TAP's Patent Application to Give Lupron to Autistic Children

Along with co-applicants Mark and David Geier, TAP Pharmaceuticals* filed an international patent application (PCT/US2007/082866), "Methods of Treating Autism and Autism Spectrum Disorders," in October of last year for the use of Lupron (leuprolide acetate, a GnRH analog), with or without chelation, in children with autism. (A big discovery hat tip for finding this patent application, along with related US patent applications, goes to Kathleen Seidel of the Neurodiversity blog.) The text of this application was published in August May of this year, and treatment descriptions in 7 children can be found if the reader is willing to wade through a lot of repetitive verbiage—including a seemingly endless string of "need in the art," "known in the art," and "skilled in the art."

Essentially, the treatment "invention" of TAP and the Geiers is intended to lower elevated mercury levels in autistic children by giving the chemical castrator Lupron. The applicants base this idea on a 1968 article, which showed that mercuric chloride complexes with testosterone in a hot benzene solution, a condition not possible in living organisms. The patent idea of TAP and the Geiers is to lower testosterone in autistic children by giving them Lupron, which then supposedly frees up toxic mercury. The idea is that the freed-up mercury can then be eliminated with the aid of chelation therapy, if necessary.

However, TAP and the Geiers don't limit their endocrinologic therapy to Lupron, nor their disease targets to autism. They also include the treatment possibilities of antiandrogen hormones (eg, cyproterone [Androcur; Schering-Plough AG]) and birth control pills and propose that mercury toxicity is implicated in Alzheimer's disease, diabetes, heart disease, obesity, amyotrophic lateral sclerosis, asthma, and immune disorders.

What follows is a summary of the pediatric "examples" of TAP's and the Geiers' so-called invention. In all cases of autism, remarkable improvements in gastrointestinal symptoms (if present) and social/cognitive skills are described, sometimes within days of what are described as well-tolerated injections of Lupron.

Subject ages: Four children were of prepubertal age (two 6-year-old boys; a 7-year-old girl; and an 8-year-old boy), and 3 children were within the age range of puberty or beyond (an 11-year-old girl, an 11-year-old boy, and an 18-year-old boy).

Previous treatments: Two of the children (a 6-year-old boy and the 8-year-old boy) had undergone previous chelation therapy with DMSA for approximately 11 and 15 months, respectively. Clinical improvement is described in the case of the 8-year-old boy; the 6-year-old boy did not demonstrate improvement with chelation, according to the patent application. The 11-year-old girl received prescription amphetamines (Adderall; Shire) for the diagnosis of attention deficit hyperactivity disorder, given at the age of 5 years.

Claims of clinical signs of precocious puberty: In no case of the prepubertal or pubertal children is the Tanner stage noted in the patent application. Signs of precocious puberty in 3 of the prepubertal children are vaguely described as increased body, leg, or facial hair; masturbation; "genital development"; or "early sexual behaviors." The 11-year-old girl showed "mild signs of precocious puberty" (whatever those may be) and "fully developed pubic hair" by 8 years of age. These descriptions were presumably obtained in retrospect by history. The girl also began menstruating at the approximate age of 10 years—which is earlier than average, but not precocious.

The performance of GnRH stimulation tests in the patient examples, as recommended by the Lupron Prescribing Information, is not described by the patent applicants. Other diagnostic criteria for central precocious puberty described in the PI, including the documentation of advanced bone age and a number of baseline tests (to exclude congenital adrenal hyperplasia, a chorionic gonadotropin-secreting tumor, a steroid-secreting testicular tumor, and an intracranial [eg, pituitary] tumor), are also not documented in the application. Addendum: Head MR imaging was performed in 2 individuals; however, the timing of the imaging is not provided by the patent applicants.

Mercury assessment: Mercury levels in the absence of chelation therapy are provided only in the case of the 11-year-old boy, whose blood showed "minimal" levels of mercury (1.5 μg/L; reference range, 0.0-14.9 μg/L) and whose urine did not reveal the presence of mercury. The patent applicants claim that urinary porphyrins (specifically urophorphyrin[sic] and hexacarboxylphorphyrins[sic]) were elevated in the 11-year-old girl. Measurements of urinary porphyrins have been proposed by the Geiers to be surrogate markers for mercury toxicity in autism on the basis of a rat study.

Thiol levels: Given that the Geiers have proposed a "decreased detoxification capacity" in children with autism, defined by certain thiol levels, these metabolites were measured in 2 children. Levels of plasma cysteine and reduced glutathione (GSH) were measured during and after the 6-year-old boy's initial chelation therapy, and selected thiol levels were measured in the 8-year-old boy after his Lupron/chelation therapy. The plasma cysteine levels, although below the reference range contained in the patent application, are within the control ranges of those in the literature. In the case of plasma GSH, the levels (when converted to units of μmol/L) are orders of magnitude greater than those found in relevant medical/science articles.

