A Levodopa Inhaler for Parkinson’s?

When asthmatics feel airways begin to tighten, they reach for their rescue inhaler. What if Parkinson’s patients could do the same thing? Scientists led by Michael Lipp and Martin Freed at Acorda Therapeutics in Chelsea, Massachusetts, have developed a levodopa inhaler. In the October 12 Science Translational Medicine, they detail results from preclinical, Phase 1, and Phase 2 studies of a powdered form of the drug called CVT-301, which can be inhaled. In dogs and healthy people, CVT-301 entered the blood much faster than an oral dose. In patients with Parkinson’s (PD), the drug immediately restored finger tapping ability and improved overall motor function. CVT-301 is now in Phase 3 trials.

“Patients already on an oral regimen of levodopa can fill the gaps in their clinical response with the same drug they’re already on, which is very appealing to doctors,” said co-author Richard Batycky at Acorda. “They know levodopa, it works, and it’s provided in a way that patients can reliably count on it getting into the systemic circulation and into the CNS.”

A levodopa inhaler. [Courtesy of Acorda Therapeutics.]

As dopaminergic neurons die away in Parkinson’s, patients become more sensitive to fluctuations of dopamine in the brain. Many people on a daily oral regimen of levodopa start to experience “off” periods—times between doses when dopamine in the central nervous system drops so low that movements become rigid and stiff. These periods are often disruptive, and can be painful or even paralyzing. A number of add-on medications have been developed to prolong levodopa’s stay in the CNS and enhance its effectiveness, but these haven’t eliminated off periods completely. Injections of apomorphine under the skin can bring relief, but are somewhat invasive and can result in skin nodules at the injection site. Reaching for a bottle of levodopa pills doesn’t work, because absorption from the gut is finicky and takes a long time. It competes with digestion of food and if taken too soon after a meal, will not be absorbed as effectively. Inhaling levodopa, on the other hand, would bypass the intestine and quickly deliver a dose to the bloodstream, the theory goes.

Batycky and colleagues have worked for years to develop a powdered version of levodopa that can be delivered in sufficient quantities. While a typical asthma inhaler only needs to deliver micrograms of medicine to the lungs, a levodopa inhaler needs to pack 1,000 times that to ensure enough LD gets into the brain to be effective. The ARCUS inhaler (see image above) delivers 25 to 50 mg in two breaths. It is designed to break open levodopa capsules so that the powder can escape. Sucking on the inhaler sets the open capsule spinning, which releases the levodopa into the air and into the lungs.

Acorda scientists first tested this technology on anaesthetized beagles. Inhalable CVT-301 peaked in the dogs’ bloodstream in 2.5 minutes and began to decline slowly after five, lasting about two hours in the system. By contrast, oral LD took about 45 minutes to reach max levels in the blood.

Shifting to Phase 1 trials, the researchers gave each of 18 healthy men three different doses and formulations of levodopa, after which they took a series of blood samples for 24 hours. The volunteers first swallowed a 100 mg levodopa pill. Two days later they breathed a 10 or 30 mg dose of CVT-301, and two days after that, a larger 20 or 50 mg dose. As it did in the dogs, inhaled levodopa got into the blood quickly, peaking after about 10 minutes. Levels consistently reached 600 ng/ml plasma within five minutes. While blood levels after the oral pill reached twice that, it took much longer (30 minutes) and absorption was inconsistent. In addition, inhaled LD washed out of the blood within two hours, whereas it was still in the blood four hours after taking the oral pill. Four of the 18 volunteers reported mild adverse events that resolved quickly. Two became dizzy, one got a headache, and one experienced muscle spasms. No one reported pulmonary problems.

In the Phase 2a trial, the researchers tested the levodopa formulations in random order on separate days in each of 24 PD patients. These people were already taking levodopa pills at least four times daily, with intervening off periods that totaled at least two hours. During one of those episodes, and at least four hours after their last pill, each patient took an extra 25 mg oral dose, or a 25 or 50 mg puff of CVT-301. Levodopa peaked in the plasma 15 minutes after breathing in CVT-301, while the pill took more than an hour. CVT-301 improved finger tapping within five minutes and general motor control after 15, according to scores on the Unified Parkinson’s Disease Rating Scale (UPDRS III). These improvements lasted 90 to 100 minutes. People fared better after taking 50 mg of the drug than they did with just 25 mg, with more statistically significant improvements relative to placebo. The authors don’t report motor improvements for the oral dose.

Six patients had coughing spells just after inhaling the levodopa. These became milder as they got used to the technique. Among those taking the higher dose there was one case each of runny nose, indigestion, cold, headache, and flu. Almost 40 percent of patients experienced dyskinesia after the oral levodopa, while 17 and 25 percent did after the 25 and 50 mg CVT-301.

The results suggest PD patients could use CVT-301 as needed between oral levodopa doses to avoid off episodes, wrote the authors. Though in this case, patients took the drug under controlled conditions in the clinic, a separate Phase 2b trial tested patients who self-administered the drug at home. They got similar boosts in motor function and experienced less off time during the day (LeWitt et al., 2016). CVT-301 is in two Phase 3 trials to test its safety and efficacy. Both studies are on track to be completed by the end of this year. If they are positive, Acorda plans to seek FDA approval.—Gwyneth Dickey Zakaib 

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References

Paper Citations

  1. LeWitt PA, Hauser RA, Grosset DG, Stocchi F, Saint-Hilaire MH, Ellenbogen A, Leinonen M, Hampson NB, DeFeo-Fraulini T, Freed MI, Kieburtz KD. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson's disease. Mov Disord. 2016 Apr 19; PubMed.

External Citations

  1. Phase 2b
  2. safety 
  3. efficacy

Further Reading

Papers

  1. Lotia M, Jankovic J. New and emerging medical therapies in Parkinson's disease. Expert Opin Pharmacother. 2016 May;17(7):895-909. Epub 2016 Feb 19 PubMed.
  2. Pilleri M, Antonini A. Novel levodopa formulations in the treatment of Parkinson's disease. Expert Rev Neurother. 2014 Feb;14(2):143-9. Epub 2014 Jan 13 PubMed.
  3. Luinstra M, Grasmeijer F, Hagedoorn P, Moes JR, Frijlink HW, de Boer AH. A levodopa dry powder inhaler for the treatment of Parkinson's disease patients in off periods. Eur J Pharm Biopharm. 2015 Nov;97(Pt A):22-9. Epub 2015 Oct 13 PubMed.
  4. Luinstra M, Rutgers AW, Dijkstra H, Grasmeijer F, Hagedoorn P, Vogelzang JM, Frijlink HW, de Boer AH. Can Patients with Parkinson's Disease Use Dry Powder Inhalers during Off Periods?. PLoS One. 2015;10(7):e0132714. Epub 2015 Jul 14 PubMed.

Primary Papers

  1. Lipp MM, Batycky R, Moore J, Leinonen M, Freed MI. Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson's disease. Sci Transl Med. 2016 Oct 12;8(360):360ra136. PubMed.

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