If I recall correctly, according to Kantarjian, part if not all of the reason cytarabine did so well in Western Europe is that after it stopped working patients were switched to HMAs
Value, look at the Sapacitabine P2 trial results that were published in 10/12. When they expanded the P2 60 persion 3 dosage arm trial (20 patients to an arm) to 105 patients with the additional 45 patients divided between Arms A and C, median OS went way down from what it appeared to be when only looking at the results for the initial 60 patients. I am sure that strongly influenced them to drop the Sapacitabine only arm. It may have also influneced managment to have the alternating combo begin with decitabine.
I am not suggesting anything other than what I comprehend from reading management's statements on the CYCC website regarding Alliances and Collaborations regarding management's strategy concering partnering.
I think managment is probalbly talking to everyone willing to talk with them about doing a deal. The only thing waiting may bring is a better deal, then again it may not. I think a Board of Directors made up of a good number of PhDs realizes this. The addition of Dr. Samuel Barker to the Board of Director's suggests the company believes it is in a position or soon will be in a position to make a deal. I just hope Spiro does not #$%$ every potential deal that comes CYCC's way.
Life, If they have always maintained it, it has not been on their website where it has been maintained. On their website under Allianaces and Collaborations, it is written:
"Cyclacel Pharmaceuticals will seek to partner clinical stage programs after establishing registration indications and securing a regulatory route to market."
I do not think a successful futility analysis secures a regulatory route to market, do you?
Regarding DACO-016 distorting both arms to DAC's advantage, read "Decitabine in Older Adults with Acute Myeloid Leukemia: Why Was the Dream Broken?" from which the following was excerpted:
"Sekeres and Steensma appropriately state that the primary study end point, survival difference at the prospectively defined time point (80% of death events), was not statistically significant (median 7.7 and 5.0 months for decitabine v treatment choice [TC], respectively; HR 0.85; 95% CI, 0.69 to 1.04, P = .108). However, they diverge from these rigorous principles and their core argument when they raise the concern that the outcome of the control arm was lower than reported in prior trials. Indeed, cross trial comparisons are fraught with bias due to differences in patient selection, and assessment methods. Similarly problematic is their criticism of the variation in efficacy among geographic regions, particularly in Western Europe. Indeed, their suggestion that the optimal use of low-dose cytarabine (LDAC), as they propose was done in Western Europe, is actually superior to decitabine is highly conjectural and lacks rigor."
I think Kantarjian is correct in pointing out: "When applying rigorous statistical principles, this subgroup analysis is only exploratory and should not influence an ODAC recomendation."
I think it is highly conjectural that DACO16 distorted both arms to DAC's advantage.
Obviously, LDAC is not part of the SEAMLESS trials. LDAC only has to do with arguements forwarded to get Sapacitabine approved if SEAMLESS fails. At that point if there is a trend toward improved overall survival, CYCC will: (1) Argue the trend, and (2) argue that the data indicates the combo is superior to LDAC, in effect the combo achieved what DAC alone could not achieve in the DACO16 trial, statistical superiority over LDAC. DAC on its on only achieved a trend toward improved overall survival over LDAC. Certainly, the argument cannot be supported scientifically without doing a combo clinical trial against LDAC, but I think the comparison will be made nonetheless.
The second paragraph of their product develop strategy as it appears on their website follows:
"Cyclacel Pharmaceuticals seeks strategic partners for certain advanced preclinical programs, where the partnership brings benefit to both parties via acceleration into first in man studies through leverage of a partner's capabilities and Cyclacel Pharmaceuticals' focus on translational biology and biomarker development to inform early clinical development."
This paragraphs suggests that it may be possible they are trying to find a partner to develop CYC065 or will try to find a partner for CYC140 when it finishes preclinical studies.
If they are trying to find a partner for CYC065, they may be using Aspire sales to buy time. However, odds are they are using Aspire to delay the time a secondary becomes necessary.
If the company is selling shares to Aspire, it is being done to delay the need to do a secondary to allow more time for either a deal to be made to fund the company or to allow the share price to increase to provide better terms for the secondary. It has been on the website for some time that the company's strategy is to derisk sapacitabine:
"Cyclacel Pharmaceuticals will seek to partner clinical stage programs after establishing registration indications and securing a regulatory route to market. Through informed early development and efficient and innovative clinical trial designs, Cyclacel Pharmaceuticals will derisk development programs prior to seeking a partner. For example, through the its innovative sequential combination strategy of sapacitabine alternating with decitabine employed in a Phase 1/2 pilot study and in the ongoing Phase 3 SEAMLESS study Cyclacel Pharmaceuticals will build risk mitigation strategies into late stage development programs.
