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What is next for the treatment of cystic fibrosis, a rare disease market that has boomed in recent years on the back of new drug approvals with hefty price tags? Pipelines are full, but securing reimbursement is a challenge.





Vertex is on track to have the most prescribed CF therapy on the US market – Orkambi – by 2025, but the market leader is facing competition on a number of fronts.
Early-stage CF pipelines are robust. Informa's Biomedtracker counts 34 preclinical programs, 25 of them new molecular entities, an indication of the broad interest in the space.
Securing reimbursement is an ongoing challenge but it is vital because annual treatment costs for some CF drugs run in the $300,000 range.


Vertex Pharmaceuticals Inc.has quickly established itself as the one to beat across the cystic fibrosis market, and the company is expecting critical data readouts for some of its pipeline products this year. Still, the early-stage pipeline for this rare disease indication is plentiful, including activity from Vertex's former hepatitis C rival, AbbVie Inc.


In parallel to new therapies coming to the fore only a few years after the launch of Vertex's standard-of-care-altering Kalydeco (ivacaftor) and Orkambi (lumacaftor/ivacaftor) products, market access issues for efficacious but pricey CF therapies continue to shadow R&D successes.


Cystic fibrosis affects about 30,000 children and adults in the US, occurring at a rate of 1 in 3,000 births. The disease results from a mutation in a single gene – the CF transmembrane regulator gene (CFTR). In normal cells, the CFTR gene codes for a protein that acts as a channel and facilitates release of chloride and water across the cell membrane. When the gene is mutated, the CFTR protein does not function to regulate transmembrane trafficking of ions, resulting in a salt imbalance. This ionic imbalance leads to the pathobiology observed in CF.


The market has changed significantly since the approval of Vertex's Kalydeco in 2013, a breakthrough product that improves treatment outcomes for certain patient populations. Now, in 2017 Vertex continues to rule the CF landscape.


According to models from Informa's Pharma Intelligence's Biomedtracker analysts, recently launched Orkambi will up its US market share to 22% this year and will steadily increase its reach to 28% by 2025 – to become the most prescribed CF therapy in the country. Orkambi, which was approved in the US in 2015, is expected to overtake by 2020 the stalwart in this market, Roche's Pulmozyme. Other currently approved CF treatments that will steadily lose market share in the US over the next three years include Novartis AG's TOBI Podhaler and Gilead Sciences Inc.'s Cayston. Worldwide, Orkambi is already the highest ranked CF therapy by sales, estimated to hit revenues of $4.9 billion in 2025. (For estimated CF global market value, See Exhibit 1.)





CF Market Leader Holds Firm

Vertex has established itself very quickly in the CF market and Datamonitor Healthcare analyst Daniel Chancellor notes that its broad portfolio strategy is going to defend the company against competition for the considerable future. "Vertex has such a lead now that there is no likelihood of a similar situation to the one in hepatitis C playing out again, in which Vertex's Incivek was quickly made redundant by Gilead and AbbVie's superior products."


Vertex's protease inhibitor Incivek (telaprevir) was approved in 2011 for the treatment of hepatitis C – and at the time was considered the top drug for treating the chronic infection. Sales of the drug rocketed in its first year and Incivek reached blockbuster status by 2012. In 2013 though the product's sales began to stutter as the market prepared for the introduction of new therapies from Gilead, AbbVie and Bristol-Myers Squibb Co. – all in the late stages of development with therapies expected to change the hep C treatment paradigm altogether. (Also see "With Incivek Deflated, Vertex’s HCV Roller Coaster Ride Hinges On Phase II Candidate VX-135" - Pink Sheet, 29 Oct, 2013.)


There may be future competition in CF in the CFTR space and AbbVie again has a program, through a partnership with Galapagos NV, targeting the same genotype. For now though Vertex is sitting pretty as the CF market leader as these programs are too early for their clinical potential to be evaluated.


Dealmaking Led By Vertex, CF Foundation

The year 2016 saw cystic fibrosis at the center of transactions for Sanofi, AstraZeneca PLC, Editas Medicine Inc. and Moderna Therapeutics LLC – deals that signify the varied and growing interest in this disease space, despite Vertex's control over the market.