^a From James et al, 2006.
^b Presented by the patent applicants in units of mg/dL.
^c From Chattaraj and Das, 1992. 

Testosterone levels: According to the patent applicants, baseline serum testosterone levels were elevated in 2 of their subjects: a 6-year-old boy (23 ng/dL; reference range, 0-20 ng/dL) and the 7-year-old girl (18 ng/dL; reference range, 0-10 ng/dL). They also emphasize high-normal levels of serum testosterone in the 8-year-old boy (25 ng/dL; reference range, 0-25 ng/dL) and the other 6-year-old boy (20 ng/dL). Follow-up testosterone levels predictably rose and then dropped during the Lupron therapy. (According to the Lupron PI, "During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed.")

Lupron therapy: The Lupron therapy for the 7 pediatric subjects is tabulated. Therapy was not uniform and, in some cases, involved supplementation with the non-depot (subcutaneous) formulation of Lupron. The recommended starting dosage for Lupron Depot-Ped, according to the PI, is 0.3 mg/kg every 4 weeks: 7.5 mg if ≤25 kg (≤55 lb); 11.25 mg if 25-37.5 kg (55-82.5 lb); and 15 mg if >37.5 kg (>82.5 lb). How the doses of 22.5 mg IM in the cases of the 8-year-old boy and a 6-year-old boy were derived is not stated by the patent applicants. The Lupron PI also indicates that, if downregulation is not achieved (via GnRH stimulation testing and Tanner staging), the dose should be titrated upward in increments of 3.75 mg every 4 weeks.

The Lupron PI states that therapy should be monitored with a GnRH stimulation test, measurements of sex steroids, and Tanner staging. Bone age for advancement should be assessed every 6-12 months. Confirming GnRH stimulation tests and Tanner staging are not described by the patent applicants, nor is there a discussion of the monitoring of bone age during therapy.

In 5 cases, the total duration of Lupron therapy is not specified in the patent application. In the case of the 18-year-old boy, his serum testosterone level dropped from a baseline of 559 ng/dL (reference range, 241-827 ng/dL) to a follow-up level of 28 ng/dL. The serum testosterone level of the 11-year-old boy dropped from a baseline of 153 ng/dL to 35 ng/dL after "several months of treatment." Essentially both boys were subjected by the applicants to chemical castration with Lupron at the end or beginning of puberty, respectively.

The 11-year-old girl, who began menstruating at the age of 10 years, most likely underwent chemically induced menopause with her Lupron therapy. This girl was also treated with "low dose birth control pills," presumably in conjunction with her Lupron therapy. The rationale for prescribing OCPs with Lupron in the 11-year-old girl is not stated by the applicants. (I'm out of my medical territory here, but I've only heard of prescribing Lupron with OCPs in the setting of infertility therapy.)

The Lupron PI states that discontinuation of the drug, when used for central precocious puberty "should be considered before age 11 for females and age 12 for males." This recommendation is presumably to allow timely puberty to begin. In adults, Lupron is FDA indicated for the treatment of prostate cancer, endometriosis, and uterine fibroids.

Chelation therapy: Only 2 subjects, the 8-year-old boy and a 6-year-old boy underwent chelation therapy. In the case of the 6-year-old boy, chelation preceded Lupron therapy. The 8-year-old boy underwent chelation after the initiation of Lupron therapy. The rationale for starting chelation therapy before Lupron injections is not stated by the applicants.

Other hormonal therapies: In addition to the OCPs prescribed for the 11-year-old girl, the 8-year-old boy began therapy with the antiandrogen cyproterone acetate (Androcur; Schering-Plough AG) 50 mg tid between his 2nd and 3rd doses of Lupron. Cyproterone acetate was prescribed for an unspecified period of time.

TAP's name* on this international patent application, along with the Geiers, is more than just a little troubling, given that pediatric subjects were treated with the company's proprietary drug in a maverick, off-label fashion on the basis of dubious theories about autism. Moreover, this off-label treatment, with TAP's evident involvement or knowledge, was performed without clinical-trial protocols (specifically those for the protection of human subjects) being noted in the patent application. In addition, adherence to on-label treatment guidelines, as recommended by the company's prescribing information, is not described. Clearly 3 autistic pediatric patients, who were at the beginning or end of puberty, received a drug that is known to disrupt reproductive function.

DMSA = dimercaptosuccinic acid; GnRH = gonadotropin-releasing hormone.

* Given the dissolution of TAP, it's unclear whether Abbott or Takeda is now the primary applicant for this international patent. Abbott has apparently taken over the Lupron franchise.