The recent merger of TranscripTx and ReCode Therapeutics created a company that combines RNA drug expertise with a non-viral lipid nanoparticle (LNP) delivery platform to develop new genetic therapies for treating the underlying causes of two rare lung diseases: cystic fibrosis and primary ciliary dyskinesia (PCD).

The new company retained the ReCode Therapeutics name and made headlines with an oversubscribed $80 million Series A round of financing in March 2020.

David Lockhart, Ph.D., former TranscripTx CEO, is the president and CEO of the merged company. He said an essential element in the success of any new genetic therapy depends on a safe, effective and targeted delivery vehicle.

The non-viral LNP delivery platform, Lockhart observed, was “a big part of getting the merged company funded. It can be used to package different types of genetic therapy payloads and can be tuned to deliver them in different ways, get them to where you want them to go, and deliver them safely and repeatedly.”

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes the CFTR protein. An absent or defective protein leads to airway hydration problems, inflammation, lack of mucociliary clearance and frequent airway infections – impairing lung function and leading to life-threatening respiratory failure. The rare disease affects more than 70,000 people worldwide.

ReCode is developing a transfer RNA (tRNA) therapy to treat a subpopulation of cystic fibrosis patients with so-called nonsense mutations. The tRNA therapy is delivered into lung cells to enable production of the functional CFTR protein and restore lung function.

PCD is caused by mutations in a number of different genes that result in dysfunctional cilia on lung cells. When working properly, the hair-like cilia wave back and forth to clear mucus and harmful bacteria from the lungs. When the cilia are defective, mucociliary clearance is impaired, and inflammation and infections damage lungs creating chronic breathing difficulties. Only 3,000 cases of PCD have been confirmed in North America, but according to the PCD Foundation, limited awareness and under diagnosis of the disease means the number of patients could be closer to 25,000.

PCD is sometimes considered less severe than cystic fibrosis. But children with PCD suffer from similar complications as those with cystic fibrosis and face shortened life spans due to respiratory failure. In addition, there are no treatments available. ReCode has developed a messenger RNA (mRNA) therapy delivered into cells to produce normal versions of the proteins that make cilia, restoring proper ciliary function on cells throughout the airways and lungs.

ReCode’s cystic fibrosis and PCD RNA therapeutics are nebulized and turned into an aerosol that patients will inhale into their lungs. The therapies are in preclinical development and the company expects to file Investigational New Drug applications with the US Food and Drug Administration (FDA) in 2021 to begin clinical trials in both programs.

As part of its ongoing series exploring the challenges of rare disease drug development, WuXi AppTec Communications discussed with Lockhart how ReCode’s RNA therapies represent a significant advance in the treatment of cystic fibrosis and PCD.

Lockhart has more than 25 years of drug discovery and development experience. Before joining ReCode, he held scientific and executive positions at Amicus Therapeutics, Ambit Biosciences and Affymetrix. Lockhart received his Ph.D. from Stanford University and was a postdoctoral fellow at the Whitehead Institute in the Biology Department at the Massachusetts Institute of Technology.

WuXi AppTec: What are the major differences between developing drugs for rare diseases and for more common diseases?

David Lockhart: As you know, approximately 7,000 rare diseases have been identified. Obviously, for some rare diseases one of the challenges is that there are so few patients that it’s hard to find enough of them for clinical trials. You have to have clinical sites all over the world and even then, it can be very challenging, especially with “ultra-rare” diseases.

Also, rare diseases are often under-diagnosed because many physicians have never seen a patient with a particular disease. So in addition to small patient populations, there is not a lot of information about some of the diseases.

WuXi AppTec: What are some of the regulatory challenges you face, such as determining the appropriate endpoints, or outcomes, for clinical trials?

David Lockhart: The challenges differ based on the disease. We’re fortunate that for cystic fibrosis and PCD the drug development and regulatory paths are fairly well-established and clear.

That’s because of the work done by Vertex Pharmaceuticals to get its drugs approved for cystic fibrosis. The clinical path and primary endpoints, and even secondary and supportive endpoints, are very similar for cystic fibrosis and PCD.

