Dornase Alfa (Pulmozyme)

Dornase alfa is a recombinant enzyme inhaled by people with cystic fibrosis to thin the thick, DNA-laden mucus that clogs their airways. It wasn't medicine's first attempt at this idea — a bovine version of the same enzyme reached the US market back in 1958, then was abandoned after allergic reactions traced to its foreign animal protein. Approved by the FDA in 1993 as a genetically engineered copy of the human enzyme instead, dornase alfa became one of the first recombinant DNA drugs developed specifically for cystic fibrosis — and more than a decade after its US and EU patents expired, it still has no FDA-approved biosimilar competing against it, even as an entirely different class of drug has transformed the rest of CF treatment.

A first attempt that failed: bovine DNase and a foreign-protein problem

Cystic fibrosis is caused by mutations in the CFTR gene that leave the mucus lining the airways abnormally thick and sticky, creating a chronic breeding ground for lung infection. Each bout of infection kills large numbers of neutrophils in the airway, and the DNA that spills out of those dead cells makes the mucus even thicker and harder to clear — a distinct, compounding problem on top of the underlying CFTR defect, since it persists even when an infection itself is treated. Researchers found as early as the 1950s that adding a DNA-digesting enzyme to infected sputum in a test tube rapidly thinned it, and a crude bovine (cow-derived) pancreatic version of that enzyme, marketed as Dornavac, reached the US market in 1958 for use in various pulmonary conditions, cystic fibrosis included. That first attempt did not last: because it was a foreign animal protein, and because the preparation also carried small amounts of contaminating pancreatic proteases such as trypsin and chymotrypsin, bovine DNase caused severe allergic and respiratory reactions in some patients, and it was eventually withdrawn from the market rather than developed further.

Genentech scientist Steven Shak and colleagues took a different approach roughly three decades later: instead of purifying more of the animal enzyme, they cloned the gene for human DNase I and expressed it as a recombinant protein in genetically engineered Chinese hamster ovary cells — an exact copy of an enzyme the human body already makes, sidestepping the foreign-protein problem that had doomed the bovine version. Their 1990 paper reported that this recombinant human DNase rapidly reduced the viscosity of cystic fibrosis sputum samples in the lab, turning a thick, non-flowing gel into a flowing liquid within minutes (Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL, "Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum," Proc Natl Acad Sci USA 1990;87(23):9188-9192, PMID 2251263, DOI: 10.1073/pnas.87.23.9188).¹ The FDA approved the resulting drug, dornase alfa, on 30 December 1993 under the brand name Pulmozyme — among the first genetically engineered drugs developed specifically to treat cystic fibrosis, arriving roughly three and a half decades after the bovine version's failed first attempt at the same underlying idea.

The trial that won approval

The pivotal evidence was a randomized, double-blind, placebo-controlled trial of 968 outpatients with cystic fibrosis, aged 5 and older, with a baseline forced vital capacity (FVC) of at least 40% of predicted. Patients were randomized to placebo (325 patients), dornase alfa 2.5 mg once daily (322 patients), or dornase alfa 2.5 mg twice daily (321 patients), for 24 weeks. Patients on dornase alfa showed a mean 5.8% relative improvement in FEV1 (forced expiratory volume in one second) over placebo, and the age-adjusted risk of a respiratory exacerbation requiring intravenous antibiotics fell by 28% in the once-daily group (P=.04) and by 37% in the twice-daily group (P<.01) (Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl ME, "Effect of Aerosolized Recombinant Human DNase on Exacerbations of Respiratory Symptoms and on Pulmonary Function in Patients with Cystic Fibrosis," N Engl J Med 1994;331(10):637-642, PMID 7503821, DOI: 10.1056/NEJM199409083311003).¹ A separate trial of 320 patients with more severe disease (FVC below 40% predicted — 162 on placebo, 158 on once-daily dornase alfa) was studied over 12 weeks and found a larger 9.4% mean improvement in FEV1 on dornase alfa versus 2.1% on placebo (P<.001), plus a similar advantage in FVC — but, unlike the larger primary trial, this more severely affected group showed no significant reduction in the risk of a respiratory infection requiring IV antibiotics (54% of dornase alfa patients versus 55% of placebo patients had one by week 12). Read together, the two trials show consistent lung-function benefit across both a broader and a more severely affected CF population, but the exacerbation-reducing benefit demonstrated in the larger trial did not clearly replicate in this smaller, sicker subgroup.

A decade of patent expiry without real US or EU competition

Pulmozyme's US patents expired in 2015 and its European patents in 2019, opening the door to biosimilar competition more than three decades after the original 1993 approval. As of 2019, the only biosimilar dornase alfa product approved anywhere in the world was Tigerase, developed by the Russian biotechnology company Generium and approved for use in Russia — not the US or the EU, where the original patents had already lapsed. No FDA-approved dornase alfa biosimilar exists as of 2026, more than a decade after US patent expiry. Why a major biosimilar developer hasn't pursued the US or EU market isn't established fact, but the drug's status as an inhaled, device-dependent protein formulation — rather than a simple injectable — and a comparatively small global cystic fibrosis patient population relative to blockbuster injectable biologics may both be contributing factors worth weighing against any biosimilar pipeline claim you encounter elsewhere.

Current status

Pulmozyme remains FDA-approved and currently marketed by Genentech, part of the Roche group. It also remains part of standard cystic fibrosis care even after the arrival of CFTR modulator drugs — small molecules such as the elexacaftor/tezacaftor/ivacaftor combination (marketed as Trikafta in the US and Kaftrio in Europe) that correct the underlying CFTR protein defect itself for a large majority of CF genotypes. Those modulators improve lung function and reduce exacerbations more broadly than dornase alfa does, but they do not eliminate the extracellular DNA that accumulates in infected or inflamed airway mucus, so dornase alfa continues to be prescribed alongside them for many patients rather than being replaced by them. No FDA-approved biosimilar had reached the US market as of this writing, leaving Genentech/Roche as the sole approved US supplier more than a decade after the underlying patents expired.