With the worst darkness of COVID-19 behind us, the world now has the opportunity to identify and explore the pandemic’s silver linings.
The calls to apply lessons learned from Operation Warp Speed to accelerate pharmacologic treatments in other disease areas are a great example. Last September, the U.S. FDA officially launched the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program. The pilot quickly picked up the nickname ‘Operation Warp Speed for Rare Diseases.’
The FDA’s rigid adherence to process has made it the gold standard of regulatory agencies. But at the same time, the agency has recognized that the flexibility it demonstrated during the pandemic facilitated rapid approval of much-needed vaccines and therapeutics.
In the same way that vaccine makers were in constant contact with the agency during the pandemic, the rare disease pilot program will allow for more frequent communication with FDA staff to provide a mechanism for addressing clinical development issues. According to the FDA, participants will be able to “obtain frequent advice and regular ad-hoc communication with FDA staff to address product-specific development issues, including, but not limited to, clinical study design, choice of control group and fine-tuning the choice of patient population.”
The FDA accepted applications to the START program between January 2, 2024 and March 1, 2024, through both its Center for Biologics Evaluation and Research (CBER) and its Center for Drug Evaluation and Research (CDER). Participants were notified of acceptance into the joint program on May 29, 2024. The agency recently confirmed with media sources that CBER has selected four participants and CDER has selected three.
So far, six companies have announced that their programs have been chosen:
Myrtelle (CBER program)
rAAV-Olig001-ASPA gene therapy
Canavan disease
New York-based Myrtelle’s oligodendrocyte-targeting rAAV vector-based gene therapy is intended to restore aspartoacylase (ASPA) function and brain development in patients with Canavan disease.
Myrtelle has an exclusive worldwide licensing agreement with Pfizer for the program. Myrtelle’s FIH trial utilizes the company’s proprietary rAAV vector to directly target oligodendrocytes, the brain cells affected in CD that are responsible for producing myelin — the insulating material that enables proper neuronal function.
Canavan disease is a fatal childhood genetic brain disease caused by mutations in the ASPA gene which prevent the normal expression of aspartoacylase, a critical enzyme produced in oligodendrocytes. Symptoms begin when patients are just a few months old and include poor head control, abnormally large head size, difficulty in eye tracking, excessive irritability, diminished muscle tone, and delays in reaching motor milestones. As the disease progresses, seizures, spasticity, difficulties in swallowing, and overall muscle deterioration emerge with most affected children developing life-threatening complications by approximately 10 years of age, according to Myrtelle.
Neurogene (CBER program)
NGN-401 gene therapy
Rett syndrome
New York-based Neurogene’s NGN-401 is an investigational AAV9 gene therapy being developed as a one-time treatment for Rett syndrome. It’s the first clinical candidate to deliver the full-length human MECP2 gene under the control of Neurogene’s EXACT technology.
Two dose levels of NGN-401 are being evaluated in a Phase 1/2 clinical trial. Company remains on track to report interim efficacy data from the trial in the fourth quarter of 2024.
Rett syndrome is a genetic disorder caused by mutations in the MECP2 gene that lead to deficiency of the methyl cytosine binding protein 2, an important protein responsible for normal function in the brain and other parts of the nervous system. It occurs almost exclusively in females, and impairs patients’ ability to speak, walk, eat and breathe, with most patients requiring 24-hour care for daily living.
Larimar Therapeutics (CDER program)
nomlabofusp
Friedreich's ataxia
Pennsylvania-based Larimar Therapeutics' nomlabofusp is a novel protein replacement therapy designed to address the root cause of Friedreich’s ataxia by delivering frataxin to mitochondria. The therapy is currently being evaluated in an open-label extension study, and Larimar is aiming to submit its BLA the second half of next year.
Friedreich's ataxia is a genetic condition caused by mutations in the FXN gene that encodes the protein frataxin. The condition, which tends to develop in children and teens, damages the spinal cord, peripheral nerves and the cerebellum portion of the brain.
Denali Therapeutics (CDER program)
DNL126 enzyme replacement therapy
MPS IIIA (Sanfilippo syndrome type A)
California-based Denali Therapeutics’ DNL126 is an investigational enzyme replacement therapy designed to cross the blood-brain barrier for the potential treatment of MPS IIIA (Sanfilippo syndrome type A). Denali is currently conducting a phase 1/2 study of DNL126 for children with MPS IIIA.
MPS III, also called Sanfilippo syndrome, is a genetic lysosomal storage disease that causes neurodegeneration. There are four main types of MPS III, depending on the enzyme affected. Type A, the most severe form, is caused by genetic defects that result in reduction in the activity of N-sulfoglucosamine sulfohydrolase (SGSH), an enzyme responsible for degrading heparan sulfate in the lysosome. It is characterized by severe hearing loss and speech delay, followed by a rapid decline in cognitive skill at a young age.
Moderna (CBER program)
mRNA-3705 therapeutic
Methylmalonic acidemia
Massachusetts-based Moderna’s mRNA-3705 is designed to instruct the body to restore the missing or dysfunctional proteins that cause Methylmalonic acidemia (MMA). The therapy consists of mRNA encoding human MUT, the mitochondrial enzyme commonly deficient in MMA, encapsulated within Moderna's proprietary lipid nanoparticle.
mRNA-3705 is being investigated in the phase 1/2 Landmark study to evaluate the safety and tolerability of the investigational therapeutic administered via intravenous infusion in patients with isolated MMA due to methylmalonyl-CoA mutase (hMUT) deficiency.
MMA is a life-threatening, inherited metabolic disorder that is most commonly (approximately 60% of cases) caused by a deficiency in the mitochondrial enzyme MUT. This deficiency can lead to metabolic crises due to a toxic buildup of acids in the body, progressing into multi-organ disease. The toxic buildup can cause seizures, strokes, growth problems, developmental delays and frequent episodes of severe illness.
Grace Science
GS-100 gene therapy
NGLY1 deficiency
California-based Grace Science’s GS-100 is an AAV9 single-stranded viral vector that encodes the full length human NGLY1 protein. Grace has successfully dosed two NGLY1 deficiency patients with GS-100, with a dose escalation planned for the third patient later this summer.
NGLY1 deficiency is caused by an inherited mutation in the NGLY1 gene. Patients suffer from debilitating symptoms that present early in life, including global developmental delay, cognitive impairment, movement disorders and other neurological symptoms, according to Grace. Approximately 50% of patients have seizures.
