Ampligen "Death Blow" Another Tragedy for CFS Sufferers

In a shocking move, the FDA yesterday refused to approved Hemispherx's drug Ampligen.  It represents a devastating blow for Hemispherx who have in vain attempted to garner approval for Ampligen for over 20 years.  In their response letter, the FDA essentially demands that Hemispherx begin their clinical trials from scratch.  They site initial clinical trials fail to convince the review panel of Ampligen's efficacy, and that new clinical trials be conducted testing different doses for at least six months, on at least 300 patients, compared to the previous study which enrolled just 230 patients.  The FDA also goes on to cite unresolved manufacturing problems.  Considering that the previous study took 6 years to complete, approval doesn't appear likely any time soon, and likely won't be approved in other jurisdictions, as other nations have followed the guidance of the FDA, with a handful of exceptions of drugs that have gained approval by the European Medicines Agency before FDA approval is granted.

For persons suffering from ME/CFS, FMS, and Gulf War Syndrome it shows that government agencies continue to recognize these conditions as a real illness.  And research dollars earmarked for CFS/ME research gets misappropriated by CDC bureaucrats as a slush fund, where not one meaningful study has come out of it.  And it appears recent developments have not shifted the groupthink mentality of the CDC - but it will come a time when they will find themselves standing pretty well alone if replication studies on XMRV are in line with those of the Whittemore-Peterson institute, which I have reason to believe will be.

I believe that psychologically Ampligen represents a huge setback, but in the end it will amount to no more than a bump in the road.  Tests on antiretrovirals are going ahead full steam in pharmaceutical labs as we speak, and I've dug up a couple of other compounds that have demonstrated activity against other retroviruses: Lamivudine and emtricitabine - both have a far greater safety profile than Zidovudine (AZT), posing a low risk of anemia, nephrotoxicity, hepatoxicity, and pancreatitis.  I'm not particularly fond of Non-nucleoside Reverse Transcriptase inhibitors, due to their unfavorable side effect profile - distressing rash in as much as 20% of patients, and severe liver damage seen with Nevirapine and Etravirine - making patient compliance and adherance to treatment an issue in itself.  I also don't favor a single drug regiment - I would like to see a combination pill of either Lamivudine or Emtricitabine with raltegravir.

Will Ampligen Ever See The Light of Day?

For many ME/CFS patients, Ampligen offered a glimmer of hope for an effective treatment.  New developments which I've been monitoring however pour some cold water on the flame of hope that was burning for ME/CFS sufferers.  In an unexpected turn, the FDA has demanded additional data from Hemispherx Biopharma regarding safety data, and to perform additional clinical trials regarding its efficacy.  This did not bode well for the securities regulators, and shareholders, who filed suit claiming that it's CEO Bill Carter provided misleading information regarding Ampligen's regulatory status.

Something of this magnitude is by no means unheard of in the pharmaceutical company - Supergen's CEO Jon Rubinfeld was involved in a similar controversy with the drug Orathecin to treat pancreatic cancer.  It certainly will have a profound impact on the approval process for Ampligen.  Given the current situation, an approval for the drug should not be expected until  Q3 2010 at the very least.  Given the litany of lawsuits Hemispherx potentially faces, it could very well derail the Ampligen approval process, and bankrupt the company.  Hopefully, if this is the case, one of the pharmaceutical giants picks up Ampligen, and does the proper filings.

Accessibility to New Treatments

Even if treatments were to be approved by the FDA, or the medicines and health products regulatory agency, likely the such drugs would be well out of reach for most people. Since most people with Chronic Fatigue, or Fibromyalgia are already significantly disabled, their ability to earn income is severely curtailed. HMO's, PPO's, primary care trusts (UK), and provincial health care plans (Canada) are unlikely to foot the bill for some time. For pharmaceutical companies, it could provide a considerable disincentive for developing new medicine - likely drugs from the current HIV portfolio will be screened for efficacy initially. Currently, these drugs vary in price from $263 a month, to $2314.50 a month. If approved, Ampligen is expected to cost around $1300 to $1500 a month.

