19 Dec 2008

November was a dreary month for those who had high hopes for insulin-like growth factor-1 as a treatment for neurodegenerative disorders. Though IGF-1 still has potential, therapies based on the growth factor failed in two clinical trials published last month. Researchers at the Mayo Clinic in Rochester, Minnesota, administered IGF-1 to patients with amyotrophic lateral sclerosis for two years, hoping to replicate the beneficial effect of a prior trial. They found no improvement in strength, daily functioning, or lifespan, as reported in the November 25 issue of Neurology. One week earlier, also writing in Neurology, scientists at Merck’s North Wales, Pennsylvania, campus reported that a drug that enhances IGF-1 secretion had no benefit for people with Alzheimer disease over a one-year trial.

There is still a shred of hope to cling to, however. The Merck scientists, led by Jeffrey Sevigny, did find benefit for patients with a specific genotype, those who did not carry the apolipoprotein E (ApoE) ε4 allele, a major risk factor for late-onset AD. And although the ALS trial, led by Mayo Clinic scientist Eric Sorenson, showed no effect for subcutaneous IGF-1 injections, it’s still possible that IGF-1 could be beneficial if delivered via an alternate route.

No Help for Struggling Motor Neurons
However, Sorenson said the most likely explanation for his results is that IGF-1 is not an effective ALS treatment. The work dashes the hopes of doctors, patients, and the drug company, Cephalon, based in Frazer, Pennsylvania, that wanted to market the therapy. The theory was promising: in animals and in vitro systems, IGF-1 promotes growth of motor neurons, the cells that degrade and die in ALS (Nagano et al., 2005; Dobrowolny et al., 2005). It also protects motor neurons from the toxic effects of the neurotransmitter glutamate, which has been linked to ALS pathology (see ARF related news story). IGF-1’s track record in ALS, however, was spotty. Two previous clinical trials in the 1990s had opposite results: one found no effect for IGF-1 (Borasio et al., 1998); the other tracked a slowing of symptom progression in patients receiving the growth factor (Lai et al., 1997). A more recent study found no benefit for overexpressed IGF-1 in a mouse ALS model (Messi et al., 2007).

Those two conflicting human trials prevented approval from the Food and Drug Administration, but IGF-1 has been used off-label in other countries, Sorenson said. The new study was the result of continuing interest from patients as well as Cephalon. “Hopefully, it provides an answer to the dilemma that this drug was in,” he said. “Our data were very clean, it was consistent, it did not leave any doubts in my mind.” Unlike the earlier work, this study followed subjects (330) for two years instead of nine months, administering the highest IGF-1 dose (0.05 mg/kg body weight twice daily) that was tolerated in the previous studies. Three straightforward outcome measures—composite strength, survival, and the ALS functional rating scale, which considers performance measures for day-to-day tasks such as swallowing, breathing, and getting dressed—showed no difference between IGF-1 and placebo. The previous positive results, Sorenson said, were likely due to chance.

Given the subcutaneous delivery method, the study results are “not so surprising,” said Antonio Musarò of the Sapienza University of Rome, Italy, who did not take part in either study. Previous research that showed a positive effect for IGF-1 in a mouse model of ALS used viral delivery of the IGF-1 gene (Kaspar et al., 2003 and see ARF related news story). “It’s very possible that the drug is not getting where it needs to get,” Sorenson agreed. Other researchers are now exploring more direct delivery of the growth factor to the cells of the central nervous system, Sorenson said, via infusion, gene therapy, or stem cell transplant.

And Apparently No Plaque Relief
The Merck study used the compound MK-677, which boosts circulating IGF-1 levels when given orally (Chapman et al., 1996). The theory behind the trial was that IGF-1 mediates clearance of Aβ in the brain, and thus should destroy the plaques that hypothetically cause Alzheimer’s symptoms (Carro et al., 2002). People with AD have decreased sensitivity to insulin and IGF-1 in the brain, and lower circulating levels of IGF-1, suggesting the hormones may not be doing their jobs effectively. However, a recent Pfizer study found increased IGF-1 did not affect Aβ clearance in several animal models (Lanz et al., 2008), hinting the IGF-1 hypothesis was “shaky” to begin with, said Konrad Talbot of the University of Pennsylvania School of Medicine in Philadelphia, who was not involved with either study.

Patients with mild to moderate AD receiving the drug showed a 60 percent or more increase in serum IGF-1 levels within six weeks. Yet the yearlong study found no benefit based on standard scores of overall symptoms, cognitive ability, dementia, and daily living function. “You get the impression that this is not the way to go to induce Aβ clearance from the brain,” Talbot said. However, the scientists did not directly monitor Aβ levels or look for clearing of plaques in the brain, so it is not certain if the drug affected Aβ pathology or not. It is also possible that Aβ, accumulated over several years, had simply caused too much damage before the treatment.

The subject number—416 patients completed the study—could have been bigger, Talbot said. Once the scientists sorted the subjects into subgroups of baseline symptoms, race, gender, ApoE genotype and other treatments used, and by drug or placebo, the number of individuals in each group was relatively small. Talbot would have liked to see twice as many patients, but said, “My gut feeling is it [patient number] didn’t affect the results they obtained.”

Talbot noted that the one group that did get some benefit from the drug was people who did not have the ApoE4 allele. “That would be worth studying,” he said. Insulin response is also sensitive to ApoE genotype (Craft et al., 2003), suggesting that people with or without the ApoE4 allele may respond differently to the insulin family of hormones.

