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Posted by on Aug 29, 2008 in Ethics, Genetics, Neurology, Pharma

More on Gunvalson v. PTC Therapeutics

More on Gunvalson v. PTC Therapeutics

Thanks to the Drug and Device Law Blog for providing a link to the opinion of New Jersey federal judge William Martini in the case of Gunvalson v. PTC Therapeutics. Comment on the reported opinion, which concerns access to an experimental drug for Duchenne muscular dystrophy (DMD), was made in a previous post, and follow-up information from a primary source is always welcomeparticularly when plenty of questions about the case remain unanswered.

One notable issue raised in the opinion (page 7), which is pretty much dismissed by the judge, is whether the plaintiff, Jacob Gunvalson, even has DMD or, instead, a related and less severe condition, Becker muscular dystrophy (BMD). The distinction is important because the 2 conditions depend on the nature and consequence of the mutation in the gene that encodes the dystrophin protein. Deletion mutations in the gene that cause an out-of-frame mRNA transcript are likely to produce nonfunctional dystrophin, which manifests clinically (in general) as the more severe DMD. Patients with BMD are believed to produce partially functional dystrophin, which accounts for the milder illness.

The nature of Jacob Gunvalson’s dystrophin mutation (if detectable), his dystrophin production, and the clinical severity of his illness are important (if not crucial) for 1) anticipating whether PTC’s experimental suppressor of nonsense mutations, PTC124, is even likely to work; and 2) ensuring the clinical uniformity of enrollees in clinical trials (if patients with BMD are not eligible).

I can only assume that these issues were laid aside by the judge because either 1) he is incapable of understanding them or their importance; 2) they weren’t argued sufficiently by the defendants; or 3) they’re resolved issues in the minds of the defendants (meaning that Jacob Gunvalson is known to harbor a nonsense mutation and, indeed, had DMD). [See information in the Addendum below, which suggests that Jacob’s diagnosis is not resolved.]

Alright, those fundamental medical concerns raised, back to the opinion:

The undisputed background on the case is that, in early 2006, PTC began a 28-day, open-label phase 2a trial of PTC124 in patients with DMD. At the time, Jacob was taking the well-known aminoglycoside antibiotic gentamicin, which is known to suppress nonsense mutations. (It is unclear how Jacob was receiving gentamicin: from his personal physician or through a clinical trial.) According to the opinion, Jacob’s mother consulted PTC vice president Claudia Hirawat about whether Jacob should discontinue gentamicin, so that he could enroll in the PTC124 clinical trial. (Why Hirawat, who is evidently not a medical professional, would be consulted over Jacob’s personal physician on this issue is not known, nor addressed, in the opinion.)

According to the affidavit of Jacob’s mother, Hirawat told her that Jacob should continue the gentamicin, “which appeared to have some beneficial effect, and wait for later PTC124 clinical trials.” This is the alleged exchange (along with similar exchanges) on which the entire case apparently rests: Whether PTC (as represented primarily by Hirawat) led Jacob and his mother to believe that Jacob would have access to the unapproved PTC124, even though he was advised not to and/or didn’t enroll in the phase 2a trial of PTC124.

As it turns out, the phase 2a trial was a “success,” as Judge Martini describes it. (Frankly it’s hard to call such a small, early-phase trial a successunless by success, one means “not a failure.”) According to the PTC web site, enrollees with DMD and a nonsense mutation in the dystrophin gene received 1 of 3 dosages of PTC124 for 28 days. Data from 26 patients who received low or medium dosages were presented at the Third Annual Congress of Myology in May. 

Muscle biopsies showed evidence of dose-dependent increases in dystrophin expression and significant reductions in creatine kinase levels. Also parents and teachers reported clinical improvement in this non-blinded, non-placebo-controlled study, and the drug appeared to be reasonably well tolerated. Given the positive phase 2a trial results, a 2-year extension phase was initiated. 

At this point in time, Jacob’s clinical status had deteriorated, according to the opinion, but it does not describe how. (News reports suggest that Jacob had become nonambulatory.) Consequently Jacob sought access to PTC124; however, he was not eligible to participate in the 2a extension trial, because he had not been enrolled in the 28-day study (which PTC had discouraged, claimed the Gunvalsons).* Therefore the Gunvalsons sought access to PTC124 through the FDA’s compassionate-use program, which PTC refused to pursue. 

By my read, Judge Martini bases his opinion in favor of the Gunvalsons primarily on whether PTC created some kind of legal obligation to provide PTC124 to Jacob. The judge refers heavily, on this issue, to the affidavit of the patient’s mother, Cherie Gunvalson, and what was said and/or promised to her by PTC employees, specifically Hirawat. However, Hirawat’s statements, as quoted by the judge, provide an important caveat to clinical-trial enrollment that is overlooked (in my opinion) by the judge. For example,

I informed Mrs. Gunvalson that Jacob’s non-enrollment in the phase 2a trials would not by itself preclude him from participating in all of PTC’s anticipated future clinical trials, for PTC 124, assuming he satisfied the eligibility requirements for those trials [emphasis added].

It is also important (at least to me) that this statement does not promise enrollment in the 2a extension trial specifically (although some may consider this point too fine to care about). In addition, the accurate quotation of other statements allegedly made to Jacob’s mother are suspect, in my mind. For instance, PTC chief medical officer Langdon Miller is claimed to have promised unqualified access to PTC124, a dubious proposition: “[O]nce positive results were back from the [phase 2a] trial, Jacob will get PTC124.”

Lawyers Jim Beck and Mark Hermann, over at the Drug and Device Law Blog, dissect some of the legal issues in the casesuch as the advisability of communications between company representatives and patients and the nontrivial nature of opening a compassionate-use program for an individual patient. They also make a lot of decent-sounding arguments for why Judge Martini’s opinion is a raw deal for any company that develops drugs for hopeless conditions. 

* A previous post discusses Jacob’s enrollment in a phase 2b trial of PTC124; however, a footnote in Judge Martini’s opinion dispels any notions that either party thought Jacob was or is eligible for enrollment in this trial (see opinion footnote, page 3).

Addendum: In its press release on Judge Martini’s opinion, PTC writes, “The decisions made about prior trials were decisions made by the Gunvalsons or the principal investigator for that trial, and not based on any promises or assurances by PTC. In fact, medical records and emails from the Gunvalsons also indicated that Jacob was ineligible for our Phase 2a trial because of the specific nature of his medical condition.”

Evidently Richard Finkel, MD, principal investigator of the 2a trial of PTC124, believed that Jacob had BMD on the basis of a record review. A diagnosis of BMD would have disqualified Jacob from PTC’s 2a trial, according to Finkel (see page 7 of Martini’s opinion). However, another principal investigator, Brenda Wong, MBBS, MRCP, believed that Jacob had DMD. The judge conferred greater weight to Wong’s diagnostic opinion.

bmartin (1082 Posts)

A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on and Twitter.