Changing the Landscape for CF Patients – A Q&A with BioMotiv CEO Ted Torphy
By: Erin Reese
May is National Cystic Fibrosis Awareness Month, an opportunity to not only raise awareness about a disease that affects more than 30,000 people in the United States, but also to encourage new research and development of treatments for what can be a devastating and life-long illness. I sat down with Ted Torphy, PhD, BioMotiv’s CEO & Chief Scientific Officer, who, in his spare time, sits on the Board of Directors of the Cystic Fibrosis Foundation, to learn more about the disease and how new advances in treatments are changing the landscape for patients living with this disease.
Most of the Cystic Fibrosis (CF) treatments available today were made possible with incentives developed by the Orphan Drug Act. Why are these incentives so important to research for CF and other rare diseases?
Although this is a bit of an oversimplification, it costs nearly as much to discover and develop an orphan drug as it does a mass market drug. And the risks are at least as great. Consequently, before the Orphan Drug Act there was little incentive for companies to go after diseases, including CF and the more than 7,000 other identified rare diseases, that had small populations.
I understand that 2020 will be a milestone year in CF treatment with the potential approval of a triple combination modulator that could eventually benefit more than 90% of people with CF. What does this treatment do?
The triple combination therapy from Vertex, if approved by the FDA, will be a landmark breakthrough. The genetic basis for CF is the production of mutated forms of the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR protein produced from the mutated gene is dysfunctional. When this happens, the body is unable to move chloride and water to the surface of epithelial cells, resulting in the production of thick, viscous mucus in various organs, especially the lungs. This is important because complications in the lungs are what pose the greatest threat to individuals with CF. The disease is autosomal recessive, which means that a defective gene needs to be received from each parent for a child to present with the disease. Individuals with only one mutation are not impacted.
Although over 1,800 mutations of CFTR have been identified, the F508 del mutation is by far the most common. Based on data from the clinical trials, we expect that anyone with at least one copy of this mutation—about 90 percent of people with CF—could eventually benefit from the triple-combination modulator. Remarkable!
A big challenge for CF patients is complications, such as infection, inflammation, excessive mucus, and GI issues. What are some of the opportunities in this space?
Lungs of CF patients are particularly susceptible to infections, primarily because the abnormal mucus layer mentioned above does not provide its normal degree of defense against bacterial colonization. Infection is a huge issue for individuals with CF. Many of these bacteria are resistant to standard antibacterials, partly because the unique mucous layer of the CF lung allows the bacteria to form biofilms. Biofilms serve as deflector shields to prevent the immune system from clearing bacteria. They also keep bacteria in an inactive state. For most antibiotics to work bacteria must be actively replicating. Targeting and destroying biofilms is a new and exciting approach to fighting these tenacious infections and could have a big impact on treating some of the complications common to CF patients. Hopefully, this will allow the CF lung to clear infections more readily. This is an important advancement, because chronic lung infections, and an over-zealous response of the immune system to them, ultimately cause destruction of lung tissue. At the end stage of CF the only option for patients is a lung transplant.
Anti-inflammatories are also of interest. Perhaps the most exciting one in development is lenabasum, a synthetic, orally active cannabinoid receptor type 2 (CB2) agonist. It belongs to a class of anti-inflammatory agents called “resolvins.” These agents do not prevent inflammation, but rather hasten its resolution. Think of it as a kinder, gentler anti-inflammatory.
The CF Foundation has committed at least $100 million to an Infection Research Initiative over the next five years as part of a sweeping effort to address the chronic and intractable infections that are a hallmark of cystic fibrosis. Can you talk about the impact of this commitment? How could this initiative benefit people with other diseases?
Despite the frightening rise in resistant strains of bacteria and the need for new antibiotics, the commercial landscape for these agents is dismal. New agents that attack these strains are typically relegated to third- or fourth-line therapy, and only used when all other antibiotics fail. The generous commitment of the Foundation to tackle this problem takes a degree of financial risk out of new efforts to develop these desperately-needed products.
How do you see the treatment landscape for CF changing in the next 10-20 years?
I see a steadily increasing number of patients with rare mutations being treated by newer generations of small-molecule modulators. However, a small percentage of patients have nonsense mutations, which means that the CFTR produced is a truncated, inactive form. For these individuals “read through” therapies are being sought. These are agents that allow the ribosome to skip erroneous stop codons and allow the full CFTR protein to be produced. In addition, a clinical trial for the first ever mRNA therapy directed at CF began enrolling participants last year. Gene therapy and gene editing also are being explored, but this work is at a very early stage.
Regardless of the approaches taken, some of which we probably have not even conceived, the CF Foundation will not stop investing in medical research until everyone with CF has a treatment for the underlying cause of their disease, and one day, a cure. In 2012, the year that the first CFTR modulator was launched, the median life span of a person with CF was 38 years. In 2017 it was 43 years. This is an enormous leap in longevity. In the long run, I believe that people with CF will live full, productive lives. They will not die from CF, they will die with CF.
A ubiquitous slogan is mounted on the walls of the CF Foundation headquarters in Bethesda, MD. It reads, “Until it’s done.”