But in other rare diseases, if no drugs have been approved, no primary endpoints have been developed for clinical trials and it may not be clear what the clinical endpoints should be. As a drug developer, you may have to create endpoints of your own, then validate them and convince the FDA they make sense. That can be a very difficult process.

And then for some rare diseases, the endpoints can be difficult to achieve. For example, if the primary endpoint involves slowing progression of the disease, it can take a long time to see a difference between the treated group and placebo group or an untreated historical control group.

For our company, we’re very fortunate to have a primary endpoint that has already been used as the basis for approval of other cystic fibrosis drugs. Just as important, that endpoint has shown rapid improvement in lung function within weeks, not just a slowing of progression over a year or two or longer. That’s a huge advantage for our programs in cystic fibrosis and PCD.

WuXi AppTec: What are some of the business challenges, such as raising funds for rare disease drug development?

David Lockhart: The primary thing we look for is unmet medical need; that we’re really going after a problem in need of a solution and that patients are in need of a therapy.

But then there also are practical matters of selecting diseases with enough patients to run clinical trials and enough patients in the world to make the drug commercially viable. In the context of raising money, the latter is an important part of the conversation. People need to know this is a disease that’s treatable, that a drug can get approved and that with approval the drug can be commercially successful.

WuXi AppTec: How important are government incentives, such as the FDA’s orphan drug designation, for rare disease drug research and development?

David Lockhart: The short answer is they are really important. With the orphan drug designation there is guaranteed market exclusivity. If your drug gets approved, and has orphan drug status, you’ll know you have a good position commercially.

The orphan drug designation also is important because there’s additional help from the FDA. There are more interactions with the agency’s regulators and specific encouragement to meet with them early and often to look at clinical trial design and to make sure things are on track. By the time you get to the more advanced clinical development stages you already know the regulators involved. You’ve established a relationship, and you’re able to work together to develop the drug.

WuXi AppTec: How much progress has been made in cystic fibrosis research and drug development? Is a cure in sight?

David Lockhart: I can take those two questions one at a time. There’s been significant progress in cystic fibrosis, especially recently.

The discovery of the gene and protein that cause cystic fibrosis occurred about 30 years ago. The hope early on was that therapies could be developed relatively rapidly. The disease turned out to be a lot more difficult to treat than people had hoped during the early days.

But the good news is there have been multiple drugs approved recently for cystic fibrosis from Vertex Pharmaceuticals. The company has had a series of different small molecule drugs approved that are appropriate for different genetic subsets of the cystic fibrosis population. As a result of all that work, there are therapies that should benefit approximately 90 percent of people with cystic fibrosis. So that’s good progress, and with our targeted genetic therapies we want to reach the 10% of patients who don’t have treatment options yet.

But note I said benefit, not cure. The drugs lead to improvement in lung function. They can lead to other improvements in cystic fibrosis symptoms and quality of life as well. But they are not a cure. People still have the disease. They have to keep taking the drugs for life, but it’s certainly better than no therapy at all.

There’s also a new type of therapy that has moved into clinical studies from Translate Bio. It’s not a small molecule. It’s a nebulized mRNA therapy that is inhaled into the lungs.

The mRNA therapy instructs cells to make the CFTR protein required for normal lung function.

Translate Bio has just started clinical studies, so it’s not clear yet whether it’s going to work and how well it will work. But it is encouraging that a new type of drug is going into clinical studies.

Do I expect a cure? It depends on what you mean by cure. A cure is a therapy that when administered the patient effectively no longer has the disease. I think that’s still a ways off.

But the next best thing is to have treatments that basically make it so the symptoms of the disease are greatly reduced and that people can live long full lives. I think that actually is possible. I don’t know if that counts as a cure, but it certainly counts as a huge improvement in which you basically turn the disease into a manageable condition. Patients still have the underlying cause. They still have the mutation in the CTFR gene. But they can take a medicine and have a long, full, rich life.

