While the anti-myostatin agents appear to be a tempting approach to restoring muscle in neuromuscular patients, of all the clinical trials in humans involving different drug molecules exercising this action (anti-myostatin antibodies, folliculin, drug molecules blocking or deceiving the myostatin receptors, etc.), none has demonstrated its efficacy, despite encouraging results in animal models, in particular in mice models.
Domagrozumab (PF-06252616) is a neutralising anti-myostatin antibody. Results in mice seemed more promising than those of MYO-029, one of the first myostatin inhibitors tested, between 2005 and 2007, without success, in Becker muscular dystrophy, Facioscapulohumeral muscular dystrophy and the limb-girdle muscular dystrophies.
Following a trial in Duchenne muscular dystrophy (DMD), Pfizer conducted, between July 2016 and January 2019, a trial evaluating three doses of domagrozumab in 19 patients with FKRP-related R9 limb-girdle muscular dystrophy (LGMD), aged 19 to 67 years.
Three cohorts were recruited consecutively:
- a first cohort of four participants received 5 mg/kg of domagrozumab every four weeks over a period of 32 weeks, then, after a treatment-free period of 16 weeks, 40 mg/kg over a period of 50 weeks;
- a second cohort of seven participants received 20 mg/kg every four weeks over a period of 32 weeks, then, after a treatment-free period of 16 weeks, 40 mg/kg over a period of 40 weeks;
- and finally, a third cohort of eight participants received the highest dose (40 mg/kg) every four weeks over a period of 32 weeks, then, after a treatment-free period of 16 weeks, 40 mg/kg once again, over a period of 24 weeks.
While domagrozumab was well tolerated, it had no significant effect on the muscle strength and function of the participants. It should be noted that it is possible that, as with Duchenne muscular dystrophy, it has a negative impact on cardiac function: the left ventricular injection fraction was lowered during treatment, but returned to normal during the treatment-free period.
Given the lack of efficacy, both in DMD and in LGMDR9, Pfizer has now discontinued the development of domagrozumab.
A phase Ib/IIa, open-label, multiple ascending-dose trial of domagrozumab in fukutin-related protein limb-girdle muscular dystrophy. Doris G Leung, Alex E Bocchieri, Shivani Ahlawat, Michael A Jacobs, Vishwa S Parekh, Vladimir Braverman, Katherine Summerton, Jennifer Mansour, Nikia Stinson, Genila Bibat, Carl Morris, Shannon Marraffino, Kathryn R Wagner. Muscle Nerve . 2021 May 7. doi: 10.1002/mus.27259. Online ahead of print