With improved delivery and targeting, it’s possible that IGF-1 could still be a beneficial treatment for neurodegenerative disorders. At least, both studies confirmed the therapies are safe. “It’s interesting enough that I would not give up on it yet,” Sorenson said.—Amber Dance

Comments

1. • Deborah Gattoni
     
   • Posted: 23 Dec 2008

   It would be appropriate to try doing a trial of IGF-1 BP3
   (Iplex) at a
   higher dose. As ALS patients, many of us do not have two years
   to waste on
   stupidity. I used Iplex briefly before the lawsuit rendered it
   unavailable. My "anecdotal" evidence supported slight improvement
   in a short period of
   time. Worth a shot when it comes to people waiting to die,
   isn't it?

   View all comments by Deborah Gattoni

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References

News Citations

1. Lactam Antibiotics Can Prevent Glutamate Neurotoxicity 7 Jan 2005
2. Repairing Damaged Tissues—Viruses Get into the Akt 12 Aug 2003

Paper Citations

1. Nagano I, Ilieva H, Shiote M, Murakami T, Yokoyama M, Shoji M, Abe K. Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of Amyotrophic Lateral Sclerosis. J Neurol Sci. 2005 Aug 15;235(1-2):61-8. PubMed.
2. Dobrowolny G, Giacinti C, Pelosi L, Nicoletti C, Winn N, Barberi L, Molinaro M, Rosenthal N, Musarò A. Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model. J Cell Biol. 2005 Jan 17;168(2):193-9. PubMed.
3. Borasio GD, Robberecht W, Leigh PN, Emile J, Guiloff RJ, Jerusalem F, Silani V, Vos PE, Wokke JH, Dobbins T. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology. 1998 Aug;51(2):583-6. PubMed.
4. Lai EC, Felice KJ, Festoff BW, Gawel MJ, Gelinas DF, Kratz R, Murphy MF, Natter HM, Norris FH, Rudnicki SA. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology. 1997 Dec;49(6):1621-30. PubMed.
5. Messi ML, Clark HM, Prevette DM, Oppenheim RW, Delbono O. The lack of effect of specific overexpression of IGF-1 in the central nervous system or skeletal muscle on pathophysiology in the G93A SOD-1 mouse model of ALS. Exp Neurol. 2007 Sep;207(1):52-63. PubMed.
6. Kaspar BK, Lladó J, Sherkat N, Rothstein JD, Gage FH. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science. 2003 Aug 8;301(5634):839-42. PubMed.
7. Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, Schilling LM, Cole KY, Skiles EH, Pezzoli SS, Hartman ML, Veldhuis JD, Gormley GJ, Thorner MO. Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 1996 Dec;81(12):4249-57. PubMed.
8. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med. 2002 Dec;8(12):1390-7. PubMed.
9. Lanz TA, Salatto CT, Semproni AR, Marconi M, Brown TM, Richter KE, Schmidt K, Nelson FR, Schachter JB. Peripheral elevation of IGF-1 fails to alter Abeta clearance in multiple in vivo models. Biochem Pharmacol. 2008 Mar 1;75(5):1093-103. PubMed.
10. Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresse S, Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology. 2003 Aug;28(6):809-22. PubMed.

Further Reading

Papers

1. Riddoch-Contreras J, Yang SY, Dick JR, Goldspink G, Orrell RW, Greensmith L. Mechano-growth factor, an IGF-I splice variant, rescues motoneurons and improves muscle function in SOD1(G93A) mice. Exp Neurol. 2009 Feb;215(2):281-9. PubMed.
2. Dodge JC, Haidet AM, Yang W, Passini MA, Hester M, Clarke J, Roskelley EM, Treleaven CM, Rizo L, Martin H, Kim SH, Kaspar R, Taksir TV, Griffiths DA, Cheng SH, Shihabuddin LS, Kaspar BK. Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol Ther. 2008 Jun;16(6):1056-64. PubMed.
3. Moloney AM, Griffin RJ, Timmons S, O'Connor R, Ravid R, O'Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010 Feb;31(2):224-43. PubMed.
4. Sharma S, Prasanthi R P J, Schommer E, Feist G, Ghribi O. Hypercholesterolemia-induced Abeta accumulation in rabbit brain is associated with alteration in IGF-1 signaling. Neurobiol Dis. 2008 Dec;32(3):426-32. PubMed.
5. Moroz N, Tong M, Longato L, Xu H, de la Monte SM. Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus. J Alzheimers Dis. 2008 Sep;15(1):29-44. PubMed.
6. Ransome MI, Turnley AM. Growth hormone signaling and hippocampal neurogenesis: insights from genetic models. Hippocampus. 2008;18(10):1034-50. PubMed.

News

1. How Sweet It Is! Longevity Linked to Insulin-like Growth Factor Signaling 6 Mar 2008
2. Insulin, Insulin-like Signaling and Neurodegeneration—Is Resistance Futile? 25 Jan 2008
3. Diabetes-Insulin Roundup: Dementia Connection Grows Stronger, Part 2 16 Jan 2008
4. Madrid: Highs and Lows of The Insulin Connection 14 Sep 2006
5. Lactam Antibiotics Can Prevent Glutamate Neurotoxicity 7 Jan 2005
6. Repairing Damaged Tissues—Viruses Get into the Akt 12 Aug 2003