Moderna's deal with CF expert Vertex, signed in July last year, focused on a single drug compound and could be worth more than $300 million to the privately held company. Moderna, in partnership with Vertex, will develop a CF therapy based on its messenger RNA (mRNA) drug development technology. Under this agreement, the Cambridge, MA-based company received $40 million up front and is eligible for up to $275 million in milestone payments. [See Deal] Moderna is focused on getting its mRNA technology into the right cell and believes a rare genetic disease is the best route for testing its technology in the lungs. Along this line of research, CEO Stéphane Bancel said the company had decided to target CF with its technology – Moderna was the one to approach Vertex for a collaborative deal in this area. (Also see "Moderna Signs Single Drug Deal With CF Expert Vertex For Up To $315m" - Scrip, 7 Jul, 2016.)


Also in 2016, gene editing company Editas signed a deal with the Cystic Fibrosis Foundation, through its affiliate the Cystic Fibrosis Foundation Therapeutics. The biotech will get up to $5 million from the foundation, as well as access to its network of scientific experts in the disease, to carry out research into a CF treatment aimed at fixing the actual gene responsible for the disease. This is a different approach to currently approved therapies and most pipeline candidates.


Meanwhile, in October 2016 Insmed Inc., a global biopharmaceutical company focused on rare diseases, signed a licensing agreement with AstraZeneca for exclusive rights to AZD7986, a novel oral inhibitor of dipeptidyl peptidase I (DPP1). Insmed has renamed the compound INS1007 and is pursuing an initial indication of non-CF bronchiectasis – a rare, progressive, neutrophil-driven pulmonary disorder in which the bronchi become permanently dilated due to chronic inflammation and infection.[See Deal] There is currently no cure for non-CF bronchiectasis. The drug also has potential in other respiratory diseases and is already being pursued as a treatment for chronic obstructive pulmonary disease outside of the US.


Early-Stage Pipeline Full Of Opportunity

Vertex currently has one CF therapy in Phase III as well as three other treatment candidates in Phase II. Competing at the later stages of development though are Bayer AG, Insmed, Horizon Pharma PLC, and PTC Therapeutics Inc.(See Exhibit 2.)


Earlier in the pipeline, Vertex and AbbVie are the most active CF drug developers: AbbVie has three compounds in Phase I, a couple of which are partnered with Galapagos. [See Deal] The big pharma also has a number of preclinical CF assets listed, also from its partnership with Galapagos.


Other companies with several preclinical programs in CF include Shire PLC, Proteostasis Therapeutics Inc., Pulmatrix Inc. and Vivalis Therapeutics. In total, Biomedtracker lists 34 preclinical programs for CF, 25 of which are considered new molecular entities (NMEs) – this rush of early-stage activity suggests CF will remain a popular rare disease development area. But newer, perhaps better treatments are unlikely to threaten Vertex's lead products during their patent lifetimes. (See Exhibit 2 and sidebar, Cystic Fibrosis: Clinical Assets In Development.)


2017: More Trials, More Data

In the first half of 2017 Vertex is expecting top-line data from Phase III trials of tezacaftor (VX-661), its experimental CFTR modulator, in combination with ivacaftor, in two important patient populations: patients with two copies of the Delta 508 mutation and those with one copy of the Delta 508 mutation and one copy of a residual function mutation. A new drug application (NDA) to the FDA and a marketing approval application (MAA) to the European Medicines Agency for this combination are expected in the second half of the year.


Vertex also has four next-generation correctors in development for CF, and the company has plans to develop these as triple combination therapies with ivacaftor and tezacaftor. VX-440 and VX-152 are in Phase II trials as part of triple combinations in people with one copy of the Delta 508 mutation and one copy of a minimal function mutation, and in people with two copies of the Delta 508 mutation. VX-659 is currently being evaluated in a Phase I study in healthy volunteers and CF patients. Finally, VX-445 is expected to enter a Phase I study next month. "2017 will be a year of multiple important data events that will inform us as to the potential of our CF pipeline to both enhance treatment and also treat many more people in the years ahead," Vertex CEO Jeffrey Leiden, MD, PhD, said during the company's January 25 fourth-quarter and full-year earnings conference call.


In addition, Corbus Pharmaceuticals Holdings Inc.expects to report Phase II data for JBT-101 (resunab) by the end of the first quarter. The novel, synthetic, oral endocannabinoid-mimetic drug is designed to resolve chronic inflammation and halt fibrosis.



