Cystic Fibrosis Conference Opens up New Treatment Possibilities

Cystic Fibrosis

Cystic Fibrosis Conference Opens up New Treatment Possibilities

Earlier this month, the Annual North American Cystic Fibrosis Conference (NACFC) took place in Arizona. Among the companies that presented were a range of public pharmas that, combined, cover the full spectrum of in-development cystic fibrosis therapies. CF is a rare disease but a big money maker, as some of the most expensive drugs in the world are CF drugs. Here’s a look at each company, with a discussion on their respective approaches.

The two basic approaches to CF are to treat the malfunctioning gene that causes it, and to treat the accompanying symptoms. Cystic fibrosis is caused by a mutation in the CFTR gene that results in blockages in the CFTR protein – a protein responsible for the channeling of sodium, chloride and water into and out of cells. A blocked CFTR protein means sodium cannot escape, which in the lungs leads to a buildup of thick salty mucus. The thickened mucus serves as an ideal breeding ground for bacteria, and also causes blockages, leading to the common CF symptoms of chronic infection and inflammation. The first approach attempts to reverse or at least lessen the impact of the genetic defect leading to a better regulation of sodium and chloride transportation. The second targets the symptoms, attempting to treat infection and reduce inflammation. Each approach has its advantages and disadvantages, as we will soon see.

Corbus Pharmaceuticals Holdings Inc. (CRBP)

Corbus Pharmaceuticals Holdings, Inc. (CRBP is one of the few companies that is developing a treatment of CF symptoms, specifically the inflammation associated with CF. Its lead candidate is Resunab, an oral therapy that tags the CB2 receptor, a natural pathway towards shutting down the inflammatory response. Resunab is a synthetic analog of the body’s normal CB2 activators, but between 50 and 100 times more potent. This reduces inflammation in the lungs without systemic immune suppression. What Corbus is trying to prove is that reduced inflammation leads to an improved FEV1, the gold standard primary endpoint in CF clinical trials. FEV1 is a measurement of lung function by volume of expelled air in the first second of exhalation.

That Corbus is targeting this endpoint may seem counterintuitive rather than say, targeting a measurement of inflammation in the lungs. After all, Resunab is designed to lessen inflammation, so why not measure that? The answer is that it is much harder to measure exact inflammation levels and whether or not a certain level corresponds with improved clinical outcomes. This would be technically termed pulmonary exacerbation, and it may differ from patient to patient. A pulmonary exacerbation is a common event in CF sufferers, and refers to a temporary worsening of symptoms. To measure this would require years of follow up. The FEV1 endpoint can be measured much more quickly, cheaply, and objectively.

Corbus is trialing Resunab in an ongoing phase II, for which the first patient enrolled during the middle of September. Primary endpoint is safety, and the secondary efficacy as measured by FEV1.

A further advantage of the anti-inflammatory approach is that it would theoretically apply to all CF mutations, since all exhibit the same inflammation problems. Drugs that seek to correct protein function are mutation-specific, and need to demonstrate efficacy on each separate type of CF mutation. Resunab would theoretically apply across the board.

Vertex Pharmaceuticals Incorporated (VRTX)

Vertex is already pretty advanced in the space, with two candidates already having reached commercialization – Kalydeco (ivacaftor) and Orkambi (lumacaftor plus ivacaftor). Both of these treatments target the underlying gene defect as opposed to the inflammatory side of the disease. Ivacaftor is what’s called a CFTR potentiator, which means its mechanism of action is to keep the CFTR channels open. In doing so, it promotes chloride and sodium transportation, helping clear mucus buildup. Lumacaftor is involved in the protein folding of a specific type of CFTR protein (F508), working to inhibit misfolding and promote normal CFTR protein production. So far, Orkambi is approved for patients aged 12 and over who have two copies of the F508 mutation that causes misfolding, but the company is looking to expand the target population with an ongoing phase III in patients aged 6-11. Primary endpoint on this one is safety – as efficacy has already been demonstrated across the elder population trials. Kalydeco has approval across a range of CF mutations, and again the company is looking to expand this population, having announced earlier this month that the FDA had accepted its supplemental NDA for CF sufferers aged two and over who have any one of 23 specific mutations.

There are many different types of mutations that cause a CFTR genetic mutation. The FDA approves treatments for one specific mutation at a time, meaning one approval can be focused on a relatively small population. However, with supplemental trials, companies like Vertex can demonstrate efficacy across different mutations and gain approval expansion. Additionally, it can combine therapies (the combination of lumacaftor and ivacaftor is an example of this) to target new mutation types. The company’s lead trial candidate is a further example of this combination therapy, with a trial of VX-661 in combination with Ivacaftor already well underway in phase III. Enrollment is expected to complete mid 2016, and could be a positive catalyst to keep an eye on going forward.

Concert Pharmaceuticals, Inc. (CNCE)

Concert is an interesting one, as its lead CF candidate is an analog of Vertex’s Kalydeco, which has been “deuterated”. Deuterium is an isotype of hydrogen with an extra neutron, an atom that happens to be used as fuel for nuclear reactors. Concert hypothesizes that this extra neutron enhances a treatment’s half life, bioavailability and metabolic profile, and so switching out the hydrogen atoms with deuterium, hence deuterating a particular treatment, can improve upon its efficacy by increasing potency. Obviously, this type of development is far cheaper and quicker than development from scratch, which makes Concert’s approach quite compelling in terms of originality.

At the conference, Concert presented the results of a phase I ascending dose trial of CTP-656, its deuterated version of Kalydeco, in which the company compared the former to the latter. Initial results are intriguing, demonstrating an extended half life, higher blood plasma levels at both 12 and 24 hours (higher plasma levels is associated with an improvement in the condition) and a reduced rate of clearance of the drug, meaning it stays in the blood longer, improving bioavailability. The company is looking to move into a phase II after it completes a second phase I, with the latter being a dose escalation set to start this quarter and finish during the first half of next year. The big question for Concert will be weather Vertex challenges its use of Kalydeco from a legal standpoint. As yet, there has been no indication that this will happen, but this is biotech, so the possibility is very real.

Synergistic Possibilities

As a final note, its worth highlighting the possibility of a new combination therapy as Orkambi is. The synergy possibilities between the inflammation suppressing approach and the CFTR-correcting approach are obvious, at least conceptually. A collaboration between Corbus and either Vertex or Concert is also a possibility. As yet, there is no single therapy that targets both the underlying cause of CF and the associated inflammation that worsens it. If Corbus can combine its Resunab candidate (assuming it can demonstrate efficacy in the ongoing phase II) with Kalydeco, for example, or CTP-656 on approval, the treatment could be the first to target both the cause and its exacerbating symptoms.

The more likely combination is with Vertex, as this would give Corbus the possibility of targeting a larger population than would a partnership with Concert, based on the assumption that a partnership with the former would open up the possibility of both a Kalydeco and an Orkambi combination. This is speculative, of course, but worth thinking on as the space advances.

It is also possible that no partnership will be needed, given that physicians may simply choose to prescribe both together on their own accord.


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