The first sentence of the first paragraph indicates to me they plan to wait until P3 has been completed successfully or an NDA has been approved for Sapacitabine before they will seek a partner. Obviously this strategy involves more risk for the shareholders than if the company sought partners early to share the risk or off load the risk. The second sentence of the first paragraph indicates to me they will try to reduce the risk of this plan by being smart in determining what to develop and how to develop it. The third sentence of the first paragraph is poorly written. I believe the writer is trying to communicate that the sequential combination strategy and the pilot study are examples of the risk mitigation strategy. He may also be trying to communicate the SEEMLESS trial design (SPA agreement with FDA) is also an example, but that may be a stretch. Again, the third sentence is poorly written.
Value, I agree. With enrollment complete and final read out in the 2nd half of 15 or more likely early 16, this trial will go to completion after having passed three safety reviews by the DSMB. It is all about curve separation, particulary the tail. If the combo fails statistical significance over decitabine alone at the end of P3, the analysis and argument for approval will turn to whether the combo has statistical significance over low dose cytarabine, the control in Daco16. So as long as there is a "trend toward improved survival" with the combo over decitabine alone and the trend is statistically significant over low dose cytarabine, CYCC will file an NDA in the US and the EU. To be able to do this, the futility bar will need to be low or ignored.
But I believe we will see Sapacitabine used in combination with other drugs for a number of different indications. I think the same will be true for CYC065 and possibly Seliciclib.
46 patients is a very small sample, 13 even more so. That the sample is non representative is the only logical explanation if it is true there as a direct correlation between age and death within 60 days. The median OS of 6 months for Dacogen 016 patients over age 75 versus 7.7 months for all the Dacogen trial patients suggests there is a direct correlation to some degree. The fact that the combination appears to have a death rate of 13% at 60 days versus 26% for Sapacitabine alone is significant in and of itself if it holds true in a larger sample. Throw in a death rate of 26% or higher at 60 days for the decitabine contol arm and it would appear the odds are better than most people think for the combo to meet or better the SPA required reduction in risk of death of 27.5%.
If Sapacitabine passes futility, CYCC will begin to be looked at very differently by the investment community. No longer will CYCC be ignored. If management doesn't do anything stupid, Institutional ownership of the company will increase significantly over the coming months as will the stock price. If SEAMLESS succeeds, the entire investment landscape for CYCC changes dramatically! Spiro goes from zero to hero at Mach 20. CYCC will have done what no other company has been able to do in over 50 years, bring a new drug to market in the US for AML. CYCC's pipeline will be viewed in an entirely different light. CYCC could become the next PCYC if SEAMLESS succeeds and managment moves smartly with respect to Sapacitabine for MDS after HMA failure and the rest of their pipe line. Sapacitabine, Seliciclib, and CYC065 when combined with other drugs appear to have attributes that create synergism and have use in a wide range of serious diseases.
Okay. Decitabine is as toxic as Sapacitabine for the same age groups: 26% is the 60 day mortality rate. Or decitabine is more toxic than Sapacitabine and has a greater than 26% death rate at 60 days. If that is true, the synergism is even greater than I imagined using the known 60 day death rate for Dacogen of 20% and the known 60 day death rate of 26% for Sapacitabine assuming the sample rates are representative for the populations they represent on the whole, Dacogen 016 trial median age 73, Sapacitabine P2 trial median age 77, SEAMLESS pilot lead in Trial median age 77.
If age is directly correlated to death rates, how do you explain the higher median OS for older patients than for younger patients in the SEAMLESS pilot lead in trial?
In any event, there is strong evidence that synergy is created by the combination of decitabine and sapacitabine. The 10 bagger question is whether there is enough for the combination of Sapacitabine and decitabine to be approved.
Along that line, CYCC hold the patents for using combinations of Sapacitabine with HMAs such as decitabine and azacitidine as well as the patents for using Sapacitabine with HDACs.
The dacogen-016 arm had a 20% 60 day mortality rate. It was the Sapacitabine Phase 2 trial reported in 10/12 that had a 26% 60 day mortality rate. Nonetheless, the reduction in the 60 day mortality rate by combining Sapacitabine and decitabine is remarkable. There is true synergy in combining Sapacitabine with other drugs. The investigators believe it is the synergy that will push the combination of decitabine and sapacitabine over the top resulting in approval, although I have yet to hear Spiro or Kantarjarian descibe it as synergy. As you point out, we are going to see Sapacitabine combined with other drugs going forward for multiple indications. Not least of which are the HDAC inhibitors such as panobinostat and vorinostat for which CYCC has the combination patents.
Agreed, Eisai could not get past the fact the median OS improvement of Dacogen over low dose cytarabine or best supportive care was not statistically significant even though the trend was favorable was in good part due to the wide disparity of results based on geographical location of the trials. Others factors that that favored disapproval included a higher incidence of adverse events in the dacogen arm versus the control arm.
I agree the trial will not be stopped. If the KM curve has a strong tail, it may make the results statisitcally significant when compared to low dose cytarabine, regardless of whether there is a 27.5% survival improvement over decitabine. The resaon Daco 16 failed, was the improvement was not statistically significant against cytarabine because the tail fell off.