In 2022 and beyond, rare disease researchers are advancing their understanding of the technology used in the discovery and development of gene therapies. In particular, the industry is experiencing rapid growth in the development of gene therapies targeting rare diseases and many are exploring further capabilities of the technology.
To learn more about how the space is evolving, PharmaVoice spoke with several biotech innovators to discuss where the science and technology is headed for rare diseases, and to learn about the latest developments in their companies.
For Ovid Therapeutics, corporate partnerships and research collaborations are key to advancing its understanding of biological pathways and their central role in rare neurological diseases. The New York-based company uses a proprietary approach — called BoldMedicine — to develop its medicines for rare neurological disorders. In the past, it has partnered with Lundbeck, and several academic research labs at Northwestern, University of Connecticut and Columbia University.
In partnership with Chung Lab at Columbia University, Ovid is running a genetic medicine program for KIF1A, an ultra-rare condition characterized by genetic defects in a motor protein called kinesin.
“Because the mutations for KIF1A are heterogeneous, Ovid is seeking a cassette-style approach to therapeutics with the hope of solving for several disease-causing genetic KIF1A variants,” says Jeremy Levin, chairman and CEO of Ovid Therapeutics.
Ovid is also targeting a 2022 Investigational New Drug (IND) submission for OV329, a next-generation GABA aminotransferase inhibitor that is being evaluated in tuberous sclerosis and infantile spasm seizures. OV329 is a small molecule, next generation pregabalin that may demonstrate a preferable safety and tolerability profile relative to therapies currently on the market.
One of Ovid’s partnerships recently turned into an acquisition when Takeda Pharmaceutical Company decided to buy Soticlestat for the treatment of developmental and epileptic encephalopathies, including Dravet syndrome and Lennox-Gastaut syndrome. Soticlestat, which was originally developed in a collaboration between the two companies, is a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), with the potential to reduce seizure susceptibility and improve seizure control. Takeda is now solely responsible for further development and worldwide commercialization of Soticlestat.
Without such partnerships and collaborations, many rare disease therapies would not be brought effectively to market.
That is why many government agencies, patient advocacy groups and individual patients are partnering with rare disease companies to help accelerate the promise of rare disease therapies. For example, a partnership between the U.S. Food and Drug Administration (FDA), the National Institutes of Health, 10 pharmaceutical companies and five nonprofit organizations was formed in late 2021 to accelerate gene therapies.
The Bespoke Gene Therapy Consortium hopes to address the challenges in the development process to bring innovative and life-saving therapies to the 30 million Americans living with rare diseases.
Developments in the future
According to Levin, the industry can expect to see advances in genetic medicines and delivery technologies for diseases of the brain beyond traditional adeno-associated virus (AAV) gene therapies. (See our Q&A with Levin for a deep dive into the ups and downs of rare disease research in 2022.)
The use of molecular engineering and the decoration of capsids with proteins, antibodies and other tools will enable scientists to cross the blood brain barrier carrying genetic payloads.
“These delivery technologies are a Trojan horse that tricks the brain into accepting the therapy and its genetic cargo hidden inside,” he says.
Indications that the FDA is willing to be flexible when accepting biomarkers for endpoints is likely to encourage developers to submit therapies with packages that rely on biomarker endpoints, Levin says.
Giacomo Chiesi, head of Chiesi Global Rare Diseases, says he expects to see significant proof-of-concept trial data readouts in 2022 for new gene therapy platforms in rare hematology and metabolic disorders. He also predicts that artificial intelligence will be used to a greater extent to help companies identify more rare disease patients, reducing the time to diagnosis.
Kent Pryor, CEO of ZZ Biotech, says technology advances will make it simpler to focus on specific genetic forms of disease.
“This creates rare diseases out of diseases that have a larger population, so if you have a genetic form of the disease, there is potential to develop a targeted drug,” he says. “However, the downside is it leaves many patients untreated, and that’s where there is a big role for drugs like 3K3A-APC, which we’re developing at ZZ Biotech for various indications.”
One area where he sees breakthroughs in 2022 is with antisense oligonucleotides to target messenger RNA.
“There hasn’t been a lot of success with antisense in the past but now the technology is there, and some big companies are really putting a lot of money behind that research, so it’s an area to watch,” he says.
Under the microscope
Innovation at Ovid is focused on several rare and ultra-rare neurological diseases. The OV815 genetic medicine program for KIF1A, an ultra-rare condition characterized by genetic defects in a type of motor protein called kinesins, is being conducted in partnership with Chung Lab at Columbia University.
Ovid is also targeting a 2022 IND submission for OV329, a next-generation GABA aminotransferase inhibitor that is being evaluated in tuberous sclerosis and infantile spasm seizures. OV329 is a small molecule, next generation pregabalin that may demonstrate a preferable safety and tolerability profile relative to therapies currently on the market.
Chiesi Global Rare Diseases, meanwhile, is focused on a recombinant enzyme therapy, PRX-102 (pegunigalsidase alfa), to treat Fabry disease in partnership with Protalix. The company is also working with the FDA on registering another recombinant enzyme therapy, Lamzede (velmanase alfa), for the treatment of alpha-mannosidosis. The company expects to file a marketing authorization application for PRX-102 to the European Medicines Agency in the first quarter of 2022 and a Biologics License Application for PRX-102 with the FDA in the second quarter of 2022.
“Lamzede is already approved by the EMA and in several other countries around the world, and is the first approved treatment with disease modifying potential for alpha-mannosidosis,” Chiesi says.
In a third program, Chiesi is partnering with Bioasis to advance its proprietary xB3 technology platform, which may deliver therapeutics across the blood brain barrier, for the potential treatment of rare diseases, including lysosomal storage disorders.
ZZ Biotech’s novel therapy 3K3A-APC is being investigated for patients with Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease (MND), by Dominic Rowe, a professor of neurology at Macquarie University in Sydney, Australia. The Macquarie University Centre for Motor Neuron Disease Research is the largest research center in Australia focused on finding the causes of MND and developing therapies for it.
The therapy is a three amino acid variant of a naturally occurring human protein called activated protein C (APC), which has an unwanted side effect of bleeding, limiting its pharmacologic dosing in humans. However, 3K3A-APC knocks out the anticoagulant activity that gives rise to potential bleeding risks while preserving the cell-protective and anti-inflammatory activities of APC. The compound has undergone more extensive testing in ischemic stroke, allowing ZZ Biotech to understand potential adverse events before the ALS study starts.
“The clinical trial started at the end of November 2021 with six patients recruited and plans to recruit a further 10,” Pryor says. “We have had some good animal data in ALS and professor Rowe is very excited about the scientific mechanism of action and its applicability to ALS.”
Perhaps the most poignant aspect of the ALS study is how it has been funded. Each year, the fire department in Sydney raise money for ALS by climbing 1,504 steps of Sydney Tower Eye while wearing 45 pounds of gear. The fundraising challenge is done in memory of one of their own who developed and has since died from ALS.
"The funds raised fit perfectly with the timing for our research into ALS, so we’re very grateful to the 'firies' for making this possible,” Pryor says.
(Look out for our one-on-one article with professor Rowe on developments in ALS research.)