylase (AADC) deficiency

Micro-dystrophin, or SRP-9001, for Duchenne muscular dystrophy (DMD)

Etranacogene dezaparvovec, or AMT-061, for severe and moderately severe hemophilia 

. This drug, from PTC Therapeutics, provides a working copy of the 

 gene. AADC deficiency is extremely rare, affecting about 100 patients in the United States; one report said the 1-time infusion, surgically injected via MRI, will cost $4 million. Infants born with AADC deficiency fail to develop and have shortened life expectancy.

. This candidate is 1 of 60 in the DMD pipeline and 1 of 2 from Sarepta Therapeutics. The gene transfer therapy is given by a single intravenous infusion. DMD affects between 500 to 5000 males worldwide. Other companies in the space include Pfizer, Solid Biosciences, and Astellas.

. Severe and moderately severe hemophilia B affects 4000 males in the United States. There are 66 candidates for this indication in the pipeline; this one is from uniQure. Current treatment options are limited to factor IX products. Genentech has a similar therapy in development (fidanacogene elaparvovec).

Three cell and gene therapies were among the drugs included in a specialty drugs pipeline forecast at the Academy of Managed Care Pharmacy 2021 meeting.

For 2021, Cell, Gene Therapies Make Prime's “Drugs to Watch” List

How do you anticipate gene therapies changing the face of treatments, especially in the oncology space?

Yeah, that's a great question and one that we're starting to see play out right now as some of the earlier cell and gene therapies have entered the market. 

Certainly, in the oncology space and more broadly, these are therapies that are 1-time administered and have a potentially more durable benefit over a longer period of time relative to more chronic therapies that are available today. In many cases, they are a treatment option for patients that have more limited options today, like maybe in the oncology space, where they have tried other treatment options that have failed. This is that next option that is available. 

I think it's also important to acknowledge that as we think about some of the gene therapies, these are for some rare pediatric conditions in many cases where there are no or very limited treatment options available today. So, this is an entry of a really new treatment, which is exciting.

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Megan Olsen, MPH, principal at Avalere, discussed how gene and cell therapies can offer new treatment options for patients with cancer.