WuXi AppTec: What is your company’s approach for treating cystic fibrosis and PCD, and how far have you progressed?

David Lockhart: For both cystic fibrosis and PCD we have been able to show we can deliver our RNA therapies into human cells using the cell-based model that’s considered to be the gold standard for studying the human airway and testing new approaches. We have been able to show that we can deliver our RNA therapies into those human cells and correct the functional deficiencies.

In the case of cystic fibrosis, we show that we get recovery of the CFTR protein function. In PCD, our therapy generates cilia that function normally on the cells.

We also have shown we can deliver these therapeutic agents into the lungs of animals and we can do that repeatedly and safely. Now the next step is to do those same types of delivery experiments in larger animals with lungs that are more like those in humans.

WuXi AppTec: What kind of RNA therapies are you developing and how do they work?

David Lockhart: They are a little bit different for the two programs.

For cystic fibrosis we’re delivering tRNA, which helps decode the instructions in mRNA to make proteins. Our tRNA therapy makes it so the CFTR mRNA with nonsense mutations can be translated into a functional version of the CFTR protein, rather than producing a truncated and non-functional protein. The nonsense mutations in the CFTR gene occur in about 5% to 10% of cystic fibrosis patients. These are people with cystic fibrosis who are not helped by the Vertex small molecule drugs.

The nonsense mutations in the CFTR gene lead to a premature stop in making the CFTR protein. When the protein is being made from the natural mRNA, the cell machinery comes to a halt so that instead of making the full length protein needed in the airway cells, only part of the protein is made, and it tends to degrade very rapidly. It’s as if the person does not have the needed protein.

Our tRNA drug reads the nonsense mutation in the mRNA and makes it possible for the cellular machinery to continue making a functional version of the CFTR protein. Basically, it reinterprets the mutated mRNA so the CFTR protein can be made. It’s very clever, and it makes great sense. It’s a new type of drug.

In PCD, people are born with mutations in particular genes responsible for making cilia that don’t move as they should. We deliver into the cells the full-length, normal mRNA that encodes the properly functioning cilia protein. The deficient mRNA is still there, we just add in the correct copy to make the correct version of the protein so that the ciliary machine can work properly.

WuXi AppTec: How important are patient advocacy groups and patients in your drug development efforts? Are they helping with clinical trial design? What roles do they play, other than participating in clinical trials, of course?

David Lockhart: The patient advocacy groups are extremely important. Sometimes one of the benefits of working on rare diseases is that the patients are very knowledgeable. They’re very engaged. They know about their disease, about the genetics, and about what works and what doesn’t. They know their doctors well.

The patient advocacy groups and foundations also set up patient registries. They often are involved in natural history studies. The registries and natural history studies are very helpful in identifying patients, monitoring them and tracking them on how their disease progresses over time.

All of these elements are immensely helpful in terms of designing clinical studies, populating the studies, interpreting the studies, and knowing what endpoints to use and what’s likely to happen in those endpoints over time.

Fortunately for both cystic fibrosis and PCD there are very well-established foundations and patient groups. It’s an incredible network that involves not only patients, but also caregivers, families, doctors and nurses.

WuXi AppTec: In general, what technological breakthroughs will be game-changers for drug developers over the next five years? Will they have an impact on improving the efficiency of drug approvals and lowering the cost?

David Lockhart: We’re getting smarter about drug discovery and development all the time. We have made significant progress in developing new kinds of therapies. But the biggest breakthrough in terms of creating better drugs and developing them more rapidly and more efficiently is the delivery.

It’s really the delivery side of the equation that can be the most challenging. We need better delivery vehicles that are safe and versatile, meaning they can be used with different types of payloads, such as RNA drugs and proteins, and even the combination of the two.

We need to be able to target the drugs so that when they’re delivered they go to the right places, in the right amounts. They go to the right tissues. They go to the right organs and the right cell types. We will speed up drug development and make it more cost-effective when we have a better tool box for delivery of all the new types of genetic therapies.