An approach that has been seen by many providers has been to restrict access to medications using certain criteria. In the case of XAND (XMRV associated Neuro Immune Disease) such as Fibromyalgia, Chronic Fatigue Syndrome, the approach insurers may likely take would be to demonstrate a certain level of disability, and have failed other drugs beforehand. A primary care trust for example might require a certain disability score and fail to respond to a course of Lyrica and Ritalin. For insurers, the cost of treatment remains to be determined, and the following questions need to be addressed over time:

• Is the new drug more effective than the old one?
• What benefit does the drug have in terms of quality adjusted life years score?
• Will a lifelong course of medication be required as in HIV?
• Will other antivirals be required to treat co-infections, such as cytomegalovirus, EBV, HHV-6?

Current and Future Approaches to Treatment

Treatment options for Fibromyalgia and CFIDS sufferers are currently few and far between. There are no FDA approved medications specifically indicated for treating Chronic Fatigue Syndrome, and Lyrica is the only drug approved for Fibromyalgia thus far, with few options coming down the pipeline. Drugs currently prescribed for the condition include:

• Amitryptilline - Based on the theory that Chronic fatigue is caused by a neurotransmitter imbalance, Amitryptilline is frequently part of the drug regiment offered to Chronic Fatigue patients, whereby it is postulated that it helps regulate sleep, as it is thought that in CFS or FM, very little time is spent in stage 4 sleep. Controlled blind studies show that it is not very effective, providing only a slight benefit over placebo.
• Ritalin (methylphenidate), Desoxyn (methamphetamine), Dexedrine (dextroamphetamine), Provigil (Modafinil) - Drugs in this category act as CNS stimulants. The first three have the effect of raising blood pressure, and are indicated in treating postural hypotension, and promote wakefulness in CFIDS individuals. Modafinil does not address postural hypotension, therefore it is of limited use. For these patients, stimulants make it possible to perform daily tasks, however they do not seem to have an appreciable effect on cognitive impairment.
• Lyrica (Pregabalin) and Gabapentin - Gabapentin is a drug used to treat epilepsy, which gained off-label use to treat neuropathic pain, Lyrica being the active metabolite of Gabapentin. Lyrica was the first drug approved for Fibromyalgia, until the approval of the antidepressant Cymbalta (duloxetine). Response to Lyrica has not resulted in statistically significant improvement in quality of life in FM patients. The cost of the drug is high, and many insurers will not cover its cost, and the opioid analgesics like Dilaudid (hydromorphone), and fentanyl seem to confer the greatest benefits. Lyrica is known to cause marked weight gain, and can be very sedating (CNS depressant).

Current experimental treatments have shifted towards anti-viral compounds. Anti-virals currently being prescribed off-label include Valtrex (Valacyclovir), Valcyte (Valgancavir), and Acyclovir - all targeted towards herpesviruses. Some patients note significant improvement, lending to the theory that having high viral titers of herpesviruses adds to the disease burden of XMRV. Equally significant results have been obtained with Isoprinosine, which is available on both sides of the border at a reasonable cost. Valcyte has the distinction of being extraordinarily expensive - >$1500 a month, and it is not without severe side effects. Ampligen is a drug if approved that would be the first drug approved specifically for treating Chronic Fatigue Syndrome - it is expected to cost ~$1500 a month for treatment.

Future treatment will likely involve treatment with anti-retrovirals. As the link between Chronic Fatigue Syndrome and XMRV becomes more clearly established, likely more practitioners will be willing to try current anti-retrovirals on Chronic Fatigue and Fibromyalgia patients. Three potential viral targets might include reverse-transcriptase, XMRV polymerase, and intergrase. Initially, AZT has shown activity in vitro against XMRV, however the toxicity of AZT limits its use - it's fine for someone who would otherwise die of AIDS, but it leads to an ethical dilemma when prescribing it in a situation where the side effects may be worse than the disease. Most NRT's and NNRT's are fraught with side effects such as lipodystrophy - which can be quite disfiguring. Protease inhibitors are slightly more benign, although some are known to cause dramatic increase in blood lipids. Integrase inhibitors are prehaps the most benign, being well tolerated, producing few metabolic abnormalities. Protease inhibitors may not work against XMRV, as the catalytic site may be sufficiently different than the HIV protease - being the case, it would require determining the atomic structure of the XMRV protease, in order to develop effective drugs. As the function of other proteins of XMRV become unravelled, other drug targets could conceivably be developed - one of these being the androgen responsive element or ard.