Also in the first half of this year, according to Informa's Pharma Intelligence's Catalysttracker,ProMetic Life Sciences Inc. will launch a Phase II study for its drug PBI-4050 in CF. Furthermore, Savara Pharmaceuticals will initiate a Phase III trial for AeroVanc, its inhaled antibiotic product that is being developed to address methicillin-resistant Staphylococcus aureus (MRSA) lung infection in people with cystic fibrosis. AeroVanc is one pipeline product that is targeting an unmet need in CF, a population that still requires better antibiotic therapies.





Unmet Needs Remain In CF

According to data collected in June 2016 by Datamonitor Healthcare, pulmonologists surveyed indicated that more effective CFTR modulators for patients with F508del mutations is the greatest unmet need in cystic fibrosis. Vertex is currently developing new combinations of CFTR correctors and potentiators, which may continue to fill in gaps in common genotypes that are currently untreated, although these therapies are further back in the pipeline.


Vertex's VX-661/ivacaftor is the most promising late-stage drug, because it can theoretically improve upon existing products in their current patient groups, while also allowing for new genotypes to have an appropriate CFTR-targeting therapy. Datamonitor Healthcare analyst Chancellor highlighted that although the failure of Vertex's het/min Phase III study back in August 2016 was a blow, if other studies for the product read out positively then Vertex will be able to grow its target population, especially with the inclusion of F508del homozygous patients.


The other top four unmet needs in CF highlighted by doctors are treatments against antibiotic resistant pathogens, CFTR modulators effective against unaddressed mutations, therapies aiding in the prevention of infections and drugs that can reduce the treatment burden associated with the disease.


Market Access Barriers Remain

Vertex has said that one of its goals for 2017 is to widen the reach of its products to treat as many eligible patients as possible.


The company has faced backlash in some markets when trying to get its CF therapies Kalydeco and Orkambi onto drug listings. For example, patients in Australia had to campaign for the introduction of Kalydeco onto the Pharmaceutical Benefits Scheme (PBS) for more than a year after the drug was approved by regulators in the country. (Also see " Australian Kalydeco decision 'deferred,' patients will fight but need a champion " - Scrip, 30 Aug, 2013.) The drug was approved in Australia in July 2013, but not made available on the PBS system in the country until October 2014. Vertex's final agreement with the Australian Pharmaceutical Benefits Advisory Committee, which assesses new drugs for effectiveness and cost effectiveness, also means that the drug will only be reimbursed if patients treated with the product respond. Kalydeco is not funded by the PBS if it does not work in a patient. (Also see "Australia thrashes out patient access deals for Soliris/Kalydeco" - Scrip, 31 Oct, 2014.)


The company also initially had trouble getting Kalydeco onto the Scottish National Health Service listings; it was rejected by pricing watchdog the Scottish Medicines Consortium (SMC) upon its first review. However, the product has since gained reimbursement in the country.


"Securing reimbursement is vital for CF therapies, considering their high price and lack of comparator therapies," Chancellor notes. In the CFTR class, treatment costs can run into the $300,000 a year range. For the moment Vertex has been able to secure very good coverage for Kalydeco and Orkambi in the US, and is negotiating access to Orkambi in the EU. However, Orkambi is going to face greater scrutiny than Kalydeco because it has a larger target population, potentially creating more pressure on health care expenditure compared with the niche patient group that Kalydeco targets.


Chancellor added that in the UK, the pricing debate for Orkambi is coinciding with a change of role for pricing committee NICE (National Institute for Health and Care Excellence), whose remit has recently been expanded to include rare diseases. NICE's initial guidance was to recommend against the reimbursement of Orkambi.


In its full-year 2016 earnings report, Vertex CEO Leiden was adamant that the company will be successful with Orkambi in Europe. He highlighted that the company has recently agreed to a price for the product in Germany, which has a notoriously complicated and strict drug assessment body. Leiden also said: "We are confident it is not a question of if we will achieve reimbursement outside of the US, but a question of when."


Stuart Arbuckle, executive vice president and chief commercial officer at Vertex, stated that the agreement with Germany for Orkambi is important as a benchmark for reimbursement discussions for the product across Europe. Orkambi's price tag in Europe is €160,000